GLP-1 Ra 삭센다, 위고비 효과 &부작용 2021 nejm

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Once-Weekly Semaglutide in Adults with Overweight or Obesity

Authors: John P.H. Wilding, D.M., Rachel L. Batterham, M.B., B.S., Ph.D., Salvatore Calanna, Ph.D., Melanie Davies, M.D., Luc F. Van Gaal, M.D., Ph.D., Ildiko Lingvay, M.D., M.P.H., M.S.C.S. https://orcid.org/0000-0001-7006-7401, Barbara M. McGowan, M.D., Ph.D., +7 , for the STEP 1 Study Group*Author Info & Affiliations

Published February 10, 2021

N Engl J Med 2021;384:989-1002

DOI: 10.1056/NEJMoa2032183

VOL. 384 NO. 11

Copyright © 2021

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Abstract

Background

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Methods

In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

Results

The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

Conclusions

In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

초록 요약:

• 배경: 비만은 전 세계적인 건강 문제이며 효과적인 약물 치료법이 많지 않습니다. 생활 습관 개입과 함께 주 1회 세마글루타이드 2.4mg을 투여했을 때 비만 성인의 체중 감소 효과가 있는지 확인하는 것이 목표였습니다.
• 방법: 이 이중 맹검 시험에는 당뇨병이 없는 BMI 30 이상(체중 관련 동반 질환이 하나 이상 있는 경우 ≥27) 성인 1961명이 참여했습니다. 이들은 생활 습관 개입과 함께 주 1회 피하 세마글루타이드 2.4mg 또는 위약군에 2:1 비율로 무작위 배정되어 68주간 치료를 받았습니다. 공동 1차 평가 변수는 체중의 백분율 변화와 최소 5%의 체중 감소였습니다.
• 결과:
  • 기준선 대비 68주차 평균 체중 변화는 세마글루타이드군에서 -14.9%, 위약군에서 -2.4%였습니다 (추정 치료 차이 -12.4%p, 95% CI, -13.4 ~ -11.5; P<0.001).
  • 68주차에 5% 이상 체중 감소를 달성한 참가자 비율은 세마글루타이드군이 86.4%(1047명), 위약군이 31.5%(182명)였습니다. 10% 이상 감소는 69.1%(838명) 대 12.0%(69명), 15% 이상 감소는 50.5%(612명) 대 4.9%(28명)였습니다 (세 가지 비교 모두 P<0.001).
  • 기준선 대비 68주차 평균 체중 감소량은 세마글루타이드군에서 -15.3kg, 위약군에서 -2.6kg였습니다 (추정 치료 차이 -12.7kg, 95% CI, -13.7 ~ -11.7).
  • 세마글루타이드 투여군은 심혈관 대사 위험 요소 개선 및 참가자가 보고한 신체 기능 향상이 위약군보다 더 컸습니다.
  • 가장 흔한 이상 반응은 메스꺼움과 설사였으며, 일반적으로 일시적이고 경미-중등도였으며 시간이 지나면서 완화되었습니다.
  • 위장관 이상 반응으로 인해 치료를 중단한 참가자 비율은 세마글루타이드군이 4.5%(59명), 위약군이 0.8%(5명)였습니다.
• 결론: 과체중 또는 비만 참가자에서 주 1회 세마글루타이드 2.4mg과 생활 습관 개입은 지속적이고 임상적으로 의미 있는 체중 감소와 관련이 있었습니다.

Quick Take

Weekly Semaglutide in Adults with Overweight or Obesity

1m 46s

Obesity is a chronic disease and global public health challenge.1-3 Obesity can lead to insulin resistance, hypertension, and dyslipidemia,4 is associated with complications such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease,2,5 and reduces life expectancy.6 More recently, obesity has been linked to increased numbers of hospitalizations, the need for mechanical ventilation, and death in persons with coronavirus disease 2019 (Covid-19).7,8

Although lifestyle intervention (diet and exercise) represents the cornerstone of weight management,1,2 sustaining weight loss over the long term is challenging.9 Clinical guidelines suggest adjunctive pharmacotherapy, particularly for adults with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or greater, or 27 or greater in persons with coexisting conditions.1,2,10 However, the use of available medications remains limited by modest efficacy, safety concerns, and cost.3

Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is approved, at doses up to 1 mg administered subcutaneously once weekly, for the treatment of type 2 diabetes in adults and for reducing the risk of cardiovascular events in persons with type 2 diabetes and cardiovascular disease.11 Semaglutide induced weight loss in persons with type 2 diabetes and in adults with obesity who were participants in a phase 2 trial,12-14 findings that supported further investigation. The global phase 3 Semaglutide Treatment Effect in People with Obesity (STEP) program aims to eval‎uate the efficacy and safety of semaglutide administered subcutaneously at a dose of 2.4 mg once weekly in persons with overweight or obesity, with or without weight-related complications.15

This 68-week trial eval‎uated the efficacy and safety of semaglutide as compared with placebo as an adjunct to lifestyle intervention for reducing body weight and meeting other related end points in adults with overweight or obesity and without diabetes.

서론 비만은 만성 질환이자 전 세계적인 공중 보건 문제입니다.1-3 비만은 인슐린 저항성, 고혈압, 이상지질혈증으로 이어질 수 있으며,4 제2형 당뇨병, 심혈관 질환, 비알코올성 지방간 질환과 같은 합병증과 관련이 있고,2,5 기대 수명을 단축시킵니다.6 최근에는 비만이 코로나19(Covid-19) 환자의 입원율 증가, 기계 환기 필요성 증가, 사망과 연관되어 있음이 밝혀졌습니다.7,8

생활 습관 개입(식단 및 운동)이 체중 관리의 핵심임에도 불구하고,1,2 장기적으로 체중 감량을 유지하는 것은 어렵습니다.9 임상 지침은 특히 체질량 지수(BMI, 킬로그램 단위 체중을 미터 단위 키의 제곱으로 나눈 값)가 30 이상인 성인, 또는 동반 질환이 있는 경우 27 이상인 성인에게는 보조 약물 요법을 제안합니다.1,2,10 그러나 현재 사용 가능한 약물의 사용은 적당한 효능, 안전성 문제 및 비용으로 인해 제한적입니다.3

세마글루타이드는

글루카곤 유사 펩타이드-1(GLP-1) 유사체로,

성인의 제2형 당뇨병 치료 및 제2형 당뇨병과 심혈관 질환이 있는 사람의

심혈관 사건 위험 감소를 위해 주 1회 피하 투여 1mg까지의 용량으로 승인되었습니다.11

세마글루타이드는 제2형 당뇨병 환자와 비만 성인이 참여한

2상 임상 시험에서 체중 감소를 유도했으며,12-14

이러한 결과는 추가 조사를 뒷받침했습니다.

전 세계적인 3상 세마글루타이드 비만 환자 치료 효과(STEP) 프로그램은

과체중 또는 비만 환자(체중 관련 합병증 유무와 관계없이)에게 주 1회 2.4mg 용량으로

피하 투여되는 세마글루타이드의 효능 및 안전성을 평가하는 것을 목표로 합니다.15

이 68주 시험은

당뇨병이 없는 과체중 또는 비만 성인의 체중 감소 및 기타 관련 평가 변수 달성을 위한

생활 습관 개입의 보조제로 세마글루타이드와 위약의 효능 및 안전성을 평가했습니다.

Methods

Trial Design and Oversight

We conducted a randomized, double-blind, placebo-controlled trial at 129 sites in 16 countries in Asia, Europe, North America, and South America. The sponsor (Novo Nordisk) designed the trial and oversaw its conduct. The design has been published previously.15 The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol (available with the full text of this article at NEJM.org) was approved by an independent ethics committee or institutional review board at each study site. Investigators were responsible for data collection, and the sponsor undertook site monitoring, data collation, and analysis. All authors had full access to study data, participated in drafting the manuscript (assisted by a sponsor-funded medical writer), approved its submission for publication, and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Participants

We enrolled adults (18 years of age or older) with one or more self-reported unsuccessful dietary efforts to lose weight and either a BMI of 30 or greater or a BMI of 27 or greater with one or more treated or untreated weight-related coexisting conditions (i.e., hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). A subgroup of participants with a BMI of 40 or less underwent dual-energy x-ray absorptiometry (DXA) to assess body composition. All participants provided written informed consent. Key exclusion criteria were diabetes, a glycated hemoglobin level of 48 mmol per mole (6.5%) or greater, a history of chronic pancreatitis, acute pancreatitis within 180 days before enrollment, previous surgical obesity treatment, and use of antiobesity medication within 90 days before enrollment. A full list of the eligibility criteria is provided in the Supplementary Appendix, available at NEJM.org.

Procedures

Participants were randomly assigned in a 2:1 ratio, through the use of an interactive Web-based response system, to receive semaglutide at a dose of 2.4 mg administered subcutaneously once a week for 68 weeks or matching placebo, in addition to lifestyle intervention; this 68-week period was followed by a 7-week period without receipt of semaglutide or placebo or lifestyle intervention. Semaglutide, administered with a prefilled pen injector, was initiated at a dose of 0.25 mg once weekly for the first 4 weeks, with the dose increased every 4 weeks to reach the maintenance dose of 2.4 mg weekly by week 16 (lower maintenance doses were permitted if participants had unacceptable side effects with the 2.4-mg dose) (Fig. S1 in the Supplementary Appendix). Participants received individual counseling sessions every 4 weeks to help them adhere to a reduced-calorie diet (500-kcal deficit per day relative to the energy expenditure estimated at the time they underwent randomization) and increased physical activity (with 150 minutes per week of physical activity, such as walking, encouraged). Both diet and activity were recorded daily in a diary or by use of a smartphone application or other tools and were reviewed during counseling sessions. Participants discontinuing treatment prematurely remained in the trial.

End Points and Assessments

The coprimary end points were the percentage change in body weight from baseline to week 68 and achievement of a reduction in body weight of 5% or more from baseline to week 68. Confirm‎atory secondary end points (in hierarchical testing order) were achievement of a reduction in body weight of 10% or more and 15% or more by week 68 and the change from baseline to week 68 in waist circumference, systolic blood pressure, physical functioning score on the 36-item Short Form Health Survey (SF-36), version 2, and physical function score on the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) questionnaire. (Assessments related to end points, along with supportive secondary and exploratory end points and safety assessments, are described in the Supplementary Appendix.) Body composition (total fat, total lean body mass, and regional [abdominal] visceral fat mass) was measured in the DXA subpopulation as a supportive secondary end point. Safety assessments included the number of adverse events occurring during the on-treatment period (the time during which participants received any dose of semaglutide or placebo within the previous 49 days, with any period of temporary interruption of the regimen excluded) and serious adverse events occurring between baseline and week 75. An independent external event adjudication committee reviewed selected adverse events (cardiovascular events and acute pancreatitis) and deaths. All standard assays were performed in a central laboratory.

Statistical Analysis

A sample size of 1950 participants provided an effective power of 99% for the coprimary and confirm‎atory secondary end points, tested in a prespecified hierarchical order. Efficacy end points were analyzed in the full analysis population (all randomly assigned participants according to the intention-to-treat principle); safety end points were analyzed in the safety analysis population (all randomly assigned participants exposed to at least one dose of semaglutide or placebo). Observation periods included the in-trial period (the time from random assignment to last contact with a trial site, regardless of treatment discontinuation or rescue intervention) and the on-treatment period. All results from statistical analyses were accompanied by a two-sided 95% confidence interval and corresponding P values (with significance defined as P<0.05). Supportive secondary end-point analyses were not controlled for multiple comparisons and should not be used to infer definitive treatment effects.

Two estimands — the treatment policy estimand (traditional intention-to-treat analysis, with effects assessed regardless of treatment discontinuation or rescue intervention) and the trial product estimand (effects assessed if the drug or placebo was taken as intended) — were used to assess treatment efficacy from different perspectives and accounted for intercurrent events and missing data differently, as described previously.16 All analyses in the statistical hierarchy were based on the primary treatment policy estimand (details on analysis methods are provided in the Supplementary Appendix). All reported results are for the treatment policy estimand, unless stated otherwise.

Results

Study Participants

From June through November 2018, a total of 1961 participants were randomly assigned to receive semaglutide (1306 participants) or placebo (655 participants). Overall, 94.3% of the participants completed the trial, 91.2% had a body-weight assessment at week 68, and 81.1% adhered to treatment (Fig. S2). Rescue interventions were received by 7 participants in the semaglutide group (2 had bariatric surgery and 5 received other antiobesity medication) and by 13 in the placebo group (3 had bariatric surgery and 10 received other antiobesity medication).

Demographics and baseline characteristics were similar in the two treatment groups (Table 1). Most participants were female (74.1%) and White (75.1%), with a mean age of 46 years. The mean body weight was 105.3 kg, the mean BMI 37.9, and the mean waist circumference 114.7 cm; 43.7% had prediabetes. At screening, most participants (75.0%) had at least one coexisting condition. The baseline characteristics of the DXA subpopulation are provided in Table S1.

방법시험 설계 및 감독 우리는 아시아, 유럽, 북미, 남미 16개국 129개 기관에서 무작위 배정, 이중 맹검, 위약 대조 시험을 수행했습니다. 스폰서(Novo Nordisk)가 시험을 설계하고 그 수행을 감독했습니다. 설계는 이전에 발표되었습니다.15 본 시험은 헬싱키 선언 및 우수 임상 실습 지침의 원칙에 따라 수행되었습니다. 프로토콜(NEJM.org의 이 기사 전문에서 사용 가능)은 각 연구 기관의 독립적인 윤리 위원회 또는 기관 검토 위원회의 승인을 받았습니다. 연구자들은 데이터 수집을 담당했고, 스폰서는 현장 모니터링, 데이터 통합 및 분석을 수행했습니다. 모든 저자는 연구 데이터에 대한 완전한 접근 권한을 가졌고, 원고 작성에 참여했으며(스폰서 자금 지원 의료 작가의 도움을 받음), 출판 제출을 승인했으며, 데이터의 정확성과 완전성 및 프로토콜에 대한 시험의 충실성을 보증했습니다.

참가자 우리는 체중 감량을 위한 스스로 보고한 한 가지 이상의 실패한 식이 요법 시도를 했으며, BMI가 30 이상이거나, BMI가 27 이상이면서 한 가지 이상의 치료 중이거나 치료되지 않은 체중 관련 동반 질환(즉, 고혈압, 이상지질혈증, 폐쇄성 수면 무호흡증 또는 심혈관 질환)이 있는 성인(18세 이상)을 등록했습니다. BMI가 40 이하인 참가자 하위 그룹은 이중 에너지 X선 흡수계측법(DXA)을 통해 체성분을 평가받았습니다. 모든 참가자는 서면 동의를 제공했습니다. 주요 제외 기준은 당뇨병, 당화혈색소 수치 48mmol/mol(6.5%) 이상, 만성 췌장염 병력, 등록 전 180일 이내 급성 췌장염, 이전 수술적 비만 치료, 등록 전 90일 이내 항비만 약물 사용이었습니다. 자격 기준의 전체 목록은 NEJM.org에서 제공되는 보충 부록에 있습니다.

절차 참가자들은 대화형 웹 기반 반응 시스템을 통해 생활 습관 개입 외에 68주 동안 주 1회 피하 투여되는 세마글루타이드 2.4mg 또는 위약을 받도록 2:1 비율로 무작위 배정되었습니다. 이 68주 기간 후에는 세마글루타이드 또는 위약 또는 생활 습관 개입 없이 7주간의 기간이 이어졌습니다. 미리 채워진 펜 주입기로 투여되는 세마글루타이드는 처음 4주 동안 주 1회 0.25mg 용량으로 시작하여, 4주마다 용량을 증량하여 16주차까지 주 2.4mg의 유지 용량에 도달했습니다(참가자가 2.4mg 용량에서 용납할 수 없는 부작용이 발생한 경우 더 낮은 유지 용량이 허용됨)(보충 부록의 그림 S1). 참가자들은 감소된 칼로리 식단(무작위 배정 시 추정된 에너지 소비량 대비 하루 500kcal 부족)을 준수하고 신체 활동을 늘리도록(걷기 등 주 150분 신체 활동 권장) 4주마다 개별 상담 세션을 받았습니다. 식단과 활동은 매일 일기에 기록되거나 스마트폰 애플리케이션 또는 기타 도구를 사용하여 기록되었고 상담 세션에서 검토되었습니다. 조기에 치료를 중단한 참가자도 시험에 계속 참여했습니다.

평가 변수 및 평가 공동 1차 평가 변수는 기준선부터 68주까지의 체중 변화율과 기준선부터 68주까지의 체중 5% 이상 감소 달성이었습니다. 확증적 2차 평가 변수(계층적 검정 순서)는 68주까지의 체중 10% 이상 및 15% 이상 감소 달성, 그리고 기준선부터 68주까지의 허리둘레, 수축기 혈압, 36개 항목 건강 설문조사(SF-36) 버전 2의 신체 기능 점수, IWQOL-Lite-CT(Impact of Weight on Quality of Life–Lite Clinical Trials Version) 설문지의 신체 기능 점수 변화였습니다. (평가 변수 관련 평가, 보조 2차 및 탐색적 평가 변수, 안전성 평가는 보충 부록에 설명되어 있습니다.) 체성분(총 지방량, 총 제지방량, 국소[복부] 내장 지방량)은 DXA 하위 모집단에서 보조 2차 평가 변수로 측정되었습니다. 안전성 평가는 치료 기간 동안 발생한 이상 반응 수(참가자가 세마글루타이드 또는 위약을 49일 이내에 어떤 용량으로든 투여받은 기간으로, 일시적인 요법 중단 기간은 제외됨) 및 기준선부터 75주까지 발생한 심각한 이상 반응을 포함했습니다. 독립적인 외부 사건 판정 위원회가 특정 이상 반응(심혈관 사건 및 급성 췌장염) 및 사망을 검토했습니다. 모든 표준 검사는 중앙 연구실에서 수행되었습니다.

통계 분석 1950명의 참가자 표본 크기는 공동 1차 및 확증적 2차 평가 변수(미리 지정된 계층적 순서로 검정)에 대해 99%의 유효 검정력을 제공했습니다. 효능 평가 변수는 전체 분석 모집단(의도-대-치료 원칙에 따른 모든 무작위 배정된 참가자)에서 분석되었고, 안전성 평가 변수는 안전성 분석 모집단(최소 1회 용량의 세마글루타이드 또는 위약에 노출된 모든 무작위 배정된 참가자)에서 분석되었습니다. 관찰 기간은 시험 내 기간(무작위 배정부터 시험 현장과의 마지막 접촉까지의 시간, 치료 중단 또는 구조 중재와 관계없이) 및 치료 기간을 포함했습니다. 통계 분석의 모든 결과에는 양측 95% 신뢰 구간과 해당 P 값(유의성은 P<0.05로 정의)이 함께 제시되었습니다. 보조 2차 평가 변수 분석은 다중 비교에 대해 통제되지 않았으므로 확정적인 치료 효과를 추론하는 데 사용되어서는 안 됩니다. 두 가지 추정량—치료 정책 추정량(치료 중단 또는 구조 중재와 관계없이 효과를 평가하는 전통적인 의도-대-치료 분석)과 시험 제품 추정량(약물 또는 위약이 의도된 대로 복용된 경우 효과를 평가)—이 다른 관점에서 치료 효능을 평가하고 이전에 설명된 대로 간헐적 사건 및 누락된 데이터를 다르게 설명하는 데 사용되었습니다.16 통계 계층의 모든 분석은 1차 치료 정책 추정량에 기반했습니다(분석 방법에 대한 자세한 내용은 보충 부록에 제공됨). 명시적으로 달리 언급되지 않는 한, 모든 보고된 결과는 치료 정책 추정량에 대한 것입니다.

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결과연구 참가자

2018년 6월부터 11월까지 총 1961명의 참가자가

세마글루타이드(1306명) 또는

위약(655명)을 받도록 무작위 배정되었습니다.

전체적으로 참가자의 94.3%가 시험을 완료했고,

91.2%가 68주차에 체중 평가를 받았으며,

81.1%가 치료를 준수했습니다(그림 S2).

구조 중재는 세마글루타이드군에서 7명(2명은 비만 수술, 5명은 다른 항비만 약물 투여), 위약군에서 13명(3명은 비만 수술, 10명은 다른 항비만 약물 투여)이 받았습니다. 인구 통계 및 기준선 특성은 두 치료군에서 유사했습니다(표 1). 대부분의 참가자는 여성(74.1%)이고 백인(75.1%)이었으며, 평균 연령은 46세였습니다. 평균 체중은 105.3kg, 평균 BMI는 37.9, 평균 허리둘레는 114.7cm였으며, 43.7%는 당뇨병 전증을 앓고 있었습니다. 선별 시 대부분의 참가자(75.0%)는 최소 한 가지 이상의 동반 질환을 가지고 있었습니다. DXA 하위 모집단의 기준선 특성은 표 S1에 제공됩니다.

Table 1

Demographic and Clinical Characteristics of the Participants at Baseline.

