Cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients without diabetes: a systematic review and meta-analysis of randomised placebo-controlled trials

Abstract

ObjectivesTo assess the cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients without diabetes.MethodsWe searched PubMed, MEDLINE, Embase and Cochrane Library for publications up to 17 August 2022. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. Random-effects meta-analyses were performed to pool effect measures across studies. Risk ratios (RRs) with 95% CIs are expressed for composite cardiovascular outcome of cardiovascular death or hospitalisation for heart failure, cardiovascular death, hospitalisation for heart failure, all-cause mortality and composite renal outcome of ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage kidney disease or renal death. Annual rate of change in eGFR is expressed as the mean difference with 95% CI.ResultsWe identified four trials with 8927 patients with heart failure or chronic kidney disease (CKD). Compared with placebo, SGLT2 inhibitors showed favourable effects on the composite cardiovascular outcome (RR: 0.79, 95% CI: 0.71 to 0.87; moderate certainty), cardiovascular death (0.85, 0.74 to 0.99; moderate certainty), hospitalisation for heart failure (0.72, 0.62 to 0.82; moderate certainty), the composite renal outcome (0.64, 0.48 to 0.85; low certainty) and the annual rate of change in eGFR (mean difference: 0.99, 0.59 to 1.39 mL/min/1.73 m2/year; moderate certainty), while there was no significant difference in all-cause mortality (0.88, 0.77 to 1.01; very low certainty). Moderate certainty evidence indicated that SGLT2 inhibitors reduced the risk of serious adverse events and acute renal failure. Low certainty evidence suggested that SGLT2 inhibitors increased the risk of urinary tract infection and genital infection, while there were no differences in discontinuation due to adverse events, amputation, fracture, hypoglycaemia, ketoacidosis or volume depletion.ConclusionsEvidence of low to moderate certainty suggests that SGLT2 inhibitors provide cardiorenal benefits but have increased risk for urinary tract infection and genital infection in patients without diabetes and with heart failure or CKD.PROSPERO registration numberCRD42021239807.

Nutraceutical activation of Sirt1: a review

“…These drugs tend to be well tolerated aside from a moderate increase in risk of bladder and genital infections reflecting the increased glucose content of urine. 133 As noted, promotion of autophagy and of mitophagy/ MB is a key mechanism whereby effective Sirt1 activity can maintain or restore health. It is therefore appropriate to comment on ancillary nutraceuticals which may complement Sirt1 in aiding these processes.…”

“…Curiously, the SGLT2 inhibitory drugs used to treat diabetes-by diminishing renal retention of glucose and hence moderating glycaemiahave been found to be therapeutically useful in heart and renal failure, even in patients who are normoglycaemic. 133 This effect has been traced to their ability to boost Sirt1 and AMPK activity, thereby promoting autophagy, mitophagy and MB. 20 134-137 While blunting postprandial rises in glucose may boost Sirt1 and AMPK activity via a reduction in oxidisable substrate-rather like caloric restriction does 135 138 -there is evidence that these drugs can exert this effect on cells in vitro, including in heart tissue, which does not express SGLT2.…”

Hypertension as Cardiovascular Risk Factor in Chronic Kidney Disease

“…123–127 Several meta-analysis of these trials have been published. 128,129 However, in terms of kidney endpoints the most relevant is probably the most recent one published by the Nuffield Department of Population Health Renal Studies Group and the SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. 130 Indeed, authors have centered their meta-analysis on kidney disease progression (defined as a sustained ≥ 50% decrease in eGFR, a sustained low eGFR, ESKD, or death from kidney failure), acute kidney injury, and a composite of cardiovascular death or hospitalization for heart failure.…”

Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease

“… 228 Meta-analysis on all 3 SGLT2 inhibitors revealed no association with a higher fracture incidence in non-T2D and T2D patients. 229 , 230 However, a study with 252 diabetic nephropathy patients (CKD stage 3) reported fractures in 8% of patients in the dapagliflozin group and none in the placebo group during a 104-week follow-up. 231 …”

“…228 Meta-analysis on all 3 SGLT2 inhibitors revealed no association with a higher fracture incidence in non-T2D and T2D patients. 229,230 However, a study with 252 diabetic nephropathy patients (CKD stage 3) reported fractures in 8% of patients in the dapagliflozin group and none in the placebo group during a 104-week follow-up. 231 In patients with T2D, the SGLT2 inhibitors tofogliflozin and empagliflozin significantly improved vascular pulse wave velocity, suggesting an effect on arterial stiffness.…”