An Update on GLP-1 Receptor Agonists

IF 3.7 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Zachary Bloomgarden
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The first therapeutically used GLP-1RA was isolated as exendin-4 from the saliva of a venomous lizard, <i>Heloderma suspectum</i> (the “Gila monster”), in 1992, with initial preclinical studies reported in 1996; although FDA approval for its use in treatment of T2D as exenatide was not granted until 2005. The next GLP-1RA used therapeutically was liraglutide, receiving approval in 2010, with dulaglutide receiving approval in 2014, semaglutide approval in 2017, and tirzepatide (a combined agonist of GLP-1 and GIP) approval in 2022; FDA approvals of liraglutide, semaglutide, and tirzepatide for treatment of obesity were granted in 2014, 2021, and 2023, respectively.</p><p>Both the GLP-1 and GIP receptor agonists enhance insulin production when glucose levels are elevated. This physiological insulin-secretory effect contrasts with the action of the older sulfonylureas, which activate the ATP-sensitive potassium channels of the pancreatic beta cells, mimicking the cellular process that physiologically acts to link insulin production to the beta cell's energy state. The consequent increase in endogenous insulin production leads the GLP-1RAs to have glucose-lowering action comparable to that of daily treatment with basal insulin [<span>1</span>]; with weight loss rather than weight gain and with lower likelihood of hypoglycemia [<span>2, 3</span>].</p><p>In addition to their glycemic benefits, GLP-1RAs are associated with improvement in mortality and in CV and renal outcomes in clinical trials [<span>4, 5</span>], both in people having and not having T2D [<span>6</span>], as well as in real-world studies of people with T2D [<span>7</span>] and of people with obesity without T2D [<span>8</span>]. In a study from the US Veteran's Affairs hospitals with mean followup of nearly 4 years comparing more than 200 000 persons receiving GLP-1RA with more than 1.2 million receiving usual care, benefits of GLP-1RAs included reduction in risk of stroke, myocardial infarction, pulmonary embolism, phlebitis, heart failure, hepatic failure, chronic kidney disease, bacterial infections, postprocedural respiratory complications, aspiration pneumonitis, chronic obstructive pulmonary disease, pneumonia and respiratory failure, as well as improvement in a variety of psychiatric issues including suicidal ideation and cannabis, alcohol and opioid use disorders [<span>9</span>].</p><p>There is, however, heterogeneity in the response to GLP-1RA in real-world studies of people with T2D, with a study of more than 4000 people with T2D showing that 43% had neither weight loss nor glycemic improvement, and that the degree of weight loss was mild, at 1.4% of basal, with a mean HbA1c decrease of just 0.49% [<span>10</span>]. Furthermore, in a Danish study of over 40 000 first-time users of GLP-1RAs with T2D followed between 2007 and 2020, 14.1% and 21.2% discontinued at 6 and 12 months, respectively [<span>11</span>].</p><p>A crucial question has been whether the combined GLP-1 and GIP receptor agonist tirzepatide is also associated with CV outcome benefit. On July 31, 2025, Eli Lilly and Co announced preliminary results of a nearly 5-year head-to-head randomized controlled CV outcome trial, SURPASS-CVOT, comparing tirzepatide with the GLP-1RA dulaglutide among 13 299 high-risk people with T2D [<span>12</span>]. The rationale for the use of an active comparator was the recognized benefit of GLP-1RA in such patients, with the use of a placebo considered unethical. The combined risk of Major Adverse Cardiovascular Events (MACE) comprised of CV mortality, myocardial infarction, or stroke, was 8% lower for tirzepatide than for dulaglutide (numerically, albeit not statistically significantly, better), satisfying the criteria for non-inferiority, with a significant reduction when combined with patient-level data from the earlier trial of dulaglutide vs. placebo [<span>13</span>]. There was a significant reduction in secondary endpoints, although not correcting for multiple comparisons: 16% lower all-cause mortality, slower rate of decline in the estimated glomerular filtration rate, greater reduction in HbA1c (1.7% vs. 0.9% from baseline of 8.4%) and 12% vs. 5% weight loss from a baseline of 93 kg. GI side effects occurred more frequently with tirzepatide than dulaglutide, with 13% vs. 10% of participants discontinuing treatment due to adverse events (12).</p><p>There is growing interest in combining GLP-1RAs with other diabetes medications, particularly SGLT2 inhibitors. This combination appears to enhance cardiovascular and renal health, showing lower risks of heart failure and mortality than among individuals using GLP-1RA alone [<span>14</span>].</p><p>Emerging research suggests GLP-1RAs may protect against neurodegenerative diseases, including Alzheimer's Disease [<span>15</span>] and Parkinson's Disease [<span>16</span>], with beneficial impacts on cognitive function [<span>17</span>]; although some of this may simply reflect GLP-1RA-related reduction in stroke. Metabolic-associated steatotic liver disease affects some two-thirds of people worldwide with T2D, of whom two-thirds have steatohepatitis, with multiple studies showing evidence of benefit of GLP-1RA with and without diabetes [<span>18, 19</span>]. GLP-1RAs are associated with a reduction in the apnea-hypopnea index among people with obstructive sleep apnea, with tirzepatide appearing to be more potent in this regard [<span>20</span>]. Innovation in GLP-1RA formulations includes oral options and dual- and triple-acting drugs targeting GIP, glucagon, and amylin as well as GLP-1 for glucose and weight management. New agents and biosimilars are being tested. Orally active GLP-1RAs have similar, although less potent, metabolic, weight-reducing, and CV-protective effects to those seen with parenterally administered GLP-1RAs.</p><p>Akin to the “statin hypothesis” that statins, to a degree proportional to their cholesterol-lowering effect, can prevent or treat CV disease, we appear to be close to confirming a “GLP-1RA hypothesis” that this extended class of agents can prevent or treat CV disease, to a degree proportional to their weight- and glucose-lowering effect, with multiple additional benefits. However, our very success with these agents has led to a dilemma: nearly 200 million people worldwide have T2D and high CVD risk [<span>21</span>]. How can we ensure that these effective but highly expensive medications can be afforded by all the patients we now recognize should be so treated?</p><p>The author declares no conflicts of interest.</p>","PeriodicalId":189,"journal":{"name":"Journal of Diabetes","volume":"17 8","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1753-0407.70147","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Diabetes","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/1753-0407.70147","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0

