Not Just for Diabetes: The Next Frontier for GLP-1 Agonists

Strength of Recommendation

B: Based on single randomized controlled trial.

Illustrative Case

A 54-year-old male with a history of obesity (BMI 35 kg/m²), hypertension, hyperlipidemia and a prior myocardial infarction comes in to your office for follow-up of his chronic conditions and to discuss weight loss. He has tried structured lifestyle interventions to help lose weight and has had little success. What else could you recommend?

Clinical Context

Despite further understanding of the poor outcomes associated with obesity, the prevalence of obesity has continued to increase dramatically over time. Per the National Health and Nutrition Examination Survey (NHANES), the age-adjusted prevalence of obesity (defined as a BMI > 30 kg/m2) in US adults was 41.9% as of 2020. This represents a substantial increase from 30.5% in 1999-2000. The prevalence of Class III obesity (defined as a BMI > 40 kg/m2) has increased from 4.7% to 9.2% in the same timeframe.¹ Obesity is associated with several comorbid conditions including diabetes mellitus, dyslipidemia, and cardiovascular disease. In fact, obesity is recognized as an independent risk factor for cardiovascular disease (CVD) in current guidelines.²

As obesity rates have grown, CVD and its complications have continue to be quite prevalent. The leading cause of death in adults in the United States continues to be ischemic heart disease. In the United States, as of the 2023 update reflecting data from 2020, the prevalence of CVD (coronary heart disease, stroke, hypertension or heart failure) in adults older than 20 years of age was 48.6%, or about 127.9 million people.³ Given all the above, it is imperative that the scientific and medical communities continue to work towards developing effective strategies to improve both obesity rates and adverse cardiovascular outcomes.

Glucagon-like peptide 1- (GLP-1) based therapies are familiar medications to clinicians for the treatment of type 2 diabetes. Their mechanism of action includes enhancing glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon. In recent years, there have been pushes to study more medications for chronic weight management and studies have shown the weight loss benefits of these agents. In 2014, liraglutide was the first GLP-1 agonist approved for use for weight loss in inidividuals with obesity. By 2021, the FDA approved semaglutide for chronic weight management – awakening a new era on the treatment of obesity in medicine.⁴

To further this, a meta-analysis from 2021 looked at randomized-controlled trials studying GLP-1 agonists in individuals with type 2 diabetes and found an overall reduction in major adverse cardiovascular events (MACE) in this population.⁵ However, no prior large-scale studies have examined the effect of these medications on CVD outcomes in individuals without diabetes who are overweight or obese.

Methods

This article was identified as a potential PURL through the standard systematic methodology.⁶ An additional literature search was conducted by searching UpToDate and DynaMed with the terms [obesity in adults] and [treatment] to find additional literature to place this research into the context of current clinical practice.

Study Summary

This placebo-controlled randomized controlled trial (RCT) involved over 17,000 patients at 804 clinical sites in 41 countries and examined the effects of semaglutide in patients without diabetes and with a history of CVD.⁷ In order to be included in the study, patients had to be age 45 years or older, have a BMI greater than or equal to 27 and pre-existing cardiovascular disease (defined as prior MI, stroke or symptomatic peripheral arterial disease).

Patients were randomized to receive either weekly subcutaneous semaglutide injection titrated to 2.4 mg or a weekly placebo injection. Statistical analysis was performed using an intention-to-treat principle. The primary study outcome was a composite endpoint that included death from cardiovascular (CV) causes, nonfatal MI or nonfatal stroke. Confirmatory secondary outcomes included death from a CV cause, a composite heart failure endpoint (death from CV cause or hospitalization/urgent medical visit for heart failure) and death from any cause.

After a mean follow-up period of almost 40 months, the primary outcome occurred less frequently in the semaglutide group compared to the placebo group (hazard ratio [HR] 0.8; 95% CI, 0.72-0.90; NNT 67). There was a trend towards reduced CV death in the semaglutide group but this outcome was not statistically significant (HR 0.85; 95% CI, 0.71-1.01). The remainder of the secondary outcomes were not tested for statistical significance per the gatekeeping testing strategy used during statistical analysis. The difference in the primary composite outcome between the two groups appears to be driven primarily by reduction in the occurrence of nonfatal MI in patients receiving semaglutide (HR 0.72, 95% CI 0.61- 0.85), though this individual endpoint was not specifically assessed for statistical significance. Regarding serious adverse events, there were slightly more occurrences of serious gastrointestinal (GI) disorders among patients in the semaglutide group, but the difference was not statistically significant (p=0.48). Permanent discontinuation of the study drug due to any adverse event occurred more often in the semaglutide group (16.6% vs 8.2%, p<0.001), and this was primarily driven by GI side effects.

What’s New

The GLP-1 agonist semaglitude reduces the risk of major adverse cardiac events (death from cardiac causes, nonfatal MI or nonfatal stroke) among individuals with a BMI of 30 or above and pre-existing cardiovascular disease. Treating around 67 individuals with these characteristics would be expected to prevent 1 major adverse cardiac event from occurring without significantly increasing the risk of major side effects.

Caveats

This large RCT included participants in many different countries and settings, though the study authors themselves mention that the primary source of bias comes from the lack of represeataion of a globally diverse population. Study participants were predominantly male (>70%) and white (>80%). Additionally, this study only included participants with pre-existing CVD, so more research is needed to examine the effects of semaglutide in primary prevention. While several high-quality trials have demonstrated the safety and efficacy of semaglutide and the broader class of GLP-1 agonists, it is also well-established that they are associated with relatively high rates of GI side effects including nausea, vomiting, diarrhea and constipation.⁸ Long-term weight effects of GLP-1 agonist treatment are unknown, but a recent RCT of semaglutide examining the effects of treatment continuation versus discontinuation demonstrated significant weight regain among individuals who stopped semglutide after 20 weeks of treatment.⁹

Challenges to Implementation

The largest barriers to wide-scale implementation of this treatment strategy are payor coverage, medication cost, and supply-chain shortages. Notably, there have been large-scale shortages of semaglutide since the popularization of GLP-1 agonist medications limiting access for patients.¹⁰ In regards to cost, given the relatively recent FDA approval of semaglutide for the indication studied in this article, it is possible that more payors will begin to offer better coverage over time. In fact, the Centers of Medicare and Medicaid (CMS) recently announced that Medicare Part D plans would be able to cover semaglutide for CV risk reduction in patients with obesity and established CVD.¹¹