GLP-1 receptor(위고비) 기전과 최신 치료 2024 네이처!!

[문형철]

문치연 모니터링 과제

만약에 위고비, 세마글루타이드가 미래 언젠가 시장에서 퇴출된다면 

그 이유는 '소장, 췌장, 시상하부 암'의 증가와 관련이 있을 듯!!

위고비가 인간의 먹는 욕망을 억제하여 

자연스럽게 소식, 간헐적 단식 효과 --> 자가포식 유도 효과....

기적의 약물로 계속 자리하기를 기도하지만!!

1. nature  
2. signal transduction and targeted therapy  
3. review articles  
4. article

• Review Article
• Open access
• Published: 18 September 2024

Glucagon-like peptide-1 receptor: mechanisms and advances in therapy

• Zhikai Zheng, 
• Yao Zong, 
• Yiyang Ma, 
• Yucheng Tian, 
• Yidan Pang, 
• Changqing Zhang & 
• Junjie Gao 

Signal Transduction and Targeted Therapy volume 9, Article number: 234 (2024) Cite this article

•  
•  
•  
•  

Abstract

The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.

GLP-1R로 알려진 글루카곤 유사 펩타이드-1(GLP-1) 수용체는

G 단백질 연결 수용체(GPCR) 계열의 중요한 구성 요소이며

주로 인체 내 다양한 세포 유형의 표면에서 발견됩니다.

이 수용체는

혈당 수치, 지질 대사 및 기타 여러 중요한 생물학적 기능을 조절하는 데

필수적인 역할을 하는 핵심 호르몬인 GLP-1과 특이적으로 상호작용합니다.

최근 몇 년 동안 GLP-1 약물은

혁신적인 치료 메커니즘,

상당한 치료 효능 및 광범위한 개발 전망으로 인해

의료계에서 초점이 되고 있습니다.

이 글은

GLP-1 약물의 초기 발견부터 임상 적용까지 개발 이정표를 철저히 추적하여

다양한 GLP-1 약물의 진화와 그들의 독특한 약리학적 특성을 상세히 설명합니다.

또한, 이 논문은

신경 보호, 항감염 조치, 다양한 유형의 염증 감소, 심혈관 기능 향상과 같은 분야에서

GLP-1 수용체 작용제(GLP-1RA)의 잠재적 적용을 탐구합니다.

이는 신경계, 심혈관계, 근골격계 및 소화계를 포함한

러 신체 시스템 전반에 걸쳐

GLP-1RA의 효과에 대한 심층적인 평가를 제공합니다.

여기에는

최신 임상 시험 데이터를 통합하고

잠재적인 신호 전달 경로 및 약리학적 메커니즘을 심층적으로 다루는 것이 포함됩니다.

이 글의 주요 목표는

비만, 심혈관 질환, 비알코올성 지방간 질환(NAFLD), 신경 퇴행성 질환, 근골격계 염증 및

다양한 형태의 암과 같은 광범위한 질병 치료에

GLP-1RA를 사용하는 광범위한 이점을 강조하는 것입니다.

GLP-1 약물의 새로운 적응증 개발은

치료 개입을 더욱 확장할 유망한 전망을 제공하며,

의료 분야에서 그들의 상당한 잠재력을 보여줍니다.

Similar content being viewed by others

GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics

Article Open access09 October 2023

GLP-1-based therapies for diabetes, obesity and beyond

Article 25 April 2025

An analysis on the role of glucagon-like peptide-1 receptor agonists in cognitive and mental health disorders

Article Open access13 February 2025

Introduction

In recent years, GLP-1R and its agonists have garnered widespread attention in the medical community. GLP-1R, a core member of the GPCR family, is widely present on the surfaces of various cells in the human body.1,2 By specifically binding to the key hormone GLP-1, it regulates blood glucose levels and lipid metabolism.3,4 This receptor and its agonists hold significant therapeutic potential, reshaping the treatment approaches for multiple diseases, including diabetes, cardiovascular disorders, and neurodegenerative diseases.5,6,7 GLP-1 is a peptide produced by the cleavage of proglucagon, mainly synthesized in the intestinal mucosal L-cells, pancreatic islet α-cells, and neurons in the nucleus of the solitary tract.3,4 GLP-1RAs mimic the action of endogenous GLP-1, activating GLP-1R, thereby enhancing insulin secretion, inhibiting glucagon release, delaying gastric emptying, and reducing food intake through central appetite suppression.8,9,10 These mechanisms make GLP-1RAs powerful tools for controlling blood glucose and improving metabolic syndrome. Furthermore, their multifaceted mechanisms of action suggest potential applications beyond traditional metabolic disorders. From the discovery of the GLP-1 fragment GLP-1(7-37) to the development of more stable and long-acting GLP-1 analogs, these milestones represent significant breakthroughs in the medical field.11,12 For instance, the success of exenatide has not only spurred the development of potent GLP-1 analogs such as liraglutide and semaglutide but also unveiled the vast potential of GLP-1RAs in treating various systemic diseases. These developments underscore the importance of GLP-1RAs in modern therapeutics. The applications of GLP-1RAs extend far beyond diabetes management.5

Here we summarized the complex mechanisms of GLP-1RAs and their latest advancements in treating various diseases, such as musculoskeletal inflammation, obesity, cardiovascular diseases, NAFLD, neurodegenerative diseases, and various cancers. We introduce recent studies that demonstrate the remarkable performance of GLP-1RAs in slowing the progression of neurodegenerative diseases, reducing inflammation, and enhancing cardiovascular health. For example, in the treatment of Alzheimer’s diseases (AD) and Parkinson’s diseases (PD), GLP-1RAs have shown potential in slowing disease progression, while their anti-inflammatory properties offer new hope for conditions such as osteoarthritis (OA), rheumatoid arthritis (RA) and cardiovascular diseases.13,14,15 By integrating the latest clinical trial data, we explore the efficacy of GLP-1RAs in treating diseases of the nervous, cardiovascular, endocrine, and digestive systems. We show readers that GLP-1RAs have also been found to significantly reduce the risks of heart failure, atherosclerosis (AS), and hypertension, highlighting their broad therapeutic potential.16,17,18,19 As new indications continue to be developed, GLP-1 drugs demonstrate immense potential in the medical field, with future research expected to expand their therapeutic applications. The comprehensive exploration of their benefits underscores their transformative potential in medicine, positioning them as a promising approach for addressing a wide array of health issues and paving the way for new research and clinical applications.

The future of GLP-1RA therapy is promising. Researchers are developing more efficient formulations, such as long-acting and oral versions, to improve patient compliance and outcomes. With increasing clinical evidence, GLP-1RAs are set to become essential in treating complex and chronic diseases, offering significant health benefits and addressing unmet medical needs, thus enhancing patient quality of life and solidifying their role in future medical advancements.

소개

최근 몇 년간 GLP-1R 및 그 작용제들은

의료계에서 광범위한 관심을 받고 있습니다.

GLP-1R은

GPCR 가족의 핵심 구성원으로,

인체 내 다양한 세포 표면에 널리 분포되어 있습니다.1,2 

이 수용체는

핵심 호르몬인 GLP-1과 특이적으로 결합하여

혈당 수치와 지질 대사를 조절합니다.3,4 

글루카곤 유사 펩티드-1(GLP-1)은 주로 장과 시상하부에서 발현되는 30개 아미노산으로 구성된 펩티드 호르몬입니다. 최근 기초 및 임상 연구에서 GLP-1은 지질 대사와의 밀접한 관련성이 확인되었으며, 지방 합성 억제, 지방 분화 촉진, 콜레스테롤 대사 활성화, 지방 조직의 갈색화 촉진 등을 통해 지질 대사 과정에 참여하는 것으로 밝혀졌습니다. GLP-1은 지방 대사 조절을 통해 비만, 비알코올성 지방간 질환, 동맥경화증 등 대사 질환의 발생과 진행에 핵심적인 역할을 합니다. 이는 대사 장애 치료의 새로운 표적으로 기대되고 있습니다. GLP-1과 이중 작용제의 지방 대사 효과는 대사 질환 치료를 위한 더 완전한 치료 계획을 제공할 수 있습니다. 본 논문은 GLP-1의 지방 대사 관련 최근 연구 진전을 검토합니다.

이 수용체와 그 작용제는

당뇨병, 심혈관 질환, 신경퇴행성 질환 등 다양한 질환의 치료 접근법을 혁신적으로 변화시킬 수 있는

중요한 치료 잠재력을 지니고 있습니다.5,6,7 

글루카곤 유사 펩티드-1(GLP-1)은 인크레틴 분비 분자입니다. GLP-1 수용체 작용제(GLP-1RAs)는 체중 감소, 췌장 베타 세포 보호, 췌장 베타 세포 증식 촉진 및 최소한의 부작용과 같은 특성으로 인해 제2형 당뇨병(T2DM) 치료에 널리 사용됩니다. 연구 결과, GLP-1R은 췌장과 다른 조직에 널리 분포되어 있으며 신경염증 감소, 신경 성장 촉진, 심장 기능 개선, 식욕 억제, 위 배출 지연, 혈액 지질 대사 조절, 지방 침착 감소 등 다양한 생물학적 효과를 나타냅니다. 또한 GLP-1RAs는 신경 보호, 항감염, 심혈관 보호, 대사 조절 효과를 보여 우수한 적용 가능성을 가지고 있습니다. 2형 당뇨병(T2DM) 환자의 종양 발생, 발달 및 예후와 GLP-1RAs의 관계에 대한 관심이 증가하고 있습니다. 본 연구에서는 GLP-1RAs의 신경계, 심혈관계, 내분비계에서의 치료 효과 및 작용 메커니즘을 검토하고, 대사, 종양 및 기타 질환과의 상관관계를 분석했습니다.

글루카곤 유사 펩티드-1(GLP-1)은 혈당 의존적 인슐린 분비 자극을 통해 인크레틴 효과를 보이는 다기능 호르몬으로 잘 알려져 있습니다. 그러나 GLP-1은 뇌에서도 생성되며, GLP-1 수용체 신호전달 경로를 활성화하여 신경 보호 및 염증 조절에 중요한 역할을 합니다. 신경퇴행성 질환의 전임상 모델을 활용한 여러 in vivo 및 in vitro 연구에서 GLP-1 수용체 활성화가 항염증 효과를 갖는 것으로 나타났습니다. 이 리뷰는 뇌 내 염증과 관련된 GLP-1 RAS의 분자적 작용 메커니즘을 탐구합니다. 이러한 결과는 GLP-1 RAS 작용이 염증 반응을 감소시키는 데 미치는 잠재적 이점에 대한 이해를 업데이트합니다. 이 분자들은 신경퇴행성 질환 및 신경염증성 질환 치료를 위한 잠재적 치료 도구로 부상하고 있습니다.

GLP-1은

프로글루카곤의 분해로 생성되는 펩타이드로,

주로 장 점막의 L세포, 췌장 섬의 α세포, 고립 신경핵의 신경세포에서 합성됩니다.3,4 

GLP-1RAs는

내인성 GLP-1의 작용을 모방하여

GLP-1R을 활성화합니다.

이로써 인슐린 분비를 증가시키고,

글루카곤 분비를 억제하며,

위 배출을 지연시키고,

중추 신경계에서의 식욕 억제를 통해 음식 섭취를 감소시킵니다.8,9,10 

이러한 메커니즘은

GLP-1RAs를 혈당 조절과 대사 증후군 개선을 위한 강력한 도구로 만들며,

다면적인 작용 메커니즘은 전통적인 대사 장애를 넘어 잠재적인 응용 가능성을 제시합니다

. GLP-1 단편 GLP-1(7-37)의 발견부터

더 안정적이고 장기 작용형 GLP-1 유사체의 개발까지,

이러한 이정표들은 의료 분야에서의 중요한 돌파구를 상징합니다.11,12 

예를 들어, 엑세나티드의 성공은 리라글루티드와 세마글루티드와 같은 강력한 GLP-1 유사체의 개발을 촉진했을 뿐만 아니라 GLP-1RAs가 다양한 체계적 질환 치료에 갖는 광범위한 잠재력을 드러냈습니다. 이러한 발전은 GLP-1RAs가 현대 치료법에서 차지하는 중요성을 강조합니다. GLP-1RAs의 적용 범위는 당뇨병 관리 beyond far beyond.5

본 논문에서는

GLP-1RAs의 복잡한 작용 메커니즘과

근골격계 염증, 비만, 심혈관 질환, NAFLD, 신경퇴행성 질환, 다양한 암 등

다양한 질환 치료에서의 최신 진전을 요약했습니다.

신경퇴행성 질환의 진행 속도를 늦추고

염증을 감소시키며

심혈관 건강을 개선하는 데 있어

GLP-1RAs의 뛰어난 성능을 보여주는 최근 연구들을 소개합니다.

예를 들어,

알츠하이머 병(AD)과 파킨슨 병(PD) 치료에서 GLP-1RAs는

질병 진행을 늦추는 잠재력을 보여주었으며,

그 항염증 성질은 골관절염(OA), 류마티스 관절염(RA) 및 심혈관 질환과 같은 질환에

새로운 희망을 제공합니다.13,14,15 

최신 임상 시험 데이터를 통합하여

GLP-1RAs가 신경계, 심혈관, 내분비, 소화계 질환 치료에 미치는 효과를 탐구합니다.

독자들에게 GLP-1RAs가

심부전, 동맥경화증(AS), 고혈압의 위험을 유의미하게 감소시킨다는 점을 보여주며,

그들의 광범위한 치료 잠재력을 강조합니다.16,17,18,19 

새로운 적응증이 지속적으로 개발됨에 따라

GLP-1 약물은 의료 분야에서 엄청난 잠재력을 보여주며,

미래 연구는 그들의 치료적 적용 범위를 확장할 것으로 기대됩니다.

그들의 혜택을 포괄적으로 탐구한 결과,

의학 분야에서 혁신적인 잠재력을 강조하며,

다양한 건강 문제 해결을 위한 유망한 접근법으로 자리매김하고

새로운 연구 및 임상 적용의 길을 열어가고 있습니다.

GLP-1RA 치료의 미래는 밝습니다.

연구자들은 환자 순응도와 치료 결과를 개선하기 위해

장기 작용형 및 경구 투여형 등 더 효율적인 제형을 개발 중입니다.

임상적 증거가 증가함에 따라

GLP-1RAs는 복잡하고 만성적인 질환 치료에 필수적인 역할을 할 것으로 예상되며,

중요한 건강 혜택을 제공하고 미충족 의료 수요를 충족시켜

환자 삶의 질을 향상시키고 미래 의료 발전에서의 역할을 공고히 할 것입니다.

Review of the history and milestones in GLP-1 research

In 1979, Richard Goodman found that anglerfish are an ideal source for pancreatic mRNA due to their concentrated cells. He extracted mRNA, spliced anglerfish DNA into bacteria, and used radioactive probes to find the somatostatin gene. In 1982, they published a paper in the Proceedings of the National Academy of Sciences (PNAS), revealing that the glucagon precursor gene actually encodes three peptides-glucagon and two new hormones expressed in the intestine.20 A year later, a research team led by Graeme Bell from Chiron Corporation published two papers in the journal Nature.21,22 They cloned and sequenced the preproglucagon gene, discovering GLP-1 and GLP-2 hormones. The focus shifted to GLP-1, with Svetlana Mojsov identifying its insulin-stimulating fragment, GLP-1(7-37), in 1983. This was inspired by prior GIP (glucose-dependent insulinotropic polypeptide) research, highlighting that besides GIP, other substances in the intestine also stimulate insulin secretion. This finding was later combined with research by Joel Habener and jointly published in JCI.11 The team of Jens Juul Holst at the University of Copenhagen in Denmark published a report in FEBS Letters, reaching the same conclusion in January 1987.23 In December 1987, Stephen Bloom’s team confirmed in a Lancet paper that GLP-1(7-36) is a human intestinal hormone that stimulates insulin production in the pancreas and lowers blood sugar.24 GLP-1, used for treating diabetes, is quickly broken down in the body, requiring high doses that can cause side effects like nausea. This led to the development of new drugs similar to GLP-1 but with a longer-lasting effect. John Eng marked a significant breakthrough; he isolated exendin-4, a peptide from the Gila monster’s venom, which is structurally similar to human GLP-1 but more stable. GLP-1 is degraded in the bloodstream in less than a minute, whereas this peptide, consisting of 39 amino acids, exendin-4, could last for more than two hours. This work was eventually published in the JBC journal in August 1991.25 In the early 1990s, despite John Eng’s team identifying a potential diabetes treatment in exendin-4, it initially lacked attention and funding for development. Eng personally secured a patent and partnered with Amylin, leading to the FDA-approved diabetes drug exenatide in 2005, the first GLP-1 analog. This sparked further advancements, including Novo Nordisk’s development of more potent analogs like liraglutide and semaglutide, with the latter achieving over $12 billion in sales by 2022. The journey began in the 1980s with research on Gila monster venom, culminating in the discovery of exendin-4, a stable, effective peptide for treating diabetes, demonstrating the progression from initial discovery to blockbuster diabetes medications. In July 2009, they published a paper in Nature Chemical Biology, reporting for the first time that dual agonists targeting GLP-1R and glucagon receptor (GCGR) had a better weight loss effect.26 This marked a significant advancement in obesity treatment research, especially in combining multiple drug targets. Matthias Tschöp and Richard DiMarchi developed the first dual and triple agonist weight loss drugs. Eli Lilly and Company is currently researching a dual agonist called tirzepatide, which has outperformed semaglutide in phase 3 clinical trials. Additionally, their under-development triple agonist, Retatrutide, has shown unprecedented weight loss effects in phase 2 clinical trials.16 Matthias Tschöp and his team discovered that dual agonists targeting both GLP-1 and GIP receptors (GIPR) are more effective in treating diabetes than those targeting only GLP-1R. These dual agonists were found to reduce blood sugar and increase insulin secretion in mice, monkeys, and humans.27 Subsequently, they investigated a triple agonist capable of simultaneously targeting the GLP-1R, the GCGR, and the GIPR. In December 2014, they published a paper in Nature Medicine, showing that the triple agonist’s weight loss effects in mice exceeded those of the dual agonists.28 (Fig. 1).

GLP-1 연구의 역사와 주요 성과

1979년, 리처드 굿맨은 농어의 농축된 세포로 인해 췌장 mRNA의 이상적인 원천임을 발견했습니다. 그는 mRNA를 추출하고 농어 DNA를 세균에 삽입한 후 방사성 탐침을 사용하여 소마토스타틴 유전자를 찾아냈습니다. 1982년, 그들은 미국 국립과학원 회보(PNAS)에 논문을 발표해 글루카곤 전구체 유전자가 실제로 세 가지 펩타이드(글루카곤과 장에서 발현되는 두 가지 새로운 호르몬)를编码한다는 사실을 공개했습니다.20 그 다음 해, Chiron Corporation의 Graeme Bell을 이끈 연구팀은 Nature 저널에 두 편의 논문을 발표했습니다.21,22 그들은 전전글루카곤 유전자를 클로닝하고 시퀀싱해 GLP-1과 GLP-2 호르몬을 발견했습니다. 연구의 초점은 GLP-1로 이동했으며, 스베틀라나 모이소프는 1983년 GLP-1의 인슐린 자극 단편인 GLP-1(7-37)을 식별했습니다. 이는 이전의 GIP(glucose-dependent insulinotropic polypeptide) 연구에서 영감을 받았으며, GIP 외에도 장 내 다른 물질이 인슐린 분비를 자극한다는 점을 강조했습니다. 이 발견은 Joel Habener의 연구와 결합되어 JCI에 공동 발표되었습니다.11 덴마크 코펜하겐 대학교의 Jens Juul Holst 연구팀은 1987년 1월 FEBS Letters에 보고서를 발표해 동일한 결론을 도출했습니다.23

1987년 12월, 스티븐 블룸(Stephen Bloom) 연구팀은

Lancet 논문을 통해

GLP-1(7-36)이 췌장에서 인슐린 생산을 자극하고 혈당을 낮추는

인간 장 호르몬임을 확인했습니다.24

인간에서 글루카곤 유사 펩티드-1 7-36 아미드(GLP-1 7-36)의 생리적 역할이 조사되었습니다. 인간 장에서 GLP-1 7-36 유사 면역반응성이 발견되었으며, 그 혈중 농도는 경구 포도당 투여 후 및 시험 식사 후 증가했습니다. 7명의 자원자에게 공복 상태에서 식후 혈장 농도를 모방하는 속도로 투여했을 때, 혈장 인슐린 농도가 유의미하게 증가했으며 포도당과 글루카곤 농도는 감소했습니다. 정맥 내 포도당 부하 시, 이는 대조군 생리식염수 주입에 비해 인슐린 분비를 크게 촉진하고 혈장 포도당 피크 농도를 유의미하게 감소시켰으며, 심지어 주입 후 반응성 저혈당증을 유발했습니다. 반면, 생리적 농도로 주입된 포도당 의존성 인슐린 분비 펩티드(GIP)는 인슐린 분비 자극 효과가 덜했습니다. 이러한 관찰 결과는 GLP-1 7-36이 생리적 인크레틴이며 GIP보다 더 강력한 효과를 갖는다는 것을 시사합니다. 위절제술 후 덤핑 증후군 환자의 식후 혈장 GLP-1 7-36 농도가 크게 증가한 것은 이 물질이 이 질환의 고인슐린혈증과 반응성 저혈당증을 매개할 수 있음을 시사합니다.

당뇨병 치료에 사용되는 GLP-1은

체내에서 빠르게 분해되어 고용량이 필요하며,

메스꺼움 같은 부작용을 일으킬 수 있습니다.

이것은

GLP-1과 유사하지만 더 오래 지속되는 효과를 가진

새로운 약물의 개발로 이어졌습니다.

존 엥은 중요한 돌파구를 마련했습니다.

그는 길라 몬스터의 독에서 추출한 펩타이드인 엑센딘-4를 분리했는데,

이는 인간 GLP-1과 구조적으로 유사하지만 더 안정적입니다.

GLP-1은

혈류에서 1분 이내에 분해되지만,

39개의 아미노산으로 구성된 이 펩타이드인 엑센딘-4는

2시간 이상 지속될 수 있습니다.

이 연구 결과는 1991년 8월 JBC 저널에 게재되었습니다.25

1990년대 초반, 존 엥의 연구팀이

엑센딘-4에서 당뇨병 치료제의 잠재성을 발견했음에도 불구하고,

초기에는 개발을 위한 관심과 자금이 부족했습니다.

엥은 개인적으로 특허를 취득하고 아밀린과 협력해

2005년 FDA 승인을 받은 당뇨병 치료제 엑세나티드(첫 번째 GLP-1 유사체)를 개발했습니다.

이 성과는 추가적인 발전을 촉진했으며,

노보 노르디스크는 리라글루티드와 세마글루티드와 같은 더 강력한 유사체를 개발했습니다.

후자는 2022년까지 $120억 달러 이상의 매출을 기록했습니다.

이 여정은 1980년대 길라 몬스터 독소 연구에서 시작되어

당뇨병 치료에 효과적인 안정적인 펩타이드인 엑센딘-4의 발견으로 이어졌으며,

초기 발견에서 블록버스터 당뇨병 약물로 발전한 과정을 보여줍니다.