Abstract

The glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are a class of medications primarily developed for the management of type 2 diabetes (T2D) and are increasingly being used for various other health effects. Here's a simplified overview of their history, effects, and future prospects:

Glucose-dependent insulinotropic polypeptide (GIP) and then GLP-1 were identified in the 1970s as peptides potentiating the insulin secretory response to nutrient ingestion. In the early 1980s, the proglucagon amino acid sequence and gene were mapped, leading to the recognition of the common derivation of GLP-1 and GLP-2, produced in the L-cells of the distal small intestine, while GIP is produced in the K-cells of the proximal small intestine. The first therapeutically used GLP-1RA was isolated as exendin-4 from the saliva of a venomous lizard, Heloderma suspectum (the “Gila monster”), in 1992, with initial preclinical studies reported in 1996; although FDA approval for its use in treatment of T2D as exenatide was not granted until 2005. The next GLP-1RA used therapeutically was liraglutide, receiving approval in 2010, with dulaglutide receiving approval in 2014, semaglutide approval in 2017, and tirzepatide (a combined agonist of GLP-1 and GIP) approval in 2022; FDA approvals of liraglutide, semaglutide, and tirzepatide for treatment of obesity were granted in 2014, 2021, and 2023, respectively.

Both the GLP-1 and GIP receptor agonists enhance insulin production when glucose levels are elevated. This physiological insulin-secretory effect contrasts with the action of the older sulfonylureas, which activate the ATP-sensitive potassium channels of the pancreatic beta cells, mimicking the cellular process that physiologically acts to link insulin production to the beta cell's energy state. The consequent increase in endogenous insulin production leads the GLP-1RAs to have glucose-lowering action comparable to that of daily treatment with basal insulin [1]; with weight loss rather than weight gain and with lower likelihood of hypoglycemia [2, 3].

In addition to their glycemic benefits, GLP-1RAs are associated with improvement in mortality and in CV and renal outcomes in clinical trials [4, 5], both in people having and not having T2D [6], as well as in real-world studies of people with T2D [7] and of people with obesity without T2D [8]. In a study from the US Veteran's Affairs hospitals with mean followup of nearly 4 years comparing more than 200 000 persons receiving GLP-1RA with more than 1.2 million receiving usual care, benefits of GLP-1RAs included reduction in risk of stroke, myocardial infarction, pulmonary embolism, phlebitis, heart failure, hepatic failure, chronic kidney disease, bacterial infections, postprocedural respiratory complications, aspiration pneumonitis, chronic obstructive pulmonary disease, pneumonia and respiratory failure, as well as improvement in a variety of psychiatric issues including suicidal ideation and cannabis, alcohol and opioid use disorders [9].

There is, however, heterogeneity in the response to GLP-1RA in real-world studies of people with T2D, with a study of more than 4000 people with T2D showing that 43% had neither weight loss nor glycemic improvement, and that the degree of weight loss was mild, at 1.4% of basal, with a mean HbA1c decrease of just 0.49% [10]. Furthermore, in a Danish study of over 40 000 first-time users of GLP-1RAs with T2D followed between 2007 and 2020, 14.1% and 21.2% discontinued at 6 and 12 months, respectively [11].

