In Heart Failure, Empagliflozin Equals the Competition and Benefits Sicker Patients

Empagliflozin, the drug that stunned the medical world when scientists showed it could prevent certain deaths in type 2 diabetes (T2D), offers heart failure benefits similar to its closest competitor, according to findings presented today during the European Society of Cardiology (ESC) 2020 Congress.

Results from the EMPEROR-Reduced trial, published simultaneously in the New England Journal of Medicine,¹ also show that empagliflozin prevents renal events and slows the process toward kidney failure, a key finding given CMS’ push to prevent renal disease progression.

The ESC meeting is being presented virtually due to the coronavirus disease 2019 (COVID-19) pandemic, which gave investigators a challenge. The study lost 42 of the 3730 patients to follow-up late in the process due to COVID-19.

The findings offer more evidence that the drug class called sodium glucose co-transporter-2 (SGLT2) inhibitors, first developed to treat T2D, can serve as all-purpose warriors against heart failure (HF) and renal decline, while offering modest weight loss benefits. SGLT2 inhibitors have a unique mechanism of action by targeting a protein that normally prevents blood glucose from leaving the body; instead, excess blood sugar is expelled through the urine.

The study, EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) is one of a pair trials studying empagliflozin in patients with heart failure, in this case HF with reduced ejection fraction (HFrEF). The other trial EMPEROR-Preserved, will produce results next year in patients with heart failure with preserved ejection fraction (HFpEF).

Among a group of patients with serious HFrEF—73% had left ventricular ejection fraction of 30% or less—empagliflozin produced the following results:

• Met its primary end point, a combination of reducing the risk of cardiovascular (CV) death or hospitalization for heart failure (HHF) by 25%, with most of that result driven by a 31% lower risk of HHF (HR, 0.75; 95% CI, 0.65-0.86, P < .001).
• Reduced the risk of first or future hospitalizations for heart failure by 30% (HR, 0.70; 95% CI, 0.58-0.85, P < .001).
• Reduced renal events by 50%, (HR, 0.50; 95% CI, 0.32-0.77, P = .0019)
• Produced slower rate of annual decline in the estimated glomerular filtration rate (eGFR) than placebo (–0.55 vs –2.28 ml per minute per 1.73 m2 of body surface area per year, P < .001).

Taken together with last year’s DAPA-HF trial for the SGLT2 inhibitor dapagliflozin, “the concordant results from these trials actually are remarkable,” said lead study author Milton Packer, MD, of Baylor University, who said there was no question that the 2 drugs had joined sacubitril-valsartan (Entresto, Novartis), beta blockers, spironolactone, and eplerenone for the treatment of HFrEF.

During his presentation, Packer was asked whether he would add individual medications slowly or use all 4 together for a newly diagnosed HFrEF patient. "The only way I can answer that question is to describe what I would to happen to me," he said. "If I was just given the diagnosis of heart failure with reduced ejection fraction, I would want my physicians to initiate therapy with all 4 classes ... within the first 4 to 6 weeks ... not on the same day [but] within a reasonably short period of time."

SGLT2s Have Multiple Uses

Competition in the drug class is fierce. In 2016, empagliflozin was the first SGLT2 inhibitor to receive a cardiovascular indication following the landmark EMPA-REG OUTCOME study. Empagliflozin later received FDA fast track designation in heart failure in June 2019, but after DAPA-HF, dapagliflozin won an indication in in May 2020.

In renal results, the maker of the first SGLT2 inhibitor, canagliflozin (Invokana, Janssen), produced an important renal outcomes study, CREDENCE, and last fall won an indication to treat diabetic kidney disease. That was followed by empagliflozin receiving fast track designation for chronic kidney disease in March 2020. Results from dapagliflozin’s DAPA-CKD study will be read out during the ESC Congress tomorrow.

During today's presentation, Packer said SGLT2 inhibitors should be prioritized "for all patients who have an injured heart or an injured kidney," whether caused by diabetes, heart failure, or chronic kidney disease. He called the EMPEROR-Reduced findings “practice changing,” but said much would depend on his fellow cardiologists prescribing SGLT2 inhibitors to patients who need them, hinting at the concern expressed that too many are wary of using a “diabetes drug” for heart failure.

“It does depend on whether physicians are paying attention,” he said, noting that the findings would be published in leading journals on both sides of the Atlantic. “But if physicians don't pay attention, and they don't prescribe these drugs, then no patients will benefit.”

Origins of the EMPEROR Trials

Both EMPEROR-Reduced and EMPEROR-Preserved were launched after 2015, when the EMPA-REG OUTCOME study showed that unexpected cardiovascular benefits from empagliflozin in T2D patients were driven in large measure by reductions in heart failure hospitalization. The findings set off a wave of new studies to learn more about SGLT2 inhibitors’ potential in heart failure and renal care, among patients with and without diabetes.

At last year’s ESC meeting in Paris, the DAPA-HF study showed that dapagliflozin (Farxiga, AstraZeneca), produced a risk reduction of 26% in CV deaths and worsening of heart failure among a slightly larger population of patients with HFrEF.

DAPA-HF found nearly identical risk reduction for patients with T2D (HR, 0.75) and without T2D (HR, 0.73). In EMPEROR-Reduced, there was slightly more separation between risk reduction for T2D (HR, 0.72) and without T2D (HR, 0.78). However, Packer said this was “almost identical,” when asked by The American Journal of Managed Care®, and noted, “We also found positive effects in diabetics and non-diabetics on renal events,” and said the benefits “do not depend and are not influenced by the presence or absence of diabetes.”

A Less Healthy Population

By design, authors of EMPEROR-Reduced said their study population was less healthy than the DAPA-HF participants. The mean left ventricular ejection fraction (LVEF) in EMPEROR-Reduced was 27.7% [6.0]; the mean LVEF of DAPA-HF participants was 31.2% [6.7]. LVEF measures how much blood is being pumped from the heart’s left ventricle, the main pumping chamber.

Unsurprisingly, the EMPEROR-Reduced authors say, their participants had more events, but thisshows the drug class can treat more types of patients. “Our trial thus extends the benefits of SGLT2 inhibitors to patients with more advanced but stable heart failure,” they wrote.

However, in an accompanying editorial, John Jarcho, MD, of Brigham and Women’s Hospital and Harvard University, discussed the different findings for the 2 drugs in cardiovascular death and pondered whether this was, in fact, the case—SGLT2 inhibitors could be less effective in advanced heart failure, and perhaps more subgroup analyses would shed light. “A definitive answer to this question would likely require a head-to-head randomized trial,” Jarcho wrote.²

Combination Therapy

The authors noted that 19.5% of the study patients entered the trial taking sacubitril-valsartan. Among patients taking this therapy at baseline, the HR for the comparison between empagliflozin and placebo for the primary outcome was 0.64 (95% CI, 0.45-0.89), compared with 0.77 (95% CI, 0.66-0.89) for those not taking the background therapy.

Packer, who was also one of the authors for PARADIGM-HF, which led to FDA approval of sacubitril-valsartan, said during the press briefing that EMPEROR-Reduced and DAPA-HF are similarly important trials. The use of empagliflozin and sacubitril-valsartan together is “additive,” Packer said.

“Physicians really should take notice of both drugs for the benefit of patients,” he said.

References

1. Packer M, Anker SD, Butler J. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. Published online August 29, 2020.DOI: 10.1056/NEJMoa2022190
2. Jarcho JA. More evidence for SGLT2 inhibitors in heart failure. N Engl J Med. Published online August 29, 2020. DOI: 10.1056/NEJMe2027915