Change in Body Weight

In the semaglutide group, weight loss was observed from the first postrandomization assessment (week 4) onward, reaching a nadir at week 60 (Figure 1A and 1B). For the treatment policy estimand (showing the effect regardless of treatment discontinuation or rescue intervention), the estimated mean weight change at week 68 was −14.9% with 2.4-mg semaglutide, as compared with −2.4% with placebo (estimated treatment difference, −12.4 percentage points; 95% CI, −13.4 to −11.5; P<0.001). For the trial product estimand (showing the effect if the drug or placebo was taken as intended), the corresponding changes were −16.9% and −2.4% (estimated treatment difference, −14.4 percentage points; 95% CI, −15.3 to −13.5).

체중 변화

세마글루타이드군에서는

첫 번째 무작위 배정 후 평가(4주차)부터 체중 감소가 관찰되었고,

60주차에 최저점에 도달했습니다(그림 1A 및 1B).

치료 정책 추정량(치료 중단 또는 구조 중재와 관계없이 효과를 보여줌)의 경우, 68주차에 추정된 평균 체중 변화는 세마글루타이드 2.4mg에서 -14.9%, 위약에서 -2.4%였습니다(추정 치료 차이, -12.4%p; 95% CI, -13.4 ~ -11.5; P<0.001). 시험 제품 추정량(약물 또는 위약이 의도된 대로 복용된 경우 효과를 보여줌)의 경우, 해당 변화는 -16.9% 및 -2.4%였습니다(추정 치료 차이, -14.4%p; 95% CI, -15.3 ~ -13.5).

Figure 1

Effect of Once-Weekly Semaglutide, as Compared with Placebo, on Body Weight.

Participants who received semaglutide were more likely to lose 5% or more, 10% or more, 15% or more, and 20% or more of baseline body weight at week 68 than those who received placebo (P<0.001 for the 5%, 10%, and 15% thresholds; the 20% threshold was not part of the statistical testing hierarchy) (Table 2, Figure 1C and 1D, and Table S2). Among the participants for whom data were available at the week 68 visit (1212 participants in the semaglutide group and 577 in the placebo group), these thresholds were reached by 86.4% (1047 participants), 69.1% (838 participants), 50.5% (612 participants), and 32.0% (388 participants), respectively, in the semaglutide group, as compared with 31.5% (182 participants), 12.0% (69 participants), 4.9% (28 participants), and 1.7% (10 participants) in the placebo group (Figure 1C, with on-treatment data shown in Figure 1D and the cumulative distribution of change from baseline shown in Fig. S3). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7) (Fig. S4). Data on change in body weight and achieved reduction in body weight of 5% or more (coprimary end points) as well as confirm‎atory and selected supportive secondary end points for the trial product estimand are provided in Table S2.

주 1회 세마글루타이드와 위약의 체중 효과 비교.

세마글루타이드를 투여받은 참가자는 위약을 투여받은 참가자보다

68주차에 기준선 체중의 5% 이상, 10% 이상, 15% 이상, 20% 이상을

감량할 가능성이 더 높았습니다(5%, 10%, 15% 임계값 모두 P<0.001; 20% 임계값은 통계적 검정 계층의 일부가 아니었음)(표 2, 그림 1C 및 1D, 표 S2).

68주차 방문 시 데이터가 사용 가능한 참가자 중(세마글루타이드군 1212명, 위약군 577명), 이 임계값은 세마글루타이드군에서 각각 86.4%(1047명), 69.1%(838명), 50.5%(612명), 32.0%(388명)에 도달했으며, 위약군에서는 31.5%(182명), 12.0%(69명), 4.9%(28명), 1.7%(10명)에 도달했습니다(그림 1C, 치료 중 데이터는 그림 1D에 표시되고 기준선으로부터의 변화의 누적 분포는 그림 S3에 표시됨). 기준선부터 68주까지의 체중 변화는 세마글루타이드군에서 -15.3kg, 위약군에서 -2.6kg였습니다(추정 치료 차이, -12.7kg; 95% CI, -13.7 ~ -11.7)(그림 S4). 체중 변화 및 5% 이상 체중 감소 달성(공동 1차 평가 변수)뿐만 아니라 시험 제품 추정량에 대한 확증적 및 선택된 보조 2차 평가 변수에 대한 데이터는 표 S2에 제공됩니다.

Table 2

Coprimary, Confirm‎atory, and Selected Supportive Secondary and Exploratory End Points for the Treatment Policy Estimand.

Other Confirm‎atory and Supportive Secondary End Points

Semaglutide was associated with greater reductions from baseline than placebo in waist circumference (–13.54 cm with semaglutide vs. –4.13 cm with placebo; estimated treatment difference, –9.42 cm; 95% CI, –10.30 to –8.53), BMI (–5.54 with semaglutide vs. –0.92 with placebo; estimated treatment difference, –4.61; 95% CI, –4.96 to –4.27), and systolic and diastolic blood pressure at week 68 (Table 2, Table S2, and Figs. S5 and S6). Benefits favoring semaglutide were also noted with respect to changes in glycated hemoglobin, fasting plasma glucose, C-reactive protein, and fasting lipid levels (Table 2).

Exploratory End Points

Among participants with prediabetes at baseline, semaglutide was associated with improvements in glycated hemoglobin levels at week 68, and 84.1% of participants in the semaglutide group who had prediabetes at baseline, as compared with 47.8% of participants in the placebo group with prediabetes at baseline, reverted to normoglycemia. Results for these and other selected exploratory end points are presented in Table 2 and Table S3.

Physical Functioning and Other Participant-Reported Outcomes

SF-36 physical functioning scores (with possible norm-based scores ranging from 19.03 to 57.60) improved significantly more with semaglutide than with placebo at week 68 (P<0.001), and both SF-36 physical and mental component summary scores favored semaglutide (Table 2, Table S2, and Fig. S7). IWQOL-Lite-CT physical function scores improved significantly more with semaglutide than with placebo at week 68 (P<0.001) (Table 2 and Table S2), and there were favorable effects over placebo on IWQOL-Lite-CT total scores. The results of SF-36 and IWQOL-Lite-CT assessments showed that participants were more likely to have clinically meaningful within-person improvements in physical functioning with semaglutide than with placebo (Table S4).

기타 확증적 및 보조 2차 평가 변수 세마글루타이드는 허리둘레(세마글루타이드 -13.54cm 대 위약 -4.13cm; 추정 치료 차이, -9.42cm; 95% CI, -10.30 ~ -8.53), BMI(세마글루타이드 -5.54 대 위약 -0.92; 추정 치료 차이, -4.61; 95% CI, -4.96 ~ -4.27) 및 68주차 수축기 및 이완기 혈압에서 기준선 대비 더 큰 감소와 관련이 있었습니다(표 2, 표 S2, 그림 S5 및 S6). 세마글루타이드에 유리한 이점은 당화혈색소, 공복 혈장 포도당, C-반응성 단백질 및 공복 지질 수치 변화에서도 나타났습니다(표 2).

탐색적 평가 변수 기준선에서 당뇨병 전증이 있었던 참가자 중, 세마글루타이드는 68주차에 당화혈색소 수치 개선과 관련이 있었으며, 기준선에서 당뇨병 전증이 있었던 세마글루타이드군 참가자의 84.1%가 정상 혈당으로 회복되었고, 위약군에서는 47.8%였습니다. 이러한 결과 및 기타 선택된 탐색적 평가 변수에 대한 결과는 표 2 및 표 S3에 제시되어 있습니다.

신체 기능 및 기타 참가자 보고 결과 SF-36 신체 기능 점수(가능한 규범 기반 점수 범위 19.03 ~ 57.60)는 68주차에 위약보다 세마글루타이드에서 유의미하게 더 많이 개선되었으며(P<0.001), SF-36 신체 및 정신 구성 요소 요약 점수 모두 세마글루타이드에 유리했습니다(표 2, 표 S2, 그림 S7). IWQOL-Lite-CT 신체 기능 점수는 68주차에 위약보다 세마글루타이드에서 유의미하게 더 많이 개선되었고(P<0.001)(표 2 및 표 S2), IWQOL-Lite-CT 총점에 대해서도 위약에 비해 유리한 효과가 있었습니다. SF-36 및 IWQOL-Lite-CT 평가 결과는 세마글루타이드가 위약보다 신체 기능에서 임상적으로 의미 있는 개인 내 개선을 보일 가능성이 더 높았음을 보여주었습니다(표 S4).

Change in Body Composition

In the DXA subpopulation (140 participants), total fat mass and regional visceral fat mass were reduced from baseline with semaglutide (Table S5). Although total lean body mass decreased in absolute terms (kg), the proportion of lean body mass relative to total body mass increased with semaglutide.

Safety and Side-Effect Profile

Similar percentages of participants in the semaglutide and placebo groups reported adverse events (89.7% and 86.4%, respectively) (Table 3). Gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation) were the most frequently reported events and occurred in more participants receiving semaglutide than those receiving placebo (74.2% vs. 47.9%). Most gastrointestinal events were mild-to-moderate in severity, were transient, and resolved without permanent discontinuation of the regimen (Fig. S8).

체성분 변화 DXA 하위 모집단(140명)에서 총 지방량 및 국소 내장 지방량은 세마글루타이드로 기준선에서 감소했습니다(표 S5). 총 제지방량은 절대적(kg)으로 감소했지만, 총 체중에 대한 제지방량의 비율은 세마글루타이드로 증가했습니다.

안전성 및 부작용 프로필

세마글루타이드군과 위약군에서 유사한 비율의 참가자가 이상 반응을 보고했습니다(각각 89.7% 및 86.4%)(표 3).

위장관 장애(일반적으로 메스꺼움, 설사, 구토 및 변비)가 가장 자주 보고된 사건이었고,

위약을 투여받은 참가자보다 세마글루타이드를 투여받은 참가자에서

더 많이 발생했습니다(74.2% 대 47.9%).

대부분의 위장관 사건은

경미-중등도였으며,

일시적이었고,

영구적인 요법 중단 없이 해결되었습니다(그림 S8).

Table 3

Adverse Events.

Serious adverse events were reported in 9.8% and 6.4% of semaglutide and placebo participants, respectively (Table 3), with the difference due primarily to a difference between the groups in the incidence of serious gastrointestinal disorders (1.4% of participants in the semaglutide group and 0% in the placebo group) and hepatobiliary disorders (1.3% with semaglutide and 0.2% with placebo). More participants in the semaglutide group than in the placebo group (7.0% vs. 3.1%) discontinued treatment owing to adverse events (mainly gastrointestinal events) (Table 3 and Fig. S9). One death was reported in each group, with neither considered by the independent external event adjudication committee to be related to receipt of semaglutide or placebo (Table 3).

Gallbladder-related disorders (mostly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively. Mild acute pancreatitis (according to the Atlanta classification18) was reported in three participants in the semaglutide group (one participant had a history of acute pancreatitis, and the other two participants had both gallstones and pancreatitis); all recovered during the trial period. There was no difference between groups in the incidence of benign and malignant neoplasms. Additional safety variables are described in Table 3 and Table S6.

이상 반응.

세마글루타이드 및 위약 참가자 중

심각한 이상 반응이 각각 9.8% 및 6.4%에서 보고되었으며(표 3),

이러한 차이는 주로 심각한 위장관 장애(세마글루타이드군 참가자의 1.4% 대 위약군 0%) 및

간담도계 장애(세마글루타이드 1.3% 대 위약 0.2%) 발생률의 그룹 간 차이 때문이었습니다.

위장관 사건(주로 위장관 사건)으로 인해 치료를 중단한 참가자는 위약군보다 세마글루타이드군이 더 많았습니다(7.0% 대 3.1%)(표 3 및 그림 S9). 각 그룹에서 한 건의 사망이 보고되었으며, 독립적인 외부 사건 판정 위원회는 어느 사망도 세마글루타이드 또는 위약 투여와 관련이 있다고 판단하지 않았습니다(표 3).

담낭 관련 장애(주로 담석증)는 세마글루타이드군과 위약군 참가자의 각각 2.6% 및 1.2%에서 보고되었습니다. 경미한 급성 췌장염(애틀랜타 분류18에 따름)은 세마글루타이드군 세 명의 참가자에게서 보고되었으며(한 참가자는 급성 췌장염 병력이 있었고, 다른 두 참가자는 담석과 췌장염을 모두 가지고 있었음), 모두 시험 기간 동안 회복되었습니다. 양성 및 악성 신생물 발생률에는 그룹 간 차이가 없었습니다. 추가 안전성 변수는 표 3 및 표 S6에 설명되어 있습니다.

Discussion

In this trial, we found that adults with obesity (or overweight with one or more weight-related coexisting conditions) and without diabetes had a mean weight loss of 14.9% from baseline with semaglutide as an adjunct to lifestyle intervention. This loss exceeded that with placebo plus lifestyle intervention by 12.4 percentage points. The 14.9% mean weight loss that we observed in the semaglutide group is substantially greater than the weight loss of 4.0 to 10.9% from baseline with approved antiobesity medications.3,19 Moreover, 86% of participants who received semaglutide, as compared with 32% of those who received placebo, lost 5% or more of baseline body weight, a widely used criterion of clinically meaningful response.2,3,20,21 Weight loss with semaglutide stems from a reduction in energy intake owing to decreased appetite, which is thought to result from direct and indirect effects on the brain.22-25 Weight loss with semaglutide was accompanied by greater improvements than placebo with respect to cardiometabolic risk factors, including reductions in waist circumference, blood pressure, glycated hemoglobin levels, and lipid levels; a greater decrease from baseline in C-reactive protein, a marker of inflammation; and a greater proportion of participants with normoglycemia. Semaglutide also improved physical functioning, as assessed by SF-36 and IWQOL-Lite-CT, a finding that is notable given that overweight and obesity significantly impair health-related quality of life.26 Statistical superiority of semaglutide over placebo was achieved for all end points in the hierarchical testing procedure.

Weight loss of 10 to 15% (or more) is recommended in people with many complications of overweight and obesity (e.g., prediabetes, hypertension, and obstructive sleep apnea).1,20,21,27 In the semaglutide group, approximately 70% of participants achieved a weight loss of at least 10%, and approximately 50% achieved a weight loss of at least 15%. Furthermore, one third of participants treated with semaglutide lost at least 20% of baseline weight, a reduction approaching that reported 1 to 3 years after bariatric surgery, particularly sleeve gastrectomy (approximately 20 to 30% weight loss).28-31 The magnitude of reduction in cardiometabolic risk is assumed to be proportional to the amount of weight lost with both approaches (i.e., pharmacotherapy or surgery).32

Analyses from the DXA substudy suggested that semaglutide led to greater reduction in fat mass than lean body mass, a finding consistent with previous findings with semaglutide (at a dose of 1.0 mg) in persons with obesity22 and in those with type 2 diabetes.33 The weight loss and improvements with respect to cardiometabolic risk factors with semaglutide reported here will be complemented by an ongoing cardiovascular outcomes trial in participants with overweight or obesity and established cardiovascular disease (the SELECT trial; ClinicalTrials.gov number, NCT03574597).

Liraglutide administered subcutaneously once daily is the only GLP-1 receptor agonist approved for weight management.3,19,34 Our trial showed greater mean placebo-corrected weight reductions with once-weekly 2.4-mg semaglutide plus lifestyle intervention (12.4%) than those reported with once-daily 3.0-mg liraglutide plus lifestyle intervention in the 56-week SCALE (Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals Obesity and Prediabetes) trial (4.5%).34,35 In addition, the weight-loss phase with semaglutide persisted longer than that reported with liraglutide35 and did not reach the nadir until week 60. However, these two studies differed in their participant population, which limits the robustness of between-study comparisons.

At week 68, 31% of participants who received placebo had lost at least 5% of baseline body weight, with 12% and 5% having achieved reductions of at least 10% and at least 15%, respectively, findings that show good adherence to lifestyle interventions. Similar results were observed at week 56 in the SCALE Obesity and Prediabetes trial.35

Currently, approved antiobesity drugs require administration once, twice, or three times daily,3,19 and a once-weekly regimen may improve treatment adherence. The once-weekly 2.4-mg dose of semaglutide was chosen for the present study on the basis of pharmacokinetic modeling that suggested that the 2.4-mg weekly dose had a maximum steady-state concentration similar to a once-daily 0.4-mg dose investigated in a phase 2 dose-finding trial in participants with obesity.14 The results of our study with once-weekly semaglutide at a 2.4-mg dose are consistent with the results of the phase 2 study, which showed an 11.6% greater reduction in body weight with once-daily semaglutide at a dose of 0.4 mg than with placebo after 52 weeks of treatment.14

The safety of semaglutide was consistent with that reported in the phase 2 study with once-daily dosing in participants with obesity14 and in the trials of once-weekly subcutaneous semaglutide in persons with type 2 diabetes (involving more than 8000 participants receiving doses up to 1 mg),12 as well as with that reported for the GLP-1 receptor agonist class in general.13,36 As is typical of this drug class,13,37 transient, mild-to-moderate gastrointestinal disorders were the most frequently reported adverse events, and more participants in the semaglutide group than in the placebo group discontinued the assigned regimen after such events. Nausea was the most common gastrointestinal event, occurring primarily during the dose-escalation period, a finding similar to that reported with liraglutide at a dose of 3.0 mg.35 Gallbladder-related disorders, principally cholelithiasis, were more common in the semaglutide group, a finding consistent with previous reports for GLP-1 receptor agonists38,39 and with the known effects of rapid weight loss.40,41 The incidence of cholelithiasis with semaglutide was in line with that of liraglutide at a dose of 3.0 mg.35 No new safety concerns arose.

Strengths of this trial included the large sample size and high rates of adherence to the treatment regimen and completion of the trial. Limitations included the preponderance of women and White participants, the relatively short duration of the trial, the exclusion of persons with type 2 diabetes, and the potential that participants who were enrolled may represent a subgroup with greater commitment to weight-loss efforts than the general population. Although the DXA data we report provide greater insight into the weight-loss effects of semaglutide, such assessments were performed in only a subpopulation of participants.

Our trial showed that among adults with overweight or obesity (without diabetes), once-weekly subcutaneous semaglutide plus lifestyle intervention was associated with substantial, sustained, clinically relevant mean weight loss of 14.9%, with 86% of participants attaining at least 5% weight loss.

고찰

이 시험에서 우리는 비만(또는 체중 관련 동반 질환이 하나 이상 있는 과체중)이며

당뇨병이 없는 성인이 생활 습관 개입에 추가하여

세마글루타이드를 사용했을 때 기준선에서

평균 14.9%의 체중 감소를 보임을 발견했습니다.

이러한 감소는

위약 및 생활 습관 개입보다 12.4%p 더 큰 수치였습니다.

우리가 세마글루타이드군에서 관찰한 14.9%의 평균 체중 감소는

승인된 항비만 약물로 기준선에서

4.0 ~ 10.9%의 체중 감소보다 실질적으로 더 큽니다.3,19

더욱이,

세마글루타이드를 투여받은 참가자의 86%가

위약을 투여받은 참가자의 32%에 비해 기준선 체중의 5% 이상을 감량했으며,

이는 임상적으로 의미 있는 반응의 널리 사용되는 기준입니다.2,3,20,21

세마글루타이드에 의한 체중 감소는

식욕 감소로 인한 에너지 섭취 감소에서 비롯되며,

이는 뇌에 대한 직접적 및 간접적 효과의 결과로 생각됩니다.22-25

세마글루타이드에 의한 체중 감소는

허리둘레, 혈압, 당화혈색소 수치 및 지질 수치 감소를 포함한

심혈관 대사 위험 요인 측면에서 위약보다 더 큰 개선을 동반했습니다.

염증 표지자인 C-반응성 단백질의 기준선 대비 더 큰 감소와

정상 혈당을 가진 참가자의 더 큰 비율도 나타났습니다.

세마글루타이드는 또한 SF-36 및 IWQOL-Lite-CT로 평가된 신체 기능을 개선했으며, 과

체중 및 비만이 건강 관련 삶의 질을 현저히 손상시킨다는 점을 고려할 때

이는 주목할 만한 결과입니다.26

세마글루타이드의 위약 대비 통계적 우월성은

계층적 검정 절차의 모든 평가 변수에서 달성되었습니다.

10~15%(또는 그 이상)의 체중 감소는

과체중 및 비만의 많은 합병증(예: 당뇨병 전증, 고혈압, 폐쇄성 수면 무호흡증)을 가진 사람들에게 권장됩니다.1,20,21,27

세마글루타이드군에서는

참가자의 약 70%가 최소 10%의 체중 감소를 달성했으며,

약 50%가 최소 15%의 체중 감소를 달성했습니다.

더욱이,

세마글루타이드로 치료받은 참가자의 3분의 1은

기준선 체중의 최소 20%를 감량했는데,

이는 비만 수술, 특히 위 소매 절제술 후

1~3년 후 보고된 감소량(약 20~30% 체중 감소)에 근접하는 수치입니다.28-31

심혈관 대사 위험 감소의 크기는

두 가지 접근 방식(즉, 약물 요법 또는 수술) 모두에서

감량된 체중량에 비례한다고 가정됩니다.32

DXA 하위 연구 분석 결과, 세마글루타이드는 제지방량보다 지방량을 더 크게 감소시키는 것으로 나타났으며, 이는 비만 환자22 및 제2형 당뇨병 환자33에서 세마글루타이드(1.0mg 용량)를 사용한 이전 연구 결과와 일치합니다. 여기에 보고된 세마글루타이드의 체중 감소 및 심혈관 대사 위험 요인 개선은 과체중 또는 비만 및 확립된 심혈관 질환 참가자를 대상으로 진행 중인 심혈관 결과 시험(SELECT 시험; ClinicalTrials.gov 번호, NCT03574597)을 통해 보완될 것입니다. 주 1회 피하 투여되는 리라글루타이드는 체중 관리를 위해 승인된 유일한 GLP-1 수용체 작용제입니다.3,19,34 우리 시험은 주 1회 2.4mg 세마글루타이드와 생활 습관 개입을 병행했을 때 주 1회 3.0mg 리라글루타이드와 생활 습관 개입을 병행한 56주 SCALE (Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals Obesity and Prediabetes) 시험에서 보고된 것(4.5%)보다 더 큰 평균 위약 보정 체중 감소(12.4%)를 보였습니다.34,35 또한, 세마글루타이드의 체중 감소 단계는 리라글루타이드35보다 더 오래 지속되었고 60주까지 최저점에 도달하지 않았습니다. 그러나 이 두 연구는 참가자 모집단이 달라서 연구 간 비교의 견고성이 제한됩니다.