2009년 7월, 그들은 Nature Chemical Biology에 논문을 발표해

GLP-1 수용체와 글루카곤 수용체(GCGR)를 표적으로 하는 이중 작용제가

체중 감량 효과에서 더 우수하다는 것을 처음으로 보고했습니다.26

우리는 글루카곤 및 GLP-1 수용체에 대한 작용제를 가진 새로운 펩타이드의 효능을 보고합니다. 이 펩타이드은 강력한 지속성 있는 포만감 유발 및 지방 분해 효과를 나타냅니다. 글루카곤에 대한 선택적 화학적 변형은 특이성을 상실시켰으나, 본래 활성은 거의 변화하지 않았습니다. 공동 작용제의 구조적 기반은 국소적 위치 상호작용과 이차 구조의 변화가 결합된 것으로 보입니다. 글루카곤 수용체 작용 활성 수준만 다른 두 개의 공동 작용제 펩타이드를 쥐 비만 모델에서 연구했습니다. PEG화 펩타이드를 주 1회 투여한 결과, 식이 유발성 비만 쥐에서 지방량과 혈당 내성이 정상화되었습니다. 체중 감소는 식이 섭취 감소와 에너지 소비 증가로 인한 체지방 감소로 달성되었습니다. 이 전임상 연구 결과는 GLP-1 작용을 적절한 수준의 글루카곤 수용체 활성화로 강화할 경우, 명백한 부작용 없이 체지방 감소를 크게 향상시킬 수 있음을 시사합니다.

이는 특히 다중 약물 표적 결합 측면에서

비만 치료 연구에 중요한 진전을 의미했습니다.

마티아스 츠호프(Matthias Tschöp)와 리차드 디마르치(Richard DiMarchi)는

첫 번째 이중 및 삼중 작용제 체중 감량 약물을 개발했습니다.

Eli Lilly and Company는

현재 세마글루타이드보다 3상 임상 시험에서 우수한 효과를 보인

이중 작용제 티르제파타이드를 연구 중입니다.

또한 개발 중인 삼중 작용제

레타트루타이드(Retatrutide)는

2상 임상 시험에서 전례 없는 체중 감량 효과를 보여주었습니다.16

마티아스 츠호프와 그의 연구팀은

GLP-1과 GIP 수용체(GIPR)를 동시에 표적하는 이중 작용제가

GLP-1R만을 표적하는 약물보다 당뇨병 치료에 더 효과적임을 발견했습니다.

이 이중 작용제는

쥐, 원숭이, 인간에서 혈당을 감소시키고

인슐린 분비를 증가시키는 것으로 확인되었습니다.27

이후 그들은

GLP-1R, GCGR, GIPR을 동시에 표적하는

삼중 작용제를 연구했습니다.

2014년 12월, 그들은 Nature Medicine에 논문을 발표해

삼중 작용제의 쥐에서의 체중 감소 효과가

이중 작용제보다 우수함을 보여주었습니다.28 (그림 1).

Fig. 1

Growth and Timescale of Medical Publications on GLP-1 and GLP-1RAs. This figure illustrates the number of published articles over time, from 1978 to 2022, related to GLP-1 and GLP-1RAs, along with significant milestones in clinical trials. The data is visualized through three layered area graphs, each representing a different category of publications: research on GLP-1 (red area), GLP-1RAs (blue area), and clinical trials (green area). Key milestones are annotated on the timeline, including the identification of GLP-1 and GLP-2 through gene sequencing in 1983, the extraction of Exendin-4 from Gila monster venom in 1991, and the first FDA approval of a GLP-1 analog, Exenatide, in 2005. Liraglutide’s clinical trials began in 2000 and the drug’s FDA approval in 2010. Notable is the steep increase in the number of publications from 2000 onwards, reflecting a growing interest and development in the field. The peak in 2022 corresponds to GLP-1 drug sales hitting $22 billion, with the approval of semaglutide by the FDA in 2021 and the initiation of the first clinical trial for an oral diabetes drug based on GLP-1 in the same year. This graph underscores the expanding research and clinical importance of GLP-1-related therapies in the treatment of diabetes. The x-axis represents the year, ranging from 1978 to 2023, and the y-axis quantifies the number of published articles, with a scale ranging from 0 to 2500 articles annual. GLP-1RAs are artificial protein formulations that exhibit partial or complete amino acid sequence similarity to endogenous GLP-1 within the human body. These compounds possess enhanced stability, extended half-lives, and heightened biological potency, enabling them to mimic the actions of GLP-1. Ongoing advancements in research and development have resulted in the production of GLP-1RA with increasingly prolonged half-lives

GLP-1 및 GLP-1RAs 관련 의학 논문 출판의 성장 및 시간 규모.

이 그림은 1978년부터 2022년까지 GLP-1 및 GLP-1RAs와 관련된 출판된 논문 수를 시간별로 보여줍니다. 또한 임상 시험의 주요 이정표도 함께 표시되어 있습니다. 데이터는 세 개의 층으로 구성된 영역 그래프로 시각화되었습니다. 각 영역은 다른 카테고리의 논문을 나타냅니다: GLP-1 연구(붉은 영역), GLP-1RAs(파란 영역), 임상 시험(녹색 영역). 시간 축에는 주요 이정표가 표시되어 있습니다.

1983년 유전자 염기서열 분석을 통해 GLP-1과 GLP-2가 발견된 것,

1991년 길라몬스터 독액에서 Exendin-4가 추출된 것,

2005년 GLP-1 유사체인 Exenatide가 FDA 승인을 받은 것이 포함됩니다.

Liraglutide의 임상 시험은 2000년에 시작되었으며, 해당 약물의 FDA 승인은 2010년에 이루어졌습니다. 2000년 이후 논문 수의 급격한 증가가 눈에 띄며, 이는 해당 분야에 대한 관심과 개발이 증가했음을 반영합니다. 2022년의 정점은 GLP-1 약물 판매액이 $220억을 기록한 시기와 일치하며, 이는 2021년 FDA의 세마글루타이드 승인 및 같은 해 GLP-1 기반 경구용 당뇨병 약물의 첫 임상 시험 시작과 관련이 있습니다. 이 그래프는 당뇨병 치료에서 GLP-1 관련 치료법의 연구 및 임상적 중요성이 확대되고 있음을 강조합니다. x축은 1978년부터 2023년까지의 연도를 나타내며, y축은 연간 발표된 논문 수를 0에서 2,500편까지의 척도로 표시합니다. GLP-1RAs는 인체 내 자연적으로 존재하는 GLP-1과 부분적 또는 완전한 아미노산 서열 유사성을 가진 인공 단백질 제제입니다. 이 화합물은 안정성이 향상되고 반감기가 연장되며 생물학적 효능이 강화되어 GLP-1의 작용을 모방할 수 있습니다. 연구 및 개발의 지속적인 발전으로 반감기가 점점 더 연장된 GLP-1RA가 생산되고 있습니다.

GLP-1

GLP-1 is a peptide hormone generated through the enzymatic breakdown of proglucagon. It is synthesized in L-cells located in the intestinal mucosa, α-cells found in the pancreatic islet, and neurons residing in the nucleus of the solitary tract.29 GLP-1, an endocrine hormone, is secreted by enteroendocrine L-cells located in the distal jejunum, ileum, and colon in response to nutrient ingestion and neuroendocrine stimulation. It originates from the preproglucagon precursor, which undergoes enzymatic processing within intestinal L-cells, ultimately giving rise to GLP-1(1-37) and GLP-1(7-36) amide or GLP-1(7-37) peptide variants.30,31 GLP-1 is an incretin hormone that plays a pivotal role in the meticulous control of human blood glucose levels.32,33 Nevertheless, its duration of action is rather ephemeral, lasting a mere 1–2 min within the circulatory system under typical physiological conditions.34,35 Subsequently, GLP-1 undergoes enzymatic degradation facilitated by dipeptidyl peptidase IV (DPP-4), leading to the loss of its biological efficacy.36

GLP-1

GLP-1은

프로글루카곤의 효소 분해를 통해 생성되는 펩티드 호르몬입니다.

이는 장 점막에 위치한

L-세포, 췌장 섬에 있는 α-세포, 고독 신경핵에 거주하는 신경세포에서 합성됩니다.29

GLP-1은

내분비 호르몬으로,

영양소 섭취와 신경내분비 자극에 반응하여 소장 하부, 회장, 결장에 위치한

장내 내분비 L-세포에서 분비됩니다.

이 호르몬은

프로프로글루카곤 전구체에서

장 L-세포 내에서 효소적 처리 과정을 거쳐

GLP-1(1-37) 및 GLP-1(7-36) 아미드 또는 GLP-1(7-37) 펩타이드 변이체로 생성됩니다.30,31

GLP-1은

인간 혈당 수치의 정교한 조절에 핵심적인 역할을 하는

인크레틴 호르몬입니다.32,33

그러나

그 작용 지속 시간은 매우 짧아,

일반적인 생리적 조건 하에서 순환계 내에서 단 1–2분 동안만 지속됩니다.34,35

이후 GLP-1은

디펩티딜펩티다제 IV(DPP-4)에 의해 촉진되는 효소적 분해 과정을 거쳐

생물학적 효능을 상실합니다.36

GLP-1R

GLP-1R, a member of the GPCR family, exhibits specific affinity for GLP-1. It predominantly localizes to the cellular membrane of diverse cell types throughout the human body.37 Indeed, GLP-1R is present beyond the confines of the pancreas and extends to a multitude of organs and tissues throughout the body. Its extensive distribution and involvement in diverse physiological processes emphasize the important role of GLP-1R beyond the regulation of glucose metabolism.38,39,40 The phenotype observed after GLP-1R knockout (KO) includes various physiological and metabolic changes. GLP-1R plays a role in the central nervous system (CNS) regulation of appetite. GLP-1R KO can lead to increased appetite, contributing to weight gain.1 GLP-1R is involved in regulating both insulin and glucagon secretion, and its knockout can impair pancreatic function, thereby affecting the balance of these hormones and glucose homeostasis.41,42 GLP-1R is expressed in the cardiovascular system, and its knockout has implications for cardiovascular function.43,44 GLP-1R is present in the CNS, and its absence might contribute to alterations in behavior, mood, or cognitive function.45,46

GLP-1R

GLP-1R은

GPCR 가족에 속하는 수용체로,

GLP-1에 대한 특이적인 친화성을 나타냅니다.

이는

인체 내 다양한 세포 유형의 세포막에 주로 분포합니다.37 

실제로 GLP-1R은

췌장의 경계를 넘어 인체 내 다양한 장기 및 조직에 널리 분포합니다.

그 광범위한 분포와 다양한 생리적 과정에의 관여는

GLP-1R이 포도당 대사 조절을 넘어 중요한 역할을 한다는 점을 강조합니다.38,39,40 

GLP-1R 결손(KO) 후 관찰되는 표현형에는

다양한 생리적 및 대사적 변화가 포함됩니다.

GLP-1R은

중추 신경계(CNS)에서의 식욕 조절에 역할을 합니다.

GLP-1R KO는

식욕 증가를 유발하여 체중 증가에 기여할 수 있습니다.1 

GLP-1R은 인슐린과 글루카곤 분비 조절에 관여하며,

그 결손은 췌장 기능을 손상시킬 수 있습니다.

이로 인해 이러한 호르몬의 균형과 포도당 항상성에 영향을 미칠 수 있습니다.41,42 

GLP-1R은 심혈관 시스템에 발현되며, 그 결손은 심혈관 기능에 영향을 미칠 수 있습니다.43,44 

GLP-1R은 CNS에 존재하며, 그 결손은 행동, 기분, 또는 인지 기능의 변화에 기여할 수 있습니다.45,46

GLP-1RAs

GLP-1RAs result from intricate structural modifications to GLP-1, enabling them to not only replicate the pharmacological functions of GLP-1 but also impede its hydrolysis by DPP-4, thereby extending the drug’s half-life.47,48 These synthetic protein preparations exhibit partial or complete amino acid sequence homology with endogenous GLP-1, rendering them resistant to degradation which resulting in a prolonged half-life and heightened biological activity.47,48 By emulating the biological activity of natural GLP-1, GLP-1RAs effectively fulfill the role of GLP-1, effectively lowering blood glucose levels without increasing the risk of hypoglycemia and demonstrating favorable safety profiles.49 GLP-1RAs represent a pharmacotherapeutic category of injectable hypoglycemic agents that are sanctioned as adjunctive therapies to diet and exercise for the management of type 2 diabetes mellitus (T2DM) in adult patients and potentially hold promise in addressing other medical conditions.7,50,51 As researchers dive deeper into their multifaceted properties, these medications exhibit the potential to offer therapeutic benefits across a spectrum of diseases in human populations.

GLP-1RAs

GLP-1RAs는

GLP-1의 복잡한 구조적 변형을 통해 생성되며,

이는 GLP-1의 약리학적 기능을 모방할 뿐만 아니라

DPP-4에 의한 분해를 차단하여 약물의 반감기를 연장합니다.47,48 

이 합성 단백질 제제는

내인성 GLP-1과 부분적 또는 완전한 아미노산 서열 동질성을 보여 분해에 저항성을 갖게 되며,

이는 반감기 연장 및 생물학적 활성 증강으로 이어집니다.47,48 

자연적 GLP-1의 생물학적 활성을 모방함으로써 GLP-1RAs는

GLP-1의 역할을 효과적으로 수행하여 저혈당 위험을 증가시키지 않으면서

혈당 수치를 효과적으로 낮추며 우수한 안전성 프로파일을 보여줍니다.49 

GLP-1RAs는

식이요법과 운동 요법에 보조 치료제로 사용되는 주사형 혈당 강하제로,

성인 환자의 제2형 당뇨병(T2DM) 관리에 승인되었으며

다른 의료 조건을 해결하는 데 잠재력을 지니고 있습니다.7,50,51 

연구자들이 그들의 다면적인 특성을 더 깊이 탐구함에 따라,

이 약물은 인간 인구에서 다양한 질환에 걸쳐

치료적 혜택을 제공할 잠재력을 보여주고 있습니다.

The development of GLP-1RAs

The Gila monster, which lives in the deserts of the Americas, can eat up to half its own body weight in one sitting, but its blood sugar remains stable, and its metabolic system runs smoothly despite this large amount of food.52,53 In 1992, Dr. John Enn discovered an exopeptide in the saliva of the Gila monster which he named exendin-4. Dr. John found that exenatide is an analog of human GLP-1RA, with 53% homology to human GLP-1RA; exenatide can stimulate human insulin secretion and regulate blood glucose levels in the body. This hormone is not readily degraded by DPP-4 to GLP-1 in the human body and can act for 12 h or longer.25

In 2005, exenatide was approved by the U.S. Food and Drug Administration (FDA) for use in treating T2DM;52 thus began the competition between various GLP-1RAs. GLP-1RAs are being developed to be more similar to the natural GLP-1 hormone found in the human body. This is achieved by replacing and modifying specific amino acids in human GLP-1.54,55 By doing so, the resulting product has a higher similarity or homology to the amino acid sequence of human GLP-1. In addition, efforts are being made to extend the duration of action of GLP-1RAs. Currently, some GLP-1RAs require daily injections, which can be inconvenient for patients. Therefore, researchers are working toward developing formulations that can be administered once a week, providing a longer-lasting effect and reducing the frequency of injections.56,57 Furthermore, there is a focus on developing GLP-1RAs that can be taken orally without the need for injections. This oral preparation would offer a more convenient and comfortable option for patients, potentially leading to better treatment compliance.58,59 Overall, the future research direction of GLP-1RAs involves making them more similar to those in the human body, extending their duration of action, and creating oral formulations for easier administration.60,61 These advancements aim to improve patient experience, compliance, and treatment outcomes.

Exenatide is the world’s first GLP-RA product; it was developed in 1995 and approved for marketing in 2005.60 Liraglutide was subsequently approved for marketing in February 2010,62 and lixisenatide was approved for marketing in the European Union in 2013 for the treatment of T2DM and in the United States in July 2016.63 Albiglutide was approved for marketing in the European Union in March 2014 and in the United States in April 2014.64 Dulaglutide was approved for marketing in the U.S. in September 2014 for the treatment of T2DM65; semaglutide was approved for marketing in the United States in September 201766; and beinaglutide is a GLP-RA product developed by a Chinese company and was approved for marketing for the treatment of T2DM in China in September 2016.67 PEG-loxenatide, China’s first long-acting GLP-RA product, was approved for marketing in China in May 2019.66 (Tables 1 and 2)

GLP-1RAs의 개발

아메리카 대륙의 사막에 서식하는 길라 몬스터는

한 번에 자신의 체중의 절반을 먹을 수 있지만,

혈당 수치는 안정적이며 이 많은 양의 음식에도 불구하고

대사 시스템이 원활하게 작동합니다.52,53

1992년 존 엔(John Enn) 박사는 길라 몬스터의 타액에서

외인성 펩타이드를 발견하고

이를 엑센딘-4(exendin-4)라고 명명했습니다.

존 박사는 엑세나티드가

인간 GLP-1RA의 아날로그로,

인간 GLP-1RA와 53%의 동질성을 갖는다는 것을 발견했습니다.

엑세나티드는

인간 인슐린 분비를 자극하고 체내 혈당 수치를 조절합니다.

이 호르몬은

인간 체내에서 DPP-4에 의해 GLP-1로 쉽게 분해되지 않으며

12시간 이상 작용할 수 있습니다.25

2005년, 엑세나티드는

미국 식품의약국(FDA)으로부터 제2형 당뇨병(T2DM) 치료제로 승인되었습니다;52

이로써

다양한 GLP-1RAs 간의 경쟁이 시작되었습니다.

GLP-1RAs는

인간 몸에 존재하는 자연적인 GLP-1 호르몬과 더 유사하도록 개발되고 있습니다.

이는

인간 GLP-1의 특정 아미노산을 대체하거나

수정함으로써 달성됩니다.54,55

이를 통해 생성된 제품은

인간 GLP-1의 아미노산 서열과 더 높은 유사성 또는 동질성을 갖게 됩니다.

또한

GLP-1RAs의 작용 시간을 연장하기 위한 노력도

진행 중입니다.

현재 일부 GLP-1RAs는 매일 주사가 필요하며,

이는 환자에게 불편을 초래할 수 있습니다.

따라서

연구자들은 주 1회 투여가 가능하며 더 오래 지속되는 효과를 제공하며

주사 빈도를 줄일 수 있는 제형 개발을 목표로 하고 있습니다.56,57

또한

주사 없이 경구로 복용할 수 있는

GLP-1RAs 개발에도 초점이 맞춰져 있습니다.

이 경구 제형은

환자에게 더 편리하고 편안한 옵션을 제공하여

치료 순응도를 향상시킬 수 있습니다.58,59

전반적으로 GLP-1RAs의 미래 연구 방향은

인체 내 작용 메커니즘과 유사하게 만들고,

작용 시간을 연장하며, 투여 편의성을 높이기 위한 경구 제형을 개발하는 것입니다.60,61

이러한 발전은

환자 경험, 순응도, 치료 결과를 개선하는 것을 목표로 합니다.

Exenatide는 세계 최초의 GLP-RA 제품으로,

1995년에 개발되어 2005년에 시판 승인을 받았습니다.60

Liraglutide는

2010년 2월에 시판 승인을 받았으며,62

lixisenatide는 2013년 유럽 연합에서 제2형 당뇨병 치료제로, 2

016년 7월 미국에서 시판 승인을 받았습니다.63

알비글루타이드(Albiglutide)는

2014년 3월에 유럽 연합에서, 2014년 4월에 미국에서 시판 승인을 받았습니다.64

두라글루타이드(Dulaglutide)는

2014년 9월에 미국에서 T2DM 치료를 위해 시판 승인을 받았으며,65

세마글루타이드(Semaglutide)는 2017년 9월에 미국에서 시판 승인을 받았습니다.66

그리고

베이나글루타이드(Beinaglutide)는

중국 기업이 개발한 GLP-RA 제품으로,

2016년 9월에 중국에서 T2DM 치료용으로 시판 승인을 받았습니다.67

PEG-로クセ나타이드(PEG-loxenatide)는

중국 최초의 장기 작용형 GLP-RA 제품으로,

2019년 5월에 중국에서 시판 승인을 받았습니다.66 (표 1 및 2)

Table 1 Comparison of GLP-1RAs used in type 2 diabetes mellitus

DateBrand nameGLP-1RAHalf-lifeDose (SC)Molecular formulaClinial trial focus

2005	Byetta	Exenatide	2.4 h	5 μg or 10 μg b.i.d sc	C149H234N40O47S	Parkinson disease
2010	Victoza/Saxenda	Liraglutide	11-13 h	0.6 mg and 1.2 or 1.8 mg q.d sc	C172H265N43O51	Cardiovascular disease
2013	Adlyxin (U.S)/Lyxumia (EU)	Lixisenatide	2–4 h	10 μg then 20 μg q.d sc	C215H347N61O65S	Early Parkinson disease
2014	Tanzeum	Albiglutide	6-8 h	30 or 50 mg q.w sc	C148H224N40O45	Cardiovascular disease
2014	Trulicity	Dulaglutide	108-112 h	0.75 or 1.5 mg q.w sc	C2646H4044N704O836S18	Type 2 diabetes
2017	BYDUREON BCise	Exenatide (ER)	2 w	2 mg q.w sc	C184H282N50O60S	Type 1 diabetes
2017	Ozempic	Semaglutide	6-7 d	0.25 mg then 0.5 mg q.w sc	C187H291N45O59	obesity-related heart failure
2019	Rybelsus	Oral Semaglutide	24 h	3 mg then 7 mg q.d po	C187H291N45O59	Type 2 diabetes

Table 2 Comparative overview of efficacy and adverse effects of mainstream GLP-1RA medications

Current GLP-1RAs

GLP-1RAs are synthetic protein preparations that have partial or complete amino acid sequence homology with GLP-1 found in the body, are not easily degraded, have longer half-lives and have stronger biological activity. They can play the role of GLP-1.49 GLP-1RA is primarily used for the treatment of T2DM68 and works by mimicking the action of the naturally occurring hormone GLP-1, which is released by the intestines in response to food intake. GLP-1 helps regulate blood sugar levels by stimulating the release of insulin, suppressing glucagon secretion (which raises blood sugar levels), and slowing the rate at which the stomach empties, leading to a feeling of fullness and reduced appetite.69 In addition to its use in diabetes management, GLP-1RA has also shown potential in other areas of research. Studies have explored its effects on weight loss, NAFLD,70 and neurodegenerative diseases such as AD.71 Furthermore, GLP-1RA has been investigated for its potential to reduce the risk of cardiovascular events in patients with or without diabetes.5,19 Like any medication, GLP-1RAs may have side effects, including nausea, vomiting, diarrhea, and injection site reactions. These side effects are often mild and tend to improve over time.72,73,74 Rare but serious side effects may include pancreatitis and allergic reactions.75

현재의 GLP-1 수용체 작용제 (GLP-1RAs)

GLP-1RAs는

체내에서 발견되는 GLP-1과 부분적 또는 완전한 아미노산 서열 동질성을 가진 합성 단백질 제제로,

쉽게 분해되지 않으며 반감기가 길고 생물학적 활성이 더 강합니다.

GLP-1의 역할을 대신할 수 있습니다.49

GLP-1RA는

주로 제2형 당뇨병(T2DM)의 치료에 사용되며,

식사 후 장에서 분비되는 자연 발생 호르몬 GLP-1의 작용을 모방하여 작용합니다.

GLP-1은

인슐린 분비를 자극하고 혈당을 상승시키는 글루카곤 분비를 억제하며

위 배출 속도를 늦추어 포만감을 느끼고 식욕을 감소시키는 방식으로

혈당 수치를 조절합니다.69

당뇨병 관리 외에도 GLP-1RA는

다른 연구 분야에서도 잠재력을 보여주고 있습니다.