A crucial question has been whether the combined GLP-1 and GIP receptor agonist tirzepatide is also associated with CV outcome benefit. On July 31, 2025, Eli Lilly and Co announced preliminary results of a nearly 5-year head-to-head randomized controlled CV outcome trial, SURPASS-CVOT, comparing tirzepatide with the GLP-1RA dulaglutide among 13 299 high-risk people with T2D [12]. The rationale for the use of an active comparator was the recognized benefit of GLP-1RA in such patients, with the use of a placebo considered unethical. The combined risk of Major Adverse Cardiovascular Events (MACE) comprised of CV mortality, myocardial infarction, or stroke, was 8% lower for tirzepatide than for dulaglutide (numerically, albeit not statistically significantly, better), satisfying the criteria for non-inferiority, with a significant reduction when combined with patient-level data from the earlier trial of dulaglutide vs. placebo [13]. There was a significant reduction in secondary endpoints, although not correcting for multiple comparisons: 16% lower all-cause mortality, slower rate of decline in the estimated glomerular filtration rate, greater reduction in HbA1c (1.7% vs. 0.9% from baseline of 8.4%) and 12% vs. 5% weight loss from a baseline of 93 kg. GI side effects occurred more frequently with tirzepatide than dulaglutide, with 13% vs. 10% of participants discontinuing treatment due to adverse events (12).

There is growing interest in combining GLP-1RAs with other diabetes medications, particularly SGLT2 inhibitors. This combination appears to enhance cardiovascular and renal health, showing lower risks of heart failure and mortality than among individuals using GLP-1RA alone [14].

Emerging research suggests GLP-1RAs may protect against neurodegenerative diseases, including Alzheimer's Disease [15] and Parkinson's Disease [16], with beneficial impacts on cognitive function [17]; although some of this may simply reflect GLP-1RA-related reduction in stroke. Metabolic-associated steatotic liver disease affects some two-thirds of people worldwide with T2D, of whom two-thirds have steatohepatitis, with multiple studies showing evidence of benefit of GLP-1RA with and without diabetes [18, 19]. GLP-1RAs are associated with a reduction in the apnea-hypopnea index among people with obstructive sleep apnea, with tirzepatide appearing to be more potent in this regard [20]. Innovation in GLP-1RA formulations includes oral options and dual- and triple-acting drugs targeting GIP, glucagon, and amylin as well as GLP-1 for glucose and weight management. New agents and biosimilars are being tested. Orally active GLP-1RAs have similar, although less potent, metabolic, weight-reducing, and CV-protective effects to those seen with parenterally administered GLP-1RAs.

Akin to the “statin hypothesis” that statins, to a degree proportional to their cholesterol-lowering effect, can prevent or treat CV disease, we appear to be close to confirming a “GLP-1RA hypothesis” that this extended class of agents can prevent or treat CV disease, to a degree proportional to their weight- and glucose-lowering effect, with multiple additional benefits. However, our very success with these agents has led to a dilemma: nearly 200 million people worldwide have T2D and high CVD risk [21]. How can we ensure that these effective but highly expensive medications can be afforded by all the patients we now recognize should be so treated?

The author declares no conflicts of interest.

GLP-1受体激动剂的最新进展
人们对GLP-1RAs与其他糖尿病药物,特别是SGLT2抑制剂联合使用的兴趣越来越大。这种组合似乎增强了心血管和肾脏健康,显示出与单独使用GLP-1RA的个体相比,心力衰竭和死亡率的风险更低。新兴研究表明,GLP-1RAs可能预防神经退行性疾病,包括阿尔茨海默病[15]和帕金森病[16],并对认知功能[17]产生有益影响;尽管其中一些可能只是反映了与glp - 1ra相关的中风减少。代谢相关的脂肪性肝病影响全球约三分之二的T2D患者,其中三分之二患有脂肪性肝炎,多项研究显示GLP-1RA对糖尿病和非糖尿病患者的益处[18,19]。GLP-1RAs与阻塞性睡眠呼吸暂停患者呼吸暂停低通气指数的降低有关,替西肽在这方面似乎更有效。GLP-1RA配方的创新包括口服选择和针对GIP、胰高血糖素、胰胰肽以及GLP-1的双作用和三作用药物,用于葡萄糖和体重管理。新药和生物仿制药正在测试中。口服活性GLP-1RAs与肠外给药GLP-1RAs具有相似的代谢、减肥和cv保护作用,尽管效力较弱。类似于“他汀假说”,他汀类药物与其降胆固醇效果成正比,可以预防或治疗心血管疾病,我们似乎接近于确认“GLP-1RA假说”,即这类扩展的药物可以预防或治疗心血管疾病,在一定程度上与其降体重和降血糖效果成正比,并具有多种额外的益处。然而,我们在这些药物上的成功也导致了一个两难的局面:全世界有近2亿人患有T2D和高心血管疾病风险。我们如何确保这些有效但非常昂贵的药物能够由我们现在认识的所有患者负担得起?作者声明无利益冲突。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Diabetes
Journal of Diabetes ENDOCRINOLOGY & METABOLISM-
CiteScore
6.50
自引率
2.20%
发文量
94
审稿时长
>12 weeks
期刊介绍: Journal of Diabetes (JDB) devotes itself to diabetes research, therapeutics, and education. It aims to involve researchers and practitioners in a dialogue between East and West via all aspects of epidemiology, etiology, pathogenesis, management, complications and prevention of diabetes, including the molecular, biochemical, and physiological aspects of diabetes. The Editorial team is international with a unique mix of Asian and Western participation. The Editors welcome submissions in form of original research articles, images, novel case reports and correspondence, and will solicit reviews, point-counterpoint, commentaries, editorials, news highlights, and educational content.
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