68주차에 위약을 투여받은 참가자의 31%가 기준선 체중의 최소 5%를 감량했으며, 12%와 5%가 각각 최소 10% 및 최소 15%의 감소를 달성했는데, 이는 생활 습관 개입에 대한 좋은 순응도를 보여줍니다. SCALE Obesity and Prediabetes 시험에서도 56주차에 유사한 결과가 관찰되었습니다.35 현재 승인된 항비만 약물은 하루 1회, 2회 또는 3회 투여해야 하지만,3,19 주 1회 요법은 치료 순응도를 향상시킬 수 있습니다. 주 1회 2.4mg 용량의 세마글루타이드는 비만 참가자를 대상으로 한 2상 용량 탐색 시험에서 조사된 주 1회 0.4mg 용량과 유사한 최대 정상 상태 농도를 가짐을 시사하는 약동학 모델링을 기반으로 본 연구를 위해 선택되었습니다.14 주 1회 2.4mg 용량의 세마글루타이드에 대한 우리 연구 결과는 52주 치료 후 주 1회 0.4mg 용량의 세마글루타이드가 위약보다 체중을 11.6% 더 많이 감소시켰음을 보여준 2상 연구 결과와 일치합니다.14 세마글루타이드의 안전성은 비만 참가자를 대상으로 한 주 1회 용량의 2상 연구14 및 제2형 당뇨병 환자를 대상으로 한 주 1회 피하 세마글루타이드 시험(8000명 이상의 참가자가 1mg까지의 용량 투여)12에서 보고된 것과 일치했으며, GLP-1 수용체 작용제 계열 전반에 대해 보고된 것과도 일치합니다.13,36 이 약물 계열의 전형적인 특성상,13,37 일시적이고 경미-중등도의 위장관 장애가 가장 자주 보고된 이상 반응이었으며, 위약군보다 세마글루타이드군에서 더 많은 참가자가 이러한 사건 후 할당된 요법을 중단했습니다. 메스꺼움이 가장 흔한 위장관 사건이었으며, 주로 용량 증량 기간 동안 발생했는데, 이는 3.0mg 용량의 리라글루타이드에서도 보고된 것과 유사합니다.35 담낭 관련 장애, 주로 담석증은 세마글루타이드군에서 더 흔했으며, 이는 GLP-1 수용체 작용제에 대한 이전 보고38,39 및 급격한 체중 감소의 알려진 효과40,41와 일치합니다. 세마글루타이드의 담석증 발생률은 3.0mg 용량의 리라글루타이드와 일치했습니다.35 새로운 안전성 문제는 발생하지 않았습니다. 이 시험의 강점은 큰 표본 크기와 치료 요법에 대한 높은 순응도 및 시험 완료율을 포함합니다. 한계점은 여성과 백인 참가자의 압도적인 비중, 비교적 짧은 시험 기간, 제2형 당뇨병 환자 제외, 그리고 등록된 참가자가 일반 인구보다 체중 감소 노력에 더 큰 의지를 가진 하위 그룹을 대표할 수 있다는 점입니다. 우리가 보고한 DXA 데이터는 세마글루타이드의 체중 감소 효과에 대한 더 깊은 통찰력을 제공하지만, 이러한 평가는 참가자의 하위 모집단에서만 수행되었습니다. 우리 시험은 과체중 또는 비만(당뇨병 없음) 성인에게 주 1회 피하 세마글루타이드와 생활 습관 개입을 병행했을 때 14.9%의 실질적이고 지속적이며 임상적으로 유의미한 평균 체중 감소와 관련이 있었으며, 참가자의 86%가 최소 5%의 체중 감소를 달성했음을 보여주었습니다.

Notes

This article was published on February 10, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by Novo Nordisk.

Dr. Wilding reports receiving advisory board fees, paid to his institution, from Astellas Pharma, grant support and fees for membership on a data and safety monitoring board, both paid to University of Liverpool, lecture fees, and travel support from AstraZeneca, advisory board fees, paid to his institution, and lecture fees from Boehringer Ingelheim, Napp, and Sanofi Pasteur, advisory board fees, paid to his institution, from Eli Lilly, Janssen Global Services, Rhythm, and Wilmington Healthcare, lecture fees from Mundipharma, grant support, advisory board fees, and fees for serving as an investigator, all paid to University of Liverpool, and lecture fees from Novo Nordisk, and advisory board fees from Takeda Medical Research Foundation; Dr. Batterham, receiving consulting fees from Boehringer Ingelheim, Pfizer, and ViiV Healthcare and consulting fees and lecture fees from Novo Nordisk; Dr. Calanna, being employed by Novo Nordisk; Dr. Davies, receiving grant support from AstraZeneca, lecture fees from AstraZeneca Pharma India, advisory board fees from BI-LLY Alliance, Lexicon Pharmaceuticals, and Sanofi, advisory board fees and lecture fees from Boehringer Ingelheim and Eli Lilly, lecture fees from Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim (Poland), Napp Pharmaceuticals, Sanofi Romania, and Sanofi (Japan), advisory board fees and lecture fees from Boehringer Ingelheim International, and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Van Gaal, receiving lecture fees from AstraZeneca and Boehringer Ingelheim and advisory board fees and lecture fees from Merck and Novo Nordisk; Dr. Lingvay, receiving advisory board fees and consulting fees from AstraZeneca, consulting fees from Bayer HealthCare Pharmaceuticals, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, MannKind, Target Pharma, Valeritas, and Zealand Pharma, advisory board fees from Boehringer Ingelheim and Sanofi US Services, grant support, paid to UT Southwestern, from Merck, grant support, paid to his institution, from Mylan Pharmaceuticals and Pfizer, and grant support, paid to UT Southwestern, advisory board fees, consulting fees, and travel support from Novo Nordisk; Dr. McGowan, receiving educational fees from AstraZeneca, Merck, and Orexigen Therapeutics, lecture fees from Janssen Biotech, advisory board fees from Johnson & Johnson Health Care Systems, grant support, paid to Guys and St. Thomas’ Hospital, consulting fees, and educational fees from Novo Nordisk, and owning stock in Reset Health Clinics; Dr. Rosenstock, receiving grant support, advisory board fees, and travel support from Applied Therapeutics, Intarcia, and Oramed, grant support and consulting fees from AstraZeneca, grant support, advisory board fees, lecture fees, and travel support from Boehringer Ingelheim, Novo Nordisk, and Sanofi US Services, grant support and advisory board fees from Eli Lilly, grant support from Genentech, GlaxoSmithKline, Janssen Biotech, Lexicon Pharmaceuticals, Novartis, Pfizer, and REMD Biotherapeutics, and advisory board fees from Zealand Pharma; Dr. Tran, being employed by and owning stock in Novo Nordisk; Dr. Wadden, receiving grant support, paid to the University of Pennsylvania, and advisory board fees from Novo Nordisk and advisory board fees from WW International; Dr. Wharton, receiving lecture fees from AstraZeneca and Bausch and Lomb and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Yokote, receiving lecture fees from Amgen, Janssen Pharmaceuticals, Kyowa Hakko Kirin, Novartis Pharma, and Sanofi, grant support and lecture fees from Astellas Pharma, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp and Dohme, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda Pharmaceutical, advisory board fees and lecture fees from AstraZeneca, grant support, lecture fees, and advisory board fees from Kowa Company and Novo Nordisk, and lecture fees and advisory board fees from Sanofi; Mr. Zeuthen, being employed by and owning stock in Novo Nordisk; and Dr. Kushner, receiving advisory board fees from Novo Nordisk and Weight Watchers. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the trial participants and the trial site staff; Lisa von Huth Smith of Novo Nordisk, Denmark, for support with data presentation of participant-reported outcomes and critical review of an earlier draft of the manuscript; and Paul Barlass of Axis, a division of Spirit Medical Communications Group, for medical writing and editorial assistance with an earlier draft of the manuscript (funded by Novo Nordisk).

Supplementary Material

Protocol (nejmoa2032183_protocol.pdf)

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References

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Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract 2016;22:Suppl 3:1-203.

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Once-Weekly Semaglutide in Adults with Overweight or Obesity

Authors: John P.H. Wilding, D.M., Rachel L. Batterham, M.B., B.S., Ph.D., Salvatore Calanna, Ph.D., Melanie Davies, M.D., Luc F. Van Gaal, M.D., Ph.D., Ildiko Lingvay, M.D., M.P.H., M.S.C.S. https://orcid.org/0000-0001-7006-7401, Barbara M. McGowan, M.D., Ph.D., +7 , for the STEP 1 Study Group*Author Info & Affiliations

Published February 10, 2021

N Engl J Med 2021;384:989-1002

DOI: 10.1056/NEJMoa2032183

VOL. 384 NO. 11

Copyright © 2021

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AbstractBackground

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Methods

In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

Research Summary

Once-Weekly Semaglutide in Adults with Overweight or Obesity

Results

The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

Conclusions

In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Quick Take

Weekly Semaglutide in Adults with Overweight or Obesity

1m 46s

Obesity is a chronic disease and global public health challenge.1-3 Obesity can lead to insulin resistance, hypertension, and dyslipidemia,4 is associated with complications such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease,2,5 and reduces life expectancy.6 More recently, obesity has been linked to increased numbers of hospitalizations, the need for mechanical ventilation, and death in persons with coronavirus disease 2019 (Covid-19).7,8

Although lifestyle intervention (diet and exercise) represents the cornerstone of weight management,1,2 sustaining weight loss over the long term is challenging.9 Clinical guidelines suggest adjunctive pharmacotherapy, particularly for adults with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or greater, or 27 or greater in persons with coexisting conditions.1,2,10 However, the use of available medications remains limited by modest efficacy, safety concerns, and cost.3

Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is approved, at doses up to 1 mg administered subcutaneously once weekly, for the treatment of type 2 diabetes in adults and for reducing the risk of cardiovascular events in persons with type 2 diabetes and cardiovascular disease.11 Semaglutide induced weight loss in persons with type 2 diabetes and in adults with obesity who were participants in a phase 2 trial,12-14 findings that supported further investigation. The global phase 3 Semaglutide Treatment Effect in People with Obesity (STEP) program aims to eval‎uate the efficacy and safety of semaglutide administered subcutaneously at a dose of 2.4 mg once weekly in persons with overweight or obesity, with or without weight-related complications.15

This 68-week trial eval‎uated the efficacy and safety of semaglutide as compared with placebo as an adjunct to lifestyle intervention for reducing body weight and meeting other related end points in adults with overweight or obesity and without diabetes.

MethodsTrial Design and Oversight

We conducted a randomized, double-blind, placebo-controlled trial at 129 sites in 16 countries in Asia, Europe, North America, and South America. The sponsor (Novo Nordisk) designed the trial and oversaw its conduct. The design has been published previously.15 The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol (available with the full text of this article at NEJM.org) was approved by an independent ethics committee or institutional review board at each study site. Investigators were responsible for data collection, and the sponsor undertook site monitoring, data collation, and analysis. All authors had full access to study data, participated in drafting the manuscript (assisted by a sponsor-funded medical writer), approved its submission for publication, and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Participants

We enrolled adults (18 years of age or older) with one or more self-reported unsuccessful dietary efforts to lose weight and either a BMI of 30 or greater or a BMI of 27 or greater with one or more treated or untreated weight-related coexisting conditions (i.e., hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). A subgroup of participants with a BMI of 40 or less underwent dual-energy x-ray absorptiometry (DXA) to assess body composition. All participants provided written informed consent. Key exclusion criteria were diabetes, a glycated hemoglobin level of 48 mmol per mole (6.5%) or greater, a history of chronic pancreatitis, acute pancreatitis within 180 days before enrollment, previous surgical obesity treatment, and use of antiobesity medication within 90 days before enrollment. A full list of the eligibility criteria is provided in the Supplementary Appendix, available at NEJM.org.

Procedures

Participants were randomly assigned in a 2:1 ratio, through the use of an interactive Web-based response system, to receive semaglutide at a dose of 2.4 mg administered subcutaneously once a week for 68 weeks or matching placebo, in addition to lifestyle intervention; this 68-week period was followed by a 7-week period without receipt of semaglutide or placebo or lifestyle intervention. Semaglutide, administered with a prefilled pen injector, was initiated at a dose of 0.25 mg once weekly for the first 4 weeks, with the dose increased every 4 weeks to reach the maintenance dose of 2.4 mg weekly by week 16 (lower maintenance doses were permitted if participants had unacceptable side effects with the 2.4-mg dose) (Fig. S1 in the Supplementary Appendix). Participants received individual counseling sessions every 4 weeks to help them adhere to a reduced-calorie diet (500-kcal deficit per day relative to the energy expenditure estimated at the time they underwent randomization) and increased physical activity (with 150 minutes per week of physical activity, such as walking, encouraged). Both diet and activity were recorded daily in a diary or by use of a smartphone application or other tools and were reviewed during counseling sessions. Participants discontinuing treatment prematurely remained in the trial.

End Points and Assessments

The coprimary end points were the percentage change in body weight from baseline to week 68 and achievement of a reduction in body weight of 5% or more from baseline to week 68. Confirm‎atory secondary end points (in hierarchical testing order) were achievement of a reduction in body weight of 10% or more and 15% or more by week 68 and the change from baseline to week 68 in waist circumference, systolic blood pressure, physical functioning score on the 36-item Short Form Health Survey (SF-36), version 2, and physical function score on the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) questionnaire. (Assessments related to end points, along with supportive secondary and exploratory end points and safety assessments, are described in the Supplementary Appendix.) Body composition (total fat, total lean body mass, and regional [abdominal] visceral fat mass) was measured in the DXA subpopulation as a supportive secondary end point. Safety assessments included the number of adverse events occurring during the on-treatment period (the time during which participants received any dose of semaglutide or placebo within the previous 49 days, with any period of temporary interruption of the regimen excluded) and serious adverse events occurring between baseline and week 75. An independent external event adjudication committee reviewed selected adverse events (cardiovascular events and acute pancreatitis) and deaths. All standard assays were performed in a central laboratory.

Statistical Analysis

A sample size of 1950 participants provided an effective power of 99% for the coprimary and confirm‎atory secondary end points, tested in a prespecified hierarchical order. Efficacy end points were analyzed in the full analysis population (all randomly assigned participants according to the intention-to-treat principle); safety end points were analyzed in the safety analysis population (all randomly assigned participants exposed to at least one dose of semaglutide or placebo). Observation periods included the in-trial period (the time from random assignment to last contact with a trial site, regardless of treatment discontinuation or rescue intervention) and the on-treatment period. All results from statistical analyses were accompanied by a two-sided 95% confidence interval and corresponding P values (with significance defined as P<0.05). Supportive secondary end-point analyses were not controlled for multiple comparisons and should not be used to infer definitive treatment effects.

Two estimands — the treatment policy estimand (traditional intention-to-treat analysis, with effects assessed regardless of treatment discontinuation or rescue intervention) and the trial product estimand (effects assessed if the drug or placebo was taken as intended) — were used to assess treatment efficacy from different perspectives and accounted for intercurrent events and missing data differently, as described previously.16 All analyses in the statistical hierarchy were based on the primary treatment policy estimand (details on analysis methods are provided in the Supplementary Appendix). All reported results are for the treatment policy estimand, unless stated otherwise.

ResultsStudy Participants

From June through November 2018, a total of 1961 participants were randomly assigned to receive semaglutide (1306 participants) or placebo (655 participants). Overall, 94.3% of the participants completed the trial, 91.2% had a body-weight assessment at week 68, and 81.1% adhered to treatment (Fig. S2). Rescue interventions were received by 7 participants in the semaglutide group (2 had bariatric surgery and 5 received other antiobesity medication) and by 13 in the placebo group (3 had bariatric surgery and 10 received other antiobesity medication).

Demographics and baseline characteristics were similar in the two treatment groups (Table 1). Most participants were female (74.1%) and White (75.1%), with a mean age of 46 years. The mean body weight was 105.3 kg, the mean BMI 37.9, and the mean waist circumference 114.7 cm; 43.7% had prediabetes. At screening, most participants (75.0%) had at least one coexisting condition. The baseline characteristics of the DXA subpopulation are provided in Table S1.

Table 1

Demographic and Clinical Characteristics of the Participants at Baseline.

Change in Body Weight

In the semaglutide group, weight loss was observed from the first postrandomization assessment (week 4) onward, reaching a nadir at week 60 (Figure 1A and 1B). For the treatment policy estimand (showing the effect regardless of treatment discontinuation or rescue intervention), the estimated mean weight change at week 68 was −14.9% with 2.4-mg semaglutide, as compared with −2.4% with placebo (estimated treatment difference, −12.4 percentage points; 95% CI, −13.4 to −11.5; P<0.001). For the trial product estimand (showing the effect if the drug or placebo was taken as intended), the corresponding changes were −16.9% and −2.4% (estimated treatment difference, −14.4 percentage points; 95% CI, −15.3 to −13.5).

Figure 1

Effect of Once-Weekly Semaglutide, as Compared with Placebo, on Body Weight.

Participants who received semaglutide were more likely to lose 5% or more, 10% or more, 15% or more, and 20% or more of baseline body weight at week 68 than those who received placebo (P<0.001 for the 5%, 10%, and 15% thresholds; the 20% threshold was not part of the statistical testing hierarchy) (Table 2, Figure 1C and 1D, and Table S2). Among the participants for whom data were available at the week 68 visit (1212 participants in the semaglutide group and 577 in the placebo group), these thresholds were reached by 86.4% (1047 participants), 69.1% (838 participants), 50.5% (612 participants), and 32.0% (388 participants), respectively, in the semaglutide group, as compared with 31.5% (182 participants), 12.0% (69 participants), 4.9% (28 participants), and 1.7% (10 participants) in the placebo group (Figure 1C, with on-treatment data shown in Figure 1D and the cumulative distribution of change from baseline shown in Fig. S3). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7) (Fig. S4). Data on change in body weight and achieved reduction in body weight of 5% or more (coprimary end points) as well as confirm‎atory and selected supportive secondary end points for the trial product estimand are provided in Table S2.

Table 2

Coprimary, Confirm‎atory, and Selected Supportive Secondary and Exploratory End Points for the Treatment Policy Estimand.

Other Confirm‎atory and Supportive Secondary End Points

Semaglutide was associated with greater reductions from baseline than placebo in waist circumference (–13.54 cm with semaglutide vs. –4.13 cm with placebo; estimated treatment difference, –9.42 cm; 95% CI, –10.30 to –8.53), BMI (–5.54 with semaglutide vs. –0.92 with placebo; estimated treatment difference, –4.61; 95% CI, –4.96 to –4.27), and systolic and diastolic blood pressure at week 68 (Table 2, Table S2, and Figs. S5 and S6). Benefits favoring semaglutide were also noted with respect to changes in glycated hemoglobin, fasting plasma glucose, C-reactive protein, and fasting lipid levels (Table 2).

Exploratory End Points

Among participants with prediabetes at baseline, semaglutide was associated with improvements in glycated hemoglobin levels at week 68, and 84.1% of participants in the semaglutide group who had prediabetes at baseline, as compared with 47.8% of participants in the placebo group with prediabetes at baseline, reverted to normoglycemia. Results for these and other selected exploratory end points are presented in Table 2 and Table S3.

Physical Functioning and Other Participant-Reported Outcomes

SF-36 physical functioning scores (with possible norm-based scores ranging from 19.03 to 57.60) improved significantly more with semaglutide than with placebo at week 68 (P<0.001), and both SF-36 physical and mental component summary scores favored semaglutide (Table 2, Table S2, and Fig. S7). IWQOL-Lite-CT physical function scores improved significantly more with semaglutide than with placebo at week 68 (P<0.001) (Table 2 and Table S2), and there were favorable effects over placebo on IWQOL-Lite-CT total scores. The results of SF-36 and IWQOL-Lite-CT assessments showed that participants were more likely to have clinically meaningful within-person improvements in physical functioning with semaglutide than with placebo (Table S4).

Change in Body Composition

In the DXA subpopulation (140 participants), total fat mass and regional visceral fat mass were reduced from baseline with semaglutide (Table S5). Although total lean body mass decreased in absolute terms (kg), the proportion of lean body mass relative to total body mass increased with semaglutide.

Safety and Side-Effect Profile

Similar percentages of participants in the semaglutide and placebo groups reported adverse events (89.7% and 86.4%, respectively) (Table 3). Gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation) were the most frequently reported events and occurred in more participants receiving semaglutide than those receiving placebo (74.2% vs. 47.9%). Most gastrointestinal events were mild-to-moderate in severity, were transient, and resolved without permanent discontinuation of the regimen (Fig. S8).

