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An Overview of Cardiovascular Outcome Trials (CVOTs) in Type 2 Diabetes
- Interview with
-
Silvio
E.
Inzucchi
MD
Dr. Silvio E. Inzucchi:
In EMPA-REG-OUTCOME, empagliflozin was associated with major cardiovascular as well as renal benefits. This is the first time that any diabetes drug has ever been shown to reduce cardiovascular mortality. The primary endpoint was MACE, Major Adverse Cardiovascular Events and that was reduced by 14%, but it was almost exclusively driven by this large 38% reduction in cardiovascular mortality. In addition, there was a 35% relative reduction in heart failure hospitalization. That’s an increasingly important outcome in these diabetes clinical trials, and lastly, there was a 39% reduction in the progression of chronic kidney disease so empagliflozin, this SGLT2 inhibitor had significant benefits, both on the heart as well as on the kidney.
In CANVAS, this was a larger study, EMPA-REG-OUTCOME had about 7000 patients, CANVAS had about 10,000 patients and the investigators used canagliflozin in CANVAS, another SGLT2 inhibitor. Here the investigators showed the same exact reduction in MACE, 14%, but no significant reduction in cardiovascular mortality. In addition, there was a similar reduction in heart failure hospitalization as well as in the reduction in chronic kidney disease. Now, in CANVAS, canagliflozin was also associated with new risks. There was almost doubling of the risk of amputation, mostly lower extremities and about a 25% increase in bone fractures. Both of these adverse effects were not seen with empagliflozin in EMPA-REG-OUTCOME.
What are some potential explanations for the heterogeneity in CV outcomes within the class of GLP-1 receptor agonists (no effect with lixisenatide & exenatide versus favorable effects with semaglutide and liraglutide)?
Dr. Silvio E. Inzucchi:
So to date there have been four studies performed, cardiovascular outcome studies performed with GLP-1 receptor agonists. The two that have shown benefit have been liraglutide and semaglutide and both of those had important reductions in major adverse cardiovascular events. Two of the GLP-1 receptor agonists, lixisenatide and exenatide long-acting were neutral on cardiovascular events. The reason for these differences is not entirely clear. It may be related to drug-specific differences or perhaps to study methodology. For instance, with the lixisenatide study, the cohort of patients all had recent acute coronary syndrome and that’s a different population than the more stable cardiovascular patients that were studied in the liraglutide or the semaglutide studies known as LEADER and SUSTAIN-6.
In light of the relative underrepresentation of women in CV outcome trials, what do we know about the relative effects of empagliflozin in women vs men?
Dr. Silvio E. Inzucchi:
Well, we’ve looked at subgroup analyses in EMPA-REG-OUTCOME and what we found was essentially identical effects in woman versus man in terms of both the renal as well as the cardiovascular outcomes. So the drug appears to be beneficial in both sexes.
What are some of the controversies or limitations surrounding cardiovascular outcome trials?
Dr. Silvio E. Inzucchi:
Well, the major limitation of these cardiovascular outcome trials is that they are not necessarily real world so patients that participate in these trials are not necessarily the more complex patients that we see in our practices so that’s always been a conundrum with any clinical trial is can you cut and paste what you learned from these trials to the patients you see in clinical practice?
How could the design of CVOTs be improved in the future?
Dr. Silvio E. Inzucchi:
Well, cardiovascular outcome trials to date have compared the study medication, for instance, in CANVAS was looking at canagliflozin versus a placebo on top of background therapy for type 2 diabetes. I think what we really want to know in practice is how drugs compare to each other so I think comparative efficacy trials and comparative effectiveness trials are what we need next to compare how this GLP-1 receptor agonist might contrast to this SGLT2 inhibitor. I think those are the trials for the future.
As a clinical triallist, you were also involved in the IRIS Trial. What is the data supporting the utility of pioglitazone in patients with insulin resistance (no prior DM history) and recent cerebrovascular event in prevention of cardiac events?
Dr. Silvio E. Inzucchi:
Well, with all the excitement about GLP-1 agonists and SGLT2 inhibitors, I think we’ve forgotten about an older drug, pioglitazone, which is a thiazolidinedione insulin sensitizer and its potent anti-atherosclerotic effects. This was initially suggested in the proactive study that is now more than 10 years old and there was a significant reduction in major adverse cardiovascular events in that trial.
In IRIS we chose a population of patients that did not have diabetes, they had insulin resistance and about 50% of them actually had prediabetes but zero had actual diabetes and the notion was to use this insulin-sensitizing drug for its cardiovascular benefits to reduce the future risk of recurrent stroke as well as myocardial infarction. And what we demonstrated in about 4000 patients is a 24% reduction in the primary endpoint, which was essentially MACE or Major Adverse Cardiovascular Effects. This is the first time that any diabetes drug has been shown to reduce cardiovascular risk in patients without diabetes.
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