연구에서는

체중 감량, NAFLD,70 및 알츠하이머 병(AD)과 같은

신경퇴행성 질환에 대한 효과를 탐구해 왔습니다.71

또한 GLP-1RA는

당뇨병이 있거나 없는 환자의 심혈관 사건 위험을 감소시키는

잠재적 효과에 대해 조사되었습니다.5,19

모든 약물과 마찬가지로 GLP-1RA는

메스꺼움, 구토, 설사, 주사 부위 반응 등 부작용을 일으킬 수 있습니다.

이러한 부작용은 일반적으로 경미하며

시간이 지나면서 개선되는 경향이 있습니다.72,73,74

드물지만 심각한 부작용으로는

췌장염과 알레르기 반응이 포함될 수 있습니다.75

Exenatide

Exenatide is a medication that belongs to the class of drugs known as GLP-1RAs. It is a synthetic version of the hormone exendin-4, which is found in the saliva of the Gila monster, a venomous lizard native to the southwestern United States.76 Exenatide is composed of 39 amino acids and shares 53% sequence identity to human GLP-1. The second position of its N-terminus is glycine (alanine in GLP-1), which is not easily degraded by the DPP-4 enzyme.77 Compared with GLP-1, the C-terminus of its amino acid sequence contains 9 additional amino acid residues (PSSGAPPPS), which are not easily degraded by peptide chain endonucleases; thus, it has a long half-life and strong biological activity.78 The average half-life of exenatide is 2.4 h, 2 to 3 times per day.78

Liraglutide

Liraglutide is a medication used to treat T2DM and obesity.79,80 In the treatment of T2DM, liraglutide helps lower blood sugar levels by increasing insulin production and reducing glucose production by the liver.81 It also slows stomach emptying, which helps control appetite and reduce food intake.82,83 In addition to lowering blood sugar levels, liraglutide helps to reduce body weight by suppressing appetite and reducing energy intake,84,85 but its associated costs and need for daily injections may limit its use in individuals with obesity.86,87,88 Liraglutide was first approved by the FDA in 2010 under the brand name Victoza for the treatment of T2DM.83,89,90,91,92 Since then, it has also been approved for other indications, such as chronic weight management, under the brand name Saxenda.62 Liraglutide has an arginine at position 34 (GLP-1(7-37)) that is lysine, and its lysine at position 26 connects to a 16-carbon palmitic acid side chain linked by glutamic acid. Liraglutide shares 97% sequence homology with human GLP-1 and can bind to and activate GLP-1R.78 The elimination half-life of liraglutide is 13 h, and only one injection per day is required.62

Lixisenatide

Lixisenatide was developed by Sanofi to treat T2DM.64,93 Structurally, lixisenatide is based on the exenatide structure but lacks proline at position 38, and six lysines are linked after serine at position 39.94 The six lysine residues increase the rigidity of the molecule’s structure, thus allowing its drug properties to be improved.78 These changes stabilize its structure, prevent protein degradation of the molecule in the circulation, and increase the circulation time enough to ensure once-daily injection (compared with exenatide, which is injected two or three times daily). The average half-life of lixisenatide is approximately 3–4 h.95 Lixisenatide is a short-acting GLP-1RA agent,96,97 and once-daily lixisenatide can improve patient compliance to a certain extent and reduce the occurrence of hypoglycemia.98,99,100 The injection is usually given within one hour before the first meal of the day, preferably at the same time each day. It is important to avoid injecting lixisenatide after a meal or in case of a missed meal. The initial recommended dosage of lixisenatide is 10 mcg once daily for at least 14 days. After the initial period, its dosage may be increased to 20 mcg once daily if additional glycemic control is needed. The maximum recommended dosage is 20 mcg once daily.101

Albiglutide

Albiglutide was approved by the FDA in 2014. As a GLP-1RA,102 albiglutide works by stimulating insulin release and reducing glucagon production, leading to improved blood sugar control in patients with T2DM.102,103 Albiglutide is a long-acting GLP-1RA injected subcutaneously once a week. The half-life of albiglutide is approximately 4 to 7 days.102 Compared with the structure of human GLP-1(7-36), the amino acid sequence of albiglutide contains an arginine at position 8 (in GLP-1, this residue is lysine), and two modified GLP-1 peptide chains are fused to human serum albumin (HSA), thereby greatly extending its half-life.104,105 Albiglutide is typically prescribed in combination with diet and exercise. The dosage of albiglutide is usually 30 mg once a week. It is administered as a subcutaneous injection (just under the skin). The injection site can be the thigh, abdomen, or upper arm.102

The FDA set several usage restrictions upon the initial approval of Tanzeum (albiglutide), reflecting considerations of suitability and safety for specific patient groups. Firstly, Tanzeum is not recommended as a first-line treatment for patients inadequately controlled with diet and exercise.49 Secondly, its safety and efficacy remain unclear in patients with a history of pancreatitis as it has not been studied in this group.106 Additionally, Tanzeum is not suitable for treating type 1 diabetes or diabetic ketoacidosis, related to its pharmacological action and target disease. It is also not recommended for patients with existing gastrointestinal disease to avoid potential side effects or exacerbating the condition.107 Further, serious risks associated with Tanzeum use include pancreatitis, acute kidney injury, renal impairment, and pneumonia, further limiting its use in specific conditions or susceptible patients. These restrictions and warnings demonstrate the FDA’s stringent consideration of patient safety in the drug approval process.108 In March 2015, the FDA required a black box warning on Tanzeum due to the observed risk of thyroid C-cell tumors in animals, although it is unclear if this effect also occurs in humans.108 Later, the FDA added a warning about the risk of anaphylactic shock to the medication’s label. This reaction is severe and potentially life-threatening, including symptoms like unease, tingling, dizziness, itching, hives, swelling, difficulty breathing, and fainting.81,107,109

Tanzeum was discontinued by GlaxoSmithKline (GSK) in 2017, primarily due to economic factors.110,111 Despite GSK’s attempts to gain a competitive edge through low pricing, Tanzeum failed to achieve sufficient market acceptance.106 In 2017, Tanzeum was removed from the preferred drug list of leading pharmacy benefit manager (PBM) company Express Scripts and was replaced by Eli Lilly’s Trulicity, highlighting Tanzeum’s weak market presence.106,108 Moreover, this decision was part of a broad strategic reform led by GSK’s new CEO Emma Walmsley.106 This reform aimed to refocus the company’s efforts on areas with higher revenue potential, such as respiratory and HIV treatments, as well as oncology and immunology.108 Additionally, Tanzeum struggled to establish a significant market share in the competitive GLP-1RA market, which was another reason GSK decided to withdraw the drug globally.108

Dulaglutide

Dulaglutide was approved by the FDA in 2014 for the treatment of T2DM.112 Dulaglutide is a once-weekly long-acting GLP-1RA. Compared with the structure of human GLP-1(7-37), the amino acid sequence of dulaglutide contains glycine at position 8, glutamic acid at position 22, and glycine at position 36.113 It was then fused to the constant region (Fc) of modified human immunoglobulin G4 (IgG4) via a “-(Gly-Gly-Gly-Gly-Ser) 3-Ala-“ bridge and exhibits an average biological half-life of 90 h.105 Dulaglutide is the first large-molecule GLP-1RA, and the weekly dosing frequency of dulaglutide can greatly improve patient compliance.33,78,104,114

Semaglutide

Semaglutide is a long-acting GLP-1RA agent used once weekly to improve glycemic control in patients with T2DM.115 Compared with the structure of human GLP-1(7-37), the amino acid sequence of semaglutide contains diaminoisobutyric acid at position 8, arginine at position 34, and acylated lysine at position 26.31 Semaglutide has a longer aliphatic chain and increased hydrophobicity, but its hydrophilicity is greatly enhanced by PEG modification of the short chain. Modified DPP-4 can not only mask the enzymatic hydrolysis site of DPP-4 but also bind closely with albumin to reduce renal excretion and prolong the half-life.35,104,116 On August 22, 2022, Novo Nordisk announced the primary results of the Phase II clinical trial for the dual-action compound CagriSema, which demonstrated effective blood sugar reduction and weight loss. CagriSema is composed of the GLP-1 RA semaglutide and the long-acting insulin analog cagrilintide, and can be administered subcutaneously once a week.117

Beinaglutide

Beinaglutide was the first original drug approved for the treatment of obesity in China and the third GLP-1 class reduction drug approved worldwide, and it represents a new treatment option for overweight and obese patients.67,118,119 Beinaglutide, a recombinant human GLP-1 (rhGLP-1) polypeptide, exhibits a remarkable resemblance to human GLP-1(7-36), with nearly 100% homology.120 This innovative compound demonstrates dose-dependent efficacy in regulating glycemic control, suppressing appetite, delaying gastric emptying, and facilitating weight reduction.121 Consequently, beinaglutide holds significant promise for advancing research in the areas of overweight/obesity and nonalcoholic steatohepatitis (NASH).67,122 Beinaglutide is a natural human GLP-1(7-36)-NH2 expressed in Escherichia coli. This product was approved for the treatment of T2DM; it has a half-life of 11 minutes and requires 3 injections per day.78

Polyethylene glycol liraglutide

Polyethylene glycol liraglutide (PEG-loxenatide) is a long-acting GLP-1RA. It was the world’s first PEGylated long-acting GLP-1RA.123 PEG-loxenatide is used for blood glucose control in adult patients with T2DM. Structurally, the product was optimized on the basis of exenatide, and the glycine 2, methionine 14 and asparagine 28 positions were modified to improve enzyme stability and chemical stability based on the polypeptide backbone. Moreover, the C-terminal serine of the peptide was replaced by cysteine via site-directed mutagenesis performed with polyethylene glycol.78 The half-life of PEG-loxenatide is approximately 1 week.123

엑세나티드

엑세나티드는

GLP-1RAs라는 약물 클래스에 속하는 약물입니다.

이는 미국 남서부 지역에 서식하는 독사인

길라 몬스터의 타액에 존재하는 호르몬

엑센딘-4의 합성 버전입니다.76

엑세나티드는

39개의 아미노산으로 구성되어 있으며

인간 GLP-1과 53%의 서열 동일성을 공유합니다.

N-말단부의 두 번째 위치는 글리신(GLP-1에서는 알라닌)으로, DPP-4 효소에 의해 쉽게 분해되지 않습니다.77

GLP-1과 비교해 아미노산 서열의 C-말단부에는 9개의 추가 아미노산 잔기(PSSGAPPPS)가 포함되어 있으며, 이는 펩타이드 사슬 내분해 효소에 의해 쉽게 분해되지 않습니다; 따라서 긴 반감기와 강한 생물학적 활성을 갖습니다.78

엑세나티드의 평균 반감기는

2.4시간이며,

하루 2~3회 투여됩니다.78

리라글루티드

리라글루티드는

제2형 당뇨병(T2DM)과 비만을 치료하기 위해 사용되는 약물입니다.79,80

T2DM 치료에서 리라글루티드는

인슐린 분비를 증가시키고 간에서 포도당 생성을 감소시켜 혈당 수치를 낮춥니다.81

또한 위 배출을 늦추어 식욕을 조절하고

음식 섭취를 줄이는 데 도움을 줍니다.82,83

혈당 수치를 낮추는 것 외에도,

리라글루티드는 식욕 억제와 에너지 섭취 감소로 체중 감소를 돕습니다.84,85

그러나

관련 비용과 매일 주사 필요성은

비만 환자의 사용을 제한할 수 있습니다.86,87,88

리라글루티드는 2010년 FDA로부터 T2DM 치료용으로 Victoza라는 상표명으로 처음 승인되었습니다.83,89,90,91,92 이후 Saxenda라는 상표명으로 만성 체중 관리 등 다른 적응증에도 승인되었습니다.62 리라글루티드는 34번 위치에 아르기닌(GLP-1(7-37))이 리신으로 대체되어 있으며, 26번 위치의 리신은 글루탐산으로 연결된 16탄소 팔미트산 측쇄와 결합되어 있습니다. 리라글루타이드(Liraglutide)는 인간 GLP-1과 97%의 서열 동질성을 공유하며 GLP-1 수용체(GLP-1R)에 결합하고 활성화시킬 수 있습니다.78 리라글루타이드의 반감기는 13시간이며, 하루에 한 번 투여만 필요합니다.62

리시세나티드

리시세나티드는

사노피에서 제2형 당뇨병(T2DM) 치료를 위해 개발되었습니다.64,93

구조적으로 리시세나티드는 엑세나티드 구조를 기반으로 하지만

38번 위치에 프로린이 결여되어 있으며,

39번 위치의 세린 이후에 6개의 라이신이 연결되어 있습니다.94

이 6개의 라이신 잔기는

분자 구조의 강성을 증가시켜 약물 특성을 개선합니다.78

이러한 변화는

분자의 구조를 안정화시키고 순환계에서의 단백질 분해를 방지하며,

순환 시간을 충분히 연장시켜 하루 한 번 투여가 가능하도록 합니다(엑세나티드는 하루 두 번 또는 세 번 투여됩니다).

리시세나티드의 평균 반감기는

약 3–4시간입니다.95

리시세나티드는

단기 작용형 GLP-1 수용체 작용제(GLP-1RA)이며,96,97

하루 한 번 투여하는 리시세나티드는 환자의 복용 순응도를 일정程度上 개선하고

저혈당 발생을 줄일 수 있습니다.98,99,100

주사는 일반적으로 하루 첫 번째 식사 1시간 이내에 투여하며, 가능하면 매일 같은 시간에 투여하는 것이 좋습니다. 식사 후나 식사를 거른 경우 리시세나티드를 투여하지 않도록 주의해야 합니다. 리시세나티드의 초기 권장 용량은 14일 이상 동안 하루에 10mcg입니다. 초기 기간 후 추가적인 혈당 조절이 필요한 경우 용량을 하루에 20mcg로 증가시킬 수 있습니다. 최대 권장 용량은 하루에 20mcg입니다.101

알비글루티드

알비글루티드는

2014년 FDA에서 승인되었습니다.

GLP-1 수용체 작용제(GLP-1RA)인 알비글루티드는

인슐린 분비를 자극하고 글루카곤 생성을 감소시켜

제2형 당뇨병 환자의 혈당 조절을 개선합니다.102,103

알비글루티드는 주 1회 피하 주사로 투여되는

장기 작용형 GLP-1RA입니다.

알비글루타이드의 반감기는

약 4~7일입니다.102

인간 GLP-1(7-36)의 구조와 비교할 때, 알비글루타이드의 아미노산 서열은 8번 위치에 아르기닌(GLP-1에서는 이 잔기는 라이신)을 포함하며, 두 개의 변형된 GLP-1 펩타이드 사슬이 인간 혈청 알부민(HSA)에 융합되어 반감기를 크게 연장합니다.104,105 알비글루타이드(albiglutide)는 일반적으로 식이요법과 운동과 함께 처방됩니다. 알비글루티드의 용량은 일반적으로 주 1회 30mg입니다. 피하 주사(피부 바로 아래)로 투여됩니다. 주사 부위는 허벅지, 복부, 또는 상완부일 수 있습니다.102

FDA는 Tanzeum(알비글루티드)의 초기 승인 시 특정 환자 집단에 대한 적합성과 안전성을 고려해 여러 사용 제한을 설정했습니다.

첫째, 식이요법과 운동으로 혈당 조절이 충분하지 않은 환자에게 Tanzeum은 첫 번째 치료제로 권장되지 않습니다.49

둘째, 췌장염 병력이 있는 환자에서 안전성과 유효성이 명확하지 않으며, 이 그룹에서 연구되지 않았기 때문입니다.106

또한, Tanzeum은 약리학적 작용과 대상 질환 특성상 제1형 당뇨병이나 당뇨병성 케톤산증 치료에 적합하지 않습니다.

또한 기존 위장관 질환이 있는 환자에게는 잠재적 부작용이나 질환 악화를 방지하기 위해 권장되지 않습니다.107

Tanzeum 사용과 관련된 심각한 위험에는 췌장염, 급성 신장 손상, 신장 기능 장애, 폐렴 등이 포함되며,

이는 특정 조건이나 취약한 환자에서의 사용을 더욱 제한합니다.

이러한 제한 사항과 경고는 FDA가 약물 승인 과정에서 환자 안전을 엄격히 고려했음을 보여줍니다.108 2015년 3월, FDA는 동물에서 갑상선 C세포 종양의 위험이 관찰됨에 따라 Tanzeum에 블랙 박스 경고를 요구했습니다. 그러나 이 효과가 인간에서도 발생한다는 것은 명확하지 않습니다.108 이후 FDA는 약물 라벨에 아나필락시스 쇼크 위험에 대한 경고를 추가했습니다. 이 반응은 심각하고 생명을 위협할 수 있으며, 불안감, 저림, 현기증, 가려움, 두드러기, 부기, 호흡 곤란, 의식 상실 등의 증상을 포함합니다.81,107,109

Tanzeum은 GlaxoSmithKline (GSK)에 의해 2017년에 주로 경제적 요인으로 인해 판매가 중단되었습니다.110,111 GSK는 저가로 경쟁 우위를 확보하려 시도했지만, Tanzeum은 충분한 시장 수용을 달성하지 못했습니다.106 2017년, Tanzeum은 주요 약품 혜택 관리업체(PBM)인 Express Scripts의 선호 약품 목록에서 제외되었으며, Eli Lilly의 Trulicity로 대체되었습니다. 이는 Tanzeum의 약한 시장 존재감을 강조했습니다.106,108 또한, 이 결정은 GSK의 신임 CEO Emma Walmsley가 주도한 광범위한 전략적 개혁의 일환이었습니다.106 이 개혁은 회사의 노력을 호흡기 질환, HIV 치료, 종양학 및 면역학 등 수익 잠재력이 높은 분야로 재집중하는 것을 목표로 했습니다.108 또한 Tanzeum은 경쟁이 치열한 GLP-1RA 시장에서 의미 있는 시장 점유율을 확보하는 데 어려움을 겪었으며, 이는 GSK가 해당 약물을 전 세계적으로 철수하기로 결정한 또 다른 이유였습니다.108

둘라글루타이드

둘라글루타이드는 2014년 FDA로부터 제2형 당뇨병(T2DM) 치료제로 승인되었습니다.112 둘라글루타이드는 주 1회 투여하는 장기 작용형 GLP-1RA입니다. 인간 GLP-1(7-37)의 구조와 비교할 때, Dulaglutide의 아미노산 서열은 8번 위치에 글라이신, 22번 위치에 글루탐산, 36번 위치에 글라이신을 포함합니다.113 이후 수정된 인간 면역글로불린 G4(IgG4)의 상수 영역(Fc)에 “-(글라이신-글라이신-글라이신-글라이신-세린) 3-알라-“ 브리지로 인간 면역글로불린 G4(IgG4)의 상수 영역(Fc)에 융합되었으며, 평균 생물학적 반감기는 90시간입니다.105 두라글루타이드(Dulaglutide)는 첫 번째 대분자 GLP-1RA이며, 주 1회 투여 빈도는 환자의 복약 순응도를 크게 개선할 수 있습니다.33,78,104,114

세마글루타이드

세마글루타이드는 제2형 당뇨병 환자의 혈당 조절을 개선하기 위해 주 1회 투여되는 장기 작용형 GLP-1RA 제제입니다.115 인간 GLP-1(7-37)의 구조와 비교할 때, 세마글루타이드의 아미노산 서열은 8번 위치에 디아미노이소부티르산, 34번 위치에 아르기닌, 26번 위치에 아실화 라이신이 포함되어 있습니다.31 세마글루타이드의 알파테릭 사슬이 더 길고 친수성이 감소했지만, 단쇄 부분의 PEG 수지로 인해 친수성이 크게 향상되었습니다. DPP-4 변형체는 DPP-4의 효소 분해 부위를 가릴 뿐만 아니라 알부민과 밀접하게 결합하여 신장 배설을 감소시키고 반감기를 연장합니다.35,104,116 2022년 8월 22일, 노보 노르디스크는 이중 작용 복합체 카그리세마의 제2상 임상 시험의 주요 결과를 발표했으며, 이는 혈당 감소와 체중 감량에 효과적임을 보여주었습니다. CagriSema는 GLP-1 RA인 semaglutide와 장시간 작용형 인슐린 유사체 cagrilintide로 구성되어 있으며, 주 1회 피하 투여가 가능합니다.117

Beinaglutide

Beinaglutide는 중국에서 비만 치료를 위해 승인된 첫 번째 원개발 약물이며, 전 세계에서 세 번째로 승인된 GLP-1 계열 체중 감량 약물로, 과체중 및 비만 환자에게 새로운 치료 옵션을 제공합니다.67,118,119 Beinaglutide는 인간 GLP-1(rhGLP-1) 폴리펩타이드로, 인간 GLP-1(7-36)과 거의 100% 동질성을 보입니다. 유사성을 보입니다.120 이 혁신적인 화합물은 혈당 조절, 식욕 억제, 위 배출 지연, 체중 감소를 조절하는 데 용량 의존적 효과를 보여줍니다.121 따라서 베이나글루타이드(Beinaglutide)는 과체중/비만 및 비알코올성 지방간염(NASH) 분야 연구 진전에 중요한 잠재력을 가지고 있습니다.67,122 베이나글루타이드(Beinaglutide)는 Escherichia coli에서 발현된 자연적 인간 GLP-1(7-36)-NH2입니다. 이 제품은 제2형 당뇨병(T2DM) 치료에 승인되었으며, 반감기는 11분이며 하루 3회 투여가 필요합니다.78

Multi agonists

In recent years, the development of dual and triple agonists related to GLP-1 has been vigorously pursued.124,125,126 The design concept of these multi-agonists is to simultaneously regulate multiple key metabolic pathways to achieve more effective control over blood sugar, body weight, and overall metabolic health.43 Currently, these drugs are primarily in the development and clinical trial stages, but preliminary research results have shown their potential powerful effects in reducing blood sugar and body weight.127,128

Dual agonists

Dual agonists target both the GLP-1R and another specific receptor.124,129 A common combination is GLP-1 with GIP or insulin-like growth factor.130 For example, a popular dual agonist, tirzepatide (brand name Mounjaro), activates both GLP-1 and GIPR.124 GLP-1, by activating its receptor, increases insulin secretion and reduces glucagon secretion, thereby lowering blood sugar levels.131,132,133 Additionally, GLP-1 helps to delay gastric emptying and suppress appetite, aiding in weight management.121,134 GIP, another insulin secretion agonist, helps release insulin, particularly after eating, enhancing the effects of GLP-1 and thereby improving the overall therapeutic efficacy of the drug.125,130 In 2022, tirzepatide was approved by the FDA for the treatment of T2DM in the United States.135,136 It is considered a significant breakthrough in diabetes treatment and is also being studied for the treatment of obesity due to its significant weight loss effects.135 Tirzepatide is developed by Eli Lilly and has proven to provide superior blood sugar control and significant weight loss, making it particularly valuable in the treatment of T2DM.136,137,138 Research and clinical trials have shown that tirzepatide not only improves blood sugar levels but also has a positive impact on cardiovascular risk factors.139,140,141 Although dual agonists show advantages in efficacy, their safety and tolerability continue to be a focus of ongoing monitoring.141 Common side effects include gastrointestinal reactions, such as nausea and vomiting, which are typically more common during the initial stages of treatment.141,142 The Phase III clinical trials of tirzepatide were conducted in 77 research centers across seven countries, including the United States, Brazil, and Japan.143 The trials recruited adult participants with T2DM and significantly reduced body weight and improved blood sugar control in these patients.143 The safety profile of tirzepatide is similar to other drugs in its class, providing an effective new treatment option for patients with T2DM and obesity. Current dual agonists under investigation also include efinopegdutide and cotadutide.144,145,146,147

