The Effects of GLP-1 Receptor Agonists on Cardiovascular Events

How important is GLP-1 RA effect on Hemoglobin A1c reduction in determining cardiovascular risk? 

Both glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT-2) inhibitors have proved to reduce cardiovascular risk in multiple trials. However, the difference between these two classes is that the reduction of cardiovascular events is not caused by better glycemic control with SGLT-2 inhibitors. The other medication class that acts through incretins is dipeptidyl peptidase-4 inhibitors; however, this class of drugs does not reduce cardiovascular risk or hemoglobin A1c levels. The researchers determined to evaluate if the reduction of hemoglobin A1c by GLP-1 RA is the reason for reduced cardiovascular risk. Previous trials including GLP-1 receptor agonist and placebo are the Action in Diabetes and Vascular Disease-PreterAx and DiamicroN Controlled Evaluation (ADVANCE), Action to Control Cardiovascular Risk in Diabetes (ACCORD), and Veterans Affairs Diabetes Trial (VADT). However, prolonged follow-ups have not been conducted in these trials to confirm if better glycemic control resulted in cardiovascular risk reduction.  

This meta-analysis study’s objective was to confirm if glycemic control is a mediator of risk reduction in cardiovascular outcome trials. This study evaluated seven safety trials on GLP-1 receptor agonists. The trials included were Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA), Exenatide Study of Cardiovascular Event Lowering (EXSCEL), A Long Term, Randomized, Double-blind, Placebo-Controlled Study to Determine the Effect of Albiglutide (HARMONY Outcomes), Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6), Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND), A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes (PIONEER 6) and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER). The two methods that were used in this study were based on glycemic exposure and cardiovascular risk. Data such as hemoglobin A1c levels, body weight, and significant adverse cardiovascular events risk were gathered from published figures. Glycemic exposure was split into two categories, hemoglobin A1c levels above 6% and hemoglobin A1C mean difference. Cardiovascular risk was determined by absolute significant adverse cardiovascular events risk and hazard ratio. The treatment arms for these trials were a GLP-1 receptor agonist versus a placebo. For method one, the cumulative glycemic exposure was estimated and then correlated with the absolute cardiovascular risk. For method two, the differential glycemic exposure was calculated and linked with a hazard ratio. 

Method 1 showed that the collective hemoglobin A1c exposure was significantly correlated with absolute significant adverse cardiovascular events risks. Also, the correlation was different in both the placebo and GLP-1 receptor agonist treatment arm. Even after adjusting for age in method one, there was no difference in the results. It was also not changed by body weight. There was a strong correlation (R2= 0.75) between the hazard ratio and hemoglobin A1c levels for method two. The results for this method were similar among all of the trials. It was concluded that for every 1% reduction in a patient’s hemoglobin A1c level, there was a 25% decrease in cardiovascular risk.  

A minor weakness of this study was that data was obtained from published figures. Also, the seven safety trials used varied in follow–up lengths. Out of the seven trials, six trials had lengths of 1.3 years, and the remaining one had a span of 5.4 years.  

Practice Pearls: 

• It can be concluded that hemoglobin A1c percentage is a mediator that helps explains the cardiovascular risk reduction in GLP-1 receptor agonists.  
• These results from this analysis should be confirmed with specific single patients with type 2 diabetes data. 
• More studies should be done to either confirm or refute specific cardiovascular effects on GLP-1 agonists.  

A Reduction of cardiovascular events by GLP-1 receptor agonists is explained by HbA1c reduction. EASD Virtual Congress. Published 2020.  

Alexandria Bartley, PharmD. Candidate, Florida Agricultural & Mechanical University, College of Pharmacy and Pharmaceutical Sciences