Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and cardiometabolic protection: historical development and future challenges

Introduction

The 2024 Lasker-DeBakey Clinical Medical Research Award recognized the groundbreaking achievements of biochemist Svetlana Mojsov, endocrinologist Joel Habener, and molecular pharmacologist Lotte Knudsen, whose collaborative efforts have revolutionized the treatment of cardiometabolic diseases. This journey began with observations in the early twentieth century that intestinal extracts could lower blood glucose and culminated in 1986 when Habener and Mojsov identified glucagon-like peptide-1 (GLP-1) as an incretin hormone derived from the precursor of glucagon. Mojsov's expertise in peptide chemistry was pivotal in the synthesis of bioactive GLP-1 peptides, and her collaboration with Habener demonstrated their potent insulinotropic effects, bridging a decades-long gap in understanding the role of the gut in glucose regulation. In the 1990s, Knudsen applied her training in molecular pharmacology at Novo Nordisk to overcome the rapid degradation of GLP-1 by developing stabilized analogs. Her work led to the development of liraglutide in 2010 and semaglutide in 2017, therapies that not only improve glycemic control, but also promote weight loss, reduce cardiovascular disease (CVD) risk and have improved the quality of life for millions of people worldwide [1, 2]. These key milestones have paved the way for the development of a growing number of GLP-1RAs, most of which are administered subcutaneously. Notably, semaglutide is also available in an oral formulation, further expanding their therapeutic applications [3].

GLP-1RAs exert significant cardiometabolic effects across multiple organs, as evidenced by both preclinical and clinical studies [4–7]. GLP-1, secreted by ileocolonic enteroendocrine L cells in response to food intake, acts as an incretin hormone to enhance glucose-dependent insulin secretion. Its actions on pancreatic islet β-, δ-, and α-cells increase insulin and somatostatin secretion while decreasing glucagon levels, thereby improving glycemic control. In the central nervous system, GLP-1 reduces appetite, leading to reduced adiposity, reduced inflammation and weight loss. In peripheral tissues, GLP-1RAs improve hepatic lipid metabolism by reducing hepatic steatosis and circulating lipid levels. They also protect renal function by reducing albuminuria and slowing the decline in estimated glomerular filtration rate (eGFR). In addition, GLP-1RAs lower blood pressure, improve microvascular and coronary blood flow, stabilize atherosclerotic plaques by reducing inflammation, and attenuate cardiac apoptosis while improving glucose metabolism [4–8].

Despite these benefits, it remains unclear whether the protective effects on specific organs result from direct receptor activation or are indirectly driven by systemic health improvements, such as weight loss [9]. For instance, GLP-1R is expressed at low levels in the heart and blood vessels [6]. In the kidney, they are localized to a subset of vascular smooth muscle cells but are absent from glomerular epithelial or tubular cells [4]. Similarly, in the liver, hepatocytes, Kupffer cells and stellate cells lack canonical GLP-1R expression [5]. These gaps emphasize the need for targeted research to elucidate the underlying mechanisms and unlock the full therapeutic potential of GLP-1RAs. Addressing these challenges will require a combination of preclinical and clinical studies to validate findings and ensure broad applicability.

Beyond their initial role in the treatment of type 2 diabetes (T2D), GLP-1RAs have evolved into versatile therapies with benefits in conditions such as obesity, chronic kidney disease (CKD) and metabolic liver disease. The interrelationship among these cardiometabolic conditions—where obesity and T2D often lead to renal and hepatic complications—highlights the need for a multidisciplinary approach to evaluate the complex interplay and pleiotropic effects of GLP-1RAs. Based on current clinical evidence, the following sections explore the therapeutic applications of GLP-1RAs in T2D, obesity, CKD, and metabolic liver disease, emphasizing their role in addressing the interconnected cardiometabolic spectrum and the challenges that remain to better unlock their potential.

Type 2 diabetes

The first GLP-1RA to receive clinical approval, exenatide, was introduced in 2005 for the treatment of T2D. Since then, additional therapies have been developed, including liraglutide, exenatide, lixisenatide, semaglutide, albiglutide, dulaglutide, and tirzepatide—the first dual agonist targeting both the GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR), whose endogenous ligand (GIP) is predominantly synthesized in enteroendocrine K cells located in the duodenum and jejunum. Among these, dulaglutide, semaglutide, and tirzepatide are the most widely used GLP-1RAs for T2D, with their efficacy supported by robust evidence from phase 3 clinical trials [8, 10].