Table 3

Adverse Events.

Serious adverse events were reported in 9.8% and 6.4% of semaglutide and placebo participants, respectively (Table 3), with the difference due primarily to a difference between the groups in the incidence of serious gastrointestinal disorders (1.4% of participants in the semaglutide group and 0% in the placebo group) and hepatobiliary disorders (1.3% with semaglutide and 0.2% with placebo). More participants in the semaglutide group than in the placebo group (7.0% vs. 3.1%) discontinued treatment owing to adverse events (mainly gastrointestinal events) (Table 3 and Fig. S9). One death was reported in each group, with neither considered by the independent external event adjudication committee to be related to receipt of semaglutide or placebo (Table 3).

Gallbladder-related disorders (mostly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively. Mild acute pancreatitis (according to the Atlanta classification18) was reported in three participants in the semaglutide group (one participant had a history of acute pancreatitis, and the other two participants had both gallstones and pancreatitis); all recovered during the trial period. There was no difference between groups in the incidence of benign and malignant neoplasms. Additional safety variables are described in Table 3 and Table S6.

Discussion

In this trial, we found that adults with obesity (or overweight with one or more weight-related coexisting conditions) and without diabetes had a mean weight loss of 14.9% from baseline with semaglutide as an adjunct to lifestyle intervention. This loss exceeded that with placebo plus lifestyle intervention by 12.4 percentage points. The 14.9% mean weight loss that we observed in the semaglutide group is substantially greater than the weight loss of 4.0 to 10.9% from baseline with approved antiobesity medications.3,19 Moreover, 86% of participants who received semaglutide, as compared with 32% of those who received placebo, lost 5% or more of baseline body weight, a widely used criterion of clinically meaningful response.2,3,20,21 Weight loss with semaglutide stems from a reduction in energy intake owing to decreased appetite, which is thought to result from direct and indirect effects on the brain.22-25 Weight loss with semaglutide was accompanied by greater improvements than placebo with respect to cardiometabolic risk factors, including reductions in waist circumference, blood pressure, glycated hemoglobin levels, and lipid levels; a greater decrease from baseline in C-reactive protein, a marker of inflammation; and a greater proportion of participants with normoglycemia. Semaglutide also improved physical functioning, as assessed by SF-36 and IWQOL-Lite-CT, a finding that is notable given that overweight and obesity significantly impair health-related quality of life.26 Statistical superiority of semaglutide over placebo was achieved for all end points in the hierarchical testing procedure.

Weight loss of 10 to 15% (or more) is recommended in people with many complications of overweight and obesity (e.g., prediabetes, hypertension, and obstructive sleep apnea).1,20,21,27 In the semaglutide group, approximately 70% of participants achieved a weight loss of at least 10%, and approximately 50% achieved a weight loss of at least 15%. Furthermore, one third of participants treated with semaglutide lost at least 20% of baseline weight, a reduction approaching that reported 1 to 3 years after bariatric surgery, particularly sleeve gastrectomy (approximately 20 to 30% weight loss).28-31 The magnitude of reduction in cardiometabolic risk is assumed to be proportional to the amount of weight lost with both approaches (i.e., pharmacotherapy or surgery).32

Analyses from the DXA substudy suggested that semaglutide led to greater reduction in fat mass than lean body mass, a finding consistent with previous findings with semaglutide (at a dose of 1.0 mg) in persons with obesity22 and in those with type 2 diabetes.33 The weight loss and improvements with respect to cardiometabolic risk factors with semaglutide reported here will be complemented by an ongoing cardiovascular outcomes trial in participants with overweight or obesity and established cardiovascular disease (the SELECT trial; ClinicalTrials.gov number, NCT03574597).

Liraglutide administered subcutaneously once daily is the only GLP-1 receptor agonist approved for weight management.3,19,34 Our trial showed greater mean placebo-corrected weight reductions with once-weekly 2.4-mg semaglutide plus lifestyle intervention (12.4%) than those reported with once-daily 3.0-mg liraglutide plus lifestyle intervention in the 56-week SCALE (Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals Obesity and Prediabetes) trial (4.5%).34,35 In addition, the weight-loss phase with semaglutide persisted longer than that reported with liraglutide35 and did not reach the nadir until week 60. However, these two studies differed in their participant population, which limits the robustness of between-study comparisons.

At week 68, 31% of participants who received placebo had lost at least 5% of baseline body weight, with 12% and 5% having achieved reductions of at least 10% and at least 15%, respectively, findings that show good adherence to lifestyle interventions. Similar results were observed at week 56 in the SCALE Obesity and Prediabetes trial.35

Currently, approved antiobesity drugs require administration once, twice, or three times daily,3,19 and a once-weekly regimen may improve treatment adherence. The once-weekly 2.4-mg dose of semaglutide was chosen for the present study on the basis of pharmacokinetic modeling that suggested that the 2.4-mg weekly dose had a maximum steady-state concentration similar to a once-daily 0.4-mg dose investigated in a phase 2 dose-finding trial in participants with obesity.14 The results of our study with once-weekly semaglutide at a 2.4-mg dose are consistent with the results of the phase 2 study, which showed an 11.6% greater reduction in body weight with once-daily semaglutide at a dose of 0.4 mg than with placebo after 52 weeks of treatment.14

The safety of semaglutide was consistent with that reported in the phase 2 study with once-daily dosing in participants with obesity14 and in the trials of once-weekly subcutaneous semaglutide in persons with type 2 diabetes (involving more than 8000 participants receiving doses up to 1 mg),12 as well as with that reported for the GLP-1 receptor agonist class in general.13,36 As is typical of this drug class,13,37 transient, mild-to-moderate gastrointestinal disorders were the most frequently reported adverse events, and more participants in the semaglutide group than in the placebo group discontinued the assigned regimen after such events. Nausea was the most common gastrointestinal event, occurring primarily during the dose-escalation period, a finding similar to that reported with liraglutide at a dose of 3.0 mg.35 Gallbladder-related disorders, principally cholelithiasis, were more common in the semaglutide group, a finding consistent with previous reports for GLP-1 receptor agonists38,39 and with the known effects of rapid weight loss.40,41 The incidence of cholelithiasis with semaglutide was in line with that of liraglutide at a dose of 3.0 mg.35 No new safety concerns arose.

Strengths of this trial included the large sample size and high rates of adherence to the treatment regimen and completion of the trial. Limitations included the preponderance of women and White participants, the relatively short duration of the trial, the exclusion of persons with type 2 diabetes, and the potential that participants who were enrolled may represent a subgroup with greater commitment to weight-loss efforts than the general population. Although the DXA data we report provide greater insight into the weight-loss effects of semaglutide, such assessments were performed in only a subpopulation of participants.

Our trial showed that among adults with overweight or obesity (without diabetes), once-weekly subcutaneous semaglutide plus lifestyle intervention was associated with substantial, sustained, clinically relevant mean weight loss of 14.9%, with 86% of participants attaining at least 5% weight loss.

Notes

This article was published on February 10, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by Novo Nordisk.

Dr. Wilding reports receiving advisory board fees, paid to his institution, from Astellas Pharma, grant support and fees for membership on a data and safety monitoring board, both paid to University of Liverpool, lecture fees, and travel support from AstraZeneca, advisory board fees, paid to his institution, and lecture fees from Boehringer Ingelheim, Napp, and Sanofi Pasteur, advisory board fees, paid to his institution, from Eli Lilly, Janssen Global Services, Rhythm, and Wilmington Healthcare, lecture fees from Mundipharma, grant support, advisory board fees, and fees for serving as an investigator, all paid to University of Liverpool, and lecture fees from Novo Nordisk, and advisory board fees from Takeda Medical Research Foundation; Dr. Batterham, receiving consulting fees from Boehringer Ingelheim, Pfizer, and ViiV Healthcare and consulting fees and lecture fees from Novo Nordisk; Dr. Calanna, being employed by Novo Nordisk; Dr. Davies, receiving grant support from AstraZeneca, lecture fees from AstraZeneca Pharma India, advisory board fees from BI-LLY Alliance, Lexicon Pharmaceuticals, and Sanofi, advisory board fees and lecture fees from Boehringer Ingelheim and Eli Lilly, lecture fees from Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim (Poland), Napp Pharmaceuticals, Sanofi Romania, and Sanofi (Japan), advisory board fees and lecture fees from Boehringer Ingelheim International, and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Van Gaal, receiving lecture fees from AstraZeneca and Boehringer Ingelheim and advisory board fees and lecture fees from Merck and Novo Nordisk; Dr. Lingvay, receiving advisory board fees and consulting fees from AstraZeneca, consulting fees from Bayer HealthCare Pharmaceuticals, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, MannKind, Target Pharma, Valeritas, and Zealand Pharma, advisory board fees from Boehringer Ingelheim and Sanofi US Services, grant support, paid to UT Southwestern, from Merck, grant support, paid to his institution, from Mylan Pharmaceuticals and Pfizer, and grant support, paid to UT Southwestern, advisory board fees, consulting fees, and travel support from Novo Nordisk; Dr. McGowan, receiving educational fees from AstraZeneca, Merck, and Orexigen Therapeutics, lecture fees from Janssen Biotech, advisory board fees from Johnson & Johnson Health Care Systems, grant support, paid to Guys and St. Thomas’ Hospital, consulting fees, and educational fees from Novo Nordisk, and owning stock in Reset Health Clinics; Dr. Rosenstock, receiving grant support, advisory board fees, and travel support from Applied Therapeutics, Intarcia, and Oramed, grant support and consulting fees from AstraZeneca, grant support, advisory board fees, lecture fees, and travel support from Boehringer Ingelheim, Novo Nordisk, and Sanofi US Services, grant support and advisory board fees from Eli Lilly, grant support from Genentech, GlaxoSmithKline, Janssen Biotech, Lexicon Pharmaceuticals, Novartis, Pfizer, and REMD Biotherapeutics, and advisory board fees from Zealand Pharma; Dr. Tran, being employed by and owning stock in Novo Nordisk; Dr. Wadden, receiving grant support, paid to the University of Pennsylvania, and advisory board fees from Novo Nordisk and advisory board fees from WW International; Dr. Wharton, receiving lecture fees from AstraZeneca and Bausch and Lomb and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Yokote, receiving lecture fees from Amgen, Janssen Pharmaceuticals, Kyowa Hakko Kirin, Novartis Pharma, and Sanofi, grant support and lecture fees from Astellas Pharma, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp and Dohme, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda Pharmaceutical, advisory board fees and lecture fees from AstraZeneca, grant support, lecture fees, and advisory board fees from Kowa Company and Novo Nordisk, and lecture fees and advisory board fees from Sanofi; Mr. Zeuthen, being employed by and owning stock in Novo Nordisk; and Dr. Kushner, receiving advisory board fees from Novo Nordisk and Weight Watchers. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the trial participants and the trial site staff; Lisa von Huth Smith of Novo Nordisk, Denmark, for support with data presentation of participant-reported outcomes and critical review of an earlier draft of the manuscript; and Paul Barlass of Axis, a division of Spirit Medical Communications Group, for medical writing and editorial assistance with an earlier draft of the manuscript (funded by Novo Nordisk).

Supplementary Material

Protocol (nejmoa2032183_protocol.pdf)

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References

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Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract 2016;22:Suppl 3:1-203.

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Once-Weekly Semaglutide in Adults with Overweight or Obesity

Authors: John P.H. Wilding, D.M., Rachel L. Batterham, M.B., B.S., Ph.D., Salvatore Calanna, Ph.D., Melanie Davies, M.D., Luc F. Van Gaal, M.D., Ph.D., Ildiko Lingvay, M.D., M.P.H., M.S.C.S. https://orcid.org/0000-0001-7006-7401, Barbara M. McGowan, M.D., Ph.D., +7 , for the STEP 1 Study Group*Author Info & Affiliations

Published February 10, 2021

N Engl J Med 2021;384:989-1002

DOI: 10.1056/NEJMoa2032183

VOL. 384 NO. 11

Copyright © 2021

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AbstractBackground

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Methods

In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

Research Summary

Once-Weekly Semaglutide in Adults with Overweight or Obesity

Results

The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

Conclusions

In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Quick Take

Weekly Semaglutide in Adults with Overweight or Obesity

1m 46s

Obesity is a chronic disease and global public health challenge.1-3 Obesity can lead to insulin resistance, hypertension, and dyslipidemia,4 is associated with complications such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease,2,5 and reduces life expectancy.6 More recently, obesity has been linked to increased numbers of hospitalizations, the need for mechanical ventilation, and death in persons with coronavirus disease 2019 (Covid-19).7,8

Although lifestyle intervention (diet and exercise) represents the cornerstone of weight management,1,2 sustaining weight loss over the long term is challenging.9 Clinical guidelines suggest adjunctive pharmacotherapy, particularly for adults with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or greater, or 27 or greater in persons with coexisting conditions.1,2,10 However, the use of available medications remains limited by modest efficacy, safety concerns, and cost.3

Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is approved, at doses up to 1 mg administered subcutaneously once weekly, for the treatment of type 2 diabetes in adults and for reducing the risk of cardiovascular events in persons with type 2 diabetes and cardiovascular disease.11 Semaglutide induced weight loss in persons with type 2 diabetes and in adults with obesity who were participants in a phase 2 trial,12-14 findings that supported further investigation. The global phase 3 Semaglutide Treatment Effect in People with Obesity (STEP) program aims to eval‎uate the efficacy and safety of semaglutide administered subcutaneously at a dose of 2.4 mg once weekly in persons with overweight or obesity, with or without weight-related complications.15

This 68-week trial eval‎uated the efficacy and safety of semaglutide as compared with placebo as an adjunct to lifestyle intervention for reducing body weight and meeting other related end points in adults with overweight or obesity and without diabetes.

MethodsTrial Design and Oversight

We conducted a randomized, double-blind, placebo-controlled trial at 129 sites in 16 countries in Asia, Europe, North America, and South America. The sponsor (Novo Nordisk) designed the trial and oversaw its conduct. The design has been published previously.15 The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol (available with the full text of this article at NEJM.org) was approved by an independent ethics committee or institutional review board at each study site. Investigators were responsible for data collection, and the sponsor undertook site monitoring, data collation, and analysis. All authors had full access to study data, participated in drafting the manuscript (assisted by a sponsor-funded medical writer), approved its submission for publication, and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Participants

We enrolled adults (18 years of age or older) with one or more self-reported unsuccessful dietary efforts to lose weight and either a BMI of 30 or greater or a BMI of 27 or greater with one or more treated or untreated weight-related coexisting conditions (i.e., hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). A subgroup of participants with a BMI of 40 or less underwent dual-energy x-ray absorptiometry (DXA) to assess body composition. All participants provided written informed consent. Key exclusion criteria were diabetes, a glycated hemoglobin level of 48 mmol per mole (6.5%) or greater, a history of chronic pancreatitis, acute pancreatitis within 180 days before enrollment, previous surgical obesity treatment, and use of antiobesity medication within 90 days before enrollment. A full list of the eligibility criteria is provided in the Supplementary Appendix, available at NEJM.org.

Procedures

Participants were randomly assigned in a 2:1 ratio, through the use of an interactive Web-based response system, to receive semaglutide at a dose of 2.4 mg administered subcutaneously once a week for 68 weeks or matching placebo, in addition to lifestyle intervention; this 68-week period was followed by a 7-week period without receipt of semaglutide or placebo or lifestyle intervention. Semaglutide, administered with a prefilled pen injector, was initiated at a dose of 0.25 mg once weekly for the first 4 weeks, with the dose increased every 4 weeks to reach the maintenance dose of 2.4 mg weekly by week 16 (lower maintenance doses were permitted if participants had unacceptable side effects with the 2.4-mg dose) (Fig. S1 in the Supplementary Appendix). Participants received individual counseling sessions every 4 weeks to help them adhere to a reduced-calorie diet (500-kcal deficit per day relative to the energy expenditure estimated at the time they underwent randomization) and increased physical activity (with 150 minutes per week of physical activity, such as walking, encouraged). Both diet and activity were recorded daily in a diary or by use of a smartphone application or other tools and were reviewed during counseling sessions. Participants discontinuing treatment prematurely remained in the trial.

End Points and Assessments

The coprimary end points were the percentage change in body weight from baseline to week 68 and achievement of a reduction in body weight of 5% or more from baseline to week 68. Confirm‎atory secondary end points (in hierarchical testing order) were achievement of a reduction in body weight of 10% or more and 15% or more by week 68 and the change from baseline to week 68 in waist circumference, systolic blood pressure, physical functioning score on the 36-item Short Form Health Survey (SF-36), version 2, and physical function score on the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) questionnaire. (Assessments related to end points, along with supportive secondary and exploratory end points and safety assessments, are described in the Supplementary Appendix.) Body composition (total fat, total lean body mass, and regional [abdominal] visceral fat mass) was measured in the DXA subpopulation as a supportive secondary end point. Safety assessments included the number of adverse events occurring during the on-treatment period (the time during which participants received any dose of semaglutide or placebo within the previous 49 days, with any period of temporary interruption of the regimen excluded) and serious adverse events occurring between baseline and week 75. An independent external event adjudication committee reviewed selected adverse events (cardiovascular events and acute pancreatitis) and deaths. All standard assays were performed in a central laboratory.

Statistical Analysis

A sample size of 1950 participants provided an effective power of 99% for the coprimary and confirm‎atory secondary end points, tested in a prespecified hierarchical order. Efficacy end points were analyzed in the full analysis population (all randomly assigned participants according to the intention-to-treat principle); safety end points were analyzed in the safety analysis population (all randomly assigned participants exposed to at least one dose of semaglutide or placebo). Observation periods included the in-trial period (the time from random assignment to last contact with a trial site, regardless of treatment discontinuation or rescue intervention) and the on-treatment period. All results from statistical analyses were accompanied by a two-sided 95% confidence interval and corresponding P values (with significance defined as P<0.05). Supportive secondary end-point analyses were not controlled for multiple comparisons and should not be used to infer definitive treatment effects.

Two estimands — the treatment policy estimand (traditional intention-to-treat analysis, with effects assessed regardless of treatment discontinuation or rescue intervention) and the trial product estimand (effects assessed if the drug or placebo was taken as intended) — were used to assess treatment efficacy from different perspectives and accounted for intercurrent events and missing data differently, as described previously.16 All analyses in the statistical hierarchy were based on the primary treatment policy estimand (details on analysis methods are provided in the Supplementary Appendix). All reported results are for the treatment policy estimand, unless stated otherwise.

ResultsStudy Participants

From June through November 2018, a total of 1961 participants were randomly assigned to receive semaglutide (1306 participants) or placebo (655 participants). Overall, 94.3% of the participants completed the trial, 91.2% had a body-weight assessment at week 68, and 81.1% adhered to treatment (Fig. S2). Rescue interventions were received by 7 participants in the semaglutide group (2 had bariatric surgery and 5 received other antiobesity medication) and by 13 in the placebo group (3 had bariatric surgery and 10 received other antiobesity medication).

Demographics and baseline characteristics were similar in the two treatment groups (Table 1). Most participants were female (74.1%) and White (75.1%), with a mean age of 46 years. The mean body weight was 105.3 kg, the mean BMI 37.9, and the mean waist circumference 114.7 cm; 43.7% had prediabetes. At screening, most participants (75.0%) had at least one coexisting condition. The baseline characteristics of the DXA subpopulation are provided in Table S1.

Table 1

Demographic and Clinical Characteristics of the Participants at Baseline.

Change in Body Weight

In the semaglutide group, weight loss was observed from the first postrandomization assessment (week 4) onward, reaching a nadir at week 60 (Figure 1A and 1B). For the treatment policy estimand (showing the effect regardless of treatment discontinuation or rescue intervention), the estimated mean weight change at week 68 was −14.9% with 2.4-mg semaglutide, as compared with −2.4% with placebo (estimated treatment difference, −12.4 percentage points; 95% CI, −13.4 to −11.5; P<0.001). For the trial product estimand (showing the effect if the drug or placebo was taken as intended), the corresponding changes were −16.9% and −2.4% (estimated treatment difference, −14.4 percentage points; 95% CI, −15.3 to −13.5).

Figure 1

Effect of Once-Weekly Semaglutide, as Compared with Placebo, on Body Weight.

Participants who received semaglutide were more likely to lose 5% or more, 10% or more, 15% or more, and 20% or more of baseline body weight at week 68 than those who received placebo (P<0.001 for the 5%, 10%, and 15% thresholds; the 20% threshold was not part of the statistical testing hierarchy) (Table 2, Figure 1C and 1D, and Table S2). Among the participants for whom data were available at the week 68 visit (1212 participants in the semaglutide group and 577 in the placebo group), these thresholds were reached by 86.4% (1047 participants), 69.1% (838 participants), 50.5% (612 participants), and 32.0% (388 participants), respectively, in the semaglutide group, as compared with 31.5% (182 participants), 12.0% (69 participants), 4.9% (28 participants), and 1.7% (10 participants) in the placebo group (Figure 1C, with on-treatment data shown in Figure 1D and the cumulative distribution of change from baseline shown in Fig. S3). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7) (Fig. S4). Data on change in body weight and achieved reduction in body weight of 5% or more (coprimary end points) as well as confirm‎atory and selected supportive secondary end points for the trial product estimand are provided in Table S2.

