Regulatory Decision Summary for Jardiance

Jardiance (empagliflozin) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor, approved to reduce cardiovascular mortality in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease, who have inadequate glycemic control. This supplement to a new drug submission (SNDS) was filed to obtain market authorization for a new indication in patients with heart failure (HF) and reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death or hospitalisation for HF.

The pivotal study in this SNDS (EMPEROR-Reduced) evaluated the efficacy and safety of empagliflozin as an add-on to standard of care treatment for HF with reduced ejection fraction (HFrEF). This was a double-blind, placebo-controlled, phase 3 trial. A total of 3,730 patients, with HF and an ejection fraction (EF) <40%, were randomised 1:1 to receive empagliflozin 10 milligram (mg) once daily (o.d.) or placebo, on top of recommended therapy.

Patients were predominantly (76%) male. Approximately half the patients had a history of T2DM. The majority (75%) patients were in the New York Health Association (NYHA) Class II (slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea [shortness of breath]) and 24% in Class III (marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea); 73% had a left ventricular ejection fraction (LVEF) of less than 30%.

Empagliflozin significantly improved the primary endpoint, which was a composite of time to cardiovascular (CV) death or first hospitalization for HF (HHF), by 25% (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.65 to 0.86). The risk of HHF was significantly lower in the empagliflozin group than in the placebo group (HR 0.69, 95% CI 0.59 to 0.81); however, the risk of CV deaths was only 8% lower in the empagliflozin group (HR 0.92, 95% CI 0.75 to 1.12). This beneficial effect of empagliflozin on the primary outcome was observed to be consistent across the pre-specified patient subgroups analysed (nondiabetics/diabetics, age <65 or older, male/female, race, body mass index <30 kg/m² or higher, estimated glomerular filtration rate [eGFR] <60 millilitres [mL]/minute [min]/1.73 metres squared [m²] of body surface/year or more, presence/absence of a history of recent HF hospitalisation, ischemic/non-ischemic cause of HF).

The rate of decline in eGFR was significantly less in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 mL/min/1.73m²). In addition, empagliflozin-treated patients had a lower risk of serious renal outcomes, including chronic dialysis and sustained eGFR reductions of >40% from baseline.

No major unexpected safety signal was identified during this trial. With a median exposure of 14 months, empagliflozin 10 mg o.d. was well tolerated and the safety data were comparable with placebo. The safety profile of empagliflozin in the EMPEROR-Reduced trial was consistent with the known safety profile of empagliflozin in patients with T2DM.

Ketoacidosis, a known serious side effect of SGLT2 inhibitors, including empagliflozin, did not occur in the pivotal trial, nor in the two non-pivotal trials.

The safety profile in patients without T2DM (~50% of trial patients) was similar to that in those with T2DM. No cases of severe hypoglycemia were reported in patients without T2DM. Concomitant use of renin-angiotensin-aldosterone system (RAAS) blockers or diuretics did not increase the risk of adverse renal events or volume depletion, including hypotension.

As was seen in previous trials with SGLT2 inhibitors, genital tract infections were more common in the empagliflozin group than the placebo group in the EMPEROR-Reduced trial. Complicated genital tract infections were infrequent and rarely led to treatment discontinuation.

Overall, the benefit risk assessment of Jardiance is considered favorable for use in adults, as an adjunct to standard of care therapy, for the treatment of HFrEF.

For further details about Jardiance, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.