Dataset Information

Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.

ABSTRACT:

Objective

To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk.

Design

Network meta-analysis.

Data sources

Medline, Embase, and Cochrane CENTRAL up to 11 August 2020.

Eligibility criteria for selecting studies

Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias.

Main outcome measures

Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review.

Results

764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes.

Conclusions

In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review.

Systematic review registration

PROSPERO CRD42019153180.

SUBMITTER: Palmer SC

PROVIDER: S-EPMC7804890 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionSodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are two classes of glucose-lowering drugs gaining popularity in the treatment of type 2 diabetes mellitus (T2DM). Current guidelines suggest patient-centred approaches when deciding between available hyperglycaemia drugs with no indication to which specific drug should be administered. Despite systematic reviews and meta-analyses being conducted within SGLT-2is and GLP-1RAs, differences across these classes of drugs have not been investigated. Therefore, this systematic review and network meta-analysis (NMA) will aim to compare the efficacy and safety profiles across and within SGLT-2is and GLP-1RAs.MethodsPubMed, the Cochrane Central Register of Controlled Trials and ISI Web of Science will be searched from inception for published randomised controlled trials conducted in patients with T2DM, with at least two arms consisting of SGLT-2is, GLP-1RAs or control/placebo. Title and abstracts will be screened by two independent reviewers with conflicts resolved by a third. Data will be extracted by the primary researcher, a random sample will be checked by an independent reviewer. Risk of bias will be assessed using the Cochrane Risk of Bias Tool and overall quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.Study characteristics, participants baseline characteristics, mean change in cardiometabolic outcomes and number of adverse events will be extracted for each study. Primary outcome will be the mean change in glycated haemoglobin (HbA1c) (%, mmol/mol). Initial random-effects pairwise meta-analysis will be conducted for each unique treatment comparison where heterogeneity will be assessed. A Bayesian NMA approach will be adopted where random-effects generalised linear models will be fitted in WinBUGS. Sensitivity analysis will be conducted to assess choices of prior distributions and length of burn-in and sample.Ethics and disseminationEthics approval is not required for this study. Results from this study will be published in a peer-review journal.Prospero registration numberCRD42018091306.

Project description:Background Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) mitigate cardiovascular risk in individuals with type 2 diabetes, but most eligible patients do not receive them. We characterized temporal trends in SGLT2i and GLP-1RA use by cardiologists compared with other groups of clinicians. Methods and Results We conducted a descriptive analysis of serial, cross-sectional data derived from IQVIA's National Prescription Audit, a comprehensive audit capturing ≈90% of US retail prescription dispensing and projected to population-level data, to estimate monthly SGLT2is and GLP-1RAs dispensed from January 2015 to December 2020, stratified by prescriber specialty and molecule. We also used the American Medical Association's Physician Masterfile to calculate average annual SGLT2is and GLP-1RAs dispensed per physician. Between January 2015 and December 2020, a total of 63.2 million SGLT2i and 63.4 million GLP-1RA prescriptions were dispensed in the United States. Monthly prescriptions from cardiologists increased 12-fold for SGLT2is (from 2228 to 25 815) and 4-fold for GLP-1RAs (from 1927 to 6981). Nonetheless, cardiologists represented only 1.5% of SGLT2i prescriptions and 0.4% of GLP-1RA prescriptions in 2020, while total use was predominated by primary care physicians/internists (57% of 2020 SGLT2is and 52% of GLP-1RAs). Endocrinologists led in terms of prescriptions dispensed per physician in 2020 (272 SGLT2is and 405 GLP-1RAs). Cardiologists, but not noncardiologists, increasingly used SGLT2is over GLP-1RAs, with accelerated uptake of empagliflozin and dapagliflozin coinciding with their landmark cardiovascular outcomes trials and subsequent US Food and Drug Administration label expansions. Conclusions While use of SGLT2is and GLP-1RAs by cardiologists in the United States increased substantially over a 6-year period, cardiologists still account for a very small proportion of all use, contributing to marked undertreatment of individuals with type 2 diabetes at high cardiovascular risk.

Project description:BackgroundSodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been demonstrated to be able to improve the cardiovascular and renal prognosis in patients with type 2 diabetes (T2D). However, the relative efficacy of various SGLT2 inhibitors and GLP-1 RAs on cardiorenal outcomes is unestablished.MethodsWe searched PubMed and Embase for relevant cardiovascular or renal outcome trials (CVOTs). Endpoints of interest were major adverse cardiovascular events (MACE), stroke, myocardial infarction (MI), cardiovascular death (CVD), all-cause death (ACD), kidney function progression (KFP), and hospitalization for heart failure (HHF). Bayesian network meta-analysis was conducted to produce pooled hazard ratio (HR) and 95% confidence interval (CI). We calculated the probability values of surface under the cumulative ranking curve to rank active and placebo interventions.ResultsFourteen COVTs were included in analysis. Sotagliflozin (HR 0.76, 95% CI 0.61-0.94), subcutaneous semaglutide, and albiglutide lowered MACE versus lixisenatide among others. Sotagliflozin (HR 0.59, 95% CI 0.40-0.89), canagliflozin, and empagliflozin lowered HHF versus subcutaneous semaglutide among others. Dapagliflozin and empagliflozin lowered KFP versus exenatide among others. Empagliflozin and oral semaglutide lowered CVD versus dapagliflozin among others. Sotagliflozin (HR 0.65, 95% CI 0.47-0.91) and albiglutide lowered MI versus ertugliflozin among others. Sotagliflozin (HR 0.56, 95% CI 0.37-0.85) and subcutaneous semaglutide lowered stroke versus empagliflozin among others. Oral semaglutide and empagliflozin lowered ACD versus subcutaneous semaglutide among others. The maximum surface under the cumulative ranking curve values followed sotagliflozin, subcutaneous semaglutide, and albiglutide in lowering MACE; sotagliflozin, canagliflozin, and empagliflozin in lowering HHF; dapagliflozin and empagliflozin in lowering KFP; empagliflozin and oral semaglutide in lowering CVD; sotagliflozin and albiglutide in lowering MI; sotagliflozin and subcutaneous semaglutide in lowering stroke; and oral semaglutide and empagliflozin in lowering ACD.ConclusionsThis updated network meta-analysis reproduced the findings in the first network meta-analysis, and moreover revealed that sotagliflozin was one of the most effective drugs as for lowering MI, stroke, MACE, and HHF, whereas ertugliflozin was not. These findings will provide the according evidence regarding the usage of specific SGLT2 inhibitors and GLP-1 RAs in T2D patients for prevention of specific cardiorenal endpoints.