GLP-1s Reduce Cardiovascular Risk Equally in Patients With Overweight, Obesity Regardless of Diabetes

Glucagon-like peptide-1 (GLP-1) receptor agonists showed a similar magnitude of effect on major adverse cardiovascular events (MACE), all-cause death, and cardiovascular-related death in overweight/obese patients without diabetes as they did in patients with type 2 diabetes, according to a study published in Clinical Cardiology.¹

Commonly used in the treatment of type 2 diabetes, GLP-1 receptor agonists are a class of medications that have helped to lower blood glucose levels; they directly stimulate GLP-1 receptors, which enhances insulin secretion.^2,3 In the past few years, GLP-1 receptor agonists have shown promise in various areas, including reducing cardiovascular events, which could be partly due to better glycemic control in patients with type 2 diabetes.¹

However, previous studies scarcely analyzed the cardiovascular efficacy of GLP-1 receptor agonists in patients without diabetes, an exception being the recent Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial.⁴ Therefore, most previous trials focused on patients with diabetes, the majority of whom were overweight or obese.¹

Consequently, the researchers conducted a meta-analysis on randomized-controlled trials (RCTs) that compared cardiovascular outcomes between patients taking GLP-1 receptor agonists and placebo, stratified by the presence or absence of diabetes. The main outcome was MACE, but other outcomes of interest included myocardial infarction, hospitalization for heart failure, stroke/transient ischemic attack, and cardiovascular and all-cause death.

GLP-1 receptor agonists provide similar reductions in major adverse cardiovascular events, all-cause death, and cardiovascular-related death in overweight/obese patients without diabetes as they do in patients with type 2 diabetes.

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To find relevant studies, they searched databases PubMed, Embase, and Scopus using keywords like semaglutide, GLP-1, and cardiovascular outcome until November 11, 2023; the researchers noted that the search results were updated on April 9, 2024. Eligible studies were randomized-controlled trials with a minimum duration of 52 weeks that assessed MACE and compared an experimental group receiving GLP-1 agonists to a placebo group; they also needed to include patients with diabetes or other conditions, like heart failure or overweight/obesity.

The researchers extracted relevant data from the eligible articles. This included the trial name, the details of the intervention provided to the experimental group, the comorbidity of the studied population, and the duration of the longest follow-up. As for outcome-related data, they extracted the sample size of both the intervention and comparator group, along with the event rates that occurred in each group.

Initially, the researchers identified 5980 relevant studies. After eliminating duplicate and ineligible studies, 24 remained. The total sample size was 94,547 patients, 50,033 of which were in the experimental group and 44,514 in the comparator group. The mean age of the population was 58.22 years (95% CI, 55.02-61.43), and the median MACE follow-up period ranged from 1 to 5.4 years. Also, 49.56% (95% CI, 41.90%-57.24%) were male. The GLP-1 receptor agonists used in the experimental groups included semaglutide, liraglutiude, and dulaglutide, which were administered either orally or by a subcutaneous injection once a day or weekly.

Compared with the placebo group, both patients with type 2 diabetes (relative risk [RR], 0.88; 95% CI, 0.81-0.96) and with overweight or obesity (RR, 0.81; 95% CI, 0.74-0.88) on GLP-1 receptor agonists had a statistically significant decrease in the RR of MACE. Additionally, there was a 12% risk reduction in all-cause death for the GLP-1 group (n = 94,524; RR, 0.88; 95% CI, 0.84-0.92; P < .0001), which was also observed in both subgroups of patients with diabetes (n = 69,024; RR, 0.89; 95% CI, 0.84-0.95) and nondiabetics (n = 25,500; RR, 0.81; 95% CI, 0.74-0.90).

Similarly, the researchers discovered a 12% risk reduction in cardiovascular-related death among the overall GLP-1 group (n = 87,434; RR, 0.88; 95% CI, 0.82-0.94; P = .0011); both subgroups of type 2 diabetics (n = 64,852; RR, 0.88; 95% CI, 0.81-0.97) and nondiabetics (n = 22,582; RR, 0.85; 95% CI, 0.73-0.98) also demonstrated a statistically significant reduced cardiovascular mortality risk.

Additionally, the GLP-1 group had a significantly lower RR of stroke (RR, 0.86; 95% CI, 0.80-0.92; P = .0006) and MI (RR, 0.87; 95% CI, 0.77-0.97; P = .0190). Although GLP-1 receptor agonists decreased the RR of stroke in the diabetic subgroup (RR, 0.85; 95% Ci, 0.78-0.92), the researchers noted that the association for MI was “marginally nonsignificant” (RR, 0.90; 95% Ci, 0.80-1.01; I2 = 42%). Conversely, in the nondiabetic group, GLP-1 receptor agonists reduced the risk of MI by 27% (RR, 0.73; 95% CI,0.55-0.96), but there was no significant change in stroke risk (RR, 0.93; 95% Ci, 0.65-1.32).

Lastly, the risk of hospitalization for heart failure decreased by 10% in patients who took GLP-1 receptor agonists (RR, 0.90; 95% CI, 0.83-0.98; P = .02). This was statistically significant in the nondiabetic subgroup (RR, 0.73; 95% CI, 0.56-0.95), however it was not statistically significant among patients with type 2 diabetes (RR, 0.93; 95% CI, 0.85-1.01; I2 = 0%).

The researchers acknowledged their limitations, one being that the trials on nondiabetics were limited compared with studies on patients with diabetes. Other than the SELECT trial, studies on patients without diabetes showed inconclusive results; they were underpowered for sample size and clinical outcomes. Despite their limitations, the researchers suggested areas for further research based on their findings.

“Our results showing a significant improvement in cardiovascular outcomes regardless of underlying diabetes are of great importance and should motivate future randomized trials to further assess the cardiovascular efficacy of GLP-1 agonists in patients with cardiovascular conditions without diabetes,” the authors wrote.

References

1. Hosseinpour A, Sood A, Kamalpour J, et al. Glucagon-like peptide-1 receptor agonists and major adverse cardiovascular events in patients with and without Diabetes: a meta-analysis of randomized-controlled trials. Clin Cardiol. 2024;47(7):e24314. doi:10.1002/clc.24314
2. Ansari HUH, Qazi SU, Sajid F, et al. Efficacy and safety of glucagon-like peptide-1 receptor agonists on body weight and cardiometabolic parameters in individuals with obesity and without diabetes: a systematic review and meta-analysis. Endocr Pract. 2024;30(2):160-171. doi:10.1016/j.eprac.2023.11.007
3. Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;2011(10):CD006423. Published 2011 Oct 5. doi:10.1002/14651858.CD006423.pub2
4. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563