Sodium-glucose cotransporter-2 inhibitors for heart failure with reduced ejection fraction

Clinical question

What is the role of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with chronic heart failure with reduced ejection fraction?

Bottom line

An SGLT2i reduces mortality, heart failure hospitalizations, and improves quality of life when added to other medications for heart failure with reduced ejection fraction—with or without diabetes. Compared with placebo, for every 100 patients treated with SGLT2i for about 1.5 years, about 2 fewer will die, roughly 4 fewer will be hospitalized for heart failure, and roughly 7 more will have improved quality of life.

Evidence

There were 2 industry-funded RCTs^1,2 of patients with heart failure (and ejection fraction of ≤ 40%) (mainly class 2-3; 47% with diabetes; average systolic blood pressure = 122 mm Hg³). Differences are statistically significant unless indicated otherwise.

• DAPA-HF trial¹ (4744 patients treated with 10 mg of dapagliflozin daily): At 18 months, mortality was 12% versus 14% (placebo; number needed to treat [NNT] = 44). Heart failure hospitalization was 10% versus 13% (placebo; NNT = 27). At 8 months, 58% versus 51% (placebo) achieved minimal improvement in quality of life (≥ 5 points on a 100-point scale; NNT = 14). There was no difference in adverse events.

• EMPEROR-Reduced trial² (3730 patients treated with 10 mg of empagliflozin daily): At 16 months, mortality was 13% versus 14% (placebo); not statistically different. Heart failure hospitalization was 13% versus 18% (placebo; NNT = 20). Genital infection was an adverse event (1.7% vs 0.6% [placebo]; number needed to harm = 91).

• In a meta-analysis⁴ including both trials, there was a reduction in mortality (NNT = 61) and heart failure hospitalization (NNT = 24). There was similar efficacy in those with or without diabetes, and in those treated with or without sacubitril-valsartan.

Context

• Efficacy of SGLT2i was indirectly compared with other heart failure medications.^5,6 For mortality, the relative risk reduction was about 13% (others 16%-35%), and for heart failure hospitalization was about 30% (others 20%-35%).

• Unlike other heart failure medications, SGLT2i do not seem to cause statistically significant hypotension or electrolyte abnormalities.^1,2,4

• Canadian guidelines⁷ recommend SGLT2i for all patients with symptomatic heart failure, although the sequence was not specified (eg, whether to consider SGLT2i before sacubitril-valsartan).

• Splitting 25 mg of empagliflozin in half (12.5 mg; trial dose is 10 mg) cuts cost in half (about $560/year).⁸

Implementation

All patients starting SGLT2i should receive education on sick day management (ie, pause SGLT2i when acutely ill and dehydrated) and be given written guidance.⁹ Similar to renin-angiotensin system blockers, starting SGLT2i acutely decreases estimated glomerular filtration rate (average 4 mL/min/1.73 m²), which does not require change to therapy^2,7; reductions greater than 30%, which occur in less than 5% of patients starting SGLT2i, should prompt clinicians to hold SGLT2i, assess for and correct hypovolemia, and assess for potential use of nephrotoxic drugs.¹⁰