Table 2

Coprimary, Confirm‎atory, and Selected Supportive Secondary and Exploratory End Points for the Treatment Policy Estimand.

Other Confirm‎atory and Supportive Secondary End Points

Semaglutide was associated with greater reductions from baseline than placebo in waist circumference (–13.54 cm with semaglutide vs. –4.13 cm with placebo; estimated treatment difference, –9.42 cm; 95% CI, –10.30 to –8.53), BMI (–5.54 with semaglutide vs. –0.92 with placebo; estimated treatment difference, –4.61; 95% CI, –4.96 to –4.27), and systolic and diastolic blood pressure at week 68 (Table 2, Table S2, and Figs. S5 and S6). Benefits favoring semaglutide were also noted with respect to changes in glycated hemoglobin, fasting plasma glucose, C-reactive protein, and fasting lipid levels (Table 2).

Exploratory End Points

Among participants with prediabetes at baseline, semaglutide was associated with improvements in glycated hemoglobin levels at week 68, and 84.1% of participants in the semaglutide group who had prediabetes at baseline, as compared with 47.8% of participants in the placebo group with prediabetes at baseline, reverted to normoglycemia. Results for these and other selected exploratory end points are presented in Table 2 and Table S3.

Physical Functioning and Other Participant-Reported Outcomes

SF-36 physical functioning scores (with possible norm-based scores ranging from 19.03 to 57.60) improved significantly more with semaglutide than with placebo at week 68 (P<0.001), and both SF-36 physical and mental component summary scores favored semaglutide (Table 2, Table S2, and Fig. S7). IWQOL-Lite-CT physical function scores improved significantly more with semaglutide than with placebo at week 68 (P<0.001) (Table 2 and Table S2), and there were favorable effects over placebo on IWQOL-Lite-CT total scores. The results of SF-36 and IWQOL-Lite-CT assessments showed that participants were more likely to have clinically meaningful within-person improvements in physical functioning with semaglutide than with placebo (Table S4).

Change in Body Composition

In the DXA subpopulation (140 participants), total fat mass and regional visceral fat mass were reduced from baseline with semaglutide (Table S5). Although total lean body mass decreased in absolute terms (kg), the proportion of lean body mass relative to total body mass increased with semaglutide.

Safety and Side-Effect Profile

Similar percentages of participants in the semaglutide and placebo groups reported adverse events (89.7% and 86.4%, respectively) (Table 3). Gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation) were the most frequently reported events and occurred in more participants receiving semaglutide than those receiving placebo (74.2% vs. 47.9%). Most gastrointestinal events were mild-to-moderate in severity, were transient, and resolved without permanent discontinuation of the regimen (Fig. S8).

Table 3

Adverse Events.

Serious adverse events were reported in 9.8% and 6.4% of semaglutide and placebo participants, respectively (Table 3), with the difference due primarily to a difference between the groups in the incidence of serious gastrointestinal disorders (1.4% of participants in the semaglutide group and 0% in the placebo group) and hepatobiliary disorders (1.3% with semaglutide and 0.2% with placebo). More participants in the semaglutide group than in the placebo group (7.0% vs. 3.1%) discontinued treatment owing to adverse events (mainly gastrointestinal events) (Table 3 and Fig. S9). One death was reported in each group, with neither considered by the independent external event adjudication committee to be related to receipt of semaglutide or placebo (Table 3).

Gallbladder-related disorders (mostly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively. Mild acute pancreatitis (according to the Atlanta classification18) was reported in three participants in the semaglutide group (one participant had a history of acute pancreatitis, and the other two participants had both gallstones and pancreatitis); all recovered during the trial period. There was no difference between groups in the incidence of benign and malignant neoplasms. Additional safety variables are described in Table 3 and Table S6.

Discussion

In this trial, we found that adults with obesity (or overweight with one or more weight-related coexisting conditions) and without diabetes had a mean weight loss of 14.9% from baseline with semaglutide as an adjunct to lifestyle intervention. This loss exceeded that with placebo plus lifestyle intervention by 12.4 percentage points. The 14.9% mean weight loss that we observed in the semaglutide group is substantially greater than the weight loss of 4.0 to 10.9% from baseline with approved antiobesity medications.3,19 Moreover, 86% of participants who received semaglutide, as compared with 32% of those who received placebo, lost 5% or more of baseline body weight, a widely used criterion of clinically meaningful response.2,3,20,21 Weight loss with semaglutide stems from a reduction in energy intake owing to decreased appetite, which is thought to result from direct and indirect effects on the brain.22-25 Weight loss with semaglutide was accompanied by greater improvements than placebo with respect to cardiometabolic risk factors, including reductions in waist circumference, blood pressure, glycated hemoglobin levels, and lipid levels; a greater decrease from baseline in C-reactive protein, a marker of inflammation; and a greater proportion of participants with normoglycemia. Semaglutide also improved physical functioning, as assessed by SF-36 and IWQOL-Lite-CT, a finding that is notable given that overweight and obesity significantly impair health-related quality of life.26 Statistical superiority of semaglutide over placebo was achieved for all end points in the hierarchical testing procedure.

Weight loss of 10 to 15% (or more) is recommended in people with many complications of overweight and obesity (e.g., prediabetes, hypertension, and obstructive sleep apnea).1,20,21,27 In the semaglutide group, approximately 70% of participants achieved a weight loss of at least 10%, and approximately 50% achieved a weight loss of at least 15%. Furthermore, one third of participants treated with semaglutide lost at least 20% of baseline weight, a reduction approaching that reported 1 to 3 years after bariatric surgery, particularly sleeve gastrectomy (approximately 20 to 30% weight loss).28-31 The magnitude of reduction in cardiometabolic risk is assumed to be proportional to the amount of weight lost with both approaches (i.e., pharmacotherapy or surgery).32

Analyses from the DXA substudy suggested that semaglutide led to greater reduction in fat mass than lean body mass, a finding consistent with previous findings with semaglutide (at a dose of 1.0 mg) in persons with obesity22 and in those with type 2 diabetes.33 The weight loss and improvements with respect to cardiometabolic risk factors with semaglutide reported here will be complemented by an ongoing cardiovascular outcomes trial in participants with overweight or obesity and established cardiovascular disease (the SELECT trial; ClinicalTrials.gov number, NCT03574597).

Liraglutide administered subcutaneously once daily is the only GLP-1 receptor agonist approved for weight management.3,19,34 Our trial showed greater mean placebo-corrected weight reductions with once-weekly 2.4-mg semaglutide plus lifestyle intervention (12.4%) than those reported with once-daily 3.0-mg liraglutide plus lifestyle intervention in the 56-week SCALE (Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals Obesity and Prediabetes) trial (4.5%).34,35 In addition, the weight-loss phase with semaglutide persisted longer than that reported with liraglutide35 and did not reach the nadir until week 60. However, these two studies differed in their participant population, which limits the robustness of between-study comparisons.

At week 68, 31% of participants who received placebo had lost at least 5% of baseline body weight, with 12% and 5% having achieved reductions of at least 10% and at least 15%, respectively, findings that show good adherence to lifestyle interventions. Similar results were observed at week 56 in the SCALE Obesity and Prediabetes trial.35

Currently, approved antiobesity drugs require administration once, twice, or three times daily,3,19 and a once-weekly regimen may improve treatment adherence. The once-weekly 2.4-mg dose of semaglutide was chosen for the present study on the basis of pharmacokinetic modeling that suggested that the 2.4-mg weekly dose had a maximum steady-state concentration similar to a once-daily 0.4-mg dose investigated in a phase 2 dose-finding trial in participants with obesity.14 The results of our study with once-weekly semaglutide at a 2.4-mg dose are consistent with the results of the phase 2 study, which showed an 11.6% greater reduction in body weight with once-daily semaglutide at a dose of 0.4 mg than with placebo after 52 weeks of treatment.14

The safety of semaglutide was consistent with that reported in the phase 2 study with once-daily dosing in participants with obesity14 and in the trials of once-weekly subcutaneous semaglutide in persons with type 2 diabetes (involving more than 8000 participants receiving doses up to 1 mg),12 as well as with that reported for the GLP-1 receptor agonist class in general.13,36 As is typical of this drug class,13,37 transient, mild-to-moderate gastrointestinal disorders were the most frequently reported adverse events, and more participants in the semaglutide group than in the placebo group discontinued the assigned regimen after such events. Nausea was the most common gastrointestinal event, occurring primarily during the dose-escalation period, a finding similar to that reported with liraglutide at a dose of 3.0 mg.35 Gallbladder-related disorders, principally cholelithiasis, were more common in the semaglutide group, a finding consistent with previous reports for GLP-1 receptor agonists38,39 and with the known effects of rapid weight loss.40,41 The incidence of cholelithiasis with semaglutide was in line with that of liraglutide at a dose of 3.0 mg.35 No new safety concerns arose.

Strengths of this trial included the large sample size and high rates of adherence to the treatment regimen and completion of the trial. Limitations included the preponderance of women and White participants, the relatively short duration of the trial, the exclusion of persons with type 2 diabetes, and the potential that participants who were enrolled may represent a subgroup with greater commitment to weight-loss efforts than the general population. Although the DXA data we report provide greater insight into the weight-loss effects of semaglutide, such assessments were performed in only a subpopulation of participants.

Our trial showed that among adults with overweight or obesity (without diabetes), once-weekly subcutaneous semaglutide plus lifestyle intervention was associated with substantial, sustained, clinically relevant mean weight loss of 14.9%, with 86% of participants attaining at least 5% weight loss.

Notes

This article was published on February 10, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by Novo Nordisk.

Dr. Wilding reports receiving advisory board fees, paid to his institution, from Astellas Pharma, grant support and fees for membership on a data and safety monitoring board, both paid to University of Liverpool, lecture fees, and travel support from AstraZeneca, advisory board fees, paid to his institution, and lecture fees from Boehringer Ingelheim, Napp, and Sanofi Pasteur, advisory board fees, paid to his institution, from Eli Lilly, Janssen Global Services, Rhythm, and Wilmington Healthcare, lecture fees from Mundipharma, grant support, advisory board fees, and fees for serving as an investigator, all paid to University of Liverpool, and lecture fees from Novo Nordisk, and advisory board fees from Takeda Medical Research Foundation; Dr. Batterham, receiving consulting fees from Boehringer Ingelheim, Pfizer, and ViiV Healthcare and consulting fees and lecture fees from Novo Nordisk; Dr. Calanna, being employed by Novo Nordisk; Dr. Davies, receiving grant support from AstraZeneca, lecture fees from AstraZeneca Pharma India, advisory board fees from BI-LLY Alliance, Lexicon Pharmaceuticals, and Sanofi, advisory board fees and lecture fees from Boehringer Ingelheim and Eli Lilly, lecture fees from Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim (Poland), Napp Pharmaceuticals, Sanofi Romania, and Sanofi (Japan), advisory board fees and lecture fees from Boehringer Ingelheim International, and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Van Gaal, receiving lecture fees from AstraZeneca and Boehringer Ingelheim and advisory board fees and lecture fees from Merck and Novo Nordisk; Dr. Lingvay, receiving advisory board fees and consulting fees from AstraZeneca, consulting fees from Bayer HealthCare Pharmaceuticals, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, MannKind, Target Pharma, Valeritas, and Zealand Pharma, advisory board fees from Boehringer Ingelheim and Sanofi US Services, grant support, paid to UT Southwestern, from Merck, grant support, paid to his institution, from Mylan Pharmaceuticals and Pfizer, and grant support, paid to UT Southwestern, advisory board fees, consulting fees, and travel support from Novo Nordisk; Dr. McGowan, receiving educational fees from AstraZeneca, Merck, and Orexigen Therapeutics, lecture fees from Janssen Biotech, advisory board fees from Johnson & Johnson Health Care Systems, grant support, paid to Guys and St. Thomas’ Hospital, consulting fees, and educational fees from Novo Nordisk, and owning stock in Reset Health Clinics; Dr. Rosenstock, receiving grant support, advisory board fees, and travel support from Applied Therapeutics, Intarcia, and Oramed, grant support and consulting fees from AstraZeneca, grant support, advisory board fees, lecture fees, and travel support from Boehringer Ingelheim, Novo Nordisk, and Sanofi US Services, grant support and advisory board fees from Eli Lilly, grant support from Genentech, GlaxoSmithKline, Janssen Biotech, Lexicon Pharmaceuticals, Novartis, Pfizer, and REMD Biotherapeutics, and advisory board fees from Zealand Pharma; Dr. Tran, being employed by and owning stock in Novo Nordisk; Dr. Wadden, receiving grant support, paid to the University of Pennsylvania, and advisory board fees from Novo Nordisk and advisory board fees from WW International; Dr. Wharton, receiving lecture fees from AstraZeneca and Bausch and Lomb and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Yokote, receiving lecture fees from Amgen, Janssen Pharmaceuticals, Kyowa Hakko Kirin, Novartis Pharma, and Sanofi, grant support and lecture fees from Astellas Pharma, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp and Dohme, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda Pharmaceutical, advisory board fees and lecture fees from AstraZeneca, grant support, lecture fees, and advisory board fees from Kowa Company and Novo Nordisk, and lecture fees and advisory board fees from Sanofi; Mr. Zeuthen, being employed by and owning stock in Novo Nordisk; and Dr. Kushner, receiving advisory board fees from Novo Nordisk and Weight Watchers. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the trial participants and the trial site staff; Lisa von Huth Smith of Novo Nordisk, Denmark, for support with data presentation of participant-reported outcomes and critical review of an earlier draft of the manuscript; and Paul Barlass of Axis, a division of Spirit Medical Communications Group, for medical writing and editorial assistance with an earlier draft of the manuscript (funded by Novo Nordisk).

Supplementary Material

Protocol (nejmoa2032183_protocol.pdf)

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References

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Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract 2016;22:Suppl 3:1-203.

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Once-Weekly Semaglutide in Adults with Overweight or Obesity

Authors: John P.H. Wilding, D.M., Rachel L. Batterham, M.B., B.S., Ph.D., Salvatore Calanna, Ph.D., Melanie Davies, M.D., Luc F. Van Gaal, M.D., Ph.D., Ildiko Lingvay, M.D., M.P.H., M.S.C.S. https://orcid.org/0000-0001-7006-7401, Barbara M. McGowan, M.D., Ph.D., +7 , for the STEP 1 Study Group*Author Info & Affiliations

Published February 10, 2021

N Engl J Med 2021;384:989-1002

DOI: 10.1056/NEJMoa2032183

VOL. 384 NO. 11

Copyright © 2021

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AbstractBackground

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Methods

In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

Research Summary

Once-Weekly Semaglutide in Adults with Overweight or Obesity

Results

The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

Conclusions

In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Quick Take

Weekly Semaglutide in Adults with Overweight or Obesity

1m 46s

Obesity is a chronic disease and global public health challenge.1-3 Obesity can lead to insulin resistance, hypertension, and dyslipidemia,4 is associated with complications such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease,2,5 and reduces life expectancy.6 More recently, obesity has been linked to increased numbers of hospitalizations, the need for mechanical ventilation, and death in persons with coronavirus disease 2019 (Covid-19).7,8

Although lifestyle intervention (diet and exercise) represents the cornerstone of weight management,1,2 sustaining weight loss over the long term is challenging.9 Clinical guidelines suggest adjunctive pharmacotherapy, particularly for adults with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or greater, or 27 or greater in persons with coexisting conditions.1,2,10 However, the use of available medications remains limited by modest efficacy, safety concerns, and cost.3

Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is approved, at doses up to 1 mg administered subcutaneously once weekly, for the treatment of type 2 diabetes in adults and for reducing the risk of cardiovascular events in persons with type 2 diabetes and cardiovascular disease.11 Semaglutide induced weight loss in persons with type 2 diabetes and in adults with obesity who were participants in a phase 2 trial,12-14 findings that supported further investigation. The global phase 3 Semaglutide Treatment Effect in People with Obesity (STEP) program aims to eval‎uate the efficacy and safety of semaglutide administered subcutaneously at a dose of 2.4 mg once weekly in persons with overweight or obesity, with or without weight-related complications.15

This 68-week trial eval‎uated the efficacy and safety of semaglutide as compared with placebo as an adjunct to lifestyle intervention for reducing body weight and meeting other related end points in adults with overweight or obesity and without diabetes.

MethodsTrial Design and Oversight

We conducted a randomized, double-blind, placebo-controlled trial at 129 sites in 16 countries in Asia, Europe, North America, and South America. The sponsor (Novo Nordisk) designed the trial and oversaw its conduct. The design has been published previously.15 The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol (available with the full text of this article at NEJM.org) was approved by an independent ethics committee or institutional review board at each study site. Investigators were responsible for data collection, and the sponsor undertook site monitoring, data collation, and analysis. All authors had full access to study data, participated in drafting the manuscript (assisted by a sponsor-funded medical writer), approved its submission for publication, and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Participants

We enrolled adults (18 years of age or older) with one or more self-reported unsuccessful dietary efforts to lose weight and either a BMI of 30 or greater or a BMI of 27 or greater with one or more treated or untreated weight-related coexisting conditions (i.e., hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). A subgroup of participants with a BMI of 40 or less underwent dual-energy x-ray absorptiometry (DXA) to assess body composition. All participants provided written informed consent. Key exclusion criteria were diabetes, a glycated hemoglobin level of 48 mmol per mole (6.5%) or greater, a history of chronic pancreatitis, acute pancreatitis within 180 days before enrollment, previous surgical obesity treatment, and use of antiobesity medication within 90 days before enrollment. A full list of the eligibility criteria is provided in the Supplementary Appendix, available at NEJM.org.

Procedures

Participants were randomly assigned in a 2:1 ratio, through the use of an interactive Web-based response system, to receive semaglutide at a dose of 2.4 mg administered subcutaneously once a week for 68 weeks or matching placebo, in addition to lifestyle intervention; this 68-week period was followed by a 7-week period without receipt of semaglutide or placebo or lifestyle intervention. Semaglutide, administered with a prefilled pen injector, was initiated at a dose of 0.25 mg once weekly for the first 4 weeks, with the dose increased every 4 weeks to reach the maintenance dose of 2.4 mg weekly by week 16 (lower maintenance doses were permitted if participants had unacceptable side effects with the 2.4-mg dose) (Fig. S1 in the Supplementary Appendix). Participants received individual counseling sessions every 4 weeks to help them adhere to a reduced-calorie diet (500-kcal deficit per day relative to the energy expenditure estimated at the time they underwent randomization) and increased physical activity (with 150 minutes per week of physical activity, such as walking, encouraged). Both diet and activity were recorded daily in a diary or by use of a smartphone application or other tools and were reviewed during counseling sessions. Participants discontinuing treatment prematurely remained in the trial.

End Points and Assessments

The coprimary end points were the percentage change in body weight from baseline to week 68 and achievement of a reduction in body weight of 5% or more from baseline to week 68. Confirm‎atory secondary end points (in hierarchical testing order) were achievement of a reduction in body weight of 10% or more and 15% or more by week 68 and the change from baseline to week 68 in waist circumference, systolic blood pressure, physical functioning score on the 36-item Short Form Health Survey (SF-36), version 2, and physical function score on the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) questionnaire. (Assessments related to end points, along with supportive secondary and exploratory end points and safety assessments, are described in the Supplementary Appendix.) Body composition (total fat, total lean body mass, and regional [abdominal] visceral fat mass) was measured in the DXA subpopulation as a supportive secondary end point. Safety assessments included the number of adverse events occurring during the on-treatment period (the time during which participants received any dose of semaglutide or placebo within the previous 49 days, with any period of temporary interruption of the regimen excluded) and serious adverse events occurring between baseline and week 75. An independent external event adjudication committee reviewed selected adverse events (cardiovascular events and acute pancreatitis) and deaths. All standard assays were performed in a central laboratory.

Statistical Analysis

A sample size of 1950 participants provided an effective power of 99% for the coprimary and confirm‎atory secondary end points, tested in a prespecified hierarchical order. Efficacy end points were analyzed in the full analysis population (all randomly assigned participants according to the intention-to-treat principle); safety end points were analyzed in the safety analysis population (all randomly assigned participants exposed to at least one dose of semaglutide or placebo). Observation periods included the in-trial period (the time from random assignment to last contact with a trial site, regardless of treatment discontinuation or rescue intervention) and the on-treatment period. All results from statistical analyses were accompanied by a two-sided 95% confidence interval and corresponding P values (with significance defined as P<0.05). Supportive secondary end-point analyses were not controlled for multiple comparisons and should not be used to infer definitive treatment effects.

Two estimands — the treatment policy estimand (traditional intention-to-treat analysis, with effects assessed regardless of treatment discontinuation or rescue intervention) and the trial product estimand (effects assessed if the drug or placebo was taken as intended) — were used to assess treatment efficacy from different perspectives and accounted for intercurrent events and missing data differently, as described previously.16 All analyses in the statistical hierarchy were based on the primary treatment policy estimand (details on analysis methods are provided in the Supplementary Appendix). All reported results are for the treatment policy estimand, unless stated otherwise.

ResultsStudy Participants

From June through November 2018, a total of 1961 participants were randomly assigned to receive semaglutide (1306 participants) or placebo (655 participants). Overall, 94.3% of the participants completed the trial, 91.2% had a body-weight assessment at week 68, and 81.1% adhered to treatment (Fig. S2). Rescue interventions were received by 7 participants in the semaglutide group (2 had bariatric surgery and 5 received other antiobesity medication) and by 13 in the placebo group (3 had bariatric surgery and 10 received other antiobesity medication).