Triple agonist

Triple agonists go even further.148 These drugs act by simultaneously targeting three different agonists GLP-1R, the GIPR, and the GCGR.149,150,151 These receptors each have independent yet complementary roles in the treatment of diabetes and obesity.150,152,153 Activation of the GLP-1R can enhance insulin secretion, reduce glucagon secretion, delay gastric emptying,154 and suppress appetite.155,156 GIPR activation also promotes insulin release, especially after meals, helping to improve glucose utilization.157,158 Activation of the insulin or Insulin-like Growth Factor 1 (IGF-1) receptor can enhance insulin sensitivity, improve glucose absorption and utilization by cells, and potentially have positive effects on cardiovascular health and long-term energy balance.159 As of now, GLP-1-related triple agonists are primarily still in the development stage and have not been widely approved for use.159 These drugs are not yet widely available on the market but have shown some potential in clinical trials.160,161 For example, HM15211, a triple agonist developed by Hanmi Pharmaceutical in South Korea that activates GLP-1R, GIPR and GCGR has entered early clinical trials for the treatment of obesity and non-alcoholic steatohepatitis (NASH).162,163 Retatrutide (LY-3437943), a novel triple agonist developed by Eli Lilly that targets GLP-1R, GIPR and GCGR, has shown potential in preliminary clinical data for providing excellent blood sugar control and significant weight reduction.158,161,164,165 However, activating multiple receptors may lead to more complex side effects, and in some experiments, dual and triple agonists have indeed shown more severe side effects.165,166 Retatrutide has now entered Phase III clinical trials.161 The results of the Phase II clinical trials of retatrutide were published in The Lancet in 2023.161 The trials involved adult participants with T2DM aged 18 to 75, conducted across 42 research and medical centers in the United States.161 Over a period of 24 weeks, all dosage groups of retatrutide showed significant improvements in reducing glycated hemoglobin (HbA1c) and body weight compared to the placebo group, especially in the higher dosage groups. In terms of safety and tolerability, the adverse events were primarily mild to moderate gastrointestinal reactions, with no reports of severe hypoglycemia or death.161

In summary, dual and triple agonists related to GLP-1 represent significant advances in the field of diabetes treatment,167,168 demonstrating the future trend of enhancing therapeutic effects by targeting multiple biomarkers.136,169,170 With the accumulation of more clinical data and the development of new drugs, these treatment options are expected to provide more effective and comprehensive treatment choices for diabetes patients.161,167

다중 작용제

최근 몇 년간 GLP-1과 관련된 이중 및 삼중 작용제의 개발이 활발히 진행되고 있습니다.124,125,126 이러한 다중 작용제의 설계 개념은 혈당, 체중, 전체 대사 건강을 더 효과적으로 조절하기 위해 여러 주요 대사 경로를 동시에 조절하는 것입니다.43 현재 이러한 약물은 주로 개발 및 임상 시험 단계에 있지만, 초기 연구 결과는 혈당 및 체중 감소에 대한 강력한 효과를 보여주고 있습니다.127,128

이중 작용제

이중 작용제는

GLP-1R과 다른 특정 수용체를 동시에 표적화합니다.124,129

일반적인 조합은

GLP-1과 GIP 또는 인슐린 유사 성장 인자입니다.130

예를 들어, 인기 있는 이중 작용제인 티르제파티드(상표명 Mounjaro)는 GLP-1과 GIPR을 모두 활성화합니다.124 GLP-1은 수용체를 활성화하여 인슐린 분비를 증가시키고 글루카곤 분비를 감소시켜 혈당 수치를 낮춥니다.131,132,133 또한, GLP-1은 위 배출을 지연시키고 식욕을 억제하여 체중 관리에 도움을 줍니다.121,134 GIP는 또 다른 인슐린 분비 작용제로, 특히 식사 후 인슐린 분비를 촉진하여 GLP-1의 효과를 강화하고 약물의 전체적인 치료 효과를 향상시킵니다.125,130 2022년, 티르제파티드는 미국에서 제2형 당뇨병 치료제로 FDA 승인을 받았습니다.135,136 이는 당뇨병 치료 분야의 중요한 혁신으로 평가되며, 상당한 체중 감량 효과로 인해 비만 치료에도 연구되고 있습니다.135 티르제파티드는 엘리 릴리에서 개발되었으며, 우수한 혈당 조절과 상당한 체중 감소를 입증해 T2DM 치료에 특히 유용합니다.136,137,138 연구 및 임상 시험 결과, 티르제파티드는 혈당 수치를 개선할 뿐만 아니라 심혈관 위험 요인에 긍정적인 영향을 미치는 것으로 나타났습니다.139,140,141 이중 작용제는 효능 측면에서 우위를 보이지만, 안전성과 내약성은 지속적인 모니터링의 대상이 되고 있습니다.141 일반적인 부작용으로는 메스꺼움과 구토와 같은 위장관 반응이 있으며, 이는 치료 초기 단계에서 더 자주 발생합니다.141,142 티르제파티드의 제3상 임상 시험은 미국, 브라질, 일본을 포함한 7개국 77개 연구 센터에서 진행되었습니다.143 이 시험은 제2형 당뇨병을 가진 성인 참가자를 대상으로 진행되었으며, 이 환자들에서 체중을 유의미하게 감소시키고 혈당 조절을 개선했습니다.143 티르제파티드의 안전성 프로파일은 같은 약물군과 유사하며, 제2형 당뇨병과 비만을 가진 환자에게 효과적인 새로운 치료 옵션을 제공합니다. 현재 연구 중인 이중 작용제에는 에피노페그두티드와 코타두티드가 포함됩니다.144,145,146,147

삼중 작용제

삼중 작용제는

한 걸음 더 나아갑니다.148

이 약물은

GLP-1R, GIPR, GCGR을 동시에 표적화합니다.149,150,151

이 수용체들은 당뇨병 및 비만 치료에서 독립적이면서도 보완적인 역할을 합니다.150,152,153

GLP-1R 활성화는

인슐린 분비를 증가시키고, 글루카곤 분비를 감소시키며, 위 배출을 지연시키고,154 식욕을 억제합니다.155,156

GIPR 활성화는 특히 식사 후 인슐린 분비를 촉진하여 포도당 이용을 개선합니다.157,158

인슐린 또는 인슐린 유사 성장 인자 1(IGF-1) 수용체의 활성화는

인슐린 감수성을 향상시키고

세포의 포도당 흡수 및 이용을 개선하며,

심혈관 건강과 장기적인 에너지 균형에 긍정적인 영향을 미칠 수 있습니다.159

현재, GLP-1 관련 삼중 작용제는

주로 개발 단계에 있으며 아직 널리 승인되지 않았습니다.159

이러한 약물은 아직 시중에 널리 공급되지 않았지만 임상 시험에서 일부 잠재력을 보여주었습니다.160,161 예를 들어, 한국 한미제약에서 개발한 GLP-1R을 활성화하는 삼중 작용제 HM15211은 GIPR 및 GCGR을 활성화하는 HM15211은 비만 및 비알코올성 지방간염(NASH) 치료를 위한 초기 임상 시험에 진입했습니다.162,163 Eli Lilly가 개발한 새로운 삼중 작용제 Retatrutide (LY-3437943)는 GLP-1R, GIPR 및 GCGR을 표적으로 하며, 초기 임상 데이터에서 우수한 혈당 조절과 유의미한 체중 감소를 보여 잠재력을 입증했습니다.158,161,164,165 그러나 다중 수용체를 활성화하는 것은 더 복잡한 부작용을 유발할 수 있으며, 일부 실험에서 이중 및 삼중 작용제는 실제로 더 심각한 부작용을 보였습니다.165,166 레타트루티드는 현재 제3상 임상 시험에 진입했습니다.161 레타트루티드의 제2상 임상 시험 결과는 2023년 《더 랜싯》에 게재되었습니다.161 이 임상 시험은 18세에서 75세 사이의 제2형 당뇨병(T2DM) 환자를 대상으로 미국 내 42개 연구 및 의료 기관에서 진행되었습니다.161 24주 동안 모든 용량 그룹의 레타트루티드는 위약 그룹에 비해 당화혈색소(HbA1c)와 체중 감소에서 유의미한 개선을 보였으며, 특히 고용량 그룹에서 더 두드러졌습니다. 안전성과 내약성 측면에서 부작용은 주로 경증에서 중등도의 위장관 반응이었으며, 심각한 저혈당이나 사망 사례는 보고되지 않았습니다.161

요약하면, GLP-1 관련 이중 및 삼중 작용제는 당뇨병 치료 분야에서 중요한 진전을 보여주고 있으며,167,168 다중 생물표지자를 표적으로 삼아 치료 효과를 향상시키는 미래 트렌드를 입증하고 있습니다.136,169,170 임상 데이터의 축적과 신규 약물의 개발을 통해 이러한 치료 옵션은 당뇨병 환자에게 더 효과적이고 포괄적인 치료 선택지를 제공할 것으로 기대됩니다.161,167

Small molecule GLP-1RAs

Currently, most GLP-1RAs are based on proteins or peptides, meaning they are large molecules typically administered via injection.37 Small molecule GLP-1RAs are chemically synthesized, and compared to protein-based drugs, they generally have smaller molecular sizes.171 The development of small molecule GLP-1RAs aims to overcome some of the limitations of traditional protein or peptide-based GLP-1RAs, such as the need for injection. Small molecule drugs may offer the possibility of oral administration, which is more convenient and acceptable for patients.171 Additionally, small molecule drugs may have better tissue permeability, longer half-lives in the body, and lower production costs. As of now, research on small molecule GLP-1RAs is still mainly in the laboratory and early clinical trial stages.172 The challenges in developing these drugs include ensuring that they can effectively mimic the biological activity of large molecule GLP-1RAs while maintaining efficacy and selectivity. This review article will introduce some of the small molecule drugs that are currently receiving significant attention:

Orforglipron

Orforglipron is an oral small molecule GLP-1RA developed jointly by Eli Lilly and Chia Tai Tianqing Pharmaceutical Group.173 Its research findings were recently presented orally at the 83rd Scientific Sessions of the American Diabetes Association and published in the New England Journal of Medicine. In a 26-week study, orforglipron demonstrated a significant dose-dependent effect on weight loss, with weight reduction ranging from 8.6% to 12.6% across various dosages, compared to only 2.0% in the placebo group. By week 36, this weight loss effect was even more pronounced, increasing from 9.4% to 14.7%, while the placebo group saw a reduction of only 2.3%. Additionally, in another Phase II study targeting patients with T2DM, orforglipron also showed significant effects in reducing A1C and weight, achieving the study’s primary and secondary endpoints. In this study, participants taking orforglipron experienced an average A1C reduction of 2.1% and an average weight loss of 10.1 kilograms at 26 weeks, which was significantly greater than those in the placebo and dulaglutide groups. Between 65% and 96% of participants taking orforglipron achieved an A1C level below 7.0% at 26 weeks.174 Currently, Eli Lilly has initiated a Phase III development program to further investigate the efficacy and safety of orforglipron in treating obesity, overweight, and T2DM.

Danuglipron

Danuglipron is an oral GLP-1RA developed by Pfizer. In May 2023, Pfizer released the results of a Phase 2b clinical trial of the drug. The study involved 411 adult patients with T2DM and was designed as a randomized, double-blind, placebo-controlled trial where patients received varying doses of danuglipron or a placebo. The results showed that during the 16-week treatment period, patients who received the highest dosage (120 mg twice daily) of danuglipron experienced an average reduction in HbA1c of 1.16 percentage points and a weight loss of 4.17 kilograms. All dosages of danuglipron significantly reduced patients’ HbA1c and fasting blood glucose levels, with more pronounced weight loss effects observed in the 80 mg and 120 mg doses compared to the placebo group. Common adverse reactions included nausea, diarrhea, and vomiting.172

GSBR-1290

GSBR-1290 is an oral small molecule GLP-1RA developed by Structure Therapeutics, aimed at treating T2DM and obesity. On December 18, 2023, Structure Therapeutics published the latest clinical data for GSBR-1290 on its official website.175 Currently, GSBR-1290 is undergoing a 12-week Phase 2a randomized, double-blind, placebo-controlled clinical trial to assess its effectiveness in treating patients with T2DM and obesity. To date, the trial has enrolled 94 participants, with 54 in the T2DM group and 40 in the obesity group. Regarding safety, the majority of reported adverse events were mild to moderate, ranging from 88% to 96%, depending on the specific study group. Among the 60 participants treated with GSBR-1290, only one (2.8%, from the T2DM group) discontinued the study due to drug-related adverse events (AEs). As for clinical outcomes, in the T2DM group, there was a significant reduction in HbA1c (decreased by 1.01% to 1.02%, placebo-adjusted) and a clinically meaningful decrease in body weight of 3.26% to 3.51% after 12 weeks of treatment. In the obesity group, there was a significant and clinically meaningful reduction in body weight of 4.74% at week 8, with weight continuously decreasing during the 8-week treatment period.175

Classical pathophysiological mechanisms of GLP-1

GLP-1 signaling pathway

GLP-1 initiates signaling by binding to its receptor, GLP-1R, which is a G-protein-coupled receptor.176,177 When GLP-1 binds to GLP-1R, it triggers the activation of G-proteins, leading to an increase in the intracellular second messenger cAMP.34,39,177 The rise in cAMP activates protein kinase A (PKA), which then promotes the synthesis and secretion of insulin and inhibits the release of glucagon.178,179 Additionally, cAMP can activate Rap1 through EPAC (Exchange Protein directly Activated by cAMP),180,181,182 which is involved in regulating insulin secretion.180,181,183 GLP-1 also activates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, which is crucial for maintaining the survival and function of pancreatic β-cells.184,185,186,187

소분자 GLP-1 수용체 작용제 (GLP-1RAs)

현재 대부분의 GLP-1RAs는 단백질이나 펩타이드를 기반으로 하며, 이는 일반적으로 주사 투여가 필요한 큰 분자입니다.37 소분자 GLP-1RAs는 화학적으로 합성되며, 단백질 기반 약물과 비교해 일반적으로 분자 크기가 더 작습니다.171 소분자 GLP-1RAs의 개발은 전통적인 단백질 또는 펩타이드 기반 GLP-1RAs의 한계, 예를 들어 주사 투여의 필요성 등을 극복하기 위해 진행되고 있습니다. 소분자 약물은 경구 투여의 가능성을 제공할 수 있으며, 이는 환자들에게 더 편리하고 수용하기 쉬운 방법입니다.171 또한 소분자 약물은 조직 투과성이 우수하고 체내 반감기가 길며 생산 비용이 낮을 수 있습니다. 현재 소분자 GLP-1RA에 대한 연구는 주로 실험실 단계와 초기 임상 시험 단계에 머물러 있습니다.172 이러한 약물을 개발하는 데 직면한 도전 과제에는 대형 분자 GLP-1RA의 생물학적 활성을 효과적으로 모방하면서 효능과 선택성을 유지하는 것이 포함됩니다. 이 리뷰 논문에서는 현재 주목받고 있는 일부 소분자 약물을 소개합니다:

Orforglipron

Orforglipron은 Eli Lilly와 Chia Tai Tianqing Pharmaceutical Group이 공동 개발한 경구용 소분자 GLP-1RA입니다.173 이 약물의 연구 결과는 최근 미국 당뇨병 협회 제83차 과학 세션에서 구두로 발표되었으며, New England Journal of Medicine에 게재되었습니다. 26주 연구에서 오르포르글리프론은 용량 의존적 체중 감소 효과를 보여주었으며, 다양한 용량에서 체중 감소율이 8.6%에서 12.6%에 달했습니다. 반면 위약 그룹에서는 2.0%의 감소에 그쳤습니다. 36주 후에는 이 체중 감소 효과가 더욱 두드러져 9.4%에서 14.7%로 증가했으며, 위약 그룹은 2.3% 감소에 그쳤습니다. 또한 제2형 당뇨병 환자를 대상으로 한 다른 제2상 연구에서 오르포르글리폰은 A1C 및 체중 감소에 유의미한 효과를 보여주며 연구의 주요 및 부차적 목표를 달성했습니다. 이 연구에서 오르포르글리폰을 복용한 참가자는 26주 후 평균 A1C 감소율 2.1%와 평균 체중 감소 10.1kg을 기록했으며, 이는 위약군 및 두라글루타이드군보다 유의미하게 높았습니다. 오르포글리폰을 복용한 참가자의 65%에서 96%가 26주 시점에서 A1C 수치 7.0% 미만을 달성했습니다.174 현재 엘리 릴리는 오르포글리폰의 비만, 과체중, T2DM 치료 효과 및 안전성을 추가로 평가하기 위해 제3상 개발 프로그램을 시작했습니다.

다누글리폰

다누글리폰은 화이자가 개발한 경구용 GLP-1 수용체 작용제입니다. 2023년 5월, 화이자는 이 약물의 Phase 2b 임상 시험 결과를 발표했습니다. 이 연구는 제2형 당뇨병을 가진 411명의 성인 환자를 대상으로 한 무작위, 이중 맹검, 위약 대조 임상 시험으로, 환자들은 다누글리폰 또는 위약을 다양한 용량으로 투여받았습니다. 결과에 따르면, 16주 치료 기간 동안 가장 높은 용량(120mg 하루 두 번)의 다누글리프론을 투여받은 환자들은 평균적으로 HbA1c가 1.16% 포인트 감소했으며, 체중은 4.17kg 감소했습니다. 다누글리프론의 모든 용량은 환자의 HbA1c 및 공복 혈당 수치를 유의미하게 감소시켰으며, 80mg 및 120mg 용량에서 위약군에 비해 체중 감소 효과가 더 두드러졌습니다. 일반적인 부작용으로는 메스꺼움, 설사, 구토가 보고되었습니다.172

GSBR-1290

GSBR-1290은 Structure Therapeutics가 개발한 경구용 소분자 GLP-1 수용체 작용제로, 제2형 당뇨병(T2DM) 및 비만 치료를 목표로 합니다. 2023년 12월 18일, Structure Therapeutics는 공식 웹사이트를 통해 GSBR-1290의 최신 임상 데이터를 공개했습니다.175 현재 GSBR-1290은 제2형 당뇨병 및 비만 환자의 치료 효과를 평가하기 위한 12주간의 제2상 무작위 이중 맹검 위약 대조 임상 시험을 진행 중입니다. 현재까지 이 임상 시험에는 94명의 참가자가 등록되었으며, 이 중 54명은 T2DM 그룹, 40명은 비만 그룹에 속합니다. 안전성 측면에서 보고된 부작용의 대부분은 경증에서 중등도였으며, 특정 연구 그룹에 따라 88%에서 96% 사이였습니다. GSBR-1290을 투여받은 60명의 참가자 중 1명(2.8%, T2DM 그룹)만이 약물 관련 부작용(AEs)으로 인해 연구를 중단했습니다. 임상 결과 측면에서, T2DM 그룹에서는 12주 치료 후 HbA1c가 유의미하게 감소했으며(플라시보 조정 후 1.01%에서 1.02% 감소) 체중도 3.26%에서 3.51% 감소하는 임상적으로 의미 있는 감소를 보였습니다. 비만 그룹에서는 8주 후 체중이 4.74% 유의미하게 감소했으며, 8주 치료 기간 동안 체중이 지속적으로 감소했습니다.175

GLP-1의 고전적인 병리생리학적 메커니즘

GLP-1 신호 전달 경로

GLP-1은 G-단백질 결합 수용체인 GLP-1R에 결합하여 신호 전달을 시작합니다.176,177 GLP-1이 GLP-1R에 결합하면 G-단백질의 활성화가 유발되어 세포 내 제2 신호 전달물질인 cAMP의 농도가 증가합니다.34,39,177 cAMP의 증가로 단백질 키나제 A (PKA)를 활성화하며, 이는 인슐린의 합성과 분비를 촉진하고 글루카곤의 분비를 억제합니다.178,179 또한 cAMP는 EPAC (cAMP에 의해 직접 활성화되는 교환 단백질)을 통해 Rap1을 활성화하며, 이는 인슐린 분비 조절에 관여합니다.180,181,183 GLP-1은 또한 췌장 β-세포의 생존과 기능을 유지하는 데 중요한 역할을 하는 인산인오시타이드 3-키나제(PI3K)/단백질 키나제 B(Akt) 경로를 활성화합니다.184,185,186,187

Interactions with other pathways

GLP-1 not only promotes the release of insulin but also enhances the response of pancreatic β-cells to insulin through the PI3K/Akt pathway, thereby improving insulin signal transduction and increasing the sensitivity of peripheral tissues to insulin.1,188 GLP-1 reduces hepatic glucose production, partly by inhibiting the expression‎ and activity of key gluconeogenic enzymes.189,190,191 Activation of GLP-1R leads to the production of cAMP (cyclic Adenosine Monophosphate), which is achieved by activating Adenylyl Cyclase (AC).191,192 Following the activation of GLP-1R, the βγ subunits of GPCRs can directly activate Class I PI3Ks.1 These PI3Ks typically include the PI3Kα and PI3Kβ isoforms, which are composed of regulatory subunits containing SH2 domains and catalytic subunits.193 These subunits can directly interact with the activated GPCR or do so via intermediary proteins such as insulin receptor substrate.194,195 The activated PI3K catalyzes the conversion of membrane phospholipid Phosphatidylinositol-4,5-bisphosphate (PIP2) into Phosphatidylinositol-3,4,5-trisphosphate (PIP3).196 The generation of PIP3 is a crucial step for the activation of Akt, as PIP3 provides a membrane docking site for Akt, facilitating its translocation to the cell membrane.197 Akt, also known as Protein Kinase B (PKB), once positioned at the membrane, can be phosphorylated by PIP3-dependent kinase 1 (PDK1) and possibly PDK2 (such as mTORC2).196,197,198 The phosphorylation of Akt is necessary for its full activation, allowing it to regulate a variety of downstream effector proteins involved in cell survival, proliferation, metabolism, and glucose transport.199 Activated Akt promotes the expression‎ and translocation of GLUT4 (Glucose Transporter Type 4) to the cell membrane, increasing cellular glucose uptake.200,201,202 Simultaneously, Akt promotes cell survival by phosphorylating and inhibiting a series of pro-apoptotic proteins, such as Bad and the FOXO family.202,203,204 Moreover, Akt can activate mTORC1, further promoting cell growth and protein synthesis. Through these molecular mechanisms, GLP-1 not only plays a crucial role in the treatment of diabetes by enhancing the function and protecting pancreatic β-cells from apoptosis, but it may also offer potential therapeutic benefits in fields such as cardiovascular and neural protection.198,205,206 GLP-1 can also enhance the uptake and utilization of glucose in muscle and adipose tissues.207,208,209 And GLP-1’s action in the brain reduces appetite and may influence energy expenditure.176,210,211 These effects involve interactions with other satiety and hunger signals, such as PYY, CCK, insulin, and leptin.212,213

