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Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.

ABSTRACT: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2D). The comparative efficacy of individual SGLT2i remains unclear. We searched PubMed, www.clinicaltrials.gov and the Cochrane Central Register of Controlled Trials for randomised controlled trials exploring the use of canagliflozin, dapagliflozin, empagliflozin or ertugliflozin in patients with T2D. Comparators included placebo or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints were cardiovascular mortality and worsening heart failure (HF). Evidence was synthesised using network meta-analysis (NMA). Sixty-four trials reporting on 74,874 patients were included. The overall quality of evidence was high. When compared with placebo, empagliflozin and canagliflozin improved all three endpoints, whereas dapagliflozin improved worsening HF. When compared with other SGLT2i, empagliflozin was superior for all-cause and cardiovascular mortality reduction. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Ertugliflozin had no effect on any of the three endpoints investigated. Sensitivity analyses including extension periods of trials or excluding studies with a treatment duration of < 52 weeks confirmed the main results. Similar results were obtained when restricting mortality analyses to patients included in cardiovascular outcome trials (n = 38,719). Empagliflozin and canagliflozin improved survival with empagliflozin being superior to the other SGLT2i. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Prospective head-to-head comparisons would be needed to confirm these results.

SUBMITTER: Tager T

PROVIDER: S-EPMC8510986 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.

Täger Tobias T Atar Dan D Agewall Stefan S Katus Hugo A HA Grundtvig Morten M Cleland John G F JGF Clark Andrew L AL Fröhlich Hanna H Frankenstein Lutz L

Heart failure reviews 20211101 6

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2D). The comparative efficacy of individual SGLT2i remains unclear. We searched PubMed, www.clinicaltrials.gov and the Cochrane Central Register of Controlled Trials for randomised controlled trials exploring the use of canagliflozin, dapagliflozin, empagliflozin or ertugliflozin in patients with T2D. Comparators included placebo or any other active treatment. The primar ...[more]

PMID: 32314085

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Project description:BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2i) are now recommended for patients with heart failure, but the mechanisms that underlie the protective role of SGLT2i in cardiac remodeling remain unclear. Aldehyde dehydrogenase 2 (ALDH2) effectively prevents cardiac remodeling. Here, the key role of ALDH2 in the efficacy of SGLT2i on cardiac remodeling was studied.MethodsAnalysis of multiple transcriptomic datasets and two-sample Mendelian randomization were performed to find out the differentially expressed genes between pathological cardiac hypertrophy models (patients) and controls. A pathological cardiac hypertrophy mouse model was established via transverse aortic constriction (TAC) or isoproterenol (ISO). Cardiomyocyte-specific ALDH2 knockout mice (ALDH2CMKO) and littermate control mice (ALDH2flox/flox) were generated to determine the critical role of ALDH2 in the preventive effects of dapagliflozin (DAPA) on cardiac remodeling. RNA sequencing, gene knockdown or overexpression, bisulfite sequencing PCR, and luciferase reporter assays were performed to explore the underlying molecular mechanisms involved.ResultsOnly ALDH2 was differentially expressed when the differentially expressed genes obtained via Mendelian analysis and the differentially expressed genes obtained from the multiple transcriptome datasets were combined. Mendelian analysis revealed that ALDH2 was negatively related to the severity of myocardial hypertrophy in patients. DAPA alleviated cardiac remodeling in mouse hearts subjected to TAC or ISO. ALDH2 expression was reduced, whereas ALDH2 expression was restored by DAPA in hypertrophic hearts. Cardiomyocyte specific ALDH2 knockout abolished the protective role of DAPA in preventing cardiac remodeling. ALDH2 expression and activity were increased in DAPA-treated neonatal rat primary cardiomyocytes (NRCMs), H9C2 cells and AC16 cells. Moreover, DAPA upregulated ALDH2 in peripheral blood mononuclear cells (PBMCs) from patients with type 2 diabetes. Sodium/proton exchanger 1 (NHE1) inhibition contributed to the regulation of ALDH2 by DAPA. DAPA suppressed the production of reactive oxygen species (ROS), downregulated DNA methyltransferase 1 (DNMT1) and subsequently reduced the ALDH2 promoter methylation level. Further studies revealed that DAPA enhanced the binding of nuclear transcription factor Y, subunit A (NFYA) to the promoter region of ALDH2, which was due to the decreased promoter methylation level of ALDH2.ConclusionsThe upregulation of ALDH2 plays a critical role in the protection of DAPA against cardiac remodeling. DAPA enhances the binding of NFYA to the ALDH2 promoter by reducing the ALDH2 promoter methylation level through NHE1/ROS/DNMT1 pathway.

Project description: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.

Dataset Information

Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.

Publications

Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.

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