Heart Failure Needs More Attention in Diabetes Drug Trials, Expert Says

The effect of drugs to treat diabetes on heart failure should be front and center in clinical trials, according to an expert at a symposium on the relationship between the 2 conditions at the 77th Scientific Sessions of the American Diabetes Association (ADA), held Saturday in San Diego, California.

Ten years ago this week, the New England Journal of Medicine’s article on rosiglitazone stunned the diabetes and cardiovascular treatment communities alike, when it connected a blockbuster glucose-lowering therapy with deaths from heart attacks. The incident led to an FDA guidance requiring pharmaceutical companies to study the effects of all new diabetes and obesity therapies for their effects on cardiovascular events and mortality.

In a sign of how much the fields are overlapping, 3 months ago leading researchers in diabetes attended the American College of Cardiology (ACC) to discuss plans for EMPEROR HF, which will study emagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in heart failure patients, including those without diabetes. And yesterday, at the symposium, “Diabetes, Drugs, and Heart Failure,” leading cardiologists took the podium, led by Darren K. McGuire, MD, MHSc, of the University of Texas Southwestern.

The cardiologists speaking at ADA asserted that heart failure, perhaps, is finally getting its due, given its $31 billion footprint on the healthcare system and its rising cost to Medicare. While 25% of those newly diagnosed with heart failure have diabetes, according to Shannon Dunlay, MD, MS, of Mayo Clinic, they tend to be sicker, accounting for 46% of heart failure hospitalizations. “This is an area we need to learn more about,” she said.

Eldrin F. Lewis, MD, MPH, of Brigham and Women’s Hospital, was more blunt in his talk that called for making heart failure a primary endpoint in cardiovascular outcomes trials, not a “secondary, or exploratory, or not even looked at endpoint.”

When scrutinizing heart failure hospitalization rates in drug trials, he said it’s essential to examine what happens to these patients afterward—death rates can be high. Looking at data for saxagliptin, which had shown a heart failure hospitalization signal that FDA examined, Lewis said, “I would rather not be joining the heart failure club.”

While Dunlay said studies have linked diabetes and heart failure for decades—going back to the Framingham Heart Study in 1974—there’s still much that isn’t known. The pathway from diabetes to heart failure “is circuitous and still ill-defined,” she said.

What is known: “If you have diabetes in the presence of heart failure, you do worse,” Dunlay said.” Diabetes increases death from heart failure by 50%; although patients with diabetes ultimately die of the same causes as other heart failure patients, she said, they die earlier.

One area under investigation is the impact that glycemic control has on heart failure, Dunlay said. The CHARM trial showed that patients’ risk of cardiovascular death and heart failure hospitalization increased as glycated hemoglobin (A1C) rose, but curiously this relationship was stronger for people without diabetes. “This tells us that glycemic control is important,” she said.

However, this may not hold for patients once heart failure reaches advanced stages; pushing A1C too low may makes things worse. “This is an area where we need to understand more what’s going on,” Dunlay said.

Lewis said short of dying, most patients would consider having a stroke the risk they would most want to avoid, due to its debilitating effects. But heart failure hospitalization is a common, undesirable outcome, and it’s is an important end point for patients with diabetes.

ADA guidelines are clear—patients should start with metformin and then take 1 or even 2 more medications if they are still struggling with glycemic control. Treatment is good, Lewis said, as long as it’s safe. Citing work by McMurray et al, in The Lancet in 2014, Lewis said that even with 150,000 patients randomized in cardiovascular outcomes trials, the trials have not looked for hospitalization for heart failure as primary cardiovascular outcome, despite its risks.

Lewis reviewed the major categories of cardiovascular outcomes trials, from the dipeptiyl peptdipeptidyl idase 4 inhibitors (DPP-4), to the glucagon-like peptide-1 receptor agonists (GLP-1), to the SGLT2 inhibitors. He noted the recent publication of CVD-REAL, which studied data from 365,000 patients taking all 3 approved SGLT2 inhibitors and suggested that SGLT2 inhibitors could reduce hospitalization for heart failure and death from any cause in patients with type 2 diabetes, including those who did not have known cardiovascular risks.

What’s exciting, he said, is that more trials are coming that examine the potential of these drugs for patients who do not have diabetes. Lewis raised several important questions for researchers to consider: What about patients with established heart failure? Can these drugs be used for prevention?

“We will need a multidisciplinary approach for the treatment of these vulnerable patients,” he said.

E. Dale Abel, MD, PhD, of the University of Iowa, raised the issue first broached by Dunlay in his discussion of the mechanisms of diabetes therapies and heart failure: are those with diabetes sicker or have they had the disease longer? He also agreed that there are unique attributes of the heart that might modulate or increase heart failure risk, in response to glucose-lowering therapies.

With a nod of what’s to come in EMPEROR HF, Abel noted that the trials reported thus far were performed on high-risk patients. “We don’t know if patients with heart failure exposed to these agents, if you have a structurally normal heart with preexisting heart failure, might (you) respond differently than those without heart failure?” Abel asked.

Jacob A. Udell, MD, MPH, of Women’s College Hospital and Toronto General Hospital, discussed the questions that come up from patients in the clinic each day: are the therapies helpful or harmful? He offered some examples of decision making working off Canadian guidelines, but had a complaint commonly heard in the United States: payers want to see clinicians work with low-cost generics first before moving on to higher-cost therapies, even if there’s an abundance of evidence.

As the work of cardiologists and diabetologists overlaps more and more, Udell encouraged the ADA to take cardiovascular risks into account with its guidelines, citing the results for empagliflozin and liraglutide, which have both been shown to reduce cardiovascular mortality in high risk patients.