Introduction

Glucagon-like peptide-1 is an incretin (gut-derived hormone) that plays a crucial role in glucose homeostasis, linking nutrient absorption to pancreatic hormone secretion. Pharmacological stimulation via glucagon-like peptide-1 receptor agonists (GLP1RAs) has become an essential tool for the treatment of type 2 diabetes mellitus (T2DM). These agents enhance glucose-dependent insulin secretion, slow gastric emptying, and reduce postprandial glucagon levels, controlling glucose levels effectively without causing hypoglycemia. Beyond glycemic control, the results of cardiovascular outcome trials (CVOTs) have demonstrated these agents' efficacy in lowering rates of major adverse cardiovascular events (MACE) in patients with T2DM, which remain the leading cause of death and complications in this population. These advances have prompted the American Diabetes Association (ADA), American Association of Clinical Endocrinology (AACE), and other professional societies to update clinical practice guidelines and recommend use of these agents in patients with diabetes mellitus (DM) and established cardiovascular disease (CVD) regardless of hemoglobin A1c concentrations, including consideration as first-line pharmacotherapy.

Specific formulations of GLP1RAs are indicated (semaglutide as Wegovy and liraglutide as Saxenda [Novo Nordisk Inc., Bagsvaerd, Denmark]) or used off-label (semaglutide as Ozempic [Novo Nordisk Inc., Bagsvaerd, Denmark] and tirzepatide as Mounjaro [Lilly USA LLC, Indianapolis, Indiana]) for chronic weight management as an adjunct to lifestyle changes. Recently, the dual-incretin agonist tirzepatide was approved for the same (as Zepbound [Lilly USA LLC, Indianapolis, Indiana]), following evidence of even more robust weight reduction in the SURMOUNT program: the SURMOUNT-1 (Tirzepatide Once Weekly for the Treatment of Obesity), SURMOUNT-2 (Tirzepatide Once Weekly for the Treatment of Obesity in People With Type 2 Diabetes), SURMOUNT-3 (A Study of Tirzepatide [LY3298176] In Participants After A Lifestyle Weight Loss Program), and SURMOUNT-4 (Tirzepatide Once Weekly for the Treatment of Obesity-4) trials. These agents and their efficacy have captured the attention of patients and media alike, with blockbuster launches leading to recurrent and disruptive supply shortages, along with reports of adverse events for which no previous causal link has been established.

This expert analysis reviews the role of GLP1RAs in cardiovascular (CV) health and risk of gastrointestinal tract (GI) adverse effects.

Role in Cardiovascular Health

GLP1RA CVOTs, initiated after the 2008 Food and Drug Administration (FDA) mandate for CV safety assessments of new T2DM pharmacological agents, have unveiled the therapeutic potential of this class.¹ The results of notable studies such as the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results), REWIND (Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes), and SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) have been instrumental in elucidating the CV impacts of GLP1RAs in patients with T2DM and highlighting benefit in both patients with or at risk of atherosclerotic cardiovascular disease (ASCVD).^2-4 These findings have been echoed by the results of pooled analyses within the SURPASS program of tirzepatide: the SURPASS-1 (A Study of Tirzepatide [LY3298176] in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone), SURPASS-2 (A Study of Tirzepatide [LY3298176] Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes), SURPASS-3 (A Study of Tirzepatide [LY3298176] Versus Insulin Degludec in Participants With Type 2 Diabetes), and SURPASS-4 (Tirzepatide Versus Insulin Glargine in Type 2 Diabetes and Increased Cardiovascular Risk).⁵ The forthcoming SURPASS-CVOT (A Study of Tirzepatide [LY3298176] Compared With Dulaglutide on Major Cardiovascular Events in Participants With Type 2 Diabetes) will directly assess the impact of dual-incretin agonism on CV outcomes in patients with T2DM.⁶

