European Association for the Study of Diabetes
European Association for the Study of Diabetes
Perspective from Robert H. Eckel, MD
September 23, 2019
4 min read
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DAPA-HF: SGLT2 inhibitor reduces heart failure risk even for patients without diabetes

Perspective from Robert H. Eckel, MD
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The diabetes medication dapagliflozin was shown to reduce the risk for worsening heart failure and cardiovascular death among adults with heart failure with reduced ejection fraction regardless of diabetes status, according to findings from the DAPA-HF trial presented at the European Association for the Study of Diabetes annual meeting and simultaneously published in The New England Journal of Medicine.

Mikhail Kosiborod

Sodium-glucose cotransporter 2 inhibitors were initially developed and approved for treatment of type 2 diabetes because they lower plasma glucose concentrations via increased urinary excretion of glucose,” Mikhail Kosiborod, MD, professor of medicine at Saint Luke’s Mid America Heart Institute in Kansas City, Missouri, said during a presentation. “Of course, we have learned over the past few years that these agents do a lot more than just lower glucose, and there are many mechanisms of actions that get triggered that provide other effects above and beyond glucose-lowering.”

Study design

Kosiborod and colleagues compared the effects of 10 mg daily dapagliflozin (Farxiga, AstraZeneca) with placebo among 4,744 adults with heart failure with reduced ejection fraction ( 40%). According to Kosiborod, participants were “well treated” for heart failure with “state-of-the-art, guideline-directed medical therapy.”

The researchers randomly assigned 2,373 participants to dapagliflozin (mean age, 66.2 years; 23.8% women) and 2,371 to placebo (mean age, 66.5 years; 23% women); type 2 diabetes was present in 45% of each group. Follow-up was a median of 18.2 months.

The primary outcome was worsening heart failure, defined as hospitalization or urgent care requiring IV therapy for heart failure, and CV death. Secondary outcomes included the number of hospitalizations for heart failure and CV deaths, and heart failure symptoms based on the Kansas City Cardiomyopathy Questionnaire at baseline and at 8 months.

Various Colored Pills 
The diabetes medication dapagliflozin was shown to reduce the risk for worsening heart failure and cardiovascular death among adults with heart failure with reduced ejection fraction regardless of diabetes status.
Source: Adobe Stock

CV effects

The researchers reported that 16.3% of the dapagliflozin group and 21.2% of the placebo group experienced the primary outcome (P < .001) and that the risk for worsening heart failure or CV death was reduced by 26% with dapagliflozin compared with placebo (HR = 0.74; 95% CI, 0.65-0.85). The benefit was greater for those with class II compared with class III of IV heart failure, according to the researchers.

Risks for all key outcomes were reduced among those taking dapagliflozin vs. placebo: heart failure hospitalization or an urgent visit requiring IV therapy (HR = 0.7; 955 CI, 0.59-0.83), heart failure hospitalization (HR = 0.7; 95% CI, 0.59-0.83), an urgent visit requiring IV therapy (HR = 0.43; 95% CI, 0.2-0.9), CV death (HR = 0.82; 95% CI, 0.69-0.98) and all-cause death (HR = 0.83; 95% CI, 0.71-0.97). Researchers also reported improvement in heart failure symptoms based on the Kansas City Cardiomyopathy Questionnaire among participants who took dapagliflozin vs. placebo.

“Not only did dapagliflozin reduce CV death and hospitalizations for heart failure, but it also reduced the symptom burden, essentially making patients heal better when it comes to their heart failure symptoms,” Kosiborod said during the presentation.

Dapagliflozin presented “no notable excess of any event,” according to researchers, with a serious renal adverse event observed among 2.7% of the placebo group vs. 1.6% of the dapagliflozin group (P = .009).

“Despite the vast majority of its patients being on diuretics and RAAS blockers and most also taking MRAs, there was no increased risk of volume-related adverse events. In fact, certain renal adverse events were actually more common in the placebo group,” Silvio E. Inzucchi, MD, professor of medicine at Yale University School of Medicine and Yale-New Haven Hospital, told Endocrine Today. “There was also no signal for hypoglycemia, amputations, fractures or [urinary tract infections]. [Diabetic ketoacidosis] cases were more common in the dapagliflozin group but were rare.”

When participants were categorized by type 2 diabetes status, “the results are identical,” Kosiborod said.

Silvio E. Inzucchi

“By collaborating with cardiologists … and by treating our patients with diabetes who have risk factors for heart failure, we can have enormous benefit in the quality of life of our patients and actually their survival,” Inzucchi said during the presentation.

‘Impressive’ findings

In a commentary accompanying the article in NEJM, James C. Fang, MD, professor of medicine and chief of the division of cardiovascular medicine at University of Utah Health in Salt Lake City, wrote that “the results are important and impressive” both for primary and secondary outcomes and build on the stage-setting work of the EMPA-REG Outcome and DECLARE-TIMI 58 trials.

He also outlined knowledge gaps, including information on patients with severe heart failure, those taking sacubitril/valsartan (Entresto, Novartis) and the amount of other heart failure drugs taken by the participants. In addition, he raised concern about translating the findings, particularly noting the slow adoption of new therapies and fear of polypharmacy.

“In the end, it is not a question of having too many medications for heart failure therapy, but rather of using these drugs at doses that have been shown to be effective,” Fang wrote. “It behooves us as clinicians to learn more about using such newer agents effectively, but we have a long way to go.” – by Phil Neuffer

References:

Inzucchi S. OP S64.2.

Kosiborod M. OP S64.1. Both presented at: European Association for the Study of Diabetes Annual Meeting; Sept. 16-20, 2019; Barcelona, Spain.

Fang JC. N Engl J Med. 2019;doi:10.1056/NEJMe1912180.

McMurray JJV, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1911303.

Disclosures: Inzucchi reports clinical trial leadership from Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon Advisor, VTV Therapeutics and Zefgen. Kosiborod reports he has received research grants from AstraZeneca and Boehringer Ingelheim and served as a consultant or on the advisory board at Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Elsal, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck, Novartis, Novo Nordisk and Sanofi. Please see the study for all other authors’ relevant financial disclosures. Fang reports that he has received grants from NIH and AHA, served as a trial national investigator for AstraZeneca (DELIVER) and served on trial steering committees for Novartis (EVALUATE) and Amgen (GALACTIC).