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In recent trials, sodium-glucose cotransporter 2 (SGLT2) inhibitors proved effective as treatment for heart failure. However, the relative efficacy of sacubitril/valsartan against SGLT2 inhibitor in patients with heart failure remains unknown. Hence, we performed a network meta-analysis to compare the effects of sacubitril/valsartan against SGLT2 inhibitors on cardiovascular outcomes in patients with heart failure. Four electronic databases (PubMed, Embase, Cochrane, SCOPUS) were searched for randomised-controlled trials (RCTs) published from 1st January 2000 to 25th September 2021. Two additional systematic reviews were conducted for RCTs of enalapril and valsartan to establish a common comparator arm. Frequentist network meta-analysis models were utilised to summarise the studies. Twenty-five RCTs were included, comprising a combined cohort of 47,275 patients. Network meta-analysis demonstrated that compared to SGLT2 inhibitors, sacubitril/valsartan achieved a larger hazard rate reduction in the composite of heart failure hospitalisation and cardiovascular death (hazard ratio [HR]: 0.86; 95% CI 0.75–0.98), cardiovascular death (HR: 0.78; 95% CI 0.65–0.94), and a larger mean change in systolic blood pressure at 8 or more months (weighted mean difference [WMD]: − 7.08 mmHg; 95% CI − 8.28 to − 5.89). There were no significant differences in treatment effects across heart failure hospitalisation, all-cause mortality, diastolic blood pressure at 12 weeks, and systolic blood pressure at 2–4 months. In patients with heart failure with reduced ejection fraction, sacubitril/valsartan achieved a 20% hazard rate reduction for cardiovascular death compared to SGLT2 inhibitors. In patients with heart failure, sacubitril/valsartan was demonstrated to be superior to SGLT2 inhibitors in the treatment effect for the composite of heart failure hospitalisation and cardiovascular death, cardiovascular death, and long-term blood pressure.

Empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin have been shown in randomized controlled trials to improve cardiovascular, metabolic, and renal outcomes in heart failure patients. To date, there has not been any meta-analysis examining the differences in clinical outcomes across different SGLT2 inhibitors in heart failure patients. Four electronic databases (PubMed, Embase, Cochrane, SCOPUS) were searched on 13 September 2020 for articles published from 1 January 2000 to 13 September 2020 examining the effect of SGLT2 inhibitors on cardiovascular, renal, and metabolic outcomes in heart failure patients. Frequentist network meta-analysis was performed on extracted data. Ten randomized controlled trials were included with a combined cohort of 15,373 patients. In heart failure patients, frequentist network meta-analysis demonstrated no demonstrable difference in treatment effect across the SGLT2 inhibitors for heart failure hospitalization, cardiovascular deaths, composite of cardiovascular deaths and heart failure hospitalizations, all-cause mortality, and a composite of cardiovascular deaths and non-fatal myocardial infarction and non-fatal stroke. There was no demonstrable difference in treatment effect for worsening renal function or the weighted mean difference for weight, hemoglobin A1c, and systolic blood pressure. There were no demonstrable treatment differences across SGLT2 inhibitors across cardiovascular, renal, and metabolic outcomes, although this needs to be interpreted considering the wide confidence intervals, limited number of included studies, and heterogeneity present. Future research of different SGLT2 inhibitors in head-to-head studies is warranted to determine if there is a drug class effect.

Background Recent studies have increasingly shown that sodium‐glucose cotransporter 2 (SGLT2) inhibitors may have beneficial cardiovascular and metabolic effects in patients without diabetes mellitus. Hence, we conducted a systematic review and meta‐analysis to determine the effect of SGLT2 inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus. Methods and Results Four electronic databases (PubMed, Embase, Cochrane, and SCOPUS) were searched on August 30, 2020 for articles published from January 1, 2000 to August 30, 2020, for studies that examined the effect of SGLT2 inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus. A random‐effects pairwise meta‐analysis model was used to summarize the studies. A total of 8 randomized‐controlled trials were included with a combined cohort of 5233 patients. In patients without diabetes mellitus, those with heart failure treated with SGLT2 inhibitors had a 20% relative risk reduction in cardiovascular deaths and heart failure hospitalizations, compared with those who were not treated (risk ratio, 0.78; P P 2 ( P P =0.04), and fasting plasma glucose of −0.38 mmol/L ( P =0.05), compared with those without. There were no between‐group differences in NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) levels, waist circumference, diastolic blood pressure, glycated hemoglobin, low‐density lipoprotein cholesterol levels, and estimated glomerular filtration rates. Across our combined cohort of 5233 patients, hypoglycemia was reported in 22 patients. Conclusions SGLT2 inhibitors improve cardiovascular outcomes in patients without diabetes mellitus with heart failure. In patients without diabetes mellitus, SGLT2 inhibitors showed positive metabolic outcomes in weight and blood pressure control.

Colchicine has received emerging interest due to its cardiovascular benefits in patients with coronary artery disease (CAD). We conducted a one-stage meta-analysis of reconstructed individual patient data (IPD) from randomized-controlled trials to summarize the effects of colchicine on cardiovascular outcomes in patients with CAD. Four databases (PubMed, Embase, Cochrane, SCOPUS) were searched for articles published from inception to 30th September 2020, examining the effect of colchicine on cardiovascular outcomes in patients with CAD, yielding 10 randomized-controlled trials with a combined cohort of 12,781 patients. IPD was reconstructed from Kaplan–Meier curves published in 3 studies and analysed using the shared-frailty Cox model. Aggregate data meta-analysis of all 10 studies was performed for outcomes unsuitable for IPD reconstruction. In patients receiving colchicine compared to placebo, one-stage meta-analysis demonstrated a hazard ratio of 0.70 (95% CI 0.61–0.80) for the composite outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent hospitalization for angina requiring coronary revascularization. Aggregate data meta-analysis demonstrated a significant reduction in hazard rate for stroke (HR 0.45; 95% CI 0.27–0.75) and urgent revascularization (HR 0.59; 95% CI 0.38–0.91); and a relative risk reduction for myocardial infarction (RR 0.72; 95% CI of 0.52–1.00) and post-operative atrial fibrillation (RR 0.64; 95% CI 0.48–0.86). Given the significant benefits of colchicine demonstrated on IPD, and its consistent benefits when analyzed using aggregate data meta-analysis, we propose that colchicine may be considered as an additional pharmacological adjunct to the first line therapy for patients with coronary artery disease.