다른 경로와의 상호작용

GLP-1은 인슐린 분비를 촉진할 뿐만 아니라 PI3K/Akt 경로를 통해 췌장 β-세포의 인슐린 반응을 강화하여 인슐린 신호 전달을 개선하고 말초 조직의 인슐린 감수성을 증가시킵니다.1,188 GLP-1은 주요 글루코네오겐시스 효소의 발현과 활성을 억제함으로써 간 글루코스 생성을 감소시킵니다.189,190,191 GLP-1R의 활성화는 아데닐릴 사이클레이즈(AC)를 활성화하여 cAMP(사이클릭 아데노신 모노포스페이트)의 생성을 유도합니다.191,192 GLP-1R 활성화 후, GPCR의 βγ 서브유닛은 Class I PI3Ks를 직접 활성화합니다.1 이 PI3Ks는 일반적으로 SH2 도메인을 포함한 조절 서브유닛과 촉매 서브유닛으로 구성된 PI3Kα 및 PI3Kβ 이소형으로 구성됩니다.193 이 서브유닛은 활성화된 GPCR과 직접 상호작용하거나 인슐린 수용체 서브스트레이트와 같은 중간 단백질을 통해 상호작용할 수 있습니다.194,195 활성화된 PI3K는 막 인산지질인 포스파티딜인오실-4,5-비스포스페이트(PIP2)를 포스파티딜인오실-3,4,5-트리스포스페이트(PIP3)로 전환하는 반응을 촉매합니다.196 PIP3의 생성은 Akt 활성화의 중요한 단계입니다. PIP3는 Akt의 막 결합 부위를 제공하여 그 이동을 촉진합니다.197 Akt(Protein Kinase B, PKB)는 막에 위치하면 PIP3 의존성 키나제 1(PDK1) 및 가능성 있는 PDK2(예: mTORC2)에 의해 인산화됩니다.196,197,198 Akt의 인산화는 그 완전한 활성화에 필수적이며, 이는 세포 생존, 증식, 대사, 포도당 운반 등에 관여하는 다양한 하류 효과 단백질을 조절합니다.199 활성화된 Akt는 GLUT4(포도당 운반체 유형 4)의 발현과 세포막으로의 이동을 촉진하여 세포 내 포도당 흡수를 증가시킵니다.200,201,202 동시에, Akt는 Bad 및 FOXO 가족과 같은 프로아포토시스 단백질을 인산화하고 억제함으로써 세포 생존을 촉진합니다.202,203,204 또한 Akt는 mTORC1을 활성화하여 세포 성장과 단백질 합성을 더욱 촉진합니다. 이러한 분자적 메커니즘을 통해 GLP-1은 췌장 β-세포의 기능 강화와 세포 사멸로부터의 보호를 통해 당뇨병 치료에 중요한 역할을 할 뿐만 아니라, 심혈관 및 신경 보호 분야에서도 잠재적인 치료적 혜택을 제공할 수 있습니다.198,205,206 GLP-1은 근육과 지방 조직에서의 포도당 흡수 및 이용을 향상시킬 수 있습니다.207,208,209 또한 GLP-1의 뇌 내 작용은 식욕을 감소시키고 에너지 소비에 영향을 미칠 수 있습니다.176,210,211 이러한 효과는 PYY, CCK, 인슐린, 레プチ민과 같은 다른 포만감 및 배고픔 신호와 상호작용합니다.212,213

The pathophysiological mechanism of GLP-1 in metabolic diseases

GLP-1 plays a crucial role in the pathophysiology of metabolic diseases, particularly in T2DM and obesity.213,214,215

Role of GLP-1 in T2DM

GLP-1 significantly influences the functionality of pancreatic β-cells and α-cells, contributing to its therapeutic effect on T2DM.132,216,217 As a vital incretin hormone, GLP-1 enhances glucose-dependent insulin secretion.3 It also promotes proliferation and reduces apoptosis of pancreatic β-cells, thereby maintaining their quality and functionality.130,218 At the molecular level, GLP-1 activates the cAMP response element-binding protein (CREB) via its receptor (GLP-1R), a transcription factor crucial for expressing the insulin gene.3,130,219 GLP-1 also activates PKA and EPAC through a cAMP-dependent pathway.1,220 PKA, a key enzyme, phosphorylates various target proteins, affecting their activity and function, which in turn promotes insulin synthesis and secretion.178,180 The PI3K/Akt signaling pathway, activated by GLP-1, plays a vital role in maintaining pancreatic β-cell survival and promoting their proliferation.221,222 Activation of Akt stimulates β-cell proliferation, reduces apoptosis, and enhances insulin secretion by regulating downstream effector molecules like Forkhead box protein O1 (FoxO1) and the glucose transporter type 2 (GLUT2).223,224

GLP-1 also inhibits glucagon release from α-cells, which is beneficial for reducing blood glucose levels since glucagon promotes hepatic gluconeogenesis.131,225 GLP-1’s action on α-cells regulates glucagon release.131 The direct impact of GLP-1 on these cells slows the secretion of glucagon, essential for maintaining glucose stability, especially postprandially.131,226 When GLP-1 binds to its receptor on α-cells, it activates intracellular cAMP production.227 In α-cells, increased cAMP affects glucagon synthesis and release.228 PKA, activated by cAMP, can regulate the activity of K-ATP channels in α-cells.228,229 The opening of these channels is controlled by the intracellular ATP/ADP ratio.229 Specifically, PKA modifies the open state of K-ATP channels through phosphorylation, affecting the cell membrane’s potential and intracellular calcium ion concentration.230,231 By modulating the activity of K-ATP channels, GLP-1 indirectly controls the calcium signaling in α-cells, thereby influencing glucagon secretion.232,233 GLP-1 inhibits the release of glucagon from α-cells through multiple mechanisms. GLP-1 can directly bind to the receptors on the surface of α-cells in the pancreas, inhibiting the secretion of glucagon from these cells.234,235 Glucagon is a hormone secreted by pancreatic α-cells that stimulates the liver to release glucose. Therefore, inhibiting the release of glucagon is crucial when blood glucose levels need to be lowered. GLP-1 can stimulate pancreatic β-cells to release insulin.236,237 Insulin not only directly lowers blood glucose levels but also further inhibits glucagon secretion from α-cells through a feedback mechanism.238 The high concentration of insulin in the local pancreatic environment creates a negative feedback effect, reducing the amount of glucagon secreted by α-cells.234 Additionally, GLP-1 can reduce blood glucose production by delaying gastric emptying and decreasing appetite, which also contributes to overall blood glucose control.239,240 In summary, GLP-1 lowers blood glucose levels and inhibits glucagon secretion through direct action on α-cells, promotion of insulin secretion, and regulation of gastrointestinal activity.241

GLP-1R is expressed not only on β-cells and α-cells but also on δ-cells in the pancreatic islets.242 δ-cells primarily secrete somatostatin, which is an important regulatory hormone.242 The expression‎ of GLP-1R on δ-cells helps to inhibit the secretion of glucagon.242 When GLP-1 binds to GLP-1R on δ-cells, it activates these cells and promotes the secretion of somatostatin.243 Somatostatin is a potent inhibitory hormone that affects the surrounding α-cells and β-cells. It acts directly on neighboring α-cells to inhibit the secretion of glucagon and can also indirectly influence α-cells by inhibiting the secretion of other hormones.243 In the local islet environment, a high concentration of somatostatin creates an inhibitory milieu, further reducing the activity of α-cells and the secretion of glucagon.244 Additionally, somatostatin can inhibit gastrointestinal activity, reducing the secretion of pancreatic enzymes and gastric acid, thereby indirectly decreasing the demand for glucagon.245,246 Hence, GLP-1 activates δ-cells and promotes somatostatin secretion, forming a multi-layered inhibitory mechanism that effectively reduces glucagon secretion.

The relative expression‎ levels of GLP-1R on α-cells and δ-cells exhibit certain differences. These variations significantly influence the role of GLP-1 in regulating islet function and glucose homeostasis.131 Research indicates that the expression‎ level of GLP-1R on α-cells is relatively low.131 Although GLP-1Rs are present, they are limited in number, making the direct inhibitory effect of GLP-1 on α-cells relatively weak.247 The primary action often occurs through indirect mechanisms, such as insulin and somatostatin.244 Conversely, the expression‎ level of GLP-1R on δ-cells is relatively high.248 GLP-1 can effectively bind to receptors on δ-cells, stimulating the secretion of somatostatin.248 As a broad-spectrum inhibitory hormone, somatostatin can effectively inhibit glucagon secretion from α-cells and insulin secretion from β-cells.249,250 Relevant studies suggest that the expression‎ of GLP-1R on δ-cells is crucial for GLP-1’s regulation of somatostatin secretion and the overall inhibitory effect on glucagon.248,251,252 This mechanism is particularly evident in the use of GLP-1-based drugs, such as GLP-1RAs, in the treatment of T2DM. In summary, the relatively higher expression‎ of GLP-1R on δ-cells allows GLP-1 to indirectly inhibit glucagon secretion by promoting somatostatin secretion. In contrast, the lower expression‎ of GLP-1R on α-cells results in a limited direct effect. Although these three types of cells each have distinct functions, it is more important to note that the somatostatin, glucagon, and insulin they secrete work together through mutual regulation and feedback mechanisms to maintain blood glucose balance and overall metabolic homeostasis.253,254

GLP-1 usually refers to GLP-1(7-36), a peptide chain consisting of 36 amino acids and the primary active molecule.255 GLP-1(7-36) stimulates the release of paracrine glucagon inhibitory factors by activating GLP-1R on β-cells and δ-cells.241 DPP-4 cleaves GLP-1(7-36) at the 8th position, generating GLP-1(9–36). GLP-1(9–36) is the product of GLP-1(7-36) degradation by DPP-4, and this process rapidly reduces the activity of GLP-1(7-36).35,256,257 Traditionally, GLP-1(9–36) was considered a metabolically inactive product of GLP-1, losing its primary function of regulating blood sugar.258 However, increasing research suggests that GLP-1(9–36) may have other physiological roles. Recent studies show that GLP-1(9–36) can activate the inhibitory G protein (Gi/o), leading to the translocation of secretory granules (SG) beneath the cell membrane, thereby inhibiting glucagon secretion.241 This mechanism is unaffected by genetic or pharmaceutical inhibition of GLP-1R, but it is sensitive to pertussis toxin. As exendin-4 is more resistant to DPP-4-induced degradation, this mechanism is not activated by exendin-4.241 GLP-1(9–36) can directly act on pancreatic α-cells to inhibit the secretion of glucagon. Recent studies have shown that GLP-1(9–36) is particularly effective at low glucose concentrations, with its inhibitory effect being similar to that of GLP-1(7-36).241 GLP-1(9–36) retains its ability to inhibit glucagon secretion even after GLP-1R inactivation, suggesting that its mechanism of action may not be entirely dependent on the GLP-1R.241 GLP-1(9–36) promotes the undocking of secretory granules (SG) by inhibiting the entry of Ca2+ through voltage-gated Ca2+ channels. As a result, GLP-1(9–36) reduces the number of granules available for exocytosis in α-cells, thereby decreasing the release of glucagon.241 This mechanism decreases intracellular Ca2+ concentration, thereby inhibiting glucagon secretion.241 Additionally, GLP-1(9–36) can effectively inhibit glucagon secretion induced by β-adrenergic stimulation, amino acids, and membrane depolarization, indicating its inhibitory effect under various stimulatory conditions.241 In α-cells of patients with T2DM, the ability of GLP-1(9–36) to inhibit glucagon secretion is lost. This may be due to altered α-cell function in diabetic patients, which impairs the efficacy of GLP-1(9–36).241 In vivo experiments have shown that high concentrations of exogenous GLP-1(9–36) can lower circulating glucagon levels during insulin-induced hypoglycemia. However, this effect is significantly diminished or absent in diabetes.241 As a degradation product of GLP-1(7-36), GLP-1(9–36) has a notable inhibitory effect on glucagon secretion, demonstrated in both in vitro and in vivo studies. However, this inhibitory effect is significantly weakened in patients with T2DM, indicating that its potential application in diabetes treatment requires further investigation.241 Through this series of complex molecular and cellular mechanisms, GLP-1 plays a vital role in the physiological and pathological processes of metabolic diseases like T2DM.232,233,241,259 (Fig. 2).

GLP-1의 대사 질환에서의 병리생리학적 메커니즘

GLP-1은 대사 질환, 특히 제2형 당뇨병(T2DM)과 비만의 병리생리학에서 중요한 역할을 합니다.213,214,215

GLP-1의 T2DM에서의 역할

GLP-1은 췌장 β-세포와 α-세포의 기능에 크게 영향을 미쳐 T2DM에 대한 치료 효과를 발휘합니다.132,216,217 중요한 인크레틴 호르몬으로서 GLP-1은 포도당 의존성 인슐린 분비를 촉진합니다.3 또한 췌장 β-세포의 증식을 촉진하고 세포 사멸을 감소시켜 그 품질과 기능을 유지합니다.130,218 분자 수준에서 GLP-1은 수용체(GLP-1R)를 통해 인슐린 유전자 발현에 필수적인 전사 인자 cAMP 반응 요소 결합 단백질(CREB)을 활성화합니다.3,130,219 GLP-1은 cAMP 의존적 경로를 통해 PKA와 EPAC을 활성화합니다.1,220 PKA는 주요 효소로, 다양한 표적 단백질을 인산화하여 그 활성과 기능을 조절하며, 이는 인슐린 합성과 분비를 촉진합니다.178,180 PI3K/GLP-1에 의해 활성화되는 Akt 신호전달 경로는 췌장 β-세포의 생존 유지와 증식을 촉진하는 데 중요한 역할을 합니다.221,222 Akt의 활성화는 Forkhead box 단백질 O1 (FoxO1)과 글루코스 운반체 유형 2 (GLUT2)와 같은 하류 효과 분자를 조절하여 β-세포 증식을 자극하고 세포 사멸을 감소시키며 인슐린 분비를 증가시킵니다.223,224

GLP-1은 α-세포에서 글루카곤 분비를 억제하며, 이는 글루카곤이 간 글루코네오게네시스를 촉진하기 때문에 혈당 수치를 낮추는 데 유익합니다.131,225 GLP-1의 α-세포에 대한 작용은 글루카곤 분비를 조절합니다.131 GLP-1의 이 세포에 대한 직접적인 영향은 글루카곤 분비를 늦추며, 이는 특히 식후 혈당 안정성을 유지하는 데 필수적입니다.131,226 GLP-1이 α-세포의 수용체에 결합하면 세포 내 cAMP 생성을 활성화합니다.227 α-세포에서 증가한 cAMP는 글루카곤 합성과 분비에 영향을 미칩니다.228 cAMP에 의해 활성화된 PKA는 α-세포의 K-ATP 채널 활성을 조절할 수 있습니다.228,229 이 채널의 개방은 세포 내 ATP/ADP 비율에 의해 조절됩니다.229 구체적으로, PKA는 인산화 과정을 통해 K-ATP 채널의 개방 상태를 조절하여 세포막의 전위와 세포 내 칼슘 이온 농도에 영향을 미칩니다.230,231 K-ATP 채널의 활성을 조절함으로써 GLP-1은 α-세포의 칼슘 신호전달을 간접적으로 조절하여 글루카곤 분비에 영향을 미칩니다.232,233 GLP-1은 다양한 메커니즘을 통해 α-세포에서 글루카곤의 분비를 억제합니다. GLP-1은 췌장의 α-세포 표면에 있는 수용체에 직접 결합하여 이 세포로부터 글루카곤 분비를 억제합니다.234,235 글루카곤은 췌장의 α-세포에서 분비되는 호르몬으로 간에 포도당 방출을 자극합니다. 따라서 혈당 수치를 낮추기 위해서는 글루카곤 분비를 억제하는 것이 중요합니다. GLP-1은 췌장의 β-세포를 자극하여 인슐린 분비를 촉진합니다.236,237 인슐린은 혈당 수치를 직접 낮추는 것 외에도 피드백 메커니즘을 통해 α-세포에서 글루카곤 분비를 추가로 억제합니다.238 췌장 내부의 높은 인슐린 농도는 음의 피드백 효과를 생성하여 α-세포에서 분비되는 글루카곤의 양을 감소시킵니다.234 또한, GLP-1은 위 배출 지연과 식욕 감소를 통해 혈당 생성을 감소시켜 전체적인 혈당 조절에 기여합니다.239,240 요약하면, GLP-1은 α-세포에 대한 직접 작용, 인슐린 분비 촉진, 위장관 활동 조절을 통해 혈당 수치를 낮추고 글루카곤 분비를 억제합니다.241

GLP-1R은 췌장 소도체에 있는 β-세포와 α-세포뿐만 아니라 δ-세포에도 발현됩니다.242 δ-세포는 주로 소마토스타틴을 분비하며, 이는 중요한 조절 호르몬입니다.242 δ-세포에 발현된 GLP-1R은 글루카곤 분비를 억제하는 데 도움을 줍니다.242 GLP-1이 δ-세포의 GLP-1R에 결합하면 이 세포를 활성화시켜 소마토스타틴 분비를 촉진합니다.243 소마토스타틴은 주변 α-세포와 β-세포에 영향을 미치는 강력한 억제 호르몬입니다. 이 호르몬은 인접한 α-세포에 직접 작용하여 글루카곤 분비를 억제하며, 다른 호르몬의 분비를 억제함으로써 α-세포에 간접적으로 영향을 미칠 수 있습니다.243 췌장 섬의 국소 환경에서 소마토스타틴의 고농도는 억제 환경을 조성하여 α-세포의 활성과 글루카곤 분비를 추가로 감소시킵니다.244 또한, 소마토스타틴은 위장관 활동을 억제하여 췌장 효소와 위산 분비를 감소시켜 간접적으로 글루카곤 수요를 감소시킵니다.245,246 따라서 GLP-1은 δ-세포를 활성화하고 소마토스타틴 분비를 촉진하여 글루카곤 분비를 효과적으로 감소시키는 다층적 억제 메커니즘을 형성합니다.

α-세포와 δ-세포에서의 GLP-1R의 상대적 발현 수준은 일정한 차이를 보입니다. 이러한 차이는 GLP-1이 췌도 기능 및 혈당 균형 조절에 미치는 역할에 크게 영향을 미칩니다.131 연구 결과, α-세포에서의 GLP-1R 발현 수준은 상대적으로 낮습니다.131 GLP-1R은 존재하지만 수량이 제한적이어서 GLP-1의 α-세포에 대한 직접적인 억제 효과가 상대적으로 약합니다.247 주요 작용은 종종 간접적 메커니즘을 통해 발생합니다, 예를 들어 인슐린과 소마토스타틴을 통해 이루어집니다.244 반면, δ-세포의 GLP-1R 발현 수준은 상대적으로 높습니다.248 GLP-1은 δ-세포의 수용체에 효과적으로 결합하여 소마토스타틴 분비를 자극합니다.248 광범위한 억제 호르몬인 소마토스타틴은 α-세포의 글루카곤 분비와 β-세포의 인슐린 분비를 효과적으로 억제합니다.249,250 관련 연구들은 δ-세포에서의 GLP-1R 발현이 GLP-1의 소마토스타틴 분비 조절 및 글루카곤에 대한 전체적인 억제 효과에 결정적 역할을 한다는 것을 제시합니다.248,251,252 이 메커니즘은 T2DM 치료에 사용되는 GLP-1 기반 약물(예: GLP-1RAs)에서 특히 명확히 관찰됩니다. 요약하면, δ-세포에서 GLP-1R의 상대적으로 높은 발현은 GLP-1이 소마토스타틴 분비를 촉진함으로써 글루카곤 분비를 간접적으로 억제합니다. 반면, α-세포에서 GLP-1R의 낮은 발현은 직접적인 효과가 제한적입니다. 이 세 가지 유형의 세포는 각각 독특한 기능을 가지고 있지만, 더 중요한 점은 그들이 분비하는 소마토스타틴, 글루카곤, 인슐린이 상호 조절 및 피드백 메커니즘을 통해 혈당 균형과 전체 대사 균형을 유지하기 위해 협력한다는 것입니다.253,254

GLP-1은 일반적으로 GLP-1(7-36)을 가리키며, 36개의 아미노산으로 구성된 펩타이드 사슬이며 주요 활성 분자입니다.255 GLP-1(7-36)은 β-세포와 δ-세포의 GLP-1R을 활성화하여 파라크린 글루카곤 억제 인자의 분비를 자극합니다.241 DPP-4는 GLP-1(7-36)을 8번째 위치에서 분해하여 GLP-1(9–36)을 생성합니다. GLP-1(9–36)은 DPP-4에 의한 GLP-1(7-36)의 분해 산물로, 이 과정은 GLP-1(7-36)의 활성을 급속히 감소시킵니다.35,256,257 전통적으로 GLP-1(9–36)은 GLP-1의 대사적으로 비활성 제품으로 간주되어 혈당 조절의 주요 기능을 상실한 것으로 여겨졌습니다.258 그러나 최근 연구들은 GLP-1(9–36)이 다른 생리적 역할을 가질 수 있음을 제시하고 있습니다. 최근 연구에서 GLP-1(9–36)은 억제성 G 단백질(Gi/o)을 활성화시켜 분비 소체(SG)가 세포막 아래로 이동하도록 유도함으로써 글루카곤 분비를 억제합니다.241 이 메커니즘은 GLP-1R의 유전적 또는 약물적 억제에 영향을 받지 않지만, 백일해 독소에 민감합니다. 엑센딘-4는 DPP-4에 의한 분해에 더 저항성이 있어 이 메커니즘은 엑센딘-4에 의해 활성화되지 않습니다.241 GLP-1(9–36)은 췌장 α-세포에 직접 작용하여 글루카곤 분비를 억제합니다. 최근 연구에서 GLP-1(9–36)은 저혈당 농도에서 특히 효과적이며, 그 억제 효과는 GLP-1(7-36)과 유사합니다.241 GLP-1(9–36)은 GLP-1 수용체(GLP-1R) 비활성화 후에도 글루카곤 분비 억제 능력을 유지하며, 이는 그 작용 메커니즘이 GLP-1R에 완전히 의존하지 않을 수 있음을 시사합니다.241 GLP-1(9–36)은 전압 의존성 칼슘 채널을 통해 칼슘 이온의 유입을 억제함으로써 분비 소체(SG)의 분리(undocking)를 촉진합니다. 이로 인해 GLP-1(9–36)은 α-세포에서 분비 가능한 소체의 수를 감소시켜 글루카곤 분비를 감소시킵니다.241 이 메커니즘은 세포 내 Ca2+ 농도를 감소시켜 글루카곤 분비를 억제합니다.241 또한, GLP-1(9–36)은 β-아드레날린 자극, 아미노산, 및 막 탈분극에 의해 유발된 글루카곤 분비를 효과적으로 억제하며, 이는 다양한 자극 조건 하에서 억제 효과를 나타냅니다.241 T2DM 환자의 α-세포에서 GLP-1(9–36)의 글루카곤 분비 억제 능력이 상실됩니다. 이는 당뇨병 환자의 α-세포 기능 변화로 인해 GLP-1(9–36)의 효능이 저하되기 때문일 수 있습니다.241 생체 내 실험에서 외인성 GLP-1(9–36)의 고농도는 인슐린 유발 저혈당 상태에서 순환 글루카곤 수치를 감소시키는 것으로 나타났습니다. 그러나 이 효과는 당뇨병 환자에서 현저히 감소하거나 사라집니다.241 GLP-1(7-36)의 분해산물인 GLP-1(9–36)은 체외 및 체내 연구에서 글루카곤 분비 억제 효과가 두드러지게 나타났습니다. 그러나 이 억제 효과는 T2DM 환자에게서 현저히 약화되어, 당뇨병 치료에의 잠재적 적용 가능성은 추가 연구가 필요합니다.241 이러한 복잡한 분자 및 세포 메커니즘을 통해 GLP-1은 T2DM과 같은 대사 질환의 생리적 및 병리적 과정에 중요한 역할을 합니다.232,233,241,259 (그림 2).