Demographics and baseline characteristics were similar in the two treatment groups (Table 1). Most participants were female (74.1%) and White (75.1%), with a mean age of 46 years. The mean body weight was 105.3 kg, the mean BMI 37.9, and the mean waist circumference 114.7 cm; 43.7% had prediabetes. At screening, most participants (75.0%) had at least one coexisting condition. The baseline characteristics of the DXA subpopulation are provided in Table S1.

Table 1

Demographic and Clinical Characteristics of the Participants at Baseline.

Change in Body Weight

In the semaglutide group, weight loss was observed from the first postrandomization assessment (week 4) onward, reaching a nadir at week 60 (Figure 1A and 1B). For the treatment policy estimand (showing the effect regardless of treatment discontinuation or rescue intervention), the estimated mean weight change at week 68 was −14.9% with 2.4-mg semaglutide, as compared with −2.4% with placebo (estimated treatment difference, −12.4 percentage points; 95% CI, −13.4 to −11.5; P<0.001). For the trial product estimand (showing the effect if the drug or placebo was taken as intended), the corresponding changes were −16.9% and −2.4% (estimated treatment difference, −14.4 percentage points; 95% CI, −15.3 to −13.5).

Figure 1

Effect of Once-Weekly Semaglutide, as Compared with Placebo, on Body Weight.

Participants who received semaglutide were more likely to lose 5% or more, 10% or more, 15% or more, and 20% or more of baseline body weight at week 68 than those who received placebo (P<0.001 for the 5%, 10%, and 15% thresholds; the 20% threshold was not part of the statistical testing hierarchy) (Table 2, Figure 1C and 1D, and Table S2). Among the participants for whom data were available at the week 68 visit (1212 participants in the semaglutide group and 577 in the placebo group), these thresholds were reached by 86.4% (1047 participants), 69.1% (838 participants), 50.5% (612 participants), and 32.0% (388 participants), respectively, in the semaglutide group, as compared with 31.5% (182 participants), 12.0% (69 participants), 4.9% (28 participants), and 1.7% (10 participants) in the placebo group (Figure 1C, with on-treatment data shown in Figure 1D and the cumulative distribution of change from baseline shown in Fig. S3). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7) (Fig. S4). Data on change in body weight and achieved reduction in body weight of 5% or more (coprimary end points) as well as confirm‎atory and selected supportive secondary end points for the trial product estimand are provided in Table S2.

Table 2

Coprimary, Confirm‎atory, and Selected Supportive Secondary and Exploratory End Points for the Treatment Policy Estimand.

Other Confirm‎atory and Supportive Secondary End Points

Semaglutide was associated with greater reductions from baseline than placebo in waist circumference (–13.54 cm with semaglutide vs. –4.13 cm with placebo; estimated treatment difference, –9.42 cm; 95% CI, –10.30 to –8.53), BMI (–5.54 with semaglutide vs. –0.92 with placebo; estimated treatment difference, –4.61; 95% CI, –4.96 to –4.27), and systolic and diastolic blood pressure at week 68 (Table 2, Table S2, and Figs. S5 and S6). Benefits favoring semaglutide were also noted with respect to changes in glycated hemoglobin, fasting plasma glucose, C-reactive protein, and fasting lipid levels (Table 2).

Exploratory End Points

Among participants with prediabetes at baseline, semaglutide was associated with improvements in glycated hemoglobin levels at week 68, and 84.1% of participants in the semaglutide group who had prediabetes at baseline, as compared with 47.8% of participants in the placebo group with prediabetes at baseline, reverted to normoglycemia. Results for these and other selected exploratory end points are presented in Table 2 and Table S3.

Physical Functioning and Other Participant-Reported Outcomes

SF-36 physical functioning scores (with possible norm-based scores ranging from 19.03 to 57.60) improved significantly more with semaglutide than with placebo at week 68 (P<0.001), and both SF-36 physical and mental component summary scores favored semaglutide (Table 2, Table S2, and Fig. S7). IWQOL-Lite-CT physical function scores improved significantly more with semaglutide than with placebo at week 68 (P<0.001) (Table 2 and Table S2), and there were favorable effects over placebo on IWQOL-Lite-CT total scores. The results of SF-36 and IWQOL-Lite-CT assessments showed that participants were more likely to have clinically meaningful within-person improvements in physical functioning with semaglutide than with placebo (Table S4).

Change in Body Composition

In the DXA subpopulation (140 participants), total fat mass and regional visceral fat mass were reduced from baseline with semaglutide (Table S5). Although total lean body mass decreased in absolute terms (kg), the proportion of lean body mass relative to total body mass increased with semaglutide.

Safety and Side-Effect Profile

Similar percentages of participants in the semaglutide and placebo groups reported adverse events (89.7% and 86.4%, respectively) (Table 3). Gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation) were the most frequently reported events and occurred in more participants receiving semaglutide than those receiving placebo (74.2% vs. 47.9%). Most gastrointestinal events were mild-to-moderate in severity, were transient, and resolved without permanent discontinuation of the regimen (Fig. S8).

Table 3

Adverse Events.

Serious adverse events were reported in 9.8% and 6.4% of semaglutide and placebo participants, respectively (Table 3), with the difference due primarily to a difference between the groups in the incidence of serious gastrointestinal disorders (1.4% of participants in the semaglutide group and 0% in the placebo group) and hepatobiliary disorders (1.3% with semaglutide and 0.2% with placebo). More participants in the semaglutide group than in the placebo group (7.0% vs. 3.1%) discontinued treatment owing to adverse events (mainly gastrointestinal events) (Table 3 and Fig. S9). One death was reported in each group, with neither considered by the independent external event adjudication committee to be related to receipt of semaglutide or placebo (Table 3).

Gallbladder-related disorders (mostly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively. Mild acute pancreatitis (according to the Atlanta classification18) was reported in three participants in the semaglutide group (one participant had a history of acute pancreatitis, and the other two participants had both gallstones and pancreatitis); all recovered during the trial period. There was no difference between groups in the incidence of benign and malignant neoplasms. Additional safety variables are described in Table 3 and Table S6.

Discussion

In this trial, we found that adults with obesity (or overweight with one or more weight-related coexisting conditions) and without diabetes had a mean weight loss of 14.9% from baseline with semaglutide as an adjunct to lifestyle intervention. This loss exceeded that with placebo plus lifestyle intervention by 12.4 percentage points. The 14.9% mean weight loss that we observed in the semaglutide group is substantially greater than the weight loss of 4.0 to 10.9% from baseline with approved antiobesity medications.3,19 Moreover, 86% of participants who received semaglutide, as compared with 32% of those who received placebo, lost 5% or more of baseline body weight, a widely used criterion of clinically meaningful response.2,3,20,21 Weight loss with semaglutide stems from a reduction in energy intake owing to decreased appetite, which is thought to result from direct and indirect effects on the brain.22-25 Weight loss with semaglutide was accompanied by greater improvements than placebo with respect to cardiometabolic risk factors, including reductions in waist circumference, blood pressure, glycated hemoglobin levels, and lipid levels; a greater decrease from baseline in C-reactive protein, a marker of inflammation; and a greater proportion of participants with normoglycemia. Semaglutide also improved physical functioning, as assessed by SF-36 and IWQOL-Lite-CT, a finding that is notable given that overweight and obesity significantly impair health-related quality of life.26 Statistical superiority of semaglutide over placebo was achieved for all end points in the hierarchical testing procedure.

Weight loss of 10 to 15% (or more) is recommended in people with many complications of overweight and obesity (e.g., prediabetes, hypertension, and obstructive sleep apnea).1,20,21,27 In the semaglutide group, approximately 70% of participants achieved a weight loss of at least 10%, and approximately 50% achieved a weight loss of at least 15%. Furthermore, one third of participants treated with semaglutide lost at least 20% of baseline weight, a reduction approaching that reported 1 to 3 years after bariatric surgery, particularly sleeve gastrectomy (approximately 20 to 30% weight loss).28-31 The magnitude of reduction in cardiometabolic risk is assumed to be proportional to the amount of weight lost with both approaches (i.e., pharmacotherapy or surgery).32

Analyses from the DXA substudy suggested that semaglutide led to greater reduction in fat mass than lean body mass, a finding consistent with previous findings with semaglutide (at a dose of 1.0 mg) in persons with obesity22 and in those with type 2 diabetes.33 The weight loss and improvements with respect to cardiometabolic risk factors with semaglutide reported here will be complemented by an ongoing cardiovascular outcomes trial in participants with overweight or obesity and established cardiovascular disease (the SELECT trial; ClinicalTrials.gov number, NCT03574597).

Liraglutide administered subcutaneously once daily is the only GLP-1 receptor agonist approved for weight management.3,19,34 Our trial showed greater mean placebo-corrected weight reductions with once-weekly 2.4-mg semaglutide plus lifestyle intervention (12.4%) than those reported with once-daily 3.0-mg liraglutide plus lifestyle intervention in the 56-week SCALE (Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals Obesity and Prediabetes) trial (4.5%).34,35 In addition, the weight-loss phase with semaglutide persisted longer than that reported with liraglutide35 and did not reach the nadir until week 60. However, these two studies differed in their participant population, which limits the robustness of between-study comparisons.

At week 68, 31% of participants who received placebo had lost at least 5% of baseline body weight, with 12% and 5% having achieved reductions of at least 10% and at least 15%, respectively, findings that show good adherence to lifestyle interventions. Similar results were observed at week 56 in the SCALE Obesity and Prediabetes trial.35

Currently, approved antiobesity drugs require administration once, twice, or three times daily,3,19 and a once-weekly regimen may improve treatment adherence. The once-weekly 2.4-mg dose of semaglutide was chosen for the present study on the basis of pharmacokinetic modeling that suggested that the 2.4-mg weekly dose had a maximum steady-state concentration similar to a once-daily 0.4-mg dose investigated in a phase 2 dose-finding trial in participants with obesity.14 The results of our study with once-weekly semaglutide at a 2.4-mg dose are consistent with the results of the phase 2 study, which showed an 11.6% greater reduction in body weight with once-daily semaglutide at a dose of 0.4 mg than with placebo after 52 weeks of treatment.14

The safety of semaglutide was consistent with that reported in the phase 2 study with once-daily dosing in participants with obesity14 and in the trials of once-weekly subcutaneous semaglutide in persons with type 2 diabetes (involving more than 8000 participants receiving doses up to 1 mg),12 as well as with that reported for the GLP-1 receptor agonist class in general.13,36 As is typical of this drug class,13,37 transient, mild-to-moderate gastrointestinal disorders were the most frequently reported adverse events, and more participants in the semaglutide group than in the placebo group discontinued the assigned regimen after such events. Nausea was the most common gastrointestinal event, occurring primarily during the dose-escalation period, a finding similar to that reported with liraglutide at a dose of 3.0 mg.35 Gallbladder-related disorders, principally cholelithiasis, were more common in the semaglutide group, a finding consistent with previous reports for GLP-1 receptor agonists38,39 and with the known effects of rapid weight loss.40,41 The incidence of cholelithiasis with semaglutide was in line with that of liraglutide at a dose of 3.0 mg.35 No new safety concerns arose.

Strengths of this trial included the large sample size and high rates of adherence to the treatment regimen and completion of the trial. Limitations included the preponderance of women and White participants, the relatively short duration of the trial, the exclusion of persons with type 2 diabetes, and the potential that participants who were enrolled may represent a subgroup with greater commitment to weight-loss efforts than the general population. Although the DXA data we report provide greater insight into the weight-loss effects of semaglutide, such assessments were performed in only a subpopulation of participants.

Our trial showed that among adults with overweight or obesity (without diabetes), once-weekly subcutaneous semaglutide plus lifestyle intervention was associated with substantial, sustained, clinically relevant mean weight loss of 14.9%, with 86% of participants attaining at least 5% weight loss.

Notes

This article was published on February 10, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by Novo Nordisk.

Dr. Wilding reports receiving advisory board fees, paid to his institution, from Astellas Pharma, grant support and fees for membership on a data and safety monitoring board, both paid to University of Liverpool, lecture fees, and travel support from AstraZeneca, advisory board fees, paid to his institution, and lecture fees from Boehringer Ingelheim, Napp, and Sanofi Pasteur, advisory board fees, paid to his institution, from Eli Lilly, Janssen Global Services, Rhythm, and Wilmington Healthcare, lecture fees from Mundipharma, grant support, advisory board fees, and fees for serving as an investigator, all paid to University of Liverpool, and lecture fees from Novo Nordisk, and advisory board fees from Takeda Medical Research Foundation; Dr. Batterham, receiving consulting fees from Boehringer Ingelheim, Pfizer, and ViiV Healthcare and consulting fees and lecture fees from Novo Nordisk; Dr. Calanna, being employed by Novo Nordisk; Dr. Davies, receiving grant support from AstraZeneca, lecture fees from AstraZeneca Pharma India, advisory board fees from BI-LLY Alliance, Lexicon Pharmaceuticals, and Sanofi, advisory board fees and lecture fees from Boehringer Ingelheim and Eli Lilly, lecture fees from Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim (Poland), Napp Pharmaceuticals, Sanofi Romania, and Sanofi (Japan), advisory board fees and lecture fees from Boehringer Ingelheim International, and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Van Gaal, receiving lecture fees from AstraZeneca and Boehringer Ingelheim and advisory board fees and lecture fees from Merck and Novo Nordisk; Dr. Lingvay, receiving advisory board fees and consulting fees from AstraZeneca, consulting fees from Bayer HealthCare Pharmaceuticals, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, MannKind, Target Pharma, Valeritas, and Zealand Pharma, advisory board fees from Boehringer Ingelheim and Sanofi US Services, grant support, paid to UT Southwestern, from Merck, grant support, paid to his institution, from Mylan Pharmaceuticals and Pfizer, and grant support, paid to UT Southwestern, advisory board fees, consulting fees, and travel support from Novo Nordisk; Dr. McGowan, receiving educational fees from AstraZeneca, Merck, and Orexigen Therapeutics, lecture fees from Janssen Biotech, advisory board fees from Johnson & Johnson Health Care Systems, grant support, paid to Guys and St. Thomas’ Hospital, consulting fees, and educational fees from Novo Nordisk, and owning stock in Reset Health Clinics; Dr. Rosenstock, receiving grant support, advisory board fees, and travel support from Applied Therapeutics, Intarcia, and Oramed, grant support and consulting fees from AstraZeneca, grant support, advisory board fees, lecture fees, and travel support from Boehringer Ingelheim, Novo Nordisk, and Sanofi US Services, grant support and advisory board fees from Eli Lilly, grant support from Genentech, GlaxoSmithKline, Janssen Biotech, Lexicon Pharmaceuticals, Novartis, Pfizer, and REMD Biotherapeutics, and advisory board fees from Zealand Pharma; Dr. Tran, being employed by and owning stock in Novo Nordisk; Dr. Wadden, receiving grant support, paid to the University of Pennsylvania, and advisory board fees from Novo Nordisk and advisory board fees from WW International; Dr. Wharton, receiving lecture fees from AstraZeneca and Bausch and Lomb and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Yokote, receiving lecture fees from Amgen, Janssen Pharmaceuticals, Kyowa Hakko Kirin, Novartis Pharma, and Sanofi, grant support and lecture fees from Astellas Pharma, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp and Dohme, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda Pharmaceutical, advisory board fees and lecture fees from AstraZeneca, grant support, lecture fees, and advisory board fees from Kowa Company and Novo Nordisk, and lecture fees and advisory board fees from Sanofi; Mr. Zeuthen, being employed by and owning stock in Novo Nordisk; and Dr. Kushner, receiving advisory board fees from Novo Nordisk and Weight Watchers. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the trial participants and the trial site staff; Lisa von Huth Smith of Novo Nordisk, Denmark, for support with data presentation of participant-reported outcomes and critical review of an earlier draft of the manuscript; and Paul Barlass of Axis, a division of Spirit Medical Communications Group, for medical writing and editorial assistance with an earlier draft of the manuscript (funded by Novo Nordisk).

Supplementary Material

Protocol (nejmoa2032183_protocol.pdf)

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References

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Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract 2016;22:Suppl 3:1-203.

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Once-Weekly Semaglutide in Adults with Overweight or Obesity

Authors: John P.H. Wilding, D.M., Rachel L. Batterham, M.B., B.S., Ph.D., Salvatore Calanna, Ph.D., Melanie Davies, M.D., Luc F. Van Gaal, M.D., Ph.D., Ildiko Lingvay, M.D., M.P.H., M.S.C.S. https://orcid.org/0000-0001-7006-7401, Barbara M. McGowan, M.D., Ph.D., +7 , for the STEP 1 Study Group*Author Info & Affiliations

Published February 10, 2021

N Engl J Med 2021;384:989-1002

DOI: 10.1056/NEJMoa2032183

VOL. 384 NO. 11

Copyright © 2021

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AbstractBackground

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Methods

In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

Research Summary

Once-Weekly Semaglutide in Adults with Overweight or Obesity

Results

The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

Conclusions

In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Quick Take

Weekly Semaglutide in Adults with Overweight or Obesity

1m 46s

Obesity is a chronic disease and global public health challenge.1-3 Obesity can lead to insulin resistance, hypertension, and dyslipidemia,4 is associated with complications such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease,2,5 and reduces life expectancy.6 More recently, obesity has been linked to increased numbers of hospitalizations, the need for mechanical ventilation, and death in persons with coronavirus disease 2019 (Covid-19).7,8

Although lifestyle intervention (diet and exercise) represents the cornerstone of weight management,1,2 sustaining weight loss over the long term is challenging.9 Clinical guidelines suggest adjunctive pharmacotherapy, particularly for adults with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or greater, or 27 or greater in persons with coexisting conditions.1,2,10 However, the use of available medications remains limited by modest efficacy, safety concerns, and cost.3

Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is approved, at doses up to 1 mg administered subcutaneously once weekly, for the treatment of type 2 diabetes in adults and for reducing the risk of cardiovascular events in persons with type 2 diabetes and cardiovascular disease.11 Semaglutide induced weight loss in persons with type 2 diabetes and in adults with obesity who were participants in a phase 2 trial,12-14 findings that supported further investigation. The global phase 3 Semaglutide Treatment Effect in People with Obesity (STEP) program aims to eval‎uate the efficacy and safety of semaglutide administered subcutaneously at a dose of 2.4 mg once weekly in persons with overweight or obesity, with or without weight-related complications.15

This 68-week trial eval‎uated the efficacy and safety of semaglutide as compared with placebo as an adjunct to lifestyle intervention for reducing body weight and meeting other related end points in adults with overweight or obesity and without diabetes.

MethodsTrial Design and Oversight

We conducted a randomized, double-blind, placebo-controlled trial at 129 sites in 16 countries in Asia, Europe, North America, and South America. The sponsor (Novo Nordisk) designed the trial and oversaw its conduct. The design has been published previously.15 The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol (available with the full text of this article at NEJM.org) was approved by an independent ethics committee or institutional review board at each study site. Investigators were responsible for data collection, and the sponsor undertook site monitoring, data collation, and analysis. All authors had full access to study data, participated in drafting the manuscript (assisted by a sponsor-funded medical writer), approved its submission for publication, and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Participants

We enrolled adults (18 years of age or older) with one or more self-reported unsuccessful dietary efforts to lose weight and either a BMI of 30 or greater or a BMI of 27 or greater with one or more treated or untreated weight-related coexisting conditions (i.e., hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). A subgroup of participants with a BMI of 40 or less underwent dual-energy x-ray absorptiometry (DXA) to assess body composition. All participants provided written informed consent. Key exclusion criteria were diabetes, a glycated hemoglobin level of 48 mmol per mole (6.5%) or greater, a history of chronic pancreatitis, acute pancreatitis within 180 days before enrollment, previous surgical obesity treatment, and use of antiobesity medication within 90 days before enrollment. A full list of the eligibility criteria is provided in the Supplementary Appendix, available at NEJM.org.

Procedures

Participants were randomly assigned in a 2:1 ratio, through the use of an interactive Web-based response system, to receive semaglutide at a dose of 2.4 mg administered subcutaneously once a week for 68 weeks or matching placebo, in addition to lifestyle intervention; this 68-week period was followed by a 7-week period without receipt of semaglutide or placebo or lifestyle intervention. Semaglutide, administered with a prefilled pen injector, was initiated at a dose of 0.25 mg once weekly for the first 4 weeks, with the dose increased every 4 weeks to reach the maintenance dose of 2.4 mg weekly by week 16 (lower maintenance doses were permitted if participants had unacceptable side effects with the 2.4-mg dose) (Fig. S1 in the Supplementary Appendix). Participants received individual counseling sessions every 4 weeks to help them adhere to a reduced-calorie diet (500-kcal deficit per day relative to the energy expenditure estimated at the time they underwent randomization) and increased physical activity (with 150 minutes per week of physical activity, such as walking, encouraged). Both diet and activity were recorded daily in a diary or by use of a smartphone application or other tools and were reviewed during counseling sessions. Participants discontinuing treatment prematurely remained in the trial.

