In an ironic twist, one of this year’s leading medical innovations can trace its origins to one of the biggest medical disappointments and controversies of the early 2000s.
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The emergence of evidence that newer diabetes drugs can substantially reduce cardiovascular events and death was hailed as the No. 2 medical innovation for the coming year in the list of top 10 medical innovations unveiled at Cleveland Clinic’s 14th annual Medical Innovation Summit in October 2016.
Studies confirming the drugs’ cardiovascular benefits were published within the last year or so, but these studies stemmed from the high-profile controversy over rosiglitazone that started in 2007, when the glucose-lowering agent was linked to an increased risk of myocardial infarction (MI). That concern was compounded by an absence of evidence demonstrating a clinical benefit with rosiglitazone.
These developments prompted Cleveland Clinic Cardiovascular Medicine Chairman Steven Nissen, MD, to call on the FDA to establish new regulations requiring cardiovascular outcome trials in order to show that new diabetes drugs do not result in an unacceptable increase in cardiovascular risk. The FDA acted on his recommendation, and Dr. Nissen helped shape the agency’s 2008 policy on these trials.
Two of the resulting studies — the EMPA-REG OUTCOME trial of the SGLT2 inhibitor empagliflozin and the LEADER study of the the GLP-1 analogue liraglutide — formed the basis for recognizing the cardiovascular benefits of newer diabetes agents as one of the year’s top medical innovations. These milestone trials showed that each drug was associated with significant reductions in death from cardiovascular causes, all-cause mortality, and nonfatal MI and stroke compared with placebo among patients with type 2 diabetes and high cardiovascular risk.
We spoke with Dr. Nissen, a co-investigator in LEADER, about the potential impact of these drugs on patients with diabetes and cardiovascular disease.
Q: Stepping forward to change a clinical trial paradigm took nerve. What prompted you?
Many endocrinologists were upset about proposing cardiovascular outcome trials for diabetes drugs. They wanted to continue performing trials on lowering blood sugar alone. I believe in evidence-based medicine. You must study the problem, not just measure biochemical markers, so I stuck my neck out by making these recommendations to the FDA. If we hadn’t changed the way these trials are done, we wouldn’t have known these benefits.
Q: What are key takeaways for cardiologists from the EMPA-REG OUTCOME and LEADER studies?
When we developed the guidance for testing these drugs, it was about ruling out harm. We hoped they would lower blood sugar and do no harm, but also reduce cardiovascular events. Our dream came true. Both drugs lower cardiovascular morbidity and mortality.
Although most cardiologists do not treat diabetic patients for their blood sugar, cardiologists should be talking to endocrinologists about the choice of drugs for patients with cardiovascular disease. They should share the decision-making process.
Q: Are there shared mechanisms between the drug classes in these two trials that may explain the results?
These are new classes of drugs with novel mechanisms of action. There are no links between them. Empagliflozin changes the way the kidneys retain sugar, causing more sugar to spill into the urine. It also reduces calories and acts like a diuretic to lower blood pressure, which may play a role in cardiovascular outcomes. The effect of liraglutide is more complicated and almost hormone-like. Its mechanism is not entirely clear.
Q: How likely is it that the EMPAG-REG and LEADER results are class effects?
No one knows. A clinical trial of a weaker drug in the same class as liraglutide was not effective. On the other hand, a longer-acting GLP-1 analogue showed benefit in the recent SUSTAIN trial.
Q: Are there more studies on the horizon that may expand on the findings to date?
There’s a huge number. We’re going to learn more about the effect of diabetes drugs on heart disease in the next couple years than we have in the previous 50 years.
Q: Do you see potential parallels here with the use of statins or other widely used drug classes for cardiovascular risk reduction?
The magnitude of benefits was quite substantial and in the range of what we see with statins. In fact, most patients in the LEADER study and two-thirds of those in EMPA-REG were being treated with statins. The new drugs provided incremental benefit on top of statins.
Q: Do you expect cardiovascular guidelines to change in light of these findings?
No, but diabetes treatment guidelines may change.
Q: Do these studies tell us anything about management of patients with pre-diabetes?
I would not extend the findings to patients with pre-diabetes. The patients in these studies had well-established type 2 diabetes and cardiovascular disease.