Fig. 2

Mechanisms of Blood Glucose Reduction by GLP-1 in Pancreatic α, β, and δ Cells. This illustration demonstrates how GLP-1 reduces blood glucose levels by acting on different pancreatic cell types. In β cells, GLP-1(9–36) activates the GLP-1R, which increases cAMP levels, subsequently activating PKA and CREB, leading to the promotion of insulin secretion. The PI3K/Akt pathway enhances glucose sensitivity in β cells, promoting insulin secretion. This pathway also supports β cell survival and proliferation, ensuring an adequate β cell mass to maintain normal insulin secretion. This signaling cascade results in increased insulin gene expression‎, enhanced protein synthesis, improved cell survival, and reduced apoptosis. Additional metabolic effects include fatty acid oxidation, gluconeogenesis, and energy expenditure. In α cells, GLP-1(7-36) mainly regulates function through indirect mechanisms. GLP-1R expression‎ is lower in α cells compared to β and δ cells, resulting in relatively less direct action of GLP-1 on α cells. Through paracrine effects via β cells, GLP-1 enhances insulin secretion, which in turn inhibits glucagon secretion from α cells. Additionally, GLP-1 promotes somatostatin secretion from δ cells, which inhibits glucagon secretion from α cells. GLP-1(7-36) can suppress glucagon secretion in α cells by increasing cAMP levels, activating PKA and EPAC, leading to a decrease in intracellular calcium concentration and reduced glucagon release. GLP-1(9–36) inhibits glucagon secretion by activating inhibitory G proteins (Gi/o) and suppressing PKA activity through a GCGR-dependent mechanism. By promoting the undocking of secretory granules (SG), GLP-1(9–36) reduces the number of granules available for exocytosis, thereby decreasing the release of glucagon. δ cells primarily secrete somatostatin. GLP-1(7-36) regulates somatostatin secretion by modulating calcium channels and affecting membrane potential changes. The action of GLP-1(7-36) on δ cells may be more indirect, such as through the influence on hormones secreted by β and α cells (insulin and glucagon), which indirectly affects δ cell somatostatin secretion. Additionally, somatostatin can inhibit gastrointestinal activities, reducing the secretion of pancreatic enzymes and gastric acid, thereby indirectly lowering the demand for glucagon

GLP-1이 췌장 α, β, 및 δ 세포에서 혈당을 감소시키는 메커니즘. 

이 그림은 GLP-1이 다양한 췌장 세포 유형에 작용하여 혈당 수치를 감소시키는 과정을 보여줍니다. β 세포에서 GLP-1(9–36)은 GLP-1 수용체를 활성화시켜 cAMP 수준을 증가시키며, 이는 PKA와 CREB를 활성화시켜 인슐린 분비를 촉진합니다. PI3K/Akt 경로는 β 세포의 포도당 감수성을 향상시켜 인슐린 분비를 촉진합니다. 이 경로는 또한 β 세포의 생존과 증식을 지원하여 정상적인 인슐린 분비를 유지하기 위해 충분한 β 세포량을 확보합니다. 이 신호 전달 경로는 인슐린 유전자 발현 증가, 단백질 합성 향상, 세포 생존 개선, 세포 사멸 감소 등을 유발합니다. 추가적인 대사 효과로는 지방산 산화, 글루코네오게네시스, 에너지 소비 증가 등이 있습니다. α 세포에서 GLP-1(7-36)은 주로 간접적 메커니즘을 통해 기능을 조절합니다. α 세포의 GLP-1R 발현은 β 및 δ 세포에 비해 낮아 GLP-1의 α 세포에 대한 직접적 작용이 상대적으로 적습니다. β 세포를 통한 파라크린 효과를 통해 GLP-1은 인슐린 분비를 촉진하며, 이는 다시 α 세포에서의 글루카곤 분비를 억제합니다. 또한 GLP-1은 δ 세포에서 소마토스타틴 분비를 촉진하여 α 세포에서의 글루카곤 분비를 억제합니다. GLP-1(7-36)은 cAMP 수준을 증가시켜 PKA와 EPAC를 활성화함으로써 세포 내 칼슘 농도를 감소시키고 글루카곤 분비를 억제합니다. GLP-1(9–36)은 GCGR 의존적 메커니즘을 통해 억제성 G 단백질(Gi/o)을 활성화하고 PKA 활성을 억제하여 글루카곤 분비를 억제합니다. 분비 소체(SG)의 분리(undocking)를 촉진함으로써 GLP-1(9–36)은 분비에 이용 가능한 소체의 수를 감소시켜 글루카곤 방출을 감소시킵니다. δ 세포는 주로 소마토스타틴을 분비합니다. GLP-1(7-36)은 칼슘 채널을 조절하고 막 전위 변화를 통해 소마토스타틴 분비를 조절합니다. GLP-1(7-36)의 δ 세포에 대한 작용은 β 및 α 세포에서 분비되는 호르몬(인슐린과 글루카곤)에 영향을 미치는 간접적인 경로를 통해 δ 세포의 소마토스타틴 분비에 간접적으로 영향을 미칠 수 있습니다. 또한 소마토스타틴은 위장관 활동을 억제하여 췌장 효소와 위산 분비를 감소시켜 간접적으로 글루카곤의 요구량을 낮춥니다.

Role of GLP-1 in obesity

GLP-1 reduces appetite and food intake through its actions in the CNS.212,260,261 By interacting with receptors in the hypothalamus, GLP-1 influences satiety and reduces the consumption of food in both animals and humans.262 It functions not only in peripheral tissues but also directly within the CNS, crossing the blood-brain barrier or being produced centrally to act on the brain.262,263 GLP-1 regulates energy balance and food intake by acting on specific brain regions, especially the hypothalamus, a key area responsible for hunger and fullness sensations.264,265,266 The hypothalamus contains various neurons that respond to different nutritional signals and hormones, like GLP-1, to regulate food intake.265,266 When GLP-1 binds to its receptors in the hypothalamus, it activates specific neurons, including those that promote satiety (POMC/CART neurons) and inhibits those that induce hunger (NPY/AgRP neurons), thereby enhancing the feeling of fullness and reducing food intake.233,267

GLP-1 can slow down gastric emptying through its effects on smooth muscles and the nervous system in the gastrointestinal tract.264,268 Released at the gut’s end, GLP-1 acts on its receptors in the gastrointestinal tract, leading to reduced gastric muscle contractions and extended food retention in the stomach.264,269 Furthermore, GLP-1 can slow down gastric emptying by activating the vagus nerve, a part of the autonomic nervous system crucial for regulating the activities of the gastrointestinal tract.268 When activated, the vagus nerve can reduce the contraction of the stomach, thereby slowing down food emptying.269 The prolonged retention of food in the stomach enhances the feeling of fullness, naturally reducing overall food intake.270,271 Additionally, slower gastric emptying helps stabilize postprandial blood glucose levels. Reducing food intake and extending satiety are significant for weight management and loss. By regulating gastric emptying, GLP-1 not only aids in short-term appetite control but may also contribute positively to long-term energy balance and weight management.176

GLP-1RAs and diseases

As a rising star in recent years, GLP-1RAs are not only effective in metabolic diseases but also play a role in non-metabolic disorders, affecting multiple systems including the musculoskeletal, nervous, cardiovascular, and digestive systems, and can even have implications in oncological diseases.

Musculoskeletal system

Disorders associated with the musculoskeletal system often cause painful swelling and permanent damage in the joints of the body, especially the hips, knees and thumbs. These diseases may affect more people in today’s aging society. Because of the close relationship between risk factors in human metabolism and the expression‎ of GLP-1R in the musculoskeletal system, GLP-1RAs may have great potential in the treatment of many diseases of the musculoskeletal system.15,272

GLP-1RAs and joint disordersGLP-1RAs in OA

GLP-1R expression‎ was detected via immunohistochemistry in articular chondrocytes from both normal and osteoarthritic individuals.273 The primary outcome of GLP-1R expression‎ involves suppressing the release of cytokines into the synovial fluid, leading to a reduction in inflammation.274,275 This, in turn, diminishes additional downstream effects, including oxidative stress, the secretion of pro-degradative substances, modifications to cell phenotype (hypertrophy, M1/M2 macrophage phenotype, fibrosis), and damage or deterioration of joint cells (apoptosis, senescence).15,276

The activation of GLP-1R is linked to decreased NF-κB pathway activity Treatment with GLP-1RAs can effectively mitigate chondrocyte apoptosis caused by endoplasmic reticulum stress and alleviate the associated inflammatory response.277,278,279,280 This effect is accomplished through the inhibition of JNK, NF-κB, and other relevant signaling pathways.273 Moreover, GLP-1RAs could decelerate the progression of OA and mitigate pathological damage in a rat OA model.273 In addition, in a rat model of inflammatory OA induced by monoiodoacetic acid (MIA), researchers have shown that the activation of GLP-1R triggers the PKA/CREB signaling pathway, leading to a reduction in cartilage inflammation.281

Inflammation in OA is closely related to the activation of macrophages.282,283 These cells accumulate in the synovial membrane and subchondral bone, releasing pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which promote the degradation of joint cartilage and the inflammatory response.284,285,286 Macrophages express GLP-1Rs, which are involved in regulating their inflammatory responses. Binding of GLP-1 or GLP-1RAs to these receptors can activate the cAMP/PKA signaling pathway, affecting key transcription factors like NF-κB.287,288

This binding initiates typical GPCR signaling, leading to G protein activation and increased intracellular cAMP.289 The rise in cAMP activates PKA, a versatile protein kinase that phosphorylates various target proteins.290,291,292 In macrophages, PKA regulates gene expression‎ by phosphorylating transcription factors like CREB.293 CREB activation can promote the expression‎ of anti-inflammatory genes while inhibiting inflammatory genes.294,295 In inflammation regulation, NF-κB is a key transcription factor.296,297,298 Typically, NF-κB binds to its inhibitor IκB in the cytoplasm.297,299 When IκB is phosphorylated and degraded, NF-κB can move to the nucleus, activating multiple inflammation-related genes.300,301 This not only affects the intracellular signaling of macrophages but also their response to the external environment, including their effects on chondrocytes and other synovial cells.302,303,304,305

GLP-1R signaling, through PKA, inhibits this process, possibly by promoting IκB stability or inhibiting its phosphorylation, thus reducing NF-κB activation and nuclear translocation.8,281 Through these mechanisms, GLP-1R signaling influences the production of inflammatory factors in macrophages.306 For example, the reduction in TNF-α, IL-1β, and IL-6 helps regulate local and systemic inflammatory responses.307,308 Additionally, GLP-1R signaling may affect other macrophage functions, such as phagocytosis, migration, and cell survival.281

By reducing macrophage-mediated inflammatory responses, GLP-1RAs have the potential to alleviate symptoms of OA, including pain and joint stiffness.281,309 Moreover, reducing inflammation may slow down the degradation of joint cartilage, providing long-term joint protection.310,311 GLP-1RAs also enhance autophagy, a process of cellular clearance of damaged and outdated components.13,312 Regulation of autophagy may help remove harmful proteins and other cellular debris accumulated under inflammatory conditions, which is potentially important for maintaining the health of joint tissues.313,314

In one study, OA was induced in rats by injecting MIA into the knee joint, mimicking the pathological changes of human OA.315 Subsequently, rats were treated with liraglutide through subcutaneous injection to observe its therapeutic effect on OA.315 The expression‎ levels of GLP-1R, PKA/CREB signaling pathway components, and inflammation-related proteins (such as TNF-α, IL-1β, and IL-6) in the rat knee cartilage tissue were measured using Western blot and immunoprecipitation techniques.315 The results showed that, in the OA rat model, liraglutide could activate the PKA/CREB signaling pathway and inhibit the inflammatory response through this pathway, thereby alleviating OA symptoms.316 These findings provide scientific evidence for developing new OA treatment strategies, confirm‎ing the potential of GLP-1 agonists in treating OA.315,316,317

GLP-1R is expressed in human monocyte-derived macrophages and the mouse macrophage cell line RAW264.7.279,318 c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase (MAPK) involved in regulating cellular stress responses and inflammation.318 Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor involved in cell growth, differentiation, and inflammatory responses.319,320,321 Researchers found that activation of GLP-1R could play a key role in regulating macrophage polarization by adjusting the phosphorylation levels of JNK and STAT3.318,322 Macrophages have two polarization states, M1 typically has pro-inflammatory properties, while M2 has anti-inflammatory properties.323,324,325 Specifically, activation of GLP-1R leads to an increase in cAMP levels, which in turn activates PKA, a widely regulating enzyme of cellular functions, capable of phosphorylating a variety of target proteins, thereby initiating the PKA/CREB signaling pathway.326,327 This not only prevents the phosphorylation of JNK but also promotes the phosphorylation of STAT3, aiding the shift of macrophages to an anti-inflammatory M2 phenotype.327 In the inflammatory environment, the M1 to M2 shift promoted by GLP-1 is crucial for reducing the expression‎ of inflammatory factors such as IL-6, TNF-α, and iNOS.8,15,328

Chondrocytes are the only cell type in joint cartilage, responsible for synthesizing and maintaining the integrity of the cartilage matrix.329,330 In degenerative joint diseases like OA, the metabolic balance of chondrocytes is disrupted, leading to the overproduction of degrading enzymes and inflammatory mediators, including iNOS, MMP-13, and ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5), which participate in cartilage degradation and inflammatory processes.331 iNOS (inducible nitric oxide synthase) produces nitric oxide (NO) during inflammation, modulating signal transduction; MMP-13 (matrix metalloproteinase-13) is involved in cartilage degradation;331 ADAMTS5 is closely related to cartilage damage and inflammation.332,333,334 The NO produced by iNOS, as a free radical, can regulate intracellular signal transduction and modulate the inflammatory response.335,336 The expression‎ of iNOS is primarily activated by the NF-κB pathway, which is activated and translocated to the nucleus upon inflammatory stimulation (such as bacterial endotoxins or pro-inflammatory cytokines), thus increasing the transcription and expression‎ of iNOS.337,338,339 GLP-1 can exert its anti-inflammatory effects by activating its receptor, GLP-1R.339 When GLP-1 binds to GLP-1R, it activates the cAMP signaling pathway, leading to increased cAMP levels.1,340 The rise in cAMP further activates PKA, which can inhibit the NF-κB signaling pathway, reducing the production of inflammatory factors such as iNOS and other inflammation-related proteins.12,340,341 The expression‎ of MMP-13 is regulated by IL-1β and TNF-α. These factors promote the transcription of the MMP-13 gene by activating the MAPK and NF-κB signaling pathways.342,343,344 The GLP-1R signaling pathway may also affect the expression‎ of MMP-13 and ADAMTS5, by reducing the signal transduction caused by IL-1β, thus decreasing their synthesis.345,346 GLP-1 may also reduce the expression‎ of cartilage-degrading enzymes by inhibiting the MAPK pathway or activating anti-inflammatory pathways such as PI3K/Akt, thereby alleviating cartilage damage.206,347

In another study, treatment of primary mouse chondrocytes with liraglutide reduced the mRNA expression‎ levels of iNOS, MMP-13, and ADAMTS5, leading to a decrease in the secretion of inflammatory markers, including NO, prostaglandin E, and IL-6.348 Similarly, in human chondrocytes stimulated by TNF, GLP-1 analogs (such as liraglutide) showed an anti-catabolic effect, reducing the mRNA expression‎ of MMP-3, MMP-13, and ADAMTS5.349,350 At the same time, the levels of two important components of the cartilage matrix, proteoglycans (a large molecule and a major component of the cartilage matrix) and type II collagen (the main structural protein of cartilage), increased.349,350 This change suggests that liraglutide not only inhibits inflammation and cartilage degradation but may also promote the synthesis and accumulation of cartilage matrix, thereby helping to protect and repair joint cartilage.273 Furthermore, a study using the anterior cruciate ligament transection (ACLT) rat model further confirmed that subcutaneous injection of liraglutide at 50 μg/kg/day, whether for 3 weeks or 6 weeks, could reduce OARSI scores, highlighting the potential of liraglutide in treating joint degeneration.273

GLP-1RAs and RA

The role of GLP-1RA was also investigated in RA, which is characterized by chronic inflammation of the synovium and joint destruction. In fibroblast-like RA synoviocytes, the administration of lixisenatide resulted in a reduction in the inflammatory response.347 This was achieved by decreasing the expression‎ of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8).15,351,352 Moreover, lixisenatide has been shown to inhibit matrix metalloproteinase (MMP) activity and effectively block various cell signaling pathways, including the JNK, activator protein-1, and NF-κB pathways.353 These findings confirm‎ that in the synovium, GLP-1R is expressed on two different cell types, macrophages and fibroblast-like synoviocytes, which are specialized cells distributed within the synovial intima and subintima, and these cell types play important roles in hyaluronic acid synthesis, metabolite processing, and clearance of matrix degradation fragments.354

GLP-1RAs and musculoskeletal healthGLP-1RAs and bone

The quality of bone depends on bone metabolism, and the main factors affecting bone metabolism include osteoclasts, osteoblasts, and calcitonin.355,356,357 According to most related studies, osteoclasts and osteoblasts are indispensable for bone remodeling, and bone resorption and bone formation are mediated by osteoclasts and osteoblasts, respectively.358 GLP-1R is present in bone marrow stem cells (BMSCs),15,359 osteoblasts,15 osteocytes,360 and osteoclasts,361 and GLP-1RAs have the potential to impact these cells.

GLP-1RAs and osteoclasts 

The greater degree of bone degradation observed in mice lacking GLP-1R indicates that GLP-1R signaling suppresses osteoclast differentiation and bone resorption.362 In an experimental study in which osteoclast formation and bone resorption were induced in mice through lipopolysaccharide (LPS) administration, researchers discovered that simultaneous treatment with exendin-4 resulted in a significant decrease in the number of osteoclasts, the proportion of bone resorption pits, and the levels of the bone resorption marker CTX compared to injection with LPS alone.363 According to previous reports, exendin-4, a GLP-1RA, has the potential to inhibit LPS-induced osteoclast formation and bone resorption in vivo.363,364 This inhibition is believed to occur through the suppression of LPS-induced TNF-α production in macrophages.15 Studies have indicated that GLP-1R KO mice exhibit greater numbers of osteoclasts and greater bone resorption than wild-type controls.364 Additionally, µCT analysis revealed that, compared with their wild-type counterparts, hyperlipidemic rats treated with subcutaneous GLP-1 for 3 days exhibited increased bone mass in the femur and vertebrae.365

Diabetic patients have a higher risk of fractures than does the general population.366 Mice with type 1 diabetes (T1D) exhibit a reduction in bone mineral density (BMD) and compromised microstructural integrity.367 The administration of liraglutide also impeded osteoclastic bone formation, thereby inhibiting bone resorption and exerting protective effects on bone health in T1D mice.367 Specifically, liraglutide, both alone and in combination with insulin, effectively suppressed the formation of osteoclasts. This effect is achieved by reducing the expression‎ of Trem2 and NFATc1 and downregulating the expression‎ of CTSK and TRAP to inhibit bone resorption activity. These findings provide further evidence for the impact of GLP-1RAs on osteoclastic bone resorption.367 A study involving 12-week-old ovariectomized mice revealed that administering liraglutide for 4 weeks effectively prevented the loss of trabecular bone. The analysis of bone tissue morphology revealed that there were no alterations in the rate of bone formation or in the levels of calcitonin or sclerostin in these mice. These findings suggest that liraglutide specifically reduces bone resorption without influencing bone formation.368

Since GLP-1R is expressed in thyroid C cells and GLP-1 directly stimulates the secretion of calcitonin, which is a potent inhibitor of bone resorption in osteoclasts, GLP-1 may contribute to the nutrient-mediated reduction in bone resorption.369,370 Genetic disruption of GLP-1R signaling leads to cortical osteopenia and heightened bone fragility, primarily caused by increased bone resorption by osteoclasts. This change was accompanied by a decrease in thyroid calcitonin expression‎. Furthermore, the administration of exogenous GLP-1 resulted in elevated calcitonin expression‎ in the thyroids of normal (wild-type) mice.362 The administration of calcitonin successfully reduced the levels of urinary deoxypyridinoline in GLP-1R knockout mice. Additionally, treatment with GLP-1RA and exendin-4 increased the expression‎ of the calcitonin gene in the thyroids of normal (wild-type) mice. These findings provide evidence that the regulatory influence of endogenous GLP-1R signaling on bone resorption is likely mediated through pathways that involve calcitonin.362 Considering the expression‎ of the GLP-1R in thyroid C cells and the ability of GLP-1 to stimulate calcitonin secretion through a cAMP-mediated mechanism in vitro, it is plausible that calcitonin plays a role in the alterations in bone metabolism observed in GLP-1R-treated animals.369,370 Later, quantitative real-time PCR analysis demonstrated that the administration of exendin-4, a GLP-1RA, resulted in significant upregulation of thyroid calcitonin mRNA levels in wild-type mice.362

GLP-1RAs and Osteoblasts 

Osteoblasts arise through the differentiation of mesenchymal stem cells and play a crucial role in the process of bone formation. Stimulating GLP-1R in BMSCs triggers the buildup of nuclear β-catenin, which, in turn, activates osteogenic genes by binding with TCF7L12.371 In osteoblasts, the administration of GLP-1 and GIP incretins suppressed the excessive expression‎ of the pro-degradative enzymes MMP-3 and MMP-13 induced by IL-1β stimulation.372 In vitro, GLP-1 disrupts the ability of osteoblasts to survive and differentiate by triggering the activation of c-Fos, which is a proto-oncogene.373 In fact, when BMSCs are exposed to exendin-4, the expression‎ of genes related to bone development factors such as Runx and Osterix, as well as genes responsible for producing the bone matrix such as Balp and Bglap, is upregulated. Moreover, stimulation of GLP-1R in BMSCs results in the accumulation of β-catenin in the cell nucleus. This accumulation facilitates the binding of β-catenin to TCF7L12, triggering the activation of genes associated with osteogenesis.371

In a study examining the effects of GLP-1RA on osteoporosis induced by ovariectomy in aged rats, administering exendin-4 for 16 weeks prevented deterioration of the trabecular microarchitecture and increased bone strength. This was achieved by inhibiting bone resorption through an increase in the OPG/RANKL ratio and promoting bone formation by enhancing the expression‎ of osteoblast-specific transcription factors.374 Exendin-4 has also been shown to stimulate osteoblast activity and mitigate bone loss in an ovariectomized mouse model.374 Liraglutide can directly enhance bone formation in the MC3T3-E1 osteoblastic cell line. This effect is achieved through the activation of signaling pathways such as the ERK1/2, PI3K/AKT, and cAMP/PKA/β-cat-Ser675 pathways, which are mediated by GLP-1RAs.375 (Fig. 3).

