New Analysis Finds Hope for Reducing Heart Failure

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The analysis discusses the strength of evidence that SGLT2 inhibitors have a class effect in preventing heart failure for patients with diabetes.

Heart failure, which occurs when the heart fails to adequately pump blood through the body, is one of the most expensive conditions in healthcare. A 2018 meta-analysis found that heart failure accounted for 1% to 2% of all healthcare expenditures worldwide, and its footprint in the United States would likely increase with an aging population.

For years, however, heart failure was something of a stepchild in the system—progress was difficult because the patients with this condition typically had other problems; diabetes is a common comorbidity.

But over the past decade, 2 things have changed, according to authors of a new paper in Diabetes Obesity and Metabolism. The arrival of a new class of type 2 diabetes (T2D) therapy—sodium glucose co-transporter 2 (SGLT2) inhibitors—and an FDA mandate to study new diabetes drugs for safety, which created cardiovascular outcomes trials (CVOTs), yielded findings in heart failure never previously seen in other glucose-lowering therapies.

As authors Dario Giugliano, MD, Juris J. Meier, MD, and Katherine Esposito write, about 5.7 million adults in the United States have heart failure and about half die within 5 years of diagnosis—for those with diabetes, death comes even sooner. “Despite this robust evidence, [heart failure] had seemed to have been neglected by clinicians and scientists who dedicate more attention to atherothombotic complications of diabetes,” they write, it is as common, if not as evident, as events like heart attacks and strokes.


Improvements seen in reducing rates of ischemic heart disease and stroke, both with and without diabetes, between 1988 and 2015 were not seen in heart failure; in fact, it increased among young adults, the authors note.

Given heart failure’s costs to the system, the arrival of the Affordable Care Act and the shift toward value-based care brought the arrival of the Hospital Readmission Reduction Program, which meant that health systems that kept readmitting heart failure patients would be penalized.

At the same time, the FDA requirement for CVOTs would soon yield unexpected results in the trial involving empagliflozin, which showed reductions in hospitalization for heart failure and overall mortality. Since then, both canagliflozin and dapagliflozin have shown similar results for heart failure, but only the CVOT for dapagliflozin, the DECLARE trial, had heart failure as a primary end point.

As Eldrin F. Lewis, MD, discussed with The American Journal of Managed Care® in December 2017, heart failure specialists tried to convince the FDA to require heart failure as an end point back when the CVOT requirements were created, but to no avail. The DECLARE investigators added a second endpoint to the original trial.

To date, note Giugliano, et al, DECLARE is the only CVOT that has included heart failure as a primary end point. Yet results thus far show, “The robust, consistent, and reproducible reduction in about 30% risk of [heart failure] by SGLT2 inhibitors may be considered a class effect.”

The authors note that this effect is unrelated to drugs’ effect on glycemic control, a point explored in a recent paper by Inzucchi and coauthors in the journal Circulation.

By contrast, the beneficial effect on major adverse cardiovascular events (heart attacks, strokes, unstable angina, or other events) “must be interpreted within the frame of the single trial.”

As effects of SGLT2 inhibitors on heart failure for patients with diabetes have become apparent, a second wave of trials is ongoing to examine the potential benefits for other patients at risk—including those without diabetes. The potential for this class to become a tool in primary prevention is being closely watched as studies proceed.

Indeed, investigators for DECLARE, presented in November at the American Heart Association Scientific Sessions, wrote in their findings, “These new data suggest that in patients without established atherosclerotic cardiovascular disease, SGLT2 inhibition can prevent serious clinical events, particularly hospitalization for heart failure, and possibly reduce the likelihood of progression of renal disease.”


Giugliano D, Meier JJ, Esposito K. Heart failure and type 2 diabetes: from CVOTs with hope [published online January 4, 2019]. Diabetes Obes Metab. doi: 10.1111/dom.13629.