End Points and Assessments

The coprimary end points were the percentage change in body weight from baseline to week 68 and achievement of a reduction in body weight of 5% or more from baseline to week 68. Confirm‎atory secondary end points (in hierarchical testing order) were achievement of a reduction in body weight of 10% or more and 15% or more by week 68 and the change from baseline to week 68 in waist circumference, systolic blood pressure, physical functioning score on the 36-item Short Form Health Survey (SF-36), version 2, and physical function score on the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) questionnaire. (Assessments related to end points, along with supportive secondary and exploratory end points and safety assessments, are described in the Supplementary Appendix.) Body composition (total fat, total lean body mass, and regional [abdominal] visceral fat mass) was measured in the DXA subpopulation as a supportive secondary end point. Safety assessments included the number of adverse events occurring during the on-treatment period (the time during which participants received any dose of semaglutide or placebo within the previous 49 days, with any period of temporary interruption of the regimen excluded) and serious adverse events occurring between baseline and week 75. An independent external event adjudication committee reviewed selected adverse events (cardiovascular events and acute pancreatitis) and deaths. All standard assays were performed in a central laboratory.

Statistical Analysis

A sample size of 1950 participants provided an effective power of 99% for the coprimary and confirm‎atory secondary end points, tested in a prespecified hierarchical order. Efficacy end points were analyzed in the full analysis population (all randomly assigned participants according to the intention-to-treat principle); safety end points were analyzed in the safety analysis population (all randomly assigned participants exposed to at least one dose of semaglutide or placebo). Observation periods included the in-trial period (the time from random assignment to last contact with a trial site, regardless of treatment discontinuation or rescue intervention) and the on-treatment period. All results from statistical analyses were accompanied by a two-sided 95% confidence interval and corresponding P values (with significance defined as P<0.05). Supportive secondary end-point analyses were not controlled for multiple comparisons and should not be used to infer definitive treatment effects.

Two estimands — the treatment policy estimand (traditional intention-to-treat analysis, with effects assessed regardless of treatment discontinuation or rescue intervention) and the trial product estimand (effects assessed if the drug or placebo was taken as intended) — were used to assess treatment efficacy from different perspectives and accounted for intercurrent events and missing data differently, as described previously.16 All analyses in the statistical hierarchy were based on the primary treatment policy estimand (details on analysis methods are provided in the Supplementary Appendix). All reported results are for the treatment policy estimand, unless stated otherwise.

ResultsStudy Participants

From June through November 2018, a total of 1961 participants were randomly assigned to receive semaglutide (1306 participants) or placebo (655 participants). Overall, 94.3% of the participants completed the trial, 91.2% had a body-weight assessment at week 68, and 81.1% adhered to treatment (Fig. S2). Rescue interventions were received by 7 participants in the semaglutide group (2 had bariatric surgery and 5 received other antiobesity medication) and by 13 in the placebo group (3 had bariatric surgery and 10 received other antiobesity medication).

Demographics and baseline characteristics were similar in the two treatment groups (Table 1). Most participants were female (74.1%) and White (75.1%), with a mean age of 46 years. The mean body weight was 105.3 kg, the mean BMI 37.9, and the mean waist circumference 114.7 cm; 43.7% had prediabetes. At screening, most participants (75.0%) had at least one coexisting condition. The baseline characteristics of the DXA subpopulation are provided in Table S1.

Table 1

Demographic and Clinical Characteristics of the Participants at Baseline.

Change in Body Weight

In the semaglutide group, weight loss was observed from the first postrandomization assessment (week 4) onward, reaching a nadir at week 60 (Figure 1A and 1B). For the treatment policy estimand (showing the effect regardless of treatment discontinuation or rescue intervention), the estimated mean weight change at week 68 was −14.9% with 2.4-mg semaglutide, as compared with −2.4% with placebo (estimated treatment difference, −12.4 percentage points; 95% CI, −13.4 to −11.5; P<0.001). For the trial product estimand (showing the effect if the drug or placebo was taken as intended), the corresponding changes were −16.9% and −2.4% (estimated treatment difference, −14.4 percentage points; 95% CI, −15.3 to −13.5).

Figure 1

Effect of Once-Weekly Semaglutide, as Compared with Placebo, on Body Weight.

Participants who received semaglutide were more likely to lose 5% or more, 10% or more, 15% or more, and 20% or more of baseline body weight at week 68 than those who received placebo (P<0.001 for the 5%, 10%, and 15% thresholds; the 20% threshold was not part of the statistical testing hierarchy) (Table 2, Figure 1C and 1D, and Table S2). Among the participants for whom data were available at the week 68 visit (1212 participants in the semaglutide group and 577 in the placebo group), these thresholds were reached by 86.4% (1047 participants), 69.1% (838 participants), 50.5% (612 participants), and 32.0% (388 participants), respectively, in the semaglutide group, as compared with 31.5% (182 participants), 12.0% (69 participants), 4.9% (28 participants), and 1.7% (10 participants) in the placebo group (Figure 1C, with on-treatment data shown in Figure 1D and the cumulative distribution of change from baseline shown in Fig. S3). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7) (Fig. S4). Data on change in body weight and achieved reduction in body weight of 5% or more (coprimary end points) as well as confirm‎atory and selected supportive secondary end points for the trial product estimand are provided in Table S2.

Table 2

Coprimary, Confirm‎atory, and Selected Supportive Secondary and Exploratory End Points for the Treatment Policy Estimand.

Other Confirm‎atory and Supportive Secondary End Points

Semaglutide was associated with greater reductions from baseline than placebo in waist circumference (–13.54 cm with semaglutide vs. –4.13 cm with placebo; estimated treatment difference, –9.42 cm; 95% CI, –10.30 to –8.53), BMI (–5.54 with semaglutide vs. –0.92 with placebo; estimated treatment difference, –4.61; 95% CI, –4.96 to –4.27), and systolic and diastolic blood pressure at week 68 (Table 2, Table S2, and Figs. S5 and S6). Benefits favoring semaglutide were also noted with respect to changes in glycated hemoglobin, fasting plasma glucose, C-reactive protein, and fasting lipid levels (Table 2).

Exploratory End Points

Among participants with prediabetes at baseline, semaglutide was associated with improvements in glycated hemoglobin levels at week 68, and 84.1% of participants in the semaglutide group who had prediabetes at baseline, as compared with 47.8% of participants in the placebo group with prediabetes at baseline, reverted to normoglycemia. Results for these and other selected exploratory end points are presented in Table 2 and Table S3.

Physical Functioning and Other Participant-Reported Outcomes

SF-36 physical functioning scores (with possible norm-based scores ranging from 19.03 to 57.60) improved significantly more with semaglutide than with placebo at week 68 (P<0.001), and both SF-36 physical and mental component summary scores favored semaglutide (Table 2, Table S2, and Fig. S7). IWQOL-Lite-CT physical function scores improved significantly more with semaglutide than with placebo at week 68 (P<0.001) (Table 2 and Table S2), and there were favorable effects over placebo on IWQOL-Lite-CT total scores. The results of SF-36 and IWQOL-Lite-CT assessments showed that participants were more likely to have clinically meaningful within-person improvements in physical functioning with semaglutide than with placebo (Table S4).

Change in Body Composition

In the DXA subpopulation (140 participants), total fat mass and regional visceral fat mass were reduced from baseline with semaglutide (Table S5). Although total lean body mass decreased in absolute terms (kg), the proportion of lean body mass relative to total body mass increased with semaglutide.

Safety and Side-Effect Profile

Similar percentages of participants in the semaglutide and placebo groups reported adverse events (89.7% and 86.4%, respectively) (Table 3). Gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation) were the most frequently reported events and occurred in more participants receiving semaglutide than those receiving placebo (74.2% vs. 47.9%). Most gastrointestinal events were mild-to-moderate in severity, were transient, and resolved without permanent discontinuation of the regimen (Fig. S8).

Table 3

Adverse Events.

Serious adverse events were reported in 9.8% and 6.4% of semaglutide and placebo participants, respectively (Table 3), with the difference due primarily to a difference between the groups in the incidence of serious gastrointestinal disorders (1.4% of participants in the semaglutide group and 0% in the placebo group) and hepatobiliary disorders (1.3% with semaglutide and 0.2% with placebo). More participants in the semaglutide group than in the placebo group (7.0% vs. 3.1%) discontinued treatment owing to adverse events (mainly gastrointestinal events) (Table 3 and Fig. S9). One death was reported in each group, with neither considered by the independent external event adjudication committee to be related to receipt of semaglutide or placebo (Table 3).

Gallbladder-related disorders (mostly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively. Mild acute pancreatitis (according to the Atlanta classification18) was reported in three participants in the semaglutide group (one participant had a history of acute pancreatitis, and the other two participants had both gallstones and pancreatitis); all recovered during the trial period. There was no difference between groups in the incidence of benign and malignant neoplasms. Additional safety variables are described in Table 3 and Table S6.

Discussion

In this trial, we found that adults with obesity (or overweight with one or more weight-related coexisting conditions) and without diabetes had a mean weight loss of 14.9% from baseline with semaglutide as an adjunct to lifestyle intervention. This loss exceeded that with placebo plus lifestyle intervention by 12.4 percentage points. The 14.9% mean weight loss that we observed in the semaglutide group is substantially greater than the weight loss of 4.0 to 10.9% from baseline with approved antiobesity medications.3,19 Moreover, 86% of participants who received semaglutide, as compared with 32% of those who received placebo, lost 5% or more of baseline body weight, a widely used criterion of clinically meaningful response.2,3,20,21 Weight loss with semaglutide stems from a reduction in energy intake owing to decreased appetite, which is thought to result from direct and indirect effects on the brain.22-25 Weight loss with semaglutide was accompanied by greater improvements than placebo with respect to cardiometabolic risk factors, including reductions in waist circumference, blood pressure, glycated hemoglobin levels, and lipid levels; a greater decrease from baseline in C-reactive protein, a marker of inflammation; and a greater proportion of participants with normoglycemia. Semaglutide also improved physical functioning, as assessed by SF-36 and IWQOL-Lite-CT, a finding that is notable given that overweight and obesity significantly impair health-related quality of life.26 Statistical superiority of semaglutide over placebo was achieved for all end points in the hierarchical testing procedure.

Weight loss of 10 to 15% (or more) is recommended in people with many complications of overweight and obesity (e.g., prediabetes, hypertension, and obstructive sleep apnea).1,20,21,27 In the semaglutide group, approximately 70% of participants achieved a weight loss of at least 10%, and approximately 50% achieved a weight loss of at least 15%. Furthermore, one third of participants treated with semaglutide lost at least 20% of baseline weight, a reduction approaching that reported 1 to 3 years after bariatric surgery, particularly sleeve gastrectomy (approximately 20 to 30% weight loss).28-31 The magnitude of reduction in cardiometabolic risk is assumed to be proportional to the amount of weight lost with both approaches (i.e., pharmacotherapy or surgery).32

Analyses from the DXA substudy suggested that semaglutide led to greater reduction in fat mass than lean body mass, a finding consistent with previous findings with semaglutide (at a dose of 1.0 mg) in persons with obesity22 and in those with type 2 diabetes.33 The weight loss and improvements with respect to cardiometabolic risk factors with semaglutide reported here will be complemented by an ongoing cardiovascular outcomes trial in participants with overweight or obesity and established cardiovascular disease (the SELECT trial; ClinicalTrials.gov number, NCT03574597).

Liraglutide administered subcutaneously once daily is the only GLP-1 receptor agonist approved for weight management.3,19,34 Our trial showed greater mean placebo-corrected weight reductions with once-weekly 2.4-mg semaglutide plus lifestyle intervention (12.4%) than those reported with once-daily 3.0-mg liraglutide plus lifestyle intervention in the 56-week SCALE (Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals Obesity and Prediabetes) trial (4.5%).34,35 In addition, the weight-loss phase with semaglutide persisted longer than that reported with liraglutide35 and did not reach the nadir until week 60. However, these two studies differed in their participant population, which limits the robustness of between-study comparisons.

At week 68, 31% of participants who received placebo had lost at least 5% of baseline body weight, with 12% and 5% having achieved reductions of at least 10% and at least 15%, respectively, findings that show good adherence to lifestyle interventions. Similar results were observed at week 56 in the SCALE Obesity and Prediabetes trial.35

Currently, approved antiobesity drugs require administration once, twice, or three times daily,3,19 and a once-weekly regimen may improve treatment adherence. The once-weekly 2.4-mg dose of semaglutide was chosen for the present study on the basis of pharmacokinetic modeling that suggested that the 2.4-mg weekly dose had a maximum steady-state concentration similar to a once-daily 0.4-mg dose investigated in a phase 2 dose-finding trial in participants with obesity.14 The results of our study with once-weekly semaglutide at a 2.4-mg dose are consistent with the results of the phase 2 study, which showed an 11.6% greater reduction in body weight with once-daily semaglutide at a dose of 0.4 mg than with placebo after 52 weeks of treatment.14

The safety of semaglutide was consistent with that reported in the phase 2 study with once-daily dosing in participants with obesity14 and in the trials of once-weekly subcutaneous semaglutide in persons with type 2 diabetes (involving more than 8000 participants receiving doses up to 1 mg),12 as well as with that reported for the GLP-1 receptor agonist class in general.13,36 As is typical of this drug class,13,37 transient, mild-to-moderate gastrointestinal disorders were the most frequently reported adverse events, and more participants in the semaglutide group than in the placebo group discontinued the assigned regimen after such events. Nausea was the most common gastrointestinal event, occurring primarily during the dose-escalation period, a finding similar to that reported with liraglutide at a dose of 3.0 mg.35 Gallbladder-related disorders, principally cholelithiasis, were more common in the semaglutide group, a finding consistent with previous reports for GLP-1 receptor agonists38,39 and with the known effects of rapid weight loss.40,41 The incidence of cholelithiasis with semaglutide was in line with that of liraglutide at a dose of 3.0 mg.35 No new safety concerns arose.

Strengths of this trial included the large sample size and high rates of adherence to the treatment regimen and completion of the trial. Limitations included the preponderance of women and White participants, the relatively short duration of the trial, the exclusion of persons with type 2 diabetes, and the potential that participants who were enrolled may represent a subgroup with greater commitment to weight-loss efforts than the general population. Although the DXA data we report provide greater insight into the weight-loss effects of semaglutide, such assessments were performed in only a subpopulation of participants.

Our trial showed that among adults with overweight or obesity (without diabetes), once-weekly subcutaneous semaglutide plus lifestyle intervention was associated with substantial, sustained, clinically relevant mean weight loss of 14.9%, with 86% of participants attaining at least 5% weight loss.

Notes

This article was published on February 10, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by Novo Nordisk.

Dr. Wilding reports receiving advisory board fees, paid to his institution, from Astellas Pharma, grant support and fees for membership on a data and safety monitoring board, both paid to University of Liverpool, lecture fees, and travel support from AstraZeneca, advisory board fees, paid to his institution, and lecture fees from Boehringer Ingelheim, Napp, and Sanofi Pasteur, advisory board fees, paid to his institution, from Eli Lilly, Janssen Global Services, Rhythm, and Wilmington Healthcare, lecture fees from Mundipharma, grant support, advisory board fees, and fees for serving as an investigator, all paid to University of Liverpool, and lecture fees from Novo Nordisk, and advisory board fees from Takeda Medical Research Foundation; Dr. Batterham, receiving consulting fees from Boehringer Ingelheim, Pfizer, and ViiV Healthcare and consulting fees and lecture fees from Novo Nordisk; Dr. Calanna, being employed by Novo Nordisk; Dr. Davies, receiving grant support from AstraZeneca, lecture fees from AstraZeneca Pharma India, advisory board fees from BI-LLY Alliance, Lexicon Pharmaceuticals, and Sanofi, advisory board fees and lecture fees from Boehringer Ingelheim and Eli Lilly, lecture fees from Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim (Poland), Napp Pharmaceuticals, Sanofi Romania, and Sanofi (Japan), advisory board fees and lecture fees from Boehringer Ingelheim International, and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Van Gaal, receiving lecture fees from AstraZeneca and Boehringer Ingelheim and advisory board fees and lecture fees from Merck and Novo Nordisk; Dr. Lingvay, receiving advisory board fees and consulting fees from AstraZeneca, consulting fees from Bayer HealthCare Pharmaceuticals, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, MannKind, Target Pharma, Valeritas, and Zealand Pharma, advisory board fees from Boehringer Ingelheim and Sanofi US Services, grant support, paid to UT Southwestern, from Merck, grant support, paid to his institution, from Mylan Pharmaceuticals and Pfizer, and grant support, paid to UT Southwestern, advisory board fees, consulting fees, and travel support from Novo Nordisk; Dr. McGowan, receiving educational fees from AstraZeneca, Merck, and Orexigen Therapeutics, lecture fees from Janssen Biotech, advisory board fees from Johnson & Johnson Health Care Systems, grant support, paid to Guys and St. Thomas’ Hospital, consulting fees, and educational fees from Novo Nordisk, and owning stock in Reset Health Clinics; Dr. Rosenstock, receiving grant support, advisory board fees, and travel support from Applied Therapeutics, Intarcia, and Oramed, grant support and consulting fees from AstraZeneca, grant support, advisory board fees, lecture fees, and travel support from Boehringer Ingelheim, Novo Nordisk, and Sanofi US Services, grant support and advisory board fees from Eli Lilly, grant support from Genentech, GlaxoSmithKline, Janssen Biotech, Lexicon Pharmaceuticals, Novartis, Pfizer, and REMD Biotherapeutics, and advisory board fees from Zealand Pharma; Dr. Tran, being employed by and owning stock in Novo Nordisk; Dr. Wadden, receiving grant support, paid to the University of Pennsylvania, and advisory board fees from Novo Nordisk and advisory board fees from WW International; Dr. Wharton, receiving lecture fees from AstraZeneca and Bausch and Lomb and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Yokote, receiving lecture fees from Amgen, Janssen Pharmaceuticals, Kyowa Hakko Kirin, Novartis Pharma, and Sanofi, grant support and lecture fees from Astellas Pharma, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp and Dohme, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda Pharmaceutical, advisory board fees and lecture fees from AstraZeneca, grant support, lecture fees, and advisory board fees from Kowa Company and Novo Nordisk, and lecture fees and advisory board fees from Sanofi; Mr. Zeuthen, being employed by and owning stock in Novo Nordisk; and Dr. Kushner, receiving advisory board fees from Novo Nordisk and Weight Watchers. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the trial participants and the trial site staff; Lisa von Huth Smith of Novo Nordisk, Denmark, for support with data presentation of participant-reported outcomes and critical review of an earlier draft of the manuscript; and Paul Barlass of Axis, a division of Spirit Medical Communications Group, for medical writing and editorial assistance with an earlier draft of the manuscript (funded by Novo Nordisk).

Supplementary Material

Protocol (nejmoa2032183_protocol.pdf)

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References

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Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract 2016;22:Suppl 3:1-203.

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Once-Weekly Semaglutide in Adults with Overweight or Obesity

Authors: John P.H. Wilding, D.M., Rachel L. Batterham, M.B., B.S., Ph.D., Salvatore Calanna, Ph.D., Melanie Davies, M.D., Luc F. Van Gaal, M.D., Ph.D., Ildiko Lingvay, M.D., M.P.H., M.S.C.S. https://orcid.org/0000-0001-7006-7401, Barbara M. McGowan, M.D., Ph.D., +7 , for the STEP 1 Study Group*Author Info & Affiliations

Published February 10, 2021

N Engl J Med 2021;384:989-1002

DOI: 10.1056/NEJMoa2032183

VOL. 384 NO. 11

Copyright © 2021

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AbstractBackground

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Methods

In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

Research Summary

Once-Weekly Semaglutide in Adults with Overweight or Obesity

Results

The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

Conclusions

In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Quick Take

Weekly Semaglutide in Adults with Overweight or Obesity

1m 46s

Obesity is a chronic disease and global public health challenge.1-3 Obesity can lead to insulin resistance, hypertension, and dyslipidemia,4 is associated with complications such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease,2,5 and reduces life expectancy.6 More recently, obesity has been linked to increased numbers of hospitalizations, the need for mechanical ventilation, and death in persons with coronavirus disease 2019 (Covid-19).7,8

Although lifestyle intervention (diet and exercise) represents the cornerstone of weight management,1,2 sustaining weight loss over the long term is challenging.9 Clinical guidelines suggest adjunctive pharmacotherapy, particularly for adults with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or greater, or 27 or greater in persons with coexisting conditions.1,2,10 However, the use of available medications remains limited by modest efficacy, safety concerns, and cost.3

Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is approved, at doses up to 1 mg administered subcutaneously once weekly, for the treatment of type 2 diabetes in adults and for reducing the risk of cardiovascular events in persons with type 2 diabetes and cardiovascular disease.11 Semaglutide induced weight loss in persons with type 2 diabetes and in adults with obesity who were participants in a phase 2 trial,12-14 findings that supported further investigation. The global phase 3 Semaglutide Treatment Effect in People with Obesity (STEP) program aims to eval‎uate the efficacy and safety of semaglutide administered subcutaneously at a dose of 2.4 mg once weekly in persons with overweight or obesity, with or without weight-related complications.15

This 68-week trial eval‎uated the efficacy and safety of semaglutide as compared with placebo as an adjunct to lifestyle intervention for reducing body weight and meeting other related end points in adults with overweight or obesity and without diabetes.