In the SUSTAIN-7 trial, semaglutide showed superiority to dulaglutide at both low and high doses in improving glycemic control and promoting weight loss, allowing more patients to achieve clinically meaningful goals while maintaining a comparable safety profile [11]. Similarly, in the SURPASS-2 trial, tirzepatide was shown to be both non-inferior and superior to semaglutide in reducing glycated hemoglobin (HbA1c) levels at 40 weeks [12]. A broader cardiovascular evaluation of tirzepatide, conducted through a prespecified meta-analysis of individual patient data from seven clinical trials, confirmed its safety in people with T2D [13]. In addition to glycemic control and weight loss, GLP-1RAs offer additional benefits such as reductions in blood pressure, postprandial lipemia, and inflammation, which likely contribute to their cardiovascular benefits [6]. In this context, a post-hoc analysis of the SURPASS clinical trial program showed that treatment with tirzepatide resulted in a clinically meaningful reduction in the prevalence of metabolic syndrome, emphasizing its potential to address broader cardiometabolic health [14].

In CVD outcomes trials (CVOTs) such as LEADER [15], SUSTAIN-6 [16], Harmony Outcomes [17], AMPLITUDE-O [18] and REWIND [19], GLP-1RAs—including liraglutide, semaglutide, albiglutide, efpeglenatide and dulaglutide—significantly reduced the incidence of three-point major adverse cardiovascular events (MACE). While these studies collectively support the use of GLP-1RAs for the treatment of T2D in patients at risk for CVD, discrepancies remain regarding the reduction of specific components of MACE, possibly due to differences in study design, treatment duration, and inclusion criteria. This highlights the importance of designing future trials with well-defined inclusion and exclusion criteria, particularly to account for variations in comorbidities such as hypertension, coronary artery disease, and heart failure (HF). Such criteria will improve stratification and allow more precise tailoring of therapies. In contrast, trials such as ELIXA [20], EXSCEL [21], and FREEDOM [22], which evaluated lixisenatide and exenatide in patients with T2D and CVD, reported neutral results for three-point MACE.

Most of the data on cardiovascular outcomes associated with GLP-1RAs come from studies conducted in overweight or obese patients with T2D [6]. These findings have stimulated further investigation into whether higher doses of GLP-1RAs could achieve greater weight loss in individuals with obesity, even in the absence of T2D [10, 23]. Expanding these investigations to include more diverse populations, particularly those underrepresented in earlier trials, is essential to improve the generalizability of the findings and to ensure that the benefits of GLP-1RAs extend equitably across all patient populations.

Obesity

Liraglutide was the first GLP-1RA approved for the treatment of obesity in 2014, followed by semaglutide and tirzepatide in 2023 [10]. When used in combination with diet and exercise, liraglutide has been associated with clinically significant weight loss in overweight or obese patients, as well as reductions in glycemic variables and multiple cardiometabolic risk factors, including waist circumference, blood pressure, and inflammatory markers, and improvements in health-related quality of life [24]. Semaglutide was also evaluated for the treatment of obesity in the STEP trial, where blood pressure, HbA1c, C-reactive protein, and fasting lipid levels were lower in patients treated with semaglutide [25]. Interestingly, the proteomic changes induced by semaglutide in participants of the STEP trial were linked to a broad spectrum of biological processes, including body weight regulation, glycemic control, lipid metabolism, and inflammatory pathways [26]. The safety of semaglutide was evaluated in the CVOT SELECT study in patients with pre-existing cardiovascular and overweight or obesity but without T2D. Semaglutide reduced the incidence of non-fatal myocardial infarction, non-fatal stroke and death from cardiovascular causes [27]. Interestingly, the benefits of semaglutide were observed earlier than those reported in clinical trials in people with T2D [6]. The cardiovascular effects of semaglutide were also evaluated in patients with HF with preserved ejection fraction (HFpEF) and obesity in the STEP-HFpEF trial. Semaglutide was associated with significant improvements in HF symptoms, physical limitation and exercise capacity, as well as a reduction in inflammation and greater weight loss compared with placebo [28]. Interestingly, the magnitude of benefit was directly related to the amount of weight lost [29].

