DECLARE: Dapagliflozin Offers Benefits for Diabetes Patients With Heart Failure

New findings for the type 2 diabetes (T2D) drug dapagliflozin show it offers benefits to a wide spectrum of patients with heart failure, and it may reduce death for those with a high-risk condition called reduced ejection fraction.

The results, drawn from the 17,000-person study DECLARE, show that the sodium glucose cotransporter 2 (SGLT2) inhibitor reduced hospitalization for patients with heart failure with and without reduced ejection fraction, but the benefits emerged earlier for those with reduced ejection fraction (HFrEF).

The findings were presented Monday at the 68th Scientific Session of the American College of Cardiology (ACC) meeting in New Orleans, Louisiana. On Sunday, ACC and leaders from the American Heart Association released updated guidelines that for the first time say physicians may use SGLT2 inhibitors and another drug class, glucagon-like peptide-1 (GLP-1) receptor agonists, in primary prevention.

Results and an accompanying editorial were simultaneously published in the journal Circulation.

Much of this year’s ACC meeting has explored the relationship between diabetes and heart failure, one of the most debilitating and costly conditions for the healthcare system. A 2008 FDA mandate required drug companies to study whether new diabetes therapies caused events like heart attacks or strokes, but less initial attention was paid to the effect of these drugs on heart failure, even though people with diabetes are 2 to 5 times more likely to develop the condition.

“Diabetes intersects with cardiovascular disease at every level,” the authors of the Circulation editorial wrote. “While there has been much focus on understanding atherosclerotic complications, less well appreciated is the relationship between diabetes and heart failure.”

“If you look at the 30 million patients living in the United States with diabetes, the earliest cardiac complication that patients are going to experience with diabetes is actually heart failure,” said Rod Wooten, MBA, vice president for cardiovascular and metabolic diseases for AstraZeneca. While heart failure is “frequent, often forgotten, and fatal,” Wooten said these results show the potential to prevent the hospitalizations and deaths associated with the condition.

DECLARE, the cardiovascular outcomes trial (CVOT) for dapagliflozin, sold as Farixga by AstraZeneca, reported its first results in November 2018. Those results showed that dapagliflozin significantly reduced hospitalization for heart failure (HHF) and appeared to slow the loss of kidney function. Unlike earlier CVOTs, DECLARE includes a second primary endpoint that examined how well the drug prevented a composite of cardiovascular death and HHF.

Findings presented Monday dive deeper into the drug’s benefits for patients with HFrEF, based on of left ventricle ejection fraction (LVEF) that 5205 patients had when they enrolled in DECLARE. LVEF is a measure of how well the heart’s left ventricle is pumping blood from the chamber, and HFrEF is an indicator of heart failure, even though some with the condition have preserved ejection fraction (HFpEF). Of the group evaluated, 671 had HFrEF.

Results presented Monday showed:

• Patients with HFrEF who took dapagliflozin saw the composite of cardiovascular death and HHF drop by 38% compared with placebo, a larger decline than the 12% decline seen for those without HFrEF.
• Patients with HFrEF saw rates of cardiovascular death fall by 45% and death from any cause fall by 41% after taking dapagliflozin, compared with placebo. Similar benefits were not seen among patients without HFrEF. However, the editorial cautions that these results are based on small numbers; a forthcoming study, DAPA-HF, will shed more light on the drug’s benefit.
• Rates of HHF fell among all patients, regardless of ejection fraction status, showing benefits in the broader population without reduced ejection fraction.

Both Wooten and AstraZeneca’s Naeem Khan, MD, vice president, US CVMD Medical Affairs, said the fact that dapagliflozin showed benefits in heart failure patients regardless of ejection fraction status will make it useful for physicians in primary care, where most patients with T2D receive treatment.

“I think the primary care perspective is really important—to be able to use one drug that covers the most number of patients,” Khan said. Primary care physicians don’t want 3 or 4 options, he said. “Give me one option that’s easy to utilize."

The study population in DECLARE, Khan said, included those with cardiovascular risk as well as those with multiple risk factors, so the drug has been studied in a much broader group of patients than other SGLT2 inhibitors.

AstraZeneca recently received an additional indication for dapagliflozin for patients with moderate renal impairment, based on results from a separate study, DERIVE. Wooten said that, in addition to heart failure, the drug’s potential to prevent renal complications is a major area of interest.

References

Kato E, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus based on ejection fraction [published online March 18, 2019]. Circulation.

Verma S, McMurray JJV. The serendipitous story of SGLT2 Inhibitors in heart failure: new insights from DECLARE-TIMI 58 [published online March 18, 2019]. Circulation.