Fig. 3

The Effects of GLP-1RAs on osteoclasts and osteoblasts. GLP-1RAs aid in weight loss by regulating the gut-brain axis and interacting with leptin, while weight loss can alleviate the harmful effects of obesity on the body, particularly in knee OA, by reducing joint loading and inflammation. Obesity disrupts bone metabolism and leads to increased bone resorption, but GLP-1RAs can inhibit this damage and improve bone health by increasing the OPG/RANKL ratio, reducing osteoclast activity, and promoting bone formation

GLP-1RAs and muscle

GLP-1RAs and Muscle Atrophy 

In previous experiments, exendin-4 (Ex-4) inhibited the expression‎ of myostatin (MSTN), atrophy-factor F-box only protein 32 (atrogin-1) and muscle ring finger protein 1 (MuRF-1) in dexamethasone-treated C2C12 myotubes.376,377,378 In a dexamethasone-induced muscle atrophy model, Ex-4 ameliorated muscle atrophy by inhibiting muscle atrophy factor and enhancing myogenic factors (MyoG and MyoD), thereby increasing muscle mass and function. In the muscle atrophy mouse model, Ex-4 also increased muscle mass and muscle fiber size and improved muscle function. In addition, treatment with the long-acting GLP-1RA duraglutide restored muscle mass and function in DBA/2J-mdx mice.379

GLP-1RAs, particularly PF1801, have demonstrated effective relief in inflammatory myopathies, such as polymyositis (PM), through preclinical studies.376,380 The therapeutic effects of PF1801 are primarily achieved by modulating several key proteins that play central roles in inflammation and cellular metabolism.380 Firstly, the expression‎ of GLP-1R is enhanced in the inflamed muscle fibers under pathological conditions, revealing the critical role of GLP-1R in regulating the muscle’s response to inflammation.381 PF1801 activates these receptors, initiating a series of biological responses that influence the inflammatory state of muscle cells, thereby alleviating inflammation. Next, PF1801 exerts its effects by activating AMP-activated protein kinase (AMPK).382 As a central node in energy sensing and metabolic regulation, the activation of AMPK helps maintain cellular energy balance and prevents cell death due to energy depletion.383,384 Importantly, the activation of AMPK reduces the expression‎ of phosphoglycerate mutase 5 (PGAM5), which plays a promotive role in cell necrosis by contributing to mitochondrial dysfunction and the production of reactive oxygen species (ROS).385,386,387 Thus, by inhibiting PGAM5, AMPK suppresses necrosis, reduces ROS accumulation, and mitigates oxidative stress.385,387 PF1801 displays its anti-inflammatory effects by lowering levels of inflammatory mediators such as TNFα, IL-6, and HMGB1, and enhances the cell’s antioxidant capability by upregulating molecules like Nfe2l2, Hmox1, Gclm, and Nqo1, which further improves cellular defense against oxidative stress and protects them from further damage.382 Through this sophisticated molecular regulation, PF1801 not only alleviates inflammation and necrosis in muscle fibers but also enhances the energy and antioxidant status of muscle cells.382 This contributes to maintaining muscle strength and reducing inflammation. This comprehensive change reflects how alterations in the expression‎ of individual key proteins can impact the entire metabolic and inflammatory pathways, thereby improving disease conditions and enhancing therapeutic efficacy.376

GLP-1RAs in Enhancing Exercise Endurance 

Studies indicate that acute exercise and short-term endurance training significantly increase GLP-1 secretion in mice. In endurance-trained men, GLP-1 plasma concentrations are elevated immediately at 30 and 45 minutes after exercise.388 To confirm‎ the role of GLP-1 in enhancing physical endurance and the possible mechanisms involved, an in vivo AAV-mediated GLP-1 overexpression‎ model and an in vitro siRNA-mediated AMPK knockdown model were generated. We demonstrated that GLP-1 enhances physical endurance by inducing skeletal muscle remodeling, which may be mediated by GLP-1R/AMPK signaling.389 Overall, GLP-1 secretion is induced by exercise. Overexpression‎ of GLP-1 in skeletal muscle can improve endurance. These results suggest that GLP-1 may improve exercise endurance in mice by enhancing skeletal muscle glycogen synthesis and glucose uptake. Mitochondrial content and function in skeletal muscle are regulated by GLP-1.389 The interaction between GLP-1 and its receptor GLP-1R initiates the AMPK signaling cascade within skeletal muscle tissue. This initiation precipitates a multitude of alterations in the cellular milieu, notably the augmentation of mitochondrial biogenesis-a mechanism responsible for the genesis of new mitochondria. Furthermore, GLP-1 augments mitochondrial efficacy, as manifested by the ameliorated oxidative metabolism of muscle tissue. This enhancement is demonstrable through an increase in mitochondrial DNA content, the upregulation of genes integral to mitochondrial biogenesis, and the increased expression‎ of proteins pivotal in oxidative phosphorylation. These cellular transformations contribute significantly to enhanced endurance during exercise, thereby underscoring the critical role that GLP-1 plays in the regulation of mitochondrial function and content in skeletal muscle.389

GLP-1RAs and fat metabolism

GLP-1RAs work via numerous mechanisms that contribute to weight loss, one of the most well-known of which is the gut-brain axis.212,213,390 Within this axis, GLP-1 functions by acting on both the gut and the brain.391 Furthermore, the combination of GLP-1-mediated signaling and the adipocyte hormone leptin has recently garnered increased interest. Notably, leptin may serve as a crucial biological signal for GLP-1, working in synergy, to decrease food intake and body weight. The effects of the leptin-GLP-1 interaction may be governed by intracellular signaling pathways, including those involving phosphorylated STAT3 and PTP1B.15,392

In Wistar rats, a diet high in fat was found to lead to a decrease in the ratio of OPG/RANKL, which resulted in increased bone resorption and ultimately a reduction in bone mass. The administration of GLP-1RA or exendin-4 to rats fed a high-fat diet resulted in an increase in the OPG/RANKL ratio and a reduction in the degree of bone loss. It was observed that the treatment of rats on a high-fat diet with exendin-4 resulted in a decrease in the number of osteoclasts and the area of eroded surfaces, while there was an increase in the osteoid area, bone mass, and trabecular bone volume. These effects were compared to those of untreated controls that were also maintained on a high-fat diet.393 As a result, GLP-1RAs could mitigate the detrimental effects of hyperlipidemia-induced skeletal defects, leading to an improved prognosis in individuals with OA.

On the surface of the cartilage, there is a layer of special phospholipids. When a joint bears weight, it functions as a lubricant, playing a crucial role in enabling the joint to continue operating efficiently and smoothly. Altering the composition of this phospholipid layer can impact the functioning of the corresponding joint. For instance, changes in the composition of this phospholipid layer have been observed by researchers, along with their detrimental effects on the bones and joints of individuals with OA.394 Surprisingly, GLP-1RAs can influence the phospholipid structure and cytokines surrounding joints, leading to beneficial transformations that safeguard joints and even facilitate partial repair of any existing damage.395 (Fig. 4).

Fig. 4

The Effects of GLP-1RAs on Musculoskeletal System. GLP-1RAs inhibit chondrocyte apoptosis, reduce inflammation, and protect articular chondrocytes in OA and RA through various mechanisms, including suppressing cytokine release, inhibiting the NF-κB pathway, and reducing inflammation-related gene expression‎. They have shown to reduce the inflammatory response by decreasing the expression‎ of proinflammatory cytokines and inhibiting matrix metalloproteinase activity and cell signaling pathways. GLP-1R expression‎ is found in macrophages and fibroblast-like synoviocytes, which are important for maintaining synovial fluid homeostasis. GLP-1R signaling stimulates calcitonin secretion, which inhibits bone resorption, and disruption of GLP-1R leads to increased bone resorption and decreased calcitonin expression‎. GLP-1RAs have pleiotropic effects on skeletal muscle, including inhibiting muscle atrophy, preserving muscle strength, and enhancing exercise endurance, through GLP-1R-mediated signaling pathways. GLP-1RAs can influence the composition of the phospholipid layer on cartilage, leading to beneficial effects on joint health and potentially facilitating repair of existing damage in individuals with OA

GLP-1RAs in nervous system

In the nervous system, GLP-1 can decrease oxidative stress and inflammatory responses, potentially through reducing the generation of ROS and decreasing the expression‎ of inflammatory cytokines. Activation of its receptor by GLP-1 can promote the phosphorylation of CREB, subsequently fostering the expression‎ of genes related to neuronal survival and regeneration.396,397,398,399

GLP-1RAs and nerve cells

GLP-1 can modulate peripheral nerves through the ERK (extracellular signal-regulated kinase) signaling pathway, reducing the occurrence of neurological dysfunction.400 Researchers have discovered that GLP-1RAs exhibit a noticeable increase in the level of phosphorylated ERK1/2 within the sciatic nerve of diabetic rats. This observation led them to speculate that GLP-1 analogs might possess distinct neurotrophic properties and exert protective effects specifically on the nerve.71,395,401,402,403

Astrocytes, the most abundant cell type in adult brain nerve tissue, have recently been recognized for their pivotal role in regulating glucose and energy homeostasis.404,405,406 These cells not only respond to signals from leptin and insulin but also adapt to alterations in brain metabolism to accommodate behavioral changes by controlling glucose transport.406,407 Furthermore, astrocytes express GLP-1R, which has been found to be crucial for their proper functioning.408 Studies have shown that the loss of GLP-1R in astrocytes can impair mitochondrial integrity, leading to the dysfunction and inhibition of glucose uptake and β-oxidation.407 GLP-1 inhibits glucose uptake in astrocytes and promotes beta-oxidation, which is essential for regulating energy balance in the brain and maintaining mitochondrial integrity.406 When GLP-1R is knocked out in astrocytes, it activates an integrated stress response, which affects the overall metabolic state by increasing the production of FGF21.405 This suggests that signaling through GLP-1R in astrocytes is crucial for maintaining the metabolic stability and functionality of the cells.406 FGF21 is recognized as a stress response factor that addresses mitochondrial dysfunction in cells. In astrocytes lacking GLP-1R, the increase in FGF21 is associated with improved systemic glucose homeostasis and memory formation.406 This indicates that FGF21 not only plays a role in cellular stress responses but also has a significant role in regulating brain function and systemic metabolism.406 Therefore, endogenous GLP-1R signaling in astrocytes plays a critical role in maintaining mitochondrial homeostasis and is dependent on FGF21 to effectively regulate glucose metabolism.406,407

GLP-1RAs can alleviate neuroinflammation by acting on the nervous system, thereby offering additional relief from pain in patients.6,409,410 During a previous experiment, researchers induced pain and observed symptoms of cognitive impairment in rats through spinal nerve ligation. Then, the researchers administered exendin-4 via intrathecal injection to the experimental rats and observed a reduction in pain sensitivity, alleviation of neural inflammation, and suppression of inflammatory factors such as IL-1β, TNF-α, and iNOS. This finding suggests a direct correlation between the analgesic effects of GLP-1R signaling and its Anti-neuroinflammatory activity.411 In another study, 3D fluorescence microscopy was used to eliminate proteins within chondrocytes in the subchondral bone of cartilage, resulting in bone transparency and the acquisition of high-resolution 3D images. By utilizing this methodology, researchers have revealed that GLP-1RAs can exhibit affect the axon terminals of sensory neurons. Ultimately, it was revealed that cholinergic fibers are present within the subchondral bone of individuals with OA, and the release of acetylcholine (Ach) triggered by vagus nerve stimulation plays a prominent role in combating inflammation across various diseases while also providing pain relief.412 Notably, GLP-1RAs, including exendin-4, have been shown to attenuate microglial activation, resulting in a reduction in the expression‎ of proinflammatory cytokines such as TNF-α and IL-1β. By modulating inflammatory responses, GLP-1RAs can help prevent the degeneration of dopamine-producing cells.413 GLP-1RAs play a neuroprotective role in neurons by facilitating neuronal survival and promoting neuronal growth, thereby preserving the structural and functional integrity of synapses.6,14 Furthermore, GLP-1 signaling indirectly enhances and restores the insulin signaling pathway in neurons, leading to a reduction in the phosphorylation of insulin receptor substrates and the burden caused by monomeric α-synuclein.414 Together, these effects contribute to the protection of dopaminergic neurons (source). Exenatide has been shown to mitigate the phosphorylation of insulin receptor substrates and the accumulation of monomeric α-synuclein.414 By activating the GLP-1 signaling pathway, exenatide exhibits neuroprotective effects and safeguards dopaminergic neurons.5

The most well-known mechanism through which GLP-1RAs affect weight loss is through the endocrine pathway, but its role in the nervous system should not be overlooked.415,416,417 GLP-1RAs can exert their local effects by activating vagal dendritic terminals that innervate the gut.418,419,420 This activation holds the ability to modulate food consumption by reducing food intake and conveying signals of satiety to the brain.391 GLP-1 and GLP-1 analogs exert their effects on food intake and body weight through a myriad of neural substrates, encompassing several hypothalamic nuclei (including the arcuate nucleus of the hypothalamus, periventricular hypothalamus, and lateral hypothalamic area), hindbrain nuclei (such as the parabrachial nucleus and medial nucleus tractus solitarius), the ventral subregion of the hippocampus (vHP), and nuclei embedded within the mesolimbic reward circuitry (including the ventral tegmental area, VTA, and nucleus accumbens, NAc).421,422 Remarkably, GLP-1R activation in certain nuclei (such as the VTA, NAc, and vHP) elicits reductions in food intake and body weight without concurrent nausea responses.392

The relationship of inflammatory response and neurodegenerative disease

In the research conducted by Daniel J. Drucker’s team, the mechanism of anti-inflammatory action of GLP-1RAs was explored, revealing a key role for the CNS in regulating this anti-inflammatory effect.423 The study began by inducing inflammation in mice through the injection of various Toll-like receptor (TLR) agonists and then assessed the inflammation by measuring plasma tumor necrosis factor-alpha (TNF-α) levels.423 It was observed that the GLP-1RA, exendin-4, significantly reduced the TNF-α levels caused by various TLR agonists, indicating that exendin-4 can lower the TNF-α levels induced by multiple TLR agonists.423 The research further demonstrated that this anti-inflammatory effect was not mediated by GLP-1R in the blood or endothelial cells but required the GLP-1R in the CNS.

Additionally, to simulate sepsis caused by polymicrobial infection and assess the impact of GLP-1RAs, the study utilized a cecal content injection method. It was found that semaglutide, a long-acting GLP-1RA, could improve symptoms caused by sepsis, reduce body temperature, and decrease the bacterial load in multiple organs, along with the levels of inflammatory factors in plasma and lungs.423 These findings further confirmed the central role of the CNS in regulating the anti-inflammatory effects of GLP-1RAs, highlighting the potential application of GLP-1RAs in anti-inflammatory treatment.

The study also discovered the roles of α1-adrenergic and δ- and κ-opioid receptors in this process. Specifically, blocking the α1-adrenergic receptors with prazosin or the opioid receptors with nalbuphine interfered with the ability of GLP-1RAs to reduce plasma TNF-α levels, indicating the critical importance of these pathways in the anti-inflammatory effects mediated by GLP-1 activation. The α1-adrenergic receptors, found on the surface of cells, facilitate various physiological responses, including regulating vascular contraction and heart rate. The use of prazosin, an α1-adrenergic receptor blocker, showed that the ability of GLP-1RAs to reduce TNF-α in plasma was disrupted, signifying the vital role of α1-adrenergic receptors in the anti-inflammatory action of GLP-1RAs. Opioid receptors, which are associated with pain regulation, mood, and immune responses, include δ and κ types. The use of nalbuphine, a blocker of δ- and κ-opioid receptors, also disrupted the effect of GLP-1RAs on reducing TNF-α levels, highlighting the essential role of these opioid receptors in the anti-inflammatory effects mediated by GLP-1RAs.423

Furthermore, the study emphasized that neurons in specific brain regions, such as the hindbrain and hypothalamus, co-express GLP-1R along with α1-adrenergic and δ-opioid receptors, suggesting a localized mechanism within the CNS that could coordinate peripheral anti-inflammatory responses. This co-expression‎ indicates a mechanism within the CNS allowing these neurons to sense and respond to the peripheral inflammatory state. Through the interaction of these receptors, the brain can receive signals of peripheral inflammation and respond through neural signaling, thereby modulating or alleviating the inflammatory response. This receptor co-expression‎ on neurons in specific brain regions may enable the brain to finely regulate the body’s response to inflammation. For instance, when peripheral tissues become inflamed, the related signals might be transmitted to the brain through these receptors on the neurons, and the brain could then respond to these signals via neural pathways, thus regulating the level of peripheral inflammation.423

GLP-1RAs and AD

AD is a progressive and irreversible neurodegenerative disorder characterized by an unclear etiology and pathogenesis.424 In AD, GLP-1(7-36) amide inhibits IL-1β transcription and prevents cognitive dysfunction, amyloid precursor protein synthesis, and cell death. It also enhances learning and memory by promoting long-term potentiation (LTP).425,426 In a murine model of AD, the administration of GLP-1RAs effectively reduced the levels of pathological markers associated with AD. These markers include oligomeric antibodies and amyloid plaque load. Furthermore, GLP-1RAs have been shown to attenuate microglial activation and improve memory-related behaviors.71 Moreover, GLP-1RAs have demonstrated considerable therapeutic promise in animal models of both PD and AD.427,428,429 The compound NLY01 is particularly effective at attenuating the activity of proinflammatory microglia and preventing the transformation of astrocytes to a reactive phenotype. This activity is instrumental in safeguarding hippocampal neurons from the deleterious impacts of glutamate-induced excitotoxicity and hypoxic conditions. In the context of AD, where neuroinflammation and neurotoxicity are prominent pathological hallmarks, the modus operandi of NLY01 offers a potential therapeutic avenue to mitigate analogous pathological mechanisms inherent to this neurodegenerative condition.430

GLP-1RAs and PD

PD is a chronic neurodegenerative disorder that affects the CNS and is the second most preval‎ent neurodegenerative disease worldwide.14 GLP-1RAs are promising pharmacological agents for treating PD due to their potential to preserve the integrity and function of dopaminergic neurons. In addition to its effects on metabolic regulation, GLP-1, when synthesized within the brain, exhibits neuroprotective properties.397,427,431 A clinical trial titled “Liraglutide in Early Parkinson’s Disease” was published in the New England Journal of Medicine, exploring the effects of liraglutide on patients with early-stage PD diagnosed within the last three years.432 The research was a 14-month Phase II double-blind randomized controlled trial. The results showed that liraglutide had a modest positive effect on improving motor function and performed well in terms of safety and tolerability, although there were some manageable gastrointestinal side effects.432 The study emphasizes the need for further research into the potential benefits and risks of liraglutide in patients at different stages of PD.432

GLP-1RAs and addictive disorders

Researchers have discovered that semaglutide has the ability to reduce both recurrent alcohol consumption and overall alcohol intake in rats by more than 50%.433 Specifically, alcohol-dependent rats were administered semaglutide, which resulted in a significant reduction in their alcohol consumption.433 Further investigation into the mechanism underlying the alcohol-reducing effects of semaglutide suggested that this effect may involve the modulation of alcohol-induced rewards and punishments within the brain. Researchers have also shown that semaglutide impacts the reward and punishment systems in the brains of mice, particularly in the nucleus accumbens region, which is part of the limbic system.433 It is believed that alcohol activates the brain’s reward and punishment system, triggering the release of dopamine, a neurotransmitter associated with pleasure and reward, both in humans and animals. However, the administration of semaglutide appeared to block this process, potentially leading to a diminished alcohol-induced reward and punishment response within the body.433 Remarkably, compared with untreated rats, treated rats exhibited a significant reduction in alcohol intake, which was reduced by half.433 These findings highlight the potential therapeutic efficacy of semaglutide in mitigating alcohol consumption.434

Interestingly, a clinical study published in “Nature Metabolism” in 2023 investigated the restorative effects of liraglutide on impaired associative learning in individuals with obesity. The study utilized a single-blind, randomized, placebo-controlled, crossover design, combined with functional magnetic resonance imaging (fMRI), to analyze the performance of 54 participants (30 with normal insulin sensitivity and 24 with impaired insulin sensitivity) on sensory associative learning tasks while receiving liraglutide and placebo treatments.435 Liraglutide significantly enhanced associative learning abilities in obese individuals with impaired insulin sensitivity. It modulated neural activity in the ventral striatum and midbrain pathways, affecting brain areas related to metabolic signaling.435,436 Liraglutide improved task performance at the behavioral level and enhanced the encoding of adaptive prediction errors, which are crucial neural signals in the learning process.435 (Fig. 5).

Fig. 5

The effects of GLP-1RAs on nervous system. GLP-1RAs have diverse effects, including alleviating neuroinflammation and pain in OA, reducing food intake and improving body weight, protecting peripheral nerves, maintaining astrocyte function and metabolic homeostasis, and showing potential therapeutic benefits in AD and PD. Semaglutide, a diabetes drug, can also reduce alcohol consumption by modulating the brain’s reward and punishment systems

Full size image

GLP-1RAs in the cardiovascular system

In the cardiovascular system, GLP-1 can reduce cardiac ischemia-reperfusion injury through the activation of specific signaling pathways, such as the PI3K/Akt pathway.437,438 This involves modulating the cell apoptosis process, for example, by decreasing the Bax/Bcl-2 ratio in cardiomyocytes, reducing cytochrome C release, and caspase activation.438,439 GLP-1 can also enhance endothelial function by promoting the production of NO, possibly through activating eNOS, thereby affecting vasodilation, anti-inflammatory actions, and anti-atherosclerosis.43,192,440,441

GLP-1RAs and AS

AS is characterized by the formation of fibrofatty plaques within arterial walls and is one of the foremost global causes of mortality.5 GLP-1RAs, as exemplified by liraglutide and semaglutide, exhibit pronounced cardiovascular protective effects.43 Liraglutide and semaglutide have been demonstrated to be effective at reducing lipid and blood pressure levels through numerous scientific investigations, thereby contributing to the mitigation of AS and cardiovascular ailments.442 Preclinical studies have documented the inhibitory effects of GLP-1RAs on the development of AS in animal models.443 These agents exert their anti-atherosclerotic effects through various mechanisms, including by improving blood lipid profiles,444 preserving endothelial integrity and regulating endothelial function,445 as well as modulating inflammatory processes.70

GLP-1RAs confer substantial benefits for individuals with AS owing to their multifaceted impact on various aspects of cardiovascular health.39,40,446 Notably, GLP-1RAs exhibit pronounced efficacy in optimizing blood lipid profiles by effectively suppressing chylomicron secretion in the intestine, thereby mitigating the occurrence of postprandial hyperlipidemia.447 Moreover, these agents promote hemodynamic equilibrium,18 diminish thrombotic propensity,448 alleviate endothelial oxidative stress,449 attenuate inflammatory processes,450 and foster a favorable balance of the gut microbiota,451 all of which collectively contribute to the salutary effects of these agents in patients with AS.

GLP-1RAs have been shown to exert beneficial effects on the maintenance of endothelial integrity. One study suggested that GLP-1RAs exert direct endothelial protective effects by activating the GLP-1R-dependent AMPK/Akt/eNOS pathway. This pathway facilitates the generation of NO, thereby contributing to the preservation of vascular health and endothelial function. Additionally, GLP-1RAs facilitate the maintenance of endothelial barrier integrity, thus playing a crucial role in preventing vascular leakage.452 Endothelial cells exhibit enhanced NO production and concurrent suppression of endothelin formation, resulting in vascular smooth muscle relaxation and vasodilation mediated by the endothelium (e.g., GLP-1, exenatide, and liraglutide).453 Indeed, GLP-1RAs, including exenatide, liraglutide, and semaglutide, have been linked to the diminished expression‎ of matrix metalloproteinases (MMPs).454,455,456 MMPs are a class of enzymes that play a crucial role in the breakdown of extracellular matrix components. Excessive MMP activity can lead to the weakening of fibrous caps and increase the risk of plaque rupture in atherosclerotic lesions.454 By reducing MMP expression‎, GLP-1R stimulation may help preserve the integrity of fibrous caps and mitigate the risk of plaque rupture.