In the SUMMIT study, tirzepatide significantly reduced the risk of cardiovascular death and worsening HFpEF and obesity [30]. In addition, tirzepatide reduced the risk of worsening HF events requiring hospitalization or urgent medical intervention, such as intravenous drug administration. The trial also reported improvements across a broad spectrum of HF severity measures, including health status, functional capacity, general well-being, quality of life, exercise tolerance and medication burden [31]. As the first trial focus specifically on patients with HFpEF and obesity, the SUMMIT trial provides critical insights that may shape future guidelines for the management of this patient population [30, 31]. These findings also highlight the expanding therapeutic applications of GLP-1RAs beyond obesity and underline their potential role in treating complex cardiometabolic conditions. In the SURMOUNT-1 trial, weight reduction with tirzepatide was associated with significant improvements in all cardiovascular and metabolic risk factors measured, including reductions in waist circumference, systolic and diastolic blood pressure, fasting insulin, lipid levels and aspartate aminotransferase levels, compared with placebo [32]. Similarly, in the SURMOUNT-3 trial, tirzepatide demonstrated clinically meaningful additional weight loss in overweight or obese adults who had previously achieved initial weight loss through an intensive lifestyle intervention. These weight reductions were associated with significant improvements in cardiometabolic risk factors, including reductions in waist circumference, systolic and diastolic blood pressure, HbA1c, fasting glucose and fasting insulin. Favorable changes in lipid profiles were also observed, with improvements in all lipid levels except for high-density lipoprotein, cholesterol and free fatty acids [33].

In a pre-specified analysis of data from the CVOT SELECT study, semaglutide was associated with clinically significant weight loss and improvements in anthropometric measures compared to placebo, with weight loss maintained over 4 years. Subgroup analyses revealed differences in outcomes based on self-reported race, sex and body mass index (BMI). Women experienced greater weight loss than men, while participants who self-identified as Asian experienced smaller reductions, possibly due to differences in BMI classification [34]. These findings are consistent with those of the SURMOUNT-CN trial, which evaluated weekly tirzepatide in Chinese adults and reported significant weight loss comparable to other SURMOUNT trials conducted in predominantly white populations. However, while weight loss continued for 72 weeks in SURMOUNT-1, it plateaued at week 44 in SURMOUNT-CN. This discrepancy has been attributed to differences in BMI thresholds and the proportion of female participants [35]. As BMI criteria for obesity vary by ethnicity—for example, Chinese adults typically have lower thresholds than Europeans [36]—these results highlight the need to tailor GLP-1RA trials to account for sex, BMI and ethnic diversity.

In the treatment of obesity in pediatric populations, GLP-1RAs have shown promising results when combined with lifestyle interventions. In adolescents aged 12 to < 18 years, liraglutide significantly reduced the BMI compared with placebo [37], a benefit also observed with semaglutide in the same age group [38]. In addition, liraglutide was associated with a greater reduction in BMI compared with placebo in children aged 6 to < 12 years [39]. These promising results in adolescents and children highlight the efficacy of GLP-1RAs in combination with lifestyle interventions, but significant challenges remain. These include limited long-term data on growth and puberty, lack of ethnic diversity in studies, and reliance on BMI as the primary measure, which is not ideal for growing children and may not accurately reflect fat mass or overall health. In addition, the high cost of these medications and the need for lifelong treatment raise concerns about accessibility, while side effects and potential effects on eating behavior raise caution. Ethically, the use of these drugs in developing bodies must be balanced against the risks of untreated severe obesity, which represents significant threats to physical and mental health. Therefore, larger and more diverse studies are needed to confirm these findings and to assess the long-term safety and efficacy of GLP-1RAs in pediatric populations.

