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CV Benefit of GLP-1 Agonists and SGLT2 Inhibitors Misleading for Black Patients? ADA

Jul 13, 2019
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Amber Satz, PharmD Candidate, LECOM School of Pharmacy

Claims of improved cardiovascular outcomes from GLP-1 agonists and SGLT2 inhibitors not proven significant for black diabetes patients.

The 2019 ADA Standards of Care for Diabetes Guideline outlined new information gathered from recent clinical trials to update practitioners on the current standards of care for patients with diabetes. Among this new information was the association of GLP-1 receptor agonists, liraglutide and semaglutide, and SGLT2 inhibitors, empagliflozin and canagliflozin, with improved cardiovascular outcomes, making them first-­­line add-on therapy for patients with diabetes and ASCVD. When analyzing the landmark trials that led to these conclusions, there is concern that the population did not include a significant portion of black and African American patients, which raises questions regarding whether or not these improved CV outcomes apply to black and African American patients.

On June 10th, Basem M. Mishriky, MD, of East Carolina University, Greenville, North Carolina presented findings from a meta-analysis of black and African American participants in seven major cardiovascular outcomes trials (CVOTs) at the American Diabetes Association 2019 Scientific Sessions. Of the seven international, multicenter trials, a total of 63,915 patients were enrolled, with only 3,471 (5%) being black. While these trials led to conclusions that GLP-1 agonists and SGLT2 inhibitors decreased risk for negative CV outcomes, the overall risk ratio compared with placebo within the black population was a nonsignificant 0.90. Within each trial, these results remain nonsignificant.

Mishriky and colleagues’ meta-analysis looked at recent cardiovascular outcomes trials with significant results that have led to changes in the ADA guidelines. GLP-1 trials included LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – A Long Term Evaluation), SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in subjects With Type 2 Diabetes), HARMONY (Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease), EXSCEL (Exenatide Study of Cardiovascular Event Lowering) and REWIND (Researching Cardiovascular Events With a Weekly Incretin in Diabetes) which used dulaglutide as the study drug. SGLT2 inhibitor trials included EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) and CANVAS (Canagliflozin Cardiovascular Assessment Study).

Most of these trials looked at a 3-point major adverse cardiovascular events (MACE) as the primary endpoint including CV death, nonfatal myocardial infarction and nonfatal stroke, with the average length of study of about 3.7 years. Looking at the entire study population for all seven trials, significant reduction in 3-point MACE endpoint occurred for each active drug compared to placebo in LEADER (hazard ratio [HR], 0.87, SUSTAIN-6 (HR, 0.74), HARMONY (HR, 0.78), EMPA-REG (HR, 0.86), CANVAS (HR, 0.86) and REWIND (HR, 0.88). The EXSCEL trial displayed a significant reduction in all-cause mortality, a pre-specified secondary outcome.

This meta-analysis initially left out the REWIND trial data, due to its very recent announcement of results. Breaking down the results to analyze the black population across the six CVOTs (excluding REWIND), 163 patients taking the study drug experienced a MACE compared to 164 patients taking placebo drug, resulting in a nonsignificant risk ratio of 0.97. When REWIND data was added, the nonsignificant risk ratio of 0.80 for the primary outcomes brought the total risk ratio for the black population on active drug versus placebo to 0.93 for all seven trials.                                  

Across the five GLP-1 agonist trials, MACE occurred in 153 black patients on the study drug and in 187 on placebo, resulting in a nonsignificant risk ratio of 0.90. In the two SGLT2 inhibitor trials, MACE occurred in 49 black patients on the study drug and in 28 on placebo, resulting in a nonsignificant risk ratio of 1.00.

In a recent systematic literature review, it was found that cardiovascular disease affects approximately 32.2% of all persons with type 2 diabetes, globally. Cardiovascular disease is also a major cause of mortality among patients with type 2 diabetes, leading to about half of deaths over the 10-year study period. Therefore, practitioners and their patients have an interest in a diabetes medication that will reduce long-term cardiovascular outcomes. Future studies are needed to evaluate the benefit of GLP-1 agonists and SGLT2 inhibitors on CV outcomes for black patients with diabetes.

 

Practice Pearls: 

  • GLP-1 agonists and SGLT2 inhibitors have been proven effective at reducing ASCVD risk long-term and therefore are the first-line add-on agent for patients with type 2 diabetes and ASCVD, according to the ADA.
  • Although trial results were nonsignificant for black diabetes patients, GLP-1 agonists and SGLT2 inhibitors may still be viable options for black patients with diabetes and ASCVD.
  • Consider explaining the nonsignificant results with black patients with T2DM when choosing to initiate GLP-1 agonists and SGLT2 inhibitors with intent to improve CV outcomes.

 

American Diabetes Association. 16. Diabetes Advocacy: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 Jan;42(Suppl 1):S182-S183. doi: 10.2337/dc19-S016. Review. PubMed PMID: 30559242

Einarson, Thomas R., et al, “Prevalence of Cardiovascular Disease in Type 2 Diabetes: a Systematic Literature Review of Scientific Evidence from across the World in 2007–2017.” Cardiovascular Diabetology, vol. 17, no. 1, 2018, doi:10.1186/s12933-018-0728-6.]

 

Amber Satz, PharmD Candidate, LECOM School of Pharmacy