An Update on the Benefits of GLP-1 Receptor Agonists for Type 2 Diabetes

GLP-1 receptor agonists are a pharmacologic treatment of type 2 diabetes with potential cardiorenal benefits.

According to the ADA guideline for managing type 2 diabetes, diabetes is a risk factor for many cardiovascular and microvascular complications, including but not limited to coronary artery disease, heart failure, chronic kidney disease, and neuropathy. Many newer pharmacologic therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists potentially reduce the incidence of major cardiovascular events (MACE) for patients with type 2 diabetes. In the previous meta-analysis conducted in 2019, the GLP-1 receptor agonists showed significant benefit in lowering the risk of MACE in patients with type 2 diabetes and a history of cardiovascular (CV) disease. However, the benefit for patients without a history of cardiovascular disease is uncertain.  

The study in this discussion is a meta-analysis of trials published up to June 2021 to examine the overall effect of GLP-1 receptor agonists on cardiorenal efficacy and provide the most updated data for clinical implications of GLP-1 receptor agonists in patients with type 2 diabetes. The author included only randomized controlled trials with cardiorenal outcomes (cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, or renal endpoints) as part of the primary, secondary, exploratory, or safety outcomes. The primary outcomes included the effect of GLP-1 receptor agonists on the incidence of MACE and the effect of GLP-1 receptor agonists on MACE risk in patients with type 2 diabetes, with or without a history of CV disease at baseline. Hazard ratio and 95% confidence interval (CI) were utilized to assess the cardiorenal efficacy outcomes. In addition, Cochran’s Q test was used to evaluate the heterogeneity between studies.

In the results, the study included eight multination, randomized, parallel-group, double-blind trials with the mean age of 64 ± 1.97 years, the median duration of follow-up ranging from 1.3 to 5.4 years, the percentage of male participants 62.8%. In comparison to the placebo, the GLP-1 receptor agonists significantly reduced the risk of MACE by 14% (HR = 0.86, 95% CI 0.79 to 0.94, p = 0.006) with no significant heterogeneity between trials. GLP-1 RA reduced the risk of MACE by 16% in patients with established CV disease (significant, HR 0.84, 95% CI 0.79 to 0.90, p < 0.001) and by 6% in patients without pre-existing CV disease (non-significant, HR 0.94, 95% CI 0.83 to 1.06, p = 0.330). 

In regards to the components of MACE, GLP-1 receptor agonists reduced the risk of cardiovascular mortality by 13% (significant, HR 0.87, 95% CI 0.78 to 0.96, p = 0.016), risk of non-fatal stroke by 16% (significant, HR 0.84, 95% CI 0.76 to 0.94, p = 0.007), risk of heart failure by 10% (significant, HR 0.90, 95% CI 0.83 to 0.98, p = 0.023), risk of all-cause mortality by 12% (significant, HR 0.88, 95% CI 0.80 to 0.96, p = 0.012), and risk of non-fatal myocardial infarction by 9% (non-significant, HR 0.91, 95% CI 0.81-1.01, p = 0.078).

For renal outcomes, GLP-1 receptor agonists significantly reduced the risk of new macroalbuminuria by 26% (HR 0.74, 95% CI 0.67 to 0.82, p < 0.001), which made a significant impact in reducing the risk of the composite kidney outcome (HR 0.83, 95% CI 0.73 to 0.94, p < 0.012).

With more than 60,000 people included in this analysis, the overall benefit of GLP-1 receptor agonists in reducing the risk of MACE is mainly driven by the majority of patients who had established CV disease (72.4% of the total participants). In previous studies, sodium-glucose co-transporter 2 (SGLT2) inhibitors have an inconclusive effect on non-fatal stroke outcomes. Meanwhile, GLP-1 receptor agonists showed benefits in stroke reduction. However, a direct comparison between the two drug classes is needed to confirm the superior benefit. Furthermore, the benefit is different among the GLP-1 RA agents. This study concluded that oral semaglutide had the most substantial evidence in reducing cardiovascular death and death from any cause. In contrast, once-weekly semaglutide had the most substantial evidence in reducing MI and stroke events. Therefore, individualized therapy is essential for the patient’s most beneficial outcome.

Practice Pearls:

• GLP-1 RAs reduce the overall incidence of major cardiovascular events in patients with type 2 diabetes by 14%.
• The benefit of GLP-1 receptor agonists is more robust in patients with established CV disease than in patients without a history of CV disease at baseline.
• GLP-1 inhibitors showed benefits on non-fatal stroke over SGLT-2 inhibitors.

Giugliano, Dario et al. “GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs.” Cardiovascular diabetology vol. 20,1 189. September 15 2021,

Giugliano, Dario et al. “GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: An updated meta-analysis including the REWIND and PIONEER 6 trials.” Diabetes, obesity & metabolism vol. 21,11 (2019): 2576-2580.

American Diabetes Association. “9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021.” Diabetes care vol. 44, Suppl 1 (2021): S111-S124.

Ding Nguyen, PharmD Candidate, University of South Florida Taneja College of Pharmacy