Chronic kidney disease

CKD is a common condition that significantly increases the risk of CVD and often progresses to kidney failure, with T2D and obesity being major risk factors for its development [40]. In this context, GLP-1RAs have shown their ability to reduce the risk of individual components of MACE, all-cause mortality, hospitalizations for HF, and worsening renal function in patients with T2D [41]. In addition, CVOTs have reported that treatment with dulaglutide [42] or semaglutide [43] slows the rate of eGFR decline in people with T2D, highlighting their cardiorenal benefits. Despite promising evidence, patients with advanced CKD have been underrepresented in previous studies, and the effect of GLP-1RAs on albuminuria has not yet been consistently translated into a reduced risk of kidney failure. Recent results from the FLOW trial address this research gap and support semaglutide as a potential first-line treatment for patients with T2D, CKD and albuminuria, alongside other therapies [44]. The FLOW trial reported that semaglutide significantly reduced the risk of major renal events, cardiovascular events and all-cause mortality, while also slowing the annual decline in renal function. Notably, these benefits appeared to result from mechanisms unrelated to changes in body weight. The authors propose that semaglutide exerts its renoprotective effects primarily by reducing inflammation within the kidney. These findings highlight the significant clinical potential of semaglutide to improve renal, cardiovascular and survival outcomes in high-risk populations, supported by its favorable safety profile [44]. These findings are complemented by a pre-specified analysis from the SELECT trial, which showed that the incidence of the composite renal endpoint—which includes outcomes such as death from kidney disease, initiation of chronic renal replacement therapy, severe decline in eGFR or the development of persistent macroalbuminuria—was lower with semaglutide compared to placebo [45]. Treatment with semaglutide also showed an overall benefit in slowing eGFR decline, with a more pronounced effect observed in individuals with lower baseline eGFR levels [45]. These findings suggest that semaglutide may have renal benefits in people who are overweight or obese, even in the absence of T2D. A recent meta-analysis of randomized controlled trials found that GLP-1RAs were effective in reducing the incidence of clinically significant renal events, renal failure, and cardiovascular complications [46].

Future directions for GLP-1RAs in CKD include understanding their potential direct effects on the kidney and immune system, independent of metabolic improvements such as weight loss and glycemic control. Mechanistic studies, such as those using single-cell transcriptomics and spatial metabolite localization, aim to map molecular changes after treatment and identify pathways activated or inhibited by GLP-1RAs. These findings may lead to more targeted and personalized therapies for CKD. In addition, expanding clinical trials to evaluate the long-term benefits of GLP-1RAs, including their use in non-diabetic CKD populations, will be critical. Given the global burden of CKD, translation of these findings into accessible and cost-effective public health strategies is essential. Multidisciplinary collaborations will play a key role in translating these advances into comprehensive care for CKD patients.

Metabolic liver disease

The term non-alcoholic fatty liver disease (NAFLD) has recently been redefined as metabolic dysfunction-associated steatotic liver disease (MASLD). This updated terminology emphasizes the presence of hepatic steatosis alongside co-existing cardiometabolic risk factors such as overweight/obesity, T2D, hypertension, or dyslipidemia, in the absence of significant alcohol consumption [47]. MASLD exhibits considerable variability in clinical outcomes, as a recent study has identified two distinct phenotypic clusters. The 'liver-specific' cluster is linked to rapid progression of chronic liver disease and strong genetic associations but limited cardiovascular risk. In contrast, the 'cardiometabolic' cluster, characterized by dysglycemia and hypertriglyceridemia, is associated with a higher risk of CVD and T2D, despite a similar incidence of chronic liver disease. These phenotypes also differ in their underlying transcriptomic and metabolomic signatures, highlighting the heterogeneity of MASLD and the need for tailored therapeutic approaches [48]. MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), a condition characterized by liver fibrosis, which is the primary determinant of adverse cardiovascular outcomes and increased mortality in affected patients [49]. Since GLP-1R signaling reduces food intake and body weight, its benefits are closely linked to reductions in hepatic steatosis, inflammation, and fibrosis, which together may collectively contribute to improvements in metabolic liver disease. Interestingly, these GLP-1R-mediated effects appear to be indirect, as the presence of the functional GLP-1R liver cells, including hepatocytes, remains a topic of debate. This controversy derives from challenges in detecting GLP-1R expression in the liver, where levels are extremely low [5].

