Aim: To determine whether the magnitude of the cardiorenal benefits of sodiumglucose co-transporter-2 inhibitors (SGLT2is) varies with baseline kidney function. Methods:We searched randomized, placebo-controlled trials testing the effects of SGLT2is on renal and cardiovascular outcomes. Efficacy outcomes, stratified by baseline estimated glomerular filtration rate (eGFR) categories, included renal disease progression, a composite heart failure (HF) outcome and mortality.Results: Thirteen trials testing SGLT2is in 90 402 participants with available eGFR data were included. The risk of bias was judged as low for all trials. SGLT2is reduced the relative risks of renal disease progression by 27% to 57% and of HF outcomes by 13% to 32% across different eGFR categories, with an overall low heterogeneity. Meta-regression analyses showed a significant direct relationship between baseline eGFR and the magnitude of SGLT2is' renal protection (P = .003). The greatest risk reduction was in participants with an eGFR of 90 ml/min/1.73m 2 or higher (HR 0.43, 95% CI: 0.32-0.58) and the smallest was in those with an eGFR of less than 30 ml/min/1.73m 2 (HR 0.73, 95% CI: 0.62-0.86, P < .001). Conversely, for HF, the greatest risk reduction was in those with an eGFR of less than 30 ml/min/1.73m 2 (HR 0.68, 95% CI: 0.48-0.96) and the smallest was in those with an eGFR of 90 ml/min/1.73m 2 or higher (HR 0.87, 95% CI: 0.56-1.34).Conclusions: SGLT2is reduce the risk of renal and HF outcomes for all eGFR categories. The greatest benefits in terms of kidney protection may be achieved by early initiation of SGLT2is in people with preserved eGFR. The greatest risk reduction for HF outcomes is observed in people with lower eGFR values.Ernesto Maddaloni and Ilaria Cavallari contributed equally to this article.

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Mitral annular disjunction (MAD) is a structural abnormality which is commonly seen in patients with myxomatous mitral valve disease and mitral valve prolapse. MAD is a marker of severe disease including a higher need for mitral valve intervention and more arrhythmic events, which can be a cause of sudden cardiac death (SCD). A 72-years-old man with several cardiovascular risk factors (hypertension, diabetes mellitus, obesity, previous smoking, family history of cardiovascular diseases, chronic kidney disease) experienced two pre-syncopal episodes. Therefore, he was referred to a 24-hour Holter EKG that showed a non-sustained ventricular tachycardia (VT). A transthoracic 2D echocardiogram evidenced a mitral valve prolapse with mild regurgitation, normal left and right heart dimensions and function. Elective coronary angiography was performed to rule out an ischemic aetiology of ventricular arrhythmias (multiple cardiovascular risk factors and strong familiarity for coronary artery disease). The coronary angiography revealed a stenosis of 30% of left anterior descending artery and an intermediate stenosis of right coronary artery. A myocardial perfusion scintigraphy was performed to evaluate the intermediate coronary stenosis. The scintigraphy showed numerous focal perfusion abnormalities non indicative for coronary disease but rather for a degenerative or inflammatory disease. Indeed, we decided to perform a cardiac magnetic resonance (CMR). The CMR revealed a MAD with detachment of the root of the mitral annulus from the postero-lateral ventricular myocardium during systole, without areas of myocardial fibrosis evidenced by late gadolinium enhancement (LGE). Factors for high risk of SCD, such as fibrosis affecting the infero-basal left ventricle free wall or the papillary muscles, family history of SCD, personal history of complex ventricular arrhythmias, were not represented in our case. Therefore, we opted for a medical therapy with beta-blockers and a careful follow-up. MAD is an under-recognized cause of ventricular arrhythmias and SCD, generally associated to mitral valve prolapse. Echocardiography and CMR can identify and quantify MAD. A comprehensive evaluation, including multimodality imaging and clinical history, is mandatory for risk stratification of SCD and for optimal treatment.

