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CV benefits of diabetes drug dapagliflozin extend to patients with reduced ejection fraction
NEW ORLEANS — Treatment with the SGLT2 inhibitor dapagliflozin reduced HF hospitalizations in patients with a broad range of left ventricular ejection fraction and may provide even greater benefit with lower CV death and mortality in patients with HF with reduced ejection fraction, researchers reported at the American College of Cardiology Scientific Session.
In the overall DECLARE-TIMI 58 CV outcome trial, dapagliflozin 10 mg (Farxiga, AstraZeneca) reduced the composite endpoint of CV death and HF hospitalization over 4 years — mainly driven by the reduction in HF hospitalization — in a broad population of patients with type 2 diabetes.
“However, the impact of baseline LVEF and the clinical benefit of SGLT2 inhibitors is unknown,” Eri T. Kato, MD, PhD, cardiologist at Kyoto University in Japan, said during presentation of the late-breaking clinical trial.
New subanalysis
The prespecified subanalysis was planned to examine the clinical benefit of dapagliflozin in patients with and without HFrEF.
Of 17,160 patients with type 2 diabetes and established or multiple risk factors for atherosclerotic CVD enrolled in the DECLARE-TIMI 58 trial, baseline EF was available in 5,202. At baseline, 88.4% had no history of HF, 7.7% had HF without known reduced EF and 3.9% had HFrEF, defined as EF less than 45%.
Patients with HFrEF assigned dapagliflozin were 38% less likely to be hospitalized for HF or die of CV causes compared with those assigned placebo (HR = 0.62; 95% CI, 0.45-0.86). According to the researchers, this was a significantly greater reduction than the 12% decrease in the likelihood of events among patients without HFrEF (HR = 0.88; 95% CI, 0.76-1.02). The treatment effect of dapagliflozin was similar among patients with HF without known reduced EF (HR = 0.88; 95% CI, 0.66-1.17) and those without HF (HR = 0.88; 95% CI, 0.74-1.03), the researchers wrote in a simultaneous publication in Circulation.
Treatment with dapagliflozin reduced the rate of HF hospitalizations among all patients, regardless of EF or HF status at the start of the study, according to the findings.
Additionally, patients with HFrEF assigned dapagliflozin had a 45% lower rate of CV death (HR = 0.55; 95% CI, 0.34-0.9) and 41% lower rate of all-cause mortality (HR = 0.59; 95% CI, 0.4-0.88) compared with placebo. According to Kato, the researchers did not observe these benefits in patients without HFrEF.
However, Kato noted that “a subgroup mortality benefit in this trial with overall neutral effect on mortality should be interpreted cautiously.”
“The key finding of the new analysis is that regardless of history of HF or EF, there is a benefit in terms of reduction of hospitalization for HF. But, the patients who are at highest risk — those with an EF less than 45% — had an even greater reduction in hospitalization for HF and we also observed a lower rate of mortality, both CV and all-cause. So, in a high-risk subset of patients, there is an even greater benefit [of dapagliflozin],” Stephen D. Wiviott, MD, senior investigator and chairman of the Clinical Events Committee with the TIMI Study Group, cardiovascular medicine specialist at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, told Cardiology Today.
‘Ejection fraction is a strong tool’
The large DECLARE-TIMI 58 trial was conducted at 882 sites in 33 countries.
This new analysis, presented at ACC 2019, is the first to examine whether dapaliflozin’s benefits can be predicted based on LVEF.
SGLT2 inhibitors have garnered attention for CV risk reduction, with empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) gaining an expanded indication in 2017. More recently, canagliflozin (Invokana, Janssen) also earned an expanded indication from the FDA for CV risk reduction in type 2 diabetes.
Currently, dapagliflozin is not indicated to reduce the risk for CV events, CV death or HF hospitalization.
“The use of the SGLT2 inhibitor dapagliflozin is beneficial in reducing hospitalizations for heart failure in patients with a broad range of left ventricular ejection fraction, but patients with reduced ejection fraction may derive an even greater benefit,” Kato said in a press release. “The clinical implication of this finding is that ejection fraction is a strong tool to identify those who are at highest risk and may derive particular benefit from SGLT2 inhibitors.”
Speaking with Cardiology Today, Deepak L. Bhatt, MD, MPH, a researcher with the DECLARE-TIMI 58 trial, said, “It is encouraging to see diabetes trials presented at cardiology meetings such as [ACC 2019].
“The trials that are ongoing now in HF patients with or without diabetes and getting SGLT2 inhibitors or placebo should nail down this question of who benefits most from SGLT2 inhibition,” he said. “This is exciting data for cardiologists, diabetologists, primary care physicians and, ultimately, hopefully, good for patients and patient care.”
Further analyses from DECLARE-TIMI 58 are planned. Kato noted that there are several other ongoing trials that are investigating SGLT2 inhibitors in patients with HF, which should provide further insights in this population. Such trials include Dapa-HF and EMPEROR-Reduced in the HFrEF population and DELIVER, PRESERVED-HF and EMPEROR-Preserved in the HFpEF population. – by Katie Kalvaitis
References:
Kato ET. Late-Breaking Clinical Trials IV. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.
Kato ET, et al. Circulation. 2019;doi:10.1161/CIRCULATIONAHA.119.040130.
Disclosures: The DECLARE-TIMI 58 study was funded by AstraZeneca. Cardiology Today could not confirm Kato’s relevant financial disclosures at the time of publication. Wiviott reports he has consulted for AstraZeneca and his spouse is an employee of Merck.
Perspective
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The DECLARE-TIMI 58 trial is yet another example of the newer classes of diabetes medications showing additional CV benefits. The SGLT2 inhibitors especially seem to have a nice impact on both HF recurrence as well as in slowing the progression of kidney disease. Rather than physicians thinking, “Well, after metformin I’m going to add a sulfonylurea, like glyburide, or something that has been around for a long period of time,” we can now can offer patients other medications that do have some favorable health outcomes from a CV standpoint.
Ciccarone Center for the Prevention of Heart Disease
Johns Hopkins Medicine