Few clinical trials have evaluated the efficacy of GLP-1RAs in MASH. A phase 2 trial in patients with MASH and stage 1–3 fibrosis reported that treatment with semaglutide resulted in significant resolution of steatohepatitis without progression or improvement in fibrosis [50]. In patients with MASH, reduction of fibrosis is considered a more important surrogate endpoint than resolution of steatohepatitis. However, semaglutide did not improve histologic outcomes in patients with MASH who had progressed to cirrhosis [51]. Tirzepatide, evaluated in adults with MASH and stage 2 or 3 fibrosis, demonstrated more effective resolution of MASH compared to placebo without worsening fibrosis. Its safety profile was consistent with previous findings in T2D and obese participants [32]. Similarly, survodutide, another dual GLP-1R/glucagon receptor agonist (GCGR), was studied in adults with MASH and stage 1–3 fibrosis and showed superiority over placebo in improving MASH without worsening fibrosis [52].

Future strategies for the management of MASH should focus on expanding clinical trials to include larger, more ethnically diverse populations and longer follow-up periods to ensure the generalizability and durability of treatment outcomes. Given the chronic nature of MASH, long-term treatment plans will likely be required to maintain histologic improvements, underscoring the need for clear criteria for when and in whom therapies can be safely discontinued. In addition, efforts must be made to mitigate the high costs and barriers to access associated with prolonged treatment, as these may exacerbate existing health disparities. Special attention should be given to patients with cirrhosis, for whom current therapies have limited efficacy, emphasizing the importance of early intervention to prevent disease progression. As the therapeutic landscape for MASH continues to expand, clinicians will need to balance benefits, risks, and patient preferences to provide personalized and equitable care.

Concluding remarks

GLP-1RAs have transformed the treatment of cardiometabolic diseases, extending benefits beyond T2D and obesity to improve cardiovascular, renal and hepatic outcomes. However, further research is needed to elucidate their organ-protective mechanisms, particularly those independent of weight loss.

Evidence suggests that reduced systemic inflammation and pleiotropic effects play a role, but the precise localization and function of GLP-1R in organ protection remain unclear. Preclinical studies have highlighted potential signaling pathways, but have revealed species-specific differences in receptor distribution, raising concerns about direct extrapolation to humans. High-throughput techniques such as transcriptomics and proteomics are essential to uncover molecular mechanisms, identify organ-specific pathways, and distinguish direct receptor effects from indirect benefits. Integrating these approaches into research could deepen our understanding of the pleiotropic effects of GLP-1RAs and contribute to the development of targeted therapies.

As their applications expand beyond T2D and obesity, understanding patient comorbidities is essential for personalized care. Clinical trials must establish clear inclusion and exclusion criteria that take into account factors such as age, sex, ethnicity, and comorbidities to improve patient stratification, tailor therapies, and account for the diversity of real-world populations.

The long-term safety, efficacy, and accessibility of GLP-1RAs require ongoing evaluation, particularly given the potential cardiometabolic deterioration associated with therapy discontinuation and the need to comprehensively assess adverse effects to ensure their safe and effective use. Addressing high costs is critical to ensuring equitable global use and maximizing therapeutic benefits. The development of orally active GLP-1RAs and next-generation multi-agonist therapies targeting glucagon, GIP, and amylin receptors offers opportunities to improve metabolic outcomes, but rigorous safety evaluations will be essential to support widespread and sustainable adoption.

In this context, the novel drug retatrutide, a triple agonist targeting GIPR, GLP-1, and GCGR, shows promise with significant glycemic control and weight loss in T2D, along with a favorable safety profile characterized by mild gastrointestinal symptoms [53]. In non-diabetic adults with obesity (BMI ≥ 27), 48 weeks of treatment resulted in significant weight loss [54], while patients with MASLD experienced a significant reduction in liver fat [55].

GLP-1RAs, initially developed for glycemic control and weight loss, have evolved into cornerstone therapies for cardiometabolic diseases, marking a paradigm shift in modern healthcare. While these medications do not represent a panacea, their broad spectrum of clinical applications positions them among the most transformative pharmacological advances of recent decades. Continued innovation and dedicated efforts to bridge the knowledge gaps are essential to fully unlock their transformative potential for global public health.

Author contributions

EF and FW jointly conceptualized the idea, outlined the structure, and wrote the manuscript. Both authors contributed equally to drafting, revising, and finalizing the editorial. EF and FW have reviewed and approved the final version of the manuscript and agree to take full responsibility for its accuracy and integrity.

Funding

No specific funding was received for the preparation of this editorial.

Declarations