SAN FRANCISCO — New study results raise concern as to whether the cardiovascular (CV) benefits seen in trials of type 2 diabetes drug classes, such as the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, extend to black and African American patients.
The findings, from a meta-analysis of black and African American participants in seven major cardiovascular outcomes trials (CVOTs) that showed overall CV benefit, were presented June 10 here at the American Diabetes Association (ADA) 2019 Scientific Sessions by Basem M. Mishriky, MD, of East Carolina University, Greenville, North Carolina.
The seven CVOTs — all international, multicenter trials — enrolled a total of 63,915 patients, of whom just 3471 (5%) were black. In contrast to the overall findings of reductions in adverse CV outcomes, the overall risk ratio compared with placebo among black participants for these endpoints was a nonsignificant 0.90, and those results remained nonsignificant for GLP-1 agonists or SGLT2 inhibitors when those trial results were analyzed separately.
Although the number of patients and events in the black/African American groups were too small to be conclusive, the findings raise concern as recent guidelines now preferentially advise using these medications in patients with type 2 diabetes at high risk for CV events based on the CVOT results, Mishriky said.
"It remains unclear whether GLP-1 receptor agonists or SGLT2 inhibitors would reduce CV risk in such patients, given that black or African American patients with type 2 diabetes were not well-represented in the CV safety trials and such trials were underpowered to evaluate racial differences. Additional studies targeting black and African American patients are urgently needed," he said.
In an interview, Mishriky told Medscape Medical News, "This is in no way to say that we shouldn't continue to use GLP-1 receptor agonists and SGLT2 inhibitors. They are great drugs. They lower HbA1c and cause weight loss. They don't cause hypoglycemia...It's just that we don't have the...data to say that they reduce CV events in black patients. It remains unclear."
Asked to comment, session moderator Tina Vilsbøll, MD, DMSc, Steno Diabetes Center, Copenhagen, Denmark, an investigator for several of the CVOTs included, said: "I think we should focus on it. We should probably have someone conduct a trial [exclusively] in African Americans...That's what science is about. We get some signals and we need to do more trials."
But, she also noted, "I actually think it's a coincidence because the numbers are so low. If I was a clinician seeing a lot of African American patients, I would still use [these drugs]."
John Buse, MD, director of the Diabetes Center at the University of North Carolina, Chapel Hill — also an investigator for many of these CVOTs — pointed out that these are global trials and the proportion of black patients at the US sites is typically higher than in European and Asian sites.
"In general we try to make sure that the proportion matches the US population. I think there's a good-faith effort to make the population representative...It's part of the discussion, although it's not top priority in global trials," he observed, when asked for comment.
Regarding Mishriky's presentation — which Buse had not seen, but was told of the main finding — he said: "It's going to be really important to look at this issue very carefully. I'm sure sponsors and the [US Food and Drug Administration] will be very interested in the issue, and if there really is a significant signal that African Americans don't benefit from these therapies, then I'm sure there will be a specific trial done."
However, like Vilsbøll, Buse said, "I think it's extremely unlikely that this is true in general."
In Blacks and African Americans, CV Outcomes Not Significant
Mishriky and colleagues conducted a meta-analysis of CVOTs that had significant results for either the primary outcome or a prespecified secondary outcome, as those are the studies that have led to recent changes in guidelines. If data on race weren't reported, they contacted the investigators to ask for them.
The initial results, which will be in the published article, were based on four trials of GLP-1 agonists and two trials of SGLT2 inhibitors.
The GLP-1 agonist trials included were 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), and EXSCEL (Exenatide Study of Cardiovascular Event Lowering).
After results from REWIND (Researching CV Events With a Weekly Incretin in Diabetes) were presented at the ADA meeting last week, as reported by Medscape Medical News, Mishriky added those data to his analysis for his presentation the following morning.
The two CVOTs of SGLT2 inhibitors analyzed were EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) and CANVAS (Canagliflozin Cardiovascular Assessment Study).
Results from DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events) were not included because data weren't reported by race and the authors were unable to provide this information.
Pooling the data without REWIND, there were 2794 black/African American patients out of a total of 54,014 (5.2%). With REWIND included, there were 3471 black patients out of 63,915 (5.4%).
For the entire study populations, significant reductions in the primary three-part major adverse CV outcomes (MACE) endpoint occurred with active drug compared with placebo in LEADER (hazard ratio [HR], 0.87), SUSTAIN-6 (HR, 0.74), HARMONY (HR, 0.78), EMPA-REG (HR, 0.86), and CANVAS (HR, 0.86). A significant reduction in all-cause mortality — a prespecified secondary outcome — was seen in EXSCEL (HR, 0.91).
Among the black patients in the six CVOTs without REWIND, MACE occurred in 163 patients taking the tested medication compared with 164 patients taking placebo, giving a nonsignificant risk ratio of 0.97. Adding in REWIND didn't change this: the risk ratio of 0.80 for the primary outcome among the black patients in that trial was also nonsignificant, bringing the overall risk ratio to 0.93 for blacks on active drug versus placebo for all the trials.
For the five GLP-1 agonist trials including REWIND, MACE occurred in 153 black participants on the study medication and in 187 on placebo, again giving a nonsignificant risk ratio of 0.90. In CANVAS and EMPA-REG, MACE occurred in 49 black patients on active drug versus 28 with placebo (risk ratio, 1.00).
Mishriky told Medscape Medical News that although he will continue to use SGLT2 inhibitors and GLP-1 agonists in his large African American patient population, based on these data, he may have to change the conversation he has with those patients until more data are available.
"Do I tell the patient that the drug I'm starting will lower their CV event risk or not? If I don't know, I can't say that it will."
Mishriky has reported no relevant financial relationships. Vilsbøll has reported personal fees from Amgen, AstraZeneca, BMS, MSD/Merck, Sanofi, Lilly, and grants and personal fees from Novo Nordisk, Boehringer Ingelheim. Buse has reported contracted consulting fees paid to the University of North Carolina by Adocia, AstraZeneca, Dance Biopharm, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, vTv Therapeutics, and Zafgen, and grant support from Novo Nordisk, Sanofi, and vTv Therapeutics. He is also a consultant to Neurimmune and holds stock options in Mellitus Health, PhaseBio, and Stability Health.
ADA 2019 Scientific Sessions. Presented June 10, 2019. Abstract 242-OR
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Cite this: CV Benefit of Newer Type 2 Diabetes Drugs Not Seen in Black Patients - Medscape - Jun 17, 2019.