GLP-1RAs have been shown to reduce the levels of systemic inflammatory markers.457,458 Importantly, the effective management of inflammation is widely acknowledged to play a crucial role in the prevention of cardiovascular diseases.459,460 The anti-inflammatory effects of GLP-1RAs contribute to the attenuation of atherosclerotic plaque lesion development through various mechanisms. First, GLP-1RAs have been shown to inhibit the expression‎ and release of proinflammatory cytokines, such as IL-6 and TNF-α, thereby inhibiting the overall inflammatory response.461 GLP-1RAs can suppress the activation of nuclear factor-kappa B (NF-κB), a key transcription factor involved in the regulation of inflammatory processes.462 Inhibition of the NF-κB signaling pathway leads to the decreased production of inflammatory mediators, including adhesion molecules and chemokines, which are crucial for the recruitment of immune cells to sites of inflammation.463 In addition, liraglutide can delay the formation of AS by inducing cell cycle arrest in vascular smooth muscle cells through the AMPK pathway.5

GLP-1RAs and hypertension

The carotid body, a vital chemoreceptor in the human body, plays a pivotal role in the regulation of respiratory and cardiovascular activity, energy homeostasis, and blood glucose sensitivity.464 Notably, the carotid body expresses GLP-1R, which is implicated in the concurrent regulation of blood pressure and blood glucose.465 The downregulation of GLP-1R expression‎ may represent a significant contributory factor to the co-occurrence of hypertension and hyperglycemia.466 One study proposed a novel mechanism wherein postprandial GLP-1 release, under normal physiological conditions, inhibits the activity of chemosensory cells in the carotid body, thereby counteracting sympathetic excitability mediated by elevated blood glucose or insulin levels.465 Impaired GLP-1 secretion or reduced GLP-1R expression‎ may result in aberrantly heightened sympathetic excitation. However, the exogenous administration of GLP-1RAs can mitigate sympathetic excitability by suppressing the peripheral chemoreflex originating from the carotid body.467 Under hyperglycemic conditions, GLP-1RAs regulate hypertension by inhibiting carotid body function.468 Specifically, these agents can attenuate the excitability of carotid body cells and diminish sympathetic activation, ultimately leading to a reduction in sympathetic responses.465 This modulatory effect holds promise for ameliorating sympathetic activity in individuals with hypertension, as these agents lower blood pressure levels.469 Importantly, the “GLP-1-carotid body pathway” may represent a novel therapeutic target for managing cardiovascular metabolism and treating patients with diabetes and hypertension who exhibit heightened sympathetic activity.465 (Fig. 6).

Fig. 6

The Effects of GLP-1RAs on Carotid Body Activation. GLP-1 by inhibiting the chemoreception in carotid body cell activity to adjust the new mechanism of sympathetic nerve excitability, and points out that GLP-1 agonists can inhibit the origin of the carotid body around chemical reflection to lighten the sympathetic nerve excitability, which is expected to improve the sympathetic activity of the patients with high blood pressure, reduce blood pressure levels

GLP-1RAs and heart failure

The preval‎ence of left ventricular ejection fraction (LVEF)-preserved heart failure continues to increase. The symptoms in patients are severe and often accompanied by functional impairments, especially in the obese population. Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases, with patients bearing a high symptomatic burden and physical limitations that impact their daily lives. These limitations include fatigue, shortness of breath, reduced exercise capacity, and limb swelling. Currently, there are no approved targeted therapies for LVEF-preserved heart failure associated with obesity. Moreover, GLP-1R has not yet been identified on human myocardial cells, negating any direct effects of GLP-1RAs on myocardial cells.470

Recently, studies have shown that the GLP-1RA Meg peptide also enters the ejection fraction reserve following heart failure therapy. The results of a trial of semaglutide in obese patients with HFpEF showed a significant amelioration of symptoms and improvements in motor function and weight loss compared with patients treated with a placebo.470 In this study, researchers randomized 529 patients with heart failure with a preserved ejection fraction and body mass index (weight in kilograms in the square of the height in meters) ≥30 to receive once-weekly injections of semaglutide (2.4 mg) or placebo for 52 weeks. The two primary endpoints were the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS, which ranges from 0 to 100) and the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS). Higher scores indicate fewer symptoms and physical limitations and weight change from baseline. The confirm‎atory secondary endpoints included the change in the 6-min walking distance, a hierarchical composite of death and heart failure events; the difference between the change in the KCCQ-CSS and the change in the 6-min walking distance; and the change in the C-reactive protein (CRP) level.470 In this trial, semaglutide benefited patients with heart failure and preserved ejection fraction by intervening with upstream metabolic drivers. This agent differs from earlier therapies that were designed to reduce myocardial loading or induce neurohumoral blockade. These positive results indicate that the change in myocardial cells may not be the primary driver of HFpEF; instead, the multisystem pathologic processes that are associated with this condition have long been well established as drivers of its clinical presentation and outcomes.470

One could argue that the success of sodium-glucose cotransporter 2 (SGLT2) inhibitors, and now of GLP-1RAs, suggests that metabolic abnormalities play an important role in driving HFpEF.470 SGLT2 inhibition is also known to benefit patients with heart failure and a reduced ejection fraction.471 The mechanisms by which SGLT2 inhibitors treat heart failure include lowering blood glucose levels by inhibiting the SGLT2 protein in the renal tubules and reducing glucose reabsorption in the tubules.472 Promoting the urinary excretion of sodium and water reduces fluid retention and hypervolaemia, thereby reducing the load on the heart.473 It also improves myocardial energy metabolism, increases fatty acid oxidation in the myocardium, and improves myocardial energy supply.474 Moreover, these agents reduce the risks of myocardial inflammation and fibrosis and improve cardiac structure and function.475 By the way, a clinical study published in “Nature Metabolism” detailed the effects of semaglutide and dapagliflozin (an SGLT2 inhibitor) on blood sugar control in patients with T2DM of different pathophysiological types.476 It was found that semaglutide performed better than dapagliflozin in reducing HbA1c levels.476 The study results suggest that semaglutide may be a more suitable choice for patients with severe insulin deficiency, while dapagliflozin might be effective for a broader range of patients with metabolic abnormalities.476

If SGLT2 inhibitors and GLP-1RAs are effective in patients with heart failure (regardless of whether the ejection fraction is reduced or preserved), the commonalities between the two types of heart failure may be greater than is often thought. If so, the two types of heart failure may be very similar, except that the cause of heart failure with a preserved ejection fraction may not be the same as that with a reduced ejection fraction.477,478,479 If this is indeed the case, then both types of heart failure are syndromes caused by multiple metabolic and inflammatory changes; however, heart failure with reduced ejection fraction also has a regional cause. Therefore, intrinsic cardiac load and capacity do not improve in patients with heart failure with reduced ejection fraction, and patients HFpEF benefit only from the treatment of abnormal metabolism and inflammation.475,480,481

The encouraging results obtained with semaglutide in patients with heart failure and a preserved ejection fraction may provide a new option for this patient population, in which additional therapy, as well as another upstream therapy for patients with a higher BMI who have indications for this condition, is urgently needed. The clinical translation of these trial results, which will be important for the comparison of GLP-1RAs with SGLT2 inhibitors in the treatment of patients with heart failure and a preserved ejection fraction, remains to be determined.470,478,482,483,484

GLP-1RAs in the digestive system

Treatment with GLP-1RAs can alleviate insulin signaling by reducing the phosphorylation of Akt protein (Decreased Akt-P) and activating Protein Kinase C-ε (PKC-ε).485,486 This affects the synthesis of triacylglycerol (TAG), phosphatidic acid (di-P PA), and diacylglycerol (DAG) in the liver.206,487 These changes lead to a reduction in the production of non-esterified fatty acids (LCFAs) and glucose, as well as a decrease in the synthesis of VLDL (Very Low-Density Lipoprotein).3

GLP-1RAs and NAFLD/NASH

When dietary nutrients are ingested, endogenous incretins (GIP and GLP-1) activate K and L cells in the gut, which then secrete GIP and GLP-1.488,489,490 In the pancreas, this stimulates the secretion of insulin and inhibits the secretion of glucagon.491 In the brain, it reduces appetite and improves satiety.130,133 In the gastrointestinal tract, it lowers the synthesis and secretion of triglycerides.491 By regulating appetite, insulin secretion, and lipid metabolism, GLP-1RAs have potential benefits in the treatment of NAFLD, NASH, and T2DM.130,492,493

NASH is a liver disease primarily caused by fat accumulation, which can progress to liver fibrosis, cirrhosis, or even liver cancer.494,495,496,497,498 The role of GLP-1 in NASH has garnered attention due to its potential in regulating metabolism, improving insulin sensitivity, and exerting anti-inflammatory effects.17,499,500,501,502,503 Insulin resistance, a common occurrence in NASH patients, is a key driver of the disease’s progression.504,505,506 GLP-1 enhances the insulin signaling pathway in the liver by activating the GLP-1R, especially through the phosphorylation of insulin receptor substrates and the activation of the PI3K/Akt signaling pathway, thereby increasing hepatic insulin sensitivity, facilitating glucose uptake and utilization, and reducing hepatic gluconeogenesis.3,507

GLP-1RAs reduce liver fat accumulation by activating AMPK, which inhibits fatty acid synthesis enzymes and promotes fatty acid β-oxidation, thus diminishing lipid droplet accumulation in hepatocytes.508,509,510,511 Additionally, GLP-1 mitigates liver inflammation and fibrosis by inhibiting the NF-κB pathway, reducing the release of pro-inflammatory cytokines such as TNF-α and IL-6, and thus suppressing inflammatory pathways.307,413

In terms of apoptosis inhibition, GLP-1 activates the PI3K/Akt signaling pathway, enhances the expression‎ of the anti-apoptotic protein Bcl-2, and inhibits the activation of caspase family proteins, reducing cell apoptosis.206 This helps prevent the progression of NASH to liver fibrosis and cirrhosis. The weight-loss effect of GLP-1RAs also benefits NASH improvement, by reducing appetite and increasing energy expenditure to promote weight loss, thereby indirectly ameliorating NASH.206,512 Thus, GLP-1 and its agonists slow down the progression of NASH and may positively impact the reversal of liver fibrosis.513,514 These signaling pathways suggest that GLP-1 and its receptor agonists may influence the progression of NASH through multiple mechanisms, providing several potential therapeutic targets including: FOXO1, a transcription factor that plays a critical role in regulating glucose and lipid metabolism. GLP-1 can improve abnormalities in glucose metabolism and excessive lipid accumulation by modulating the activity of FOXO1.5,514 Sirt1, a protein deacetylase, plays a key role in delaying cellular aging and regulating metabolism.515,516,517 GLP-1 may improve the liver’s antioxidant capacity and metabolic function by activating Sirt1, thereby helping to alleviate the pathological changes associated with NASH.

A 2023 study published in the “Journal of Hepatology” reported on a Phase IIa trial aimed at eval‎uating the efficacy and safety of efinopegdutide in patients with NAFLD, comparing it to semaglutide.144 Efinopegdutide is a dual agonist for GLP-1R and GIPR.144 The study used a randomized, open-label design and employed magnetic resonance imaging technology (MRI-PDFF) to measure liver fat content (LFC) after 24 weeks of treatment. Results showed that efinopegdutide was more effective in reducing LFC compared to semaglutide. Additionally, the study assessed weight and metabolic responses, finding that efinopegdutide’s tolerability was similar to that of semaglutide, although certain gastrointestinal side effects were more common. Overall, efinopegdutide emerged as a promising option for the treatment of NAFLD.144

GLP-1RAs and gastrointestinal cancers

GLP-1 and its receptor agonists show some potential in the treatment of gastrointestinal cancers, although this remains an emerging area of research.518,519,520,521

Hepatocellular carcinoma (HCC)

Initially developed for treating diabetes, GLP-1RAs have shown potential in treating NASH, which is closely related to HCC.513 Studies suggest that the anti-inflammatory and metabolic effects of GLP-1RAs might also influence the progression of liver diseases, including HCC.503,512,518 These effects include modulating cell proliferation, inflammation, and oxidative stress in liver cells, all of which are key factors in the development and progression of HCC.513,522 In a mouse model induced with NASH-related HCC, treatment with liraglutide (a type of GLP-1RA) was shown to prevent the progression of hepatocellular carcinoma.518 This was observed through improved glycemic control, reduced occurrence of liver cancer, and better liver histology compared to the control group.518 Studies indicate that liraglutide may inhibit liver carcinogenesis through its metabolic effects, suggesting that GLP-1RAs could potentially play a role in preventing or managing HCC in the context of NASH.523 Not only hepatocellular carcinoma, but GLP-1 has also shown potential in the treatment of other gastrointestinal tumors.524,525

Pancreatic cancer

Researchers first compared the expression‎ of GLP-1R in human pancreatic cancer tissues with adjacent non-tumorous pancreatic tissues, finding generally lower or absent expression‎ of GLP-1R in pancreatic cancer tissues.520 Subsequently, the study observed that treatment with liraglutide, both in vitro (cell culture models) and in vivo (mouse models), inhibited the tumor formation and metastatic capabilities of pancreatic cancer cells by activating GLP-1R.520 The anti-tumor effect of liraglutide is related to its inhibition of the PI3K/Akt signaling pathway, as the activation of Akt is crucial for promoting cell survival and proliferation, and liraglutide can inhibit this process in a dose-dependent manner.520,526 In the context of T2DM, liraglutide, by regulating the PI3K/Akt pathway and activating GLP-1R, effectively inhibits the growth and spread of pancreatic cancer cells.520

Colorectal cancer

The potential impact of GLP-1RAs on colorectal cancer (CRC) treatment is achieved through the modulation of Bone Morphogenetic Protein 4 (BMP4).519 In T2DM and CRC, the regulation of BMP4 is abnormal, which is a key focus of the research.519 Specifically, high blood glucose-induced insulin resistance in CRC cells leads to increased BMP4 expression‎, which activates the BMP4-Smad1/5/8 signaling pathway.519 The activation of this pathway enhances cell proliferation and metastatic capabilities by promoting epithelial-mesenchymal transition (EMT), thereby increasing the invasiveness and metastatic potential of tumors. However, GLP-1RAs have been shown to reduce BMP4 levels through exogenous administration. Studies have shown that treating CRC cells with GLP-1RA can inhibit cell proliferation induced by insulin resistance by downregulating BMP4. Therefore, BMP4 becomes a potential therapeutic target in CRC, especially in a diabetic context where high blood glucose significantly affects cancer progression through the BMP4 pathway.519 Ultimately, GLP-1RA, by regulating BMP4 and its effects on cell proliferation and metastasis, provides a promising treatment approach.519 This not only demonstrates the role of GLP-1RA in diabetes management but also offers potential for integrating diabetes and cancer treatment.520 This finding emphasizes the importance of considering metabolic status in cancer treatment and the necessity for further research in this area.519 While early models have shown promising results, the application of GLP-1RAs in cancer treatment has not yet been established and requires further clinical trials.527

Conclusions and perspective

Primarily recognized for their role in diabetes mellitus treatment, GLP-1RAs have demonstrated significant benefits in cardiovascular health, skeletal muscle-related diseases, obesity management, and neurodegenerative conditions, among others. In this review, we delved into the multifaceted role of GLP-1R, especially its significance in disease contexts beyond traditional glucose metabolism. It explored the mechanisms of action of GLP-1RAs and their therapeutic potential in a wide array of diseases, such as diabetes mellitus, providing new insights into metabolic disease management. These findings underscore the multifunctionality of GLP-1R as a therapeutic target and its involvement in various biological processes, emphasizing its role in addressing complex disease mechanisms. GLP-1 acts on the GLP-1R, activating multiple intracellular signaling pathways, including the cAMP/PKA pathway, the PI3K/Akt signaling pathway, and pathways related to anti-inflammatory and anti-oxidative stress responses, among others. These pathways play a crucial role in its wide-ranging therapeutic effects, extending the benefits of GLP-1RAs beyond metabolic diseases. While the therapeutic benefits of GLP-1RAs in diabetes management are well-established, their emerging role in other diseases suggests novel treatment strategies. Conclusively, research on GLP-1R and its agonists marks a promising direction in metabolic disease therapy, extending their potential beyond glucose regulation and offering hope for more comprehensive approaches in addressing metabolic diseases. This research necessitates continued exploration, potentially revolutionizing future therapeutic strategies.

In the intensely competitive GLP-1 drug market, simply enhancing drug efficacy is no longer sufficient to make new products stand out. Looking ahead, the key strategies for product innovation and differentiation are likely to focus on five main directions: expanding the therapeutic indications, achieving precision treatment with multiple biological targets, optimizing the clinical application of drug combinations, developing new formulations of oral medications, and extending the duration of drug action. These strategies not only illustrate the depth and breadth of pharmaceutical research but also signify the frontier of future medical innovations. Firstly, expanding indications is a current hotspot in GLP-1 drug research. GLP-1 drugs have been found applicable for various diseases such as cardiovascular disease, NASH, AD, and chronic kidney disease. For instance, semaglutide has been approved and is being researched for indications including obesity, T2DM, reducing cardiovascular risk, chronic kidney disease, NAFLD, and AD, indicating that the development of new indications could provide new growth opportunities for GLP-1 drugs. Secondly, efficacy is the core criterion for eval‎uating drugs, and currently, multi-target GLP-1 drugs have shown better efficacy. For example, triple-target agonists like retatrutide are leading multi-target GLP-1 drugs. Moreover, combination therapies have demonstrated significant advantages, such as Novo Nordisk’s CagriSema (semaglutide + cagrilintide), which shows superior glycemic control and weight reduction effects compared to semaglutide alone, demonstrating that combination therapy can achieve more than the sum of its parts while reducing side effects.117 Additionally, to improve patient compliance, it is crucial to extend the drug’s half-life. This has been achieved through techniques such as peptide sequence modification, peptide lipidation, albumin fusion, and Fc fusion. For example, scientists are developing GLP-1 drugs that require only monthly injections. Lastly, considering some patients’ resistance to injections, oral medications have become the preferred option. However, the oral GLP-1 product, Rybelsus, has low bioavailability and requires cumbersome daily administration, which reduces its convenience. Therefore, enhancing bioavailability and stability will be key in the future, although breakthroughs in once-weekly oral GLP-1 drugs are still awaited. With the increasing preval‎ence of metabolic diseases globally, interventions targeting GLP-1R could play an important role in reducing the burden of these conditions. Collaborative efforts among researchers, clinicians, and pharmaceutical developers are essential to translate these scientific insights into effective and accessible treatments.

결론 및 전망

당뇨병 치료에서 주로 인정받아온 GLP-1 수용체 작용제(GLP-1RAs)는 심혈관 건강, 골격근 관련 질환, 비만 관리, 신경퇴행성 질환 등 다양한 분야에서 유의미한 효과를 보여주었습니다.

이 리뷰에서는 GLP-1 수용체의 다면적인 역할을 탐구했으며, 특히 전통적인 포도당 대사

GLP-1RAs의 작용 메커니즘과 당뇨병을 포함한 다양한 질환에서의 치료 잠재력을 탐구했으며, 이는 대사 질환 관리에 대한 새로운 통찰을 제공했습니다. 이러한 결과는 GLP-1R이 치료 표적으로서의 다기능성과 다양한 생물학적 과정에의 관여를 강조하며, 복잡한 질환 메커니즘 해결에 기여하는 역할을 부각시켰습니다. GLP-1은 GLP-1R에 작용하여 cAMP/PKA 경로, PI3K/Akt 신호전달 경로, 항염증 및 항산화 스트레스 반응과 관련된 경로 등 다양한 세포 내 신호전달 경로를 활성화합니다. 이러한 경로는 GLP-1RAs의 광범위한 치료 효과를 결정하는 핵심 역할을 하며, 그 혜택을 대사 질환을 넘어 확장시킵니다. GLP-1RAs의 당뇨병 관리에서의 치료적 혜택은 잘 확립되어 있지만, 다른 질환에서의 새로운 역할은 혁신적인 치료 전략을 제시합니다. 결론적으로, GLP-1R 및 그 작용제에 대한 연구는 대사 질환 치료 분야에서 유망한 방향을 제시하며, 혈당 조절을 넘어 대사 질환을 포괄적으로 접근하는 새로운 가능성을 열어줍니다. 이 연구는 지속적인 탐구가 필요하며, 미래 치료 전략을 혁신할 잠재력을 지니고 있습니다.

강력한 경쟁이 치열한 GLP-1 약물 시장에서 단순히 약물 효능을 향상시키는 것만으로는 새로운 제품을 차별화하기에 충분하지 않습니다.

미래를 내다보면, 제품 혁신과 차별화의 핵심 전략은 다섯 가지 주요 방향에 초점을 맞출 것으로 예상됩니다:

치료 적응증 확대,

다중 생물학적 표적을 활용한 정밀 치료 달성,

약물 조합의 임상적 적용 최적화,

경구용 약물의 새로운 제형 개발,

약물 작용 시간 연장.

이러한 전략은 제약 연구의 깊이와 폭을 보여주는 동시에 미래 의료 혁신의 최전선을 상징합니다.

첫째, 적응증 확대는 현재 GLP-1 약물 연구의 주요 핫이슈입니다. GLP-1 약물은 심혈관 질환, NASH, AD, 만성 신장 질환 등 다양한 질환에 적용 가능함이 확인되었습니다. 예를 들어, 세마글루타이드(semaglutide)는 비만, 제2형 당뇨병(T2DM), 심혈관 위험 감소, 만성 신장 질환, NAFLD, AD 등 다양한 적응증에 대해 승인되었으며 연구 중입니다. 이는 새로운 적응증 개발이 GLP-1 약물의 새로운 성장 기회를 제공할 수 있음을 시사합니다.

둘째, 효능은 약물을 평가하는 핵심 기준이며, 현재 다중 표적 GLP-1 약물이 더 우수한 효능을 보여주고 있습니다. 예를 들어, 트리플 표적 작용제인 레타트루티드(retatrutide)는 다중 표적 GLP-1 약물의 선두주자로 자리매김하고 있습니다.

또한, 복합 요법은 Novo Nordisk의 CagriSema(semaglutide + cagrilintide)처럼 semaglutide 단독 투여보다 우수한 혈당 조절 및 체중 감소 효과를 보여, 복합 요법이 각 성분의 합보다 더 큰 효과를 내며 부작용을 줄일 수 있음을 입증했습니다.117

또한, 환자 순응도를 개선하기 위해 약물의 반감기를 연장하는 것이 중요합니다. 이는 펩타이드 서열 수정, 펩타이드 지질화, 알부민 융합, Fc 융합 등 기술로 달성되었습니다. 예를 들어, 과학자들은 월 1회 주사만으로 투여 가능한 GLP-1 약물을 개발 중입니다.

마지막으로, 일부 환자의 주사 거부감을 고려할 때 경구 투여제가 선호되는 옵션이 되었습니다.

그러나 경구용 GLP-1 제품인 Rybelsus는 생체 이용률이 낮고 번거로운 매일 투여가 필요해 편의성이 떨어집니다.

따라서 생체 이용률과 안정성을 향상시키는 것이 미래의 핵심 과제입니다.

다만 주 1회 경구용 GLP-1 약물의 혁신은 여전히 기대되고 있습니다. 전 세계적으로 대사 질환의 유병률이 증가함에 따라 GLP-1 수용체를 표적으로 하는 치료법은 이러한 질환의 부담을 줄이는 데 중요한 역할을 할 수 있습니다. 연구자, 임상 의사, 제약 개발자 간의 협력이 이러한 과학적 통찰을 효과적이고 접근 가능한 치료법으로 전환하는 데 필수적입니다.

References

1.  
2.