Background: sodium-glucose cotransoporter-2 inhibitors (SGLT-2Is) improve prognosis in heart failure patients both with reduced (HFrEF) and preserved ejection fraction (HFpEF). However, these drugs can have some side effects.
Purpose: estimate the relative risk of side effects in HF patients treated with SGLT-2Is irrespectively from left ventricular EF and setting (acute and chronic HF).
Methods: 4 randomized controlled trials (RCTs) enrolling patients with HFrEF 3 RCTs enrolling acute HF and 3 RCTs enrolling HFpEF were included. Among side effects, urinary infection, genital infection, acute kidney injury diabetic ketoacidosis, hypotension, hypoglycemia, hyperkalemia, hypokalemia, bone fractures and amputations were considered in the analysis.
Results: overall 22687 patients were included in the analysis: 8830 (39%) patients with HFrEF, 12563 (55%) with HFpEF and 1295 (6%) with acute HF. There weren’t differences between SGLT-2Is and placebo in the risk to develop diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures and amputations. HFrEF patients treated with SGLT-2is had a significative reduction of acute kidney injury [RR 0.54; 95% CI 0.33-0.87) p= 0.011], whereas no differences have been reported in the HFpEF [RR 0.94 (95% CI 083-1.07) p=0.348] and acute setting [RR 0.97; 95% CI 0.58-1.64) p= 0.915] (Fig 1A). A higher risk to develop genital infection [overall 2.82; 95% CI 1.96-4.05) p <0.001] was found irrespectively from EF [HFrEF 2.38 (95%CI 1.34-4.24) p= 0.003; HFpEF RR 3.04 (95%CI 1.88-4.90) p <0.001] (Fig 1B). The risk to develop urinary infections and hypotension was increased in the overall HF population with a RR of 1.15 (95%CI 1.02-1.30) p= 0.028 and RR 1.15; 95%CI 1.02-1.29) p= 0.017, respectively (Fig 2 A-B). This risk was mainly driven by HFpEF patients [RR urinary infections 1.19 (95%CI 1.02-1.38) p= 0.029; RR hypotension 1.23 (95% CI 1.05-1.43) p= 0.011], whereas no differences have been reported in HFrEF [RR urinary infection 1.04 (95%CI 0.80-1.35) p= 0.774; RR hypotension 1.04 (95%CI 0.87-1.24) p= 0.687] and in the acute setting [RR urinary infections 1.19 (95%CI 0.81-1.74) p= 0.375; RR hypotension 1.23 (95%CI 0.78-1.96) p= 0.371].
Conclusions: SGLT-2is increase the risk of genital infections in HF patients. In HFpEF patients SGLT-2Is increase the risk of urinary infections and hypotension compared to placebo, whereas reduce the risk of acute kidney disease in patients with HFrEF