MethodsTrial Design and Oversight

We conducted a randomized, double-blind, placebo-controlled trial at 129 sites in 16 countries in Asia, Europe, North America, and South America. The sponsor (Novo Nordisk) designed the trial and oversaw its conduct. The design has been published previously.15 The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol (available with the full text of this article at NEJM.org) was approved by an independent ethics committee or institutional review board at each study site. Investigators were responsible for data collection, and the sponsor undertook site monitoring, data collation, and analysis. All authors had full access to study data, participated in drafting the manuscript (assisted by a sponsor-funded medical writer), approved its submission for publication, and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Participants

We enrolled adults (18 years of age or older) with one or more self-reported unsuccessful dietary efforts to lose weight and either a BMI of 30 or greater or a BMI of 27 or greater with one or more treated or untreated weight-related coexisting conditions (i.e., hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). A subgroup of participants with a BMI of 40 or less underwent dual-energy x-ray absorptiometry (DXA) to assess body composition. All participants provided written informed consent. Key exclusion criteria were diabetes, a glycated hemoglobin level of 48 mmol per mole (6.5%) or greater, a history of chronic pancreatitis, acute pancreatitis within 180 days before enrollment, previous surgical obesity treatment, and use of antiobesity medication within 90 days before enrollment. A full list of the eligibility criteria is provided in the Supplementary Appendix, available at NEJM.org.

Procedures

Participants were randomly assigned in a 2:1 ratio, through the use of an interactive Web-based response system, to receive semaglutide at a dose of 2.4 mg administered subcutaneously once a week for 68 weeks or matching placebo, in addition to lifestyle intervention; this 68-week period was followed by a 7-week period without receipt of semaglutide or placebo or lifestyle intervention. Semaglutide, administered with a prefilled pen injector, was initiated at a dose of 0.25 mg once weekly for the first 4 weeks, with the dose increased every 4 weeks to reach the maintenance dose of 2.4 mg weekly by week 16 (lower maintenance doses were permitted if participants had unacceptable side effects with the 2.4-mg dose) (Fig. S1 in the Supplementary Appendix). Participants received individual counseling sessions every 4 weeks to help them adhere to a reduced-calorie diet (500-kcal deficit per day relative to the energy expenditure estimated at the time they underwent randomization) and increased physical activity (with 150 minutes per week of physical activity, such as walking, encouraged). Both diet and activity were recorded daily in a diary or by use of a smartphone application or other tools and were reviewed during counseling sessions. Participants discontinuing treatment prematurely remained in the trial.

End Points and Assessments

The coprimary end points were the percentage change in body weight from baseline to week 68 and achievement of a reduction in body weight of 5% or more from baseline to week 68. Confirm‎atory secondary end points (in hierarchical testing order) were achievement of a reduction in body weight of 10% or more and 15% or more by week 68 and the change from baseline to week 68 in waist circumference, systolic blood pressure, physical functioning score on the 36-item Short Form Health Survey (SF-36), version 2, and physical function score on the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) questionnaire. (Assessments related to end points, along with supportive secondary and exploratory end points and safety assessments, are described in the Supplementary Appendix.) Body composition (total fat, total lean body mass, and regional [abdominal] visceral fat mass) was measured in the DXA subpopulation as a supportive secondary end point. Safety assessments included the number of adverse events occurring during the on-treatment period (the time during which participants received any dose of semaglutide or placebo within the previous 49 days, with any period of temporary interruption of the regimen excluded) and serious adverse events occurring between baseline and week 75. An independent external event adjudication committee reviewed selected adverse events (cardiovascular events and acute pancreatitis) and deaths. All standard assays were performed in a central laboratory.

Statistical Analysis

A sample size of 1950 participants provided an effective power of 99% for the coprimary and confirm‎atory secondary end points, tested in a prespecified hierarchical order. Efficacy end points were analyzed in the full analysis population (all randomly assigned participants according to the intention-to-treat principle); safety end points were analyzed in the safety analysis population (all randomly assigned participants exposed to at least one dose of semaglutide or placebo). Observation periods included the in-trial period (the time from random assignment to last contact with a trial site, regardless of treatment discontinuation or rescue intervention) and the on-treatment period. All results from statistical analyses were accompanied by a two-sided 95% confidence interval and corresponding P values (with significance defined as P<0.05). Supportive secondary end-point analyses were not controlled for multiple comparisons and should not be used to infer definitive treatment effects.

Two estimands — the treatment policy estimand (traditional intention-to-treat analysis, with effects assessed regardless of treatment discontinuation or rescue intervention) and the trial product estimand (effects assessed if the drug or placebo was taken as intended) — were used to assess treatment efficacy from different perspectives and accounted for intercurrent events and missing data differently, as described previously.16 All analyses in the statistical hierarchy were based on the primary treatment policy estimand (details on analysis methods are provided in the Supplementary Appendix). All reported results are for the treatment policy estimand, unless stated otherwise.

ResultsStudy Participants

From June through November 2018, a total of 1961 participants were randomly assigned to receive semaglutide (1306 participants) or placebo (655 participants). Overall, 94.3% of the participants completed the trial, 91.2% had a body-weight assessment at week 68, and 81.1% adhered to treatment (Fig. S2). Rescue interventions were received by 7 participants in the semaglutide group (2 had bariatric surgery and 5 received other antiobesity medication) and by 13 in the placebo group (3 had bariatric surgery and 10 received other antiobesity medication).

Demographics and baseline characteristics were similar in the two treatment groups (Table 1). Most participants were female (74.1%) and White (75.1%), with a mean age of 46 years. The mean body weight was 105.3 kg, the mean BMI 37.9, and the mean waist circumference 114.7 cm; 43.7% had prediabetes. At screening, most participants (75.0%) had at least one coexisting condition. The baseline characteristics of the DXA subpopulation are provided in Table S1.

Table 1

Demographic and Clinical Characteristics of the Participants at Baseline.

Change in Body Weight

In the semaglutide group, weight loss was observed from the first postrandomization assessment (week 4) onward, reaching a nadir at week 60 (Figure 1A and 1B). For the treatment policy estimand (showing the effect regardless of treatment discontinuation or rescue intervention), the estimated mean weight change at week 68 was −14.9% with 2.4-mg semaglutide, as compared with −2.4% with placebo (estimated treatment difference, −12.4 percentage points; 95% CI, −13.4 to −11.5; P<0.001). For the trial product estimand (showing the effect if the drug or placebo was taken as intended), the corresponding changes were −16.9% and −2.4% (estimated treatment difference, −14.4 percentage points; 95% CI, −15.3 to −13.5).

Figure 1

Effect of Once-Weekly Semaglutide, as Compared with Placebo, on Body Weight.

Participants who received semaglutide were more likely to lose 5% or more, 10% or more, 15% or more, and 20% or more of baseline body weight at week 68 than those who received placebo (P<0.001 for the 5%, 10%, and 15% thresholds; the 20% threshold was not part of the statistical testing hierarchy) (Table 2, Figure 1C and 1D, and Table S2). Among the participants for whom data were available at the week 68 visit (1212 participants in the semaglutide group and 577 in the placebo group), these thresholds were reached by 86.4% (1047 participants), 69.1% (838 participants), 50.5% (612 participants), and 32.0% (388 participants), respectively, in the semaglutide group, as compared with 31.5% (182 participants), 12.0% (69 participants), 4.9% (28 participants), and 1.7% (10 participants) in the placebo group (Figure 1C, with on-treatment data shown in Figure 1D and the cumulative distribution of change from baseline shown in Fig. S3). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7) (Fig. S4). Data on change in body weight and achieved reduction in body weight of 5% or more (coprimary end points) as well as confirm‎atory and selected supportive secondary end points for the trial product estimand are provided in Table S2.

Table 2

Coprimary, Confirm‎atory, and Selected Supportive Secondary and Exploratory End Points for the Treatment Policy Estimand.

Other Confirm‎atory and Supportive Secondary End Points

Semaglutide was associated with greater reductions from baseline than placebo in waist circumference (–13.54 cm with semaglutide vs. –4.13 cm with placebo; estimated treatment difference, –9.42 cm; 95% CI, –10.30 to –8.53), BMI (–5.54 with semaglutide vs. –0.92 with placebo; estimated treatment difference, –4.61; 95% CI, –4.96 to –4.27), and systolic and diastolic blood pressure at week 68 (Table 2, Table S2, and Figs. S5 and S6). Benefits favoring semaglutide were also noted with respect to changes in glycated hemoglobin, fasting plasma glucose, C-reactive protein, and fasting lipid levels (Table 2).

Exploratory End Points

Among participants with prediabetes at baseline, semaglutide was associated with improvements in glycated hemoglobin levels at week 68, and 84.1% of participants in the semaglutide group who had prediabetes at baseline, as compared with 47.8% of participants in the placebo group with prediabetes at baseline, reverted to normoglycemia. Results for these and other selected exploratory end points are presented in Table 2 and Table S3.

Physical Functioning and Other Participant-Reported Outcomes

SF-36 physical functioning scores (with possible norm-based scores ranging from 19.03 to 57.60) improved significantly more with semaglutide than with placebo at week 68 (P<0.001), and both SF-36 physical and mental component summary scores favored semaglutide (Table 2, Table S2, and Fig. S7). IWQOL-Lite-CT physical function scores improved significantly more with semaglutide than with placebo at week 68 (P<0.001) (Table 2 and Table S2), and there were favorable effects over placebo on IWQOL-Lite-CT total scores. The results of SF-36 and IWQOL-Lite-CT assessments showed that participants were more likely to have clinically meaningful within-person improvements in physical functioning with semaglutide than with placebo (Table S4).

Change in Body Composition

In the DXA subpopulation (140 participants), total fat mass and regional visceral fat mass were reduced from baseline with semaglutide (Table S5). Although total lean body mass decreased in absolute terms (kg), the proportion of lean body mass relative to total body mass increased with semaglutide.

Safety and Side-Effect Profile

Similar percentages of participants in the semaglutide and placebo groups reported adverse events (89.7% and 86.4%, respectively) (Table 3). Gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation) were the most frequently reported events and occurred in more participants receiving semaglutide than those receiving placebo (74.2% vs. 47.9%). Most gastrointestinal events were mild-to-moderate in severity, were transient, and resolved without permanent discontinuation of the regimen (Fig. S8).

Table 3

Adverse Events.

Serious adverse events were reported in 9.8% and 6.4% of semaglutide and placebo participants, respectively (Table 3), with the difference due primarily to a difference between the groups in the incidence of serious gastrointestinal disorders (1.4% of participants in the semaglutide group and 0% in the placebo group) and hepatobiliary disorders (1.3% with semaglutide and 0.2% with placebo). More participants in the semaglutide group than in the placebo group (7.0% vs. 3.1%) discontinued treatment owing to adverse events (mainly gastrointestinal events) (Table 3 and Fig. S9). One death was reported in each group, with neither considered by the independent external event adjudication committee to be related to receipt of semaglutide or placebo (Table 3).

Gallbladder-related disorders (mostly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively. Mild acute pancreatitis (according to the Atlanta classification18) was reported in three participants in the semaglutide group (one participant had a history of acute pancreatitis, and the other two participants had both gallstones and pancreatitis); all recovered during the trial period. There was no difference between groups in the incidence of benign and malignant neoplasms. Additional safety variables are described in Table 3 and Table S6.

Discussion

In this trial, we found that adults with obesity (or overweight with one or more weight-related coexisting conditions) and without diabetes had a mean weight loss of 14.9% from baseline with semaglutide as an adjunct to lifestyle intervention. This loss exceeded that with placebo plus lifestyle intervention by 12.4 percentage points. The 14.9% mean weight loss that we observed in the semaglutide group is substantially greater than the weight loss of 4.0 to 10.9% from baseline with approved antiobesity medications.3,19 Moreover, 86% of participants who received semaglutide, as compared with 32% of those who received placebo, lost 5% or more of baseline body weight, a widely used criterion of clinically meaningful response.2,3,20,21 Weight loss with semaglutide stems from a reduction in energy intake owing to decreased appetite, which is thought to result from direct and indirect effects on the brain.22-25 Weight loss with semaglutide was accompanied by greater improvements than placebo with respect to cardiometabolic risk factors, including reductions in waist circumference, blood pressure, glycated hemoglobin levels, and lipid levels; a greater decrease from baseline in C-reactive protein, a marker of inflammation; and a greater proportion of participants with normoglycemia. Semaglutide also improved physical functioning, as assessed by SF-36 and IWQOL-Lite-CT, a finding that is notable given that overweight and obesity significantly impair health-related quality of life.26 Statistical superiority of semaglutide over placebo was achieved for all end points in the hierarchical testing procedure.

Weight loss of 10 to 15% (or more) is recommended in people with many complications of overweight and obesity (e.g., prediabetes, hypertension, and obstructive sleep apnea).1,20,21,27 In the semaglutide group, approximately 70% of participants achieved a weight loss of at least 10%, and approximately 50% achieved a weight loss of at least 15%. Furthermore, one third of participants treated with semaglutide lost at least 20% of baseline weight, a reduction approaching that reported 1 to 3 years after bariatric surgery, particularly sleeve gastrectomy (approximately 20 to 30% weight loss).28-31 The magnitude of reduction in cardiometabolic risk is assumed to be proportional to the amount of weight lost with both approaches (i.e., pharmacotherapy or surgery).32

Analyses from the DXA substudy suggested that semaglutide led to greater reduction in fat mass than lean body mass, a finding consistent with previous findings with semaglutide (at a dose of 1.0 mg) in persons with obesity22 and in those with type 2 diabetes.33 The weight loss and improvements with respect to cardiometabolic risk factors with semaglutide reported here will be complemented by an ongoing cardiovascular outcomes trial in participants with overweight or obesity and established cardiovascular disease (the SELECT trial; ClinicalTrials.gov number, NCT03574597).

Liraglutide administered subcutaneously once daily is the only GLP-1 receptor agonist approved for weight management.3,19,34 Our trial showed greater mean placebo-corrected weight reductions with once-weekly 2.4-mg semaglutide plus lifestyle intervention (12.4%) than those reported with once-daily 3.0-mg liraglutide plus lifestyle intervention in the 56-week SCALE (Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals Obesity and Prediabetes) trial (4.5%).34,35 In addition, the weight-loss phase with semaglutide persisted longer than that reported with liraglutide35 and did not reach the nadir until week 60. However, these two studies differed in their participant population, which limits the robustness of between-study comparisons.

At week 68, 31% of participants who received placebo had lost at least 5% of baseline body weight, with 12% and 5% having achieved reductions of at least 10% and at least 15%, respectively, findings that show good adherence to lifestyle interventions. Similar results were observed at week 56 in the SCALE Obesity and Prediabetes trial.35

Currently, approved antiobesity drugs require administration once, twice, or three times daily,3,19 and a once-weekly regimen may improve treatment adherence. The once-weekly 2.4-mg dose of semaglutide was chosen for the present study on the basis of pharmacokinetic modeling that suggested that the 2.4-mg weekly dose had a maximum steady-state concentration similar to a once-daily 0.4-mg dose investigated in a phase 2 dose-finding trial in participants with obesity.14 The results of our study with once-weekly semaglutide at a 2.4-mg dose are consistent with the results of the phase 2 study, which showed an 11.6% greater reduction in body weight with once-daily semaglutide at a dose of 0.4 mg than with placebo after 52 weeks of treatment.14

The safety of semaglutide was consistent with that reported in the phase 2 study with once-daily dosing in participants with obesity14 and in the trials of once-weekly subcutaneous semaglutide in persons with type 2 diabetes (involving more than 8000 participants receiving doses up to 1 mg),12 as well as with that reported for the GLP-1 receptor agonist class in general.13,36 As is typical of this drug class,13,37 transient, mild-to-moderate gastrointestinal disorders were the most frequently reported adverse events, and more participants in the semaglutide group than in the placebo group discontinued the assigned regimen after such events. Nausea was the most common gastrointestinal event, occurring primarily during the dose-escalation period, a finding similar to that reported with liraglutide at a dose of 3.0 mg.35 Gallbladder-related disorders, principally cholelithiasis, were more common in the semaglutide group, a finding consistent with previous reports for GLP-1 receptor agonists38,39 and with the known effects of rapid weight loss.40,41 The incidence of cholelithiasis with semaglutide was in line with that of liraglutide at a dose of 3.0 mg.35 No new safety concerns arose.

Strengths of this trial included the large sample size and high rates of adherence to the treatment regimen and completion of the trial. Limitations included the preponderance of women and White participants, the relatively short duration of the trial, the exclusion of persons with type 2 diabetes, and the potential that participants who were enrolled may represent a subgroup with greater commitment to weight-loss efforts than the general population. Although the DXA data we report provide greater insight into the weight-loss effects of semaglutide, such assessments were performed in only a subpopulation of participants.

Our trial showed that among adults with overweight or obesity (without diabetes), once-weekly subcutaneous semaglutide plus lifestyle intervention was associated with substantial, sustained, clinically relevant mean weight loss of 14.9%, with 86% of participants attaining at least 5% weight loss.

Notes

This article was published on February 10, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by Novo Nordisk.

Dr. Wilding reports receiving advisory board fees, paid to his institution, from Astellas Pharma, grant support and fees for membership on a data and safety monitoring board, both paid to University of Liverpool, lecture fees, and travel support from AstraZeneca, advisory board fees, paid to his institution, and lecture fees from Boehringer Ingelheim, Napp, and Sanofi Pasteur, advisory board fees, paid to his institution, from Eli Lilly, Janssen Global Services, Rhythm, and Wilmington Healthcare, lecture fees from Mundipharma, grant support, advisory board fees, and fees for serving as an investigator, all paid to University of Liverpool, and lecture fees from Novo Nordisk, and advisory board fees from Takeda Medical Research Foundation; Dr. Batterham, receiving consulting fees from Boehringer Ingelheim, Pfizer, and ViiV Healthcare and consulting fees and lecture fees from Novo Nordisk; Dr. Calanna, being employed by Novo Nordisk; Dr. Davies, receiving grant support from AstraZeneca, lecture fees from AstraZeneca Pharma India, advisory board fees from BI-LLY Alliance, Lexicon Pharmaceuticals, and Sanofi, advisory board fees and lecture fees from Boehringer Ingelheim and Eli Lilly, lecture fees from Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim (Poland), Napp Pharmaceuticals, Sanofi Romania, and Sanofi (Japan), advisory board fees and lecture fees from Boehringer Ingelheim International, and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Van Gaal, receiving lecture fees from AstraZeneca and Boehringer Ingelheim and advisory board fees and lecture fees from Merck and Novo Nordisk; Dr. Lingvay, receiving advisory board fees and consulting fees from AstraZeneca, consulting fees from Bayer HealthCare Pharmaceuticals, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, MannKind, Target Pharma, Valeritas, and Zealand Pharma, advisory board fees from Boehringer Ingelheim and Sanofi US Services, grant support, paid to UT Southwestern, from Merck, grant support, paid to his institution, from Mylan Pharmaceuticals and Pfizer, and grant support, paid to UT Southwestern, advisory board fees, consulting fees, and travel support from Novo Nordisk; Dr. McGowan, receiving educational fees from AstraZeneca, Merck, and Orexigen Therapeutics, lecture fees from Janssen Biotech, advisory board fees from Johnson & Johnson Health Care Systems, grant support, paid to Guys and St. Thomas’ Hospital, consulting fees, and educational fees from Novo Nordisk, and owning stock in Reset Health Clinics; Dr. Rosenstock, receiving grant support, advisory board fees, and travel support from Applied Therapeutics, Intarcia, and Oramed, grant support and consulting fees from AstraZeneca, grant support, advisory board fees, lecture fees, and travel support from Boehringer Ingelheim, Novo Nordisk, and Sanofi US Services, grant support and advisory board fees from Eli Lilly, grant support from Genentech, GlaxoSmithKline, Janssen Biotech, Lexicon Pharmaceuticals, Novartis, Pfizer, and REMD Biotherapeutics, and advisory board fees from Zealand Pharma; Dr. Tran, being employed by and owning stock in Novo Nordisk; Dr. Wadden, receiving grant support, paid to the University of Pennsylvania, and advisory board fees from Novo Nordisk and advisory board fees from WW International; Dr. Wharton, receiving lecture fees from AstraZeneca and Bausch and Lomb and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Yokote, receiving lecture fees from Amgen, Janssen Pharmaceuticals, Kyowa Hakko Kirin, Novartis Pharma, and Sanofi, grant support and lecture fees from Astellas Pharma, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp and Dohme, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda Pharmaceutical, advisory board fees and lecture fees from AstraZeneca, grant support, lecture fees, and advisory board fees from Kowa Company and Novo Nordisk, and lecture fees and advisory board fees from Sanofi; Mr. Zeuthen, being employed by and owning stock in Novo Nordisk; and Dr. Kushner, receiving advisory board fees from Novo Nordisk and Weight Watchers. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the trial participants and the trial site staff; Lisa von Huth Smith of Novo Nordisk, Denmark, for support with data presentation of participant-reported outcomes and critical review of an earlier draft of the manuscript; and Paul Barlass of Axis, a division of Spirit Medical Communications Group, for medical writing and editorial assistance with an earlier draft of the manuscript (funded by Novo Nordisk).

Supplementary Material

Protocol (nejmoa2032183_protocol.pdf)

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Supplementary Appendix (nejmoa2032183_appendix.pdf)

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Disclosure Forms (nejmoa2032183_disclosures.pdf)

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Data Sharing Statement (nejmoa2032183_data-sharing.pdf)

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References

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