The expanding use of GLP1RAs for chronic weight management in individuals without DM has spurred interest in CV implications in the population without DM. Recently, the results of the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity) trial highlighted the impact of semaglutide 2.4 mg in a population with ASCVD but without DM, demonstrating a 20% relative risk reduction (1.5% absolute risk reduction) in three-point MACE and a 19% relative risk reduction in all-cause mortality over a mean follow-up of 3.3 years in 17,604 patients without DM who were receiving standard-of-care therapies for secondary CV risk reduction (albeit, arguably, suboptimal control of hypertension and hyperlipidemia in the context of more modern guidelines).⁷ It is noteworthy that this therapy was approved by the FDA on March 8, 2024 for reduction of CVD events in persons with CVD and overweight or obesity.⁸

However, it is important to mention that long-term adherence to the medication will probably be needed to ensure stable weight loss and cardiometabolic benefits, as some study data have shown significant rebound weight gain.⁹

Other cardiometabolic benefits have been shown or are being actively studied. In the STEP-HFpEF (Semaglutide Treatment Effect in People With Obesity and HFpEF) trial, use of semaglutide led to potent improvement of symptoms, physical limitations, and exercise function in patients with heart failure with preserved ejection fraction.¹⁰ The FLOW (A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease), a study examining major adverse kidney outcomes in patients with diabetic nephropathy, was halted early because of overwhelming efficacy, with anticipated release of results in 2024.¹¹ Upcoming trials are set to further explore the wide-ranging impacts of monoincretin and dual-incretin agonists (Table 1).

Table 1: Upcoming Trials of Monoincretin and Dual-Incretin Agonists

Risk of Gastrointestinal Tract Adverse Effects

GI adverse effects are the predominant adverse effect of this class and have been demonstrated in the results of every GLP1RA trial. Effects are dependent on agent potency and dose, and typically include various upper GI (nausea, vomiting) and lower GI (diarrhea, constipation) symptoms.^2,3 Notably, participants receiving placebo in these trials often also report significant rates of these symptoms, and between-group differences in cessation due to intolerable adverse effects remain low.³ In addition to slower dose uptitration, various toolkits have been developed to assist in tolerability, as highlighted and summarized in the text and figures of a recent review.¹⁰

Although all incretin-based therapies slow gastric emptying and use should be reconsidered in patients with gastroparesis, recent media reports of isolated cases of rare and irreversible gastroparesis, even after agent cessation, have thus far not been observed in trials.^12-14

Adjudicated cases of pancreatitis across GLP1RA trials of populations with and without T2DM have not been statistically significant and have sometimes been numerically higher in placebo-treated groups.^2,3 Notably, these trials typically exclude patients with a history of pancreatitis. The findings of a recent retrospective observational study suggested higher rates of pancreatitis by documentation of international classification of disease codes in patients taking GLP1RAs compared with those taking bupropion/naltrexone, an antiobesity medication.¹⁵ Although some trials of GLP1RAs have reported mild increases in baseline levels of lipase and amylase, these levels often remain within normal ranges and, crucially, have not been associated with subsequent development of acute pancreatitis.¹⁶

The study also explored other potential adverse effects, such as bowel obstruction, and found higher rates in patients taking GLP1RAs versus those taking bupropion/naltrexone. Notably, this finding was exclusively driven by liraglutide use, with patients taking semaglutide showing numerically fewer cases than those taking bupropion/naltrexone.

Overall, the results of prospective, randomized, placebo-controlled trials have not substantiated or supported concerns about increased risk of pancreatitis, bowel obstruction, or irreversible gastroparesis in patients taking GLP1RAs.

Conclusion

GLP1RAs have significantly advanced the management of T2DM, kidney health, and CV health, supported by robust findings from CVOTs. Although GI adverse effects are commonly reported, their overall safety profile remains strong, and concerns about severe adverse effects such as gastroparesis and pancreatitis have not been substantiated in findings from prospective trials. The expanding use of GLP1RAs for chronic weight management and the exploration of their broader cardiometabolic impacts highlight their growing significance and expansive potential in modern therapeutic strategies.

References

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