Background Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have demonstrated to reduce heart failure (HF) and renal outcomes irrespective of diabetes status. The cardiovascular efficacy and the mortality benefit of these agents in patients without HF and across the spectrum of left ventricular ejection fraction (EF) are a matter of debate. Methods This study-level meta-analysis included 11 controlled randomized trials and 76,520 patients randomized to a SGLT-2 inhibitor (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin and sotagliflozin) or placebo in different clinical settings including diabetes, HF with reduced or preserved EF and chronic kidney disease. Data were stratified by history of HF, HF with reduced EF (≤40%), mid-range EF (40-49%) and preserved EF (≥50%). The incidence of the following outcomes, when available, was evaluated: HF composite outcome, defined as cardiovascular death or hospitalization/urgent visit for HF, its individual components and all-cause mortality. An additional sensitivity analysis tested the efficacy of SGLT-2 inhibitors in patients with extremely reduced EF (≤30%). Results Overall, there were 22,653 patients with HF (33.8%) and 44,304 patients without HF (66.2%). In patients without history of HF, SGLT-2 inhibitors significantly reduced the risk of HF outcomes (HR 0.76, 95% CI 0.68-0.86) and all-cause mortality (HR 0.84, 95% CI 0.73-0.95). In patients with HF, a significant reduction in the composite of cardiovascular death and HF events was consistently observed in those with reduced EF (HR 0.71, 95% CI 0.65-0.78), mid-range EF (HR 0.68, 95% CI 0.57-0.81) and preserved EF (HR 0.78, 95% CI 0.69-0.89; Figure). There was a significant reduction in all-cause mortality also in patients with HF treated with SGLT-2 inhibitors (HR 0.87, 95% CI 0.80-0.95). Conclusions SGLT-2 inhibitors demonstrated cardiovascular and mortality benefits irrespective from history of HF and across the spectrum of left ventricular EF.

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce renal and heart failure (HF) events in people with and without diabetes. Although their glycemic efficacy is dependent on kidney function, it remains unclear to what extent baseline kidney function influences the magnitude of SGLT2i cardiorenal effects. Methods We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials testing the effects of SGLT2i on renal and CV outcomes (PROSPERO registration number CRD42022325976). Efficacy outcomes, stratified by five estimated glomerular filtration rate (eGFR) categories, included progression of renal disease (as defined in each trial), a composite HF outcome (defined as CV death or hospitalization/urgent visit for HF), and all-cause mortality. Results Eleven trials testing five SGLT2i (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin and sotagliflozin) in 77,541 participants were included. The majority of participants (39.8%) had eGFR values between 60 and 90 ml/min/1.73m2, with only 1.3% having advanced kidney disease (eGFR between 20 and 30 ml/min/1.73m2). Overall, SGLT2i reduced the risk of renal disease progression by 41% (HR 0.59, 95%CI 0.54–0.65, p&lt;0.001) and the risk of HF outcomes by 22% (HR 0.78, 95%CI 0.73–0.83, p&lt;0.001). Meta-regression analyses showed a significant direct relationship between baseline eGFR and the magnitude of SGLT2i renal protection (p=0.040). The greatest relative risk reduction was in participants with eGFR values ≥90 ml/min/1.73m2 (HR 0.43, 95%CI 0.32–0.58) and the smallest was in those with an eGFR between 30 and 45 ml/min/1.73m2 (HR 0.64, 95%CI 0.55–0.76). Conversely, the HF outcome showed a non-significant trend to greater benefit in participants with lower eGFR categories (p=0.086). The greatest relative risk reduction was in those with an eGFR between 20 and 30 ml/min/1.73m2 (HR 0.68, 95%CI 0.48–0.96, p=0.026) and the smallest was in those with an eGFR ≥90ml/min/1.73m2 (HR 0.87, 95%CI 0.56–1.35, p=0.52). Conclusions SGLT2i reduce risk of renal disease progression and HF outcomes for all eGFR subgroups. However, the opposite trends for the influence of baseline kidney function between renal and HF outcomes suggest different SGLT2i mechanisms for renal and cardiac protection.