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Background: Heart failure is prevalent worldwide. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective in heart failure patients with reduced ejection fraction, whether SGLT2i are effective in heart failure with preserved ejection fraction (HFpEF) remains to be determined. Methods: All relevant citations in the PubMed, Embase and Cochrane databases were identified from inception to September, 2022. The primary outcome was a composite endpoint of cardiovascular death and hospitalization for heart failure (HHF). A subgroup analysis was performed according to diabetes mellitus status and the ejection fraction. Secondary endpoints were cardiovascular death, hospitalization for heart failure and all cause death. Results: Seven studies involving 11,604 patients were included in the metaanalysis. Compared with placebo, sodium-glucose cotransporter 2 inhibitors reduced the incidence of the primary outcome by 24%, with an odds ratio (OR) and 95% confidence interval (CI) 0.76 [0.69, 0.84]. For secondary outcomes, sodium-glucose cotransporter 2 inhibitors were associated with a lower incidence of hospitalization for heart failure, but not cardiovascular or all-cause death; the OR and 95% CI were 0.73 [0.66, 0.82], 0.92 [0.81, 1.04], 0.96 [0.88, 1.05], respectively. Conclusions: This study proves the clinical efficacy of SGLT2i for treatment of HFpEF patients with or without diabetes, which was mainly driven by prevention of HHF rather than cardiovascular or all-cause death. [ABSTRACT FROM AUTHOR]

Clinical trials of sodium glucose co-transporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and comorbid cardiovascular and kidney disease have shown reductions in major adverse cardiovascular events, heart failure hospitalizations, and attenuation of the progression of kidney disease. The magnitude of benefit appears to be greater than expected due to glycemic control, reduced blood pressure, and loss of adiposity. This impact is also independent from reduced renal function and lesser degrees of natriuresis and glycosuria. However, these agents have also been associated with limb amputation, Fournier's gangrene, diabetic ketoacidosis, metabolic bone disease, and increased hematopoiesis. A strong off-target effect of SGLT2i on the sodium-proton antiporter (exchanger) on the cell surface and intracellular organelles explains the wide-ranging effects of these agents. By slowing the restoration of pH within cells, SGLT2i activate secondary processes that mimic ischemic preconditioning in the heart and kidney and increased hematopoiesis in bone marrow which would explain salutary effects. Conversely, the inability to rapidly recover pH in ischemic peripheral tissues explains the progression of diabetic extremity ulcers, gangrene, propensity for metabolic bone disease, and diabetic ketoacidosis in patients who are predisposed. This paper will review the evidence for the strong off-target effect of SGLT2i on the sodium-proton exchanger and its potential effect on the organ systems and processes in which SGLT2i appear to have activity. [ABSTRACT FROM AUTHOR]

In this systematic review, we sought to summarize the 3 recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials (Dapagliflozin Effect on CardiovasculAR Events (DECLARE-TIMI 58), Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, and Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME)) and to explore the potential causes for their different results. We found that the major adverse cardiovascular event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14% for DECLARE-TIMI 58, CANVAS, and EMPA-REG OUTCOME, respectively. DECLARETIMI 58 had the fewest cardiorenal events (across treatment and control arms) and EMPA-REG OUTCOME the most. DECLARE-TIMI 58 used alternative inclusion criterion for baseline renal function (creatinine clearance ≧ 60 mL/min) compared to the other trials (estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 bodysurface area). Therefore, the DECLARE-TIMI 58 study cohort had higher eGFR (mean eGFR 85.2 mL/min/1.73 m2 compared to 76.5 and 74 in CANVAS and EMPAREG OUTCOME, respectively); this may have caused the difference in results. Additionally contributing to the high event rate in EMPA-REG OUTCOME was the requirement of prior confirmed cardiovascular disease (CVD), resulting in 99.2% of patients with CVD compared to only 65.6% and 40.6% in CANVAS and DECLARE-TIMI 58, respectively (which did not require CVD). In conclusion, there is a need for large-scale studies of SGLT2i with matching inclusion/exclusion criteria and appropriate endpoints to ensure a truly direct comparison of the drugs. [ABSTRACT FROM AUTHOR]

Background: Heart failure is prevalent worldwide. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective in heart failure patients with reduced ejection fraction, whether SGLT2i are effective in heart failure with preserved ejection fraction (HFpEF) remains to be determined., Methods: All relevant citations in the PubMed, Embase and Cochrane databases were identified from inception to September, 2022. The primary outcome was a composite endpoint of cardiovascular death and hospitalization for heart failure (HHF). A subgroup analysis was performed according to diabetes mellitus status and the ejection fraction. Secondary endpoints were cardiovascular death, hospitalization for heart failure and all cause death., Results: Seven studies involving 11,604 patients were included in the meta-analysis. Compared with placebo, sodium-glucose cotransporter 2 inhibitors reduced the incidence of the primary outcome by 24%, with an odds ratio (OR) and 95% confidence interval (CI) 0.76 [0.69, 0.84]. For secondary outcomes, sodium-glucose cotransporter 2 inhibitors were associated with a lower incidence of hospitalization for heart failure, but not cardiovascular or all-cause death; the OR and 95% CI were 0.73 [0.66, 0.82], 0.92 [0.81, 1.04], 0.96 [0.88, 1.05], respectively., Conclusions: This study proves the clinical efficacy of SGLT2i for treatment of HFpEF patients with or without diabetes, which was mainly driven by prevention of HHF rather than cardiovascular or all-cause death., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 The Author(s). Published by IMR Press.)