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Empagliflozin shows CV benefit in patients with PAD

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ANAHEIM, Calif. — Among patients with peripheral artery disease at baseline enrolled in the EMPA-REG OUTCOME trial, treatment with empagliflozin reduced the risk for mortality, CV events, HF hospitalization and incident or worsening nephropathy compared with placebo, with no increase in the risk for lower-limb amputation.

Results of the subanalysis focusing on patients with and without PAD were presented at the American Heart Association Scientific Sessions and simultaneously published in Circulation.

Among 7,020 patients with type 2 diabetes and established CVD enrolled in the EMPA-REG OUTCOME trial, 21% had PAD at baseline. Of those, 982 were assigned to treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) 10 mg or 25 mg and 479 were treated with placebo. Study medication was given on top of standard of care including glucose-lowering therapy.

Among the patients with PAD at baseline, treatment with empagliflozin, compared with placebo, was associated with the following:

• 43% reduction in CV mortality (HR = 0.57; 95% CI, 0.37-0.88);

• 38% reduction in all-cause mortality (HR = 0.62; 95% CI, 0.44-0.88);

• 16% reduction in 3-point major adverse CV events, including CV mortality, nonfatal MI and nonfatal stroke (HR = 0.84; 95% CI, 0.62-1.14);

• 7% reduction in 4-point major adverse CV events, including unstable angina (HR = 0.93; 95% CI, 0.7-1.24);

• 44% reduction in hospitalization for HF (HR = 0.56; 95% CI, 0.35-0.92); and

• 46% reduction in incident or worsening nephropathy (HR = 0.54; 95% CI, 0.41-0.71).

The decrease observed in CV mortality appeared early during the trial and persisted during follow-up.

The results were consistent across subpopulations with and without PAD at baseline, Subodh Verma, MD, PhD, FRCSC, from St. Michael’s Hospital, University of Toronto, said during a presentation.

The researchers noted in Circulation that “the reduction in cardiovascular death with empagliflozin in patients with type 2 diabetes and PAD translates to a number needed to treat of 29 patients over 3.1 years to prevent one event.”

For this study, PAD was defined as the presence of limb angiography, stenting or bypass surgery, limb or foot amputation, significant peripheral artery stenosis in at least one limb and/or ankle brachial index less than 0.9 in at least one ankle.

In other findings, adverse event rates were similar between the treatment groups in patients with and without PAD. Among patients with PAD, lower-limb amputation occurred in 5.5% of patients assigned empagliflozin vs. 6.3% assigned placebo (HR = 0.84; 95% CI, 0.54-1.32). Among patients without PAD, lower-limb amputation occurred in 0.9% vs. 0.7%, respectively (HR = 1.3; 95% CI, 0.69-2.46).

During a discussion of the trial results, Renato D. Lopes, MD, MHS, PhD, from the division of cardiovascular medicine at Duke Clinical Research Institute, noted that lower-limb amputation is “one of the major concerns in patients with PAD.”

“Importantly, there was no signal of increase risk of amputation,” Lopes said. However, “this is different from other SGLT2 inhibitor programs, like CANVAS ... which showed a significant increase in both minor and major amputation in patients treated with canagliflozin (Invokana, Janssen) ... and deserves further investigation.”

Potential reasons for this difference in amputation could be related to drug differences, despite being from the same class; differences in amputation event ascertainment; varying populations; and/or chance, according to Lopes.

The findings of this subanalysis build on data from the overall EMPA-REG OUTCOME trial, which showed similar reductions in CV mortality and hospitalization for HF with empagliflozin in patients with type 2 diabetes and established CVD.

“Given the substantial risk reductions observed in this vulnerable population of patients with type 2 diabetes and PAD, these results may have important translational implications for patients and physicians,” Verma said at a press conference.

“We are living in a new paradigm of treatment of patients with type 2 diabetes, which includes an integrated management team of endocrinologists, cardiologists, vascular surgeons, primary care physicians and other health care providers that should work together to provide the best care for this high-risk group of patients,” Lopes said. – by Katie Kalvaitis

References:

Verma S. LBS.04 – Sweet Spot in Cardiometabolic Care. Presented at: American Heart Association Scientific Sessions; Nov. 11-15, 2017; Anaheim, Calif.

Verma S, et al. Circulation. 2017;doi:10.1161/CIRCULATIONAHA.117.032031.

Disclosures: The EMPA-REG OUTCOME trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Verma reports he has received research grants and/or speaking honoraria from Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Janssen and Merck. Lopes reports he has consulted or served on advisory boards for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer and Portola, and has received research grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic and Pfizer.