Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs. To assess the efficacy and safety of SGLT2 inhibitors in adults with type 2 diabetes. MEDLINE, EMBASE, and the Cochrane Library from inception through April 2013 without language restrictions; regulatory authorities' reports; and gray literature. Randomized trials comparing SGLT2 inhibitors with placebo or other medication for type 2 diabetes. Three reviewers extracted or checked data for study characteristics, outcomes of interest, and risk of bias, and 3 reviewers summarized strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. Sodium–glucose cotransporter 2 inhibitors were compared with placebo in 45 studies (n = 11 232) and with active comparators in 13 studies (n = 5175). They had a favorable effect on hemoglobin A_1c level (mean difference vs. placebo, −0.66% [95% CI, −0.73% to −0.58%]; mean difference vs. active comparators, −0.06% [CI, −0.18% to 0.05%]). Sensitivity analyses incorporating unpublished data showed similar effect estimates. Compared with other agents, SGLT2 inhibitors reduced body weight (mean difference, −1.80 kg [CI, −3.50 to −0.11 kg]) and systolic blood pressure (mean difference, −4.45 mm Hg [CI, −5.73 to −3.18 mm Hg]). Urinary and genital tract infections were more common with SGLT2 inhibitors (odds ratios, 1.42 [CI, 1.06 to 1.90] and 5.06 [CI, 3.44 to 7.45], respectively). Hypoglycemic risk was similar to that of other agents. Results for cardiovascular outcomes and death were inconclusive. An imbalance in incidence of bladder and breast cancer was noted with dapagliflozin compared with control. Most trials were rated as high risk of bias because of missing data and last-observation-carried-forward methods. Sodium–glucose cotransporter 2 inhibitors may improve short-term outcomes in adults with type 2 diabetes, but effects on long-term outcomes and safety are unclear. None.

This network meta-analysis involving 453 trials compares the benefits and harms of 21 antidiabetic interventions from 9 drug classes for adults with type 2 diabetes. Efficacy of the regimens appear... Background: Several pharmacologic options for type 2 diabetes are available. Purpose: To compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes. Data Sources: Several d...

Aims/hypothesis: Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently under review for marketing approval. Individual trials have assessed the clinical profile of tirzepatide vs different comparators. We conducted a systematic review and meta-analysis to assess the efficacy and safety of tirzepatide for type 2 diabetes. Methods: We searched PubMed, Embase, Cochrane and ClinicalTrials.gov up until 27 October 2021 for randomised controlled trials with a duration of at least 12 weeks that compared once-weekly tirzepatide 5, 10 or 15 mg with placebo or other glucose-lowering drugs in adults with type 2 diabetes irrespective of their background glucose-lowering treatment. The primary outcome was change in HbA_1c from baseline. Secondary efficacy outcomes included change in body weight, proportion of individuals reaching the HbA_1c target of <53 mmol/mol (<7.0%), ≤48 mmol/mol (≤6.5%) or <39 mmol/mol (<5.7%), and proportion of individuals with body weight loss of at least 5%, 10% or 15%. Safety outcomes included hypoglycaemia, gastrointestinal adverse events, treatment discontinuation due to adverse events, serious adverse events, and mortality. We used version 2 of the Cochrane risk-of-bias tool for randomised trials to assess risk of bias for the primary outcome. Results: Seven trials (6609 participants) were included. A dose-dependent superiority in lowering HbA_1c was evident with all three tirzepatide doses vs all comparators, with mean differences ranging from −17.71 mmol/mol (−1.62%) to −22.35 mmol/mol (−2.06%) vs placebo, −3.22 mmol/mol (−0.29%) to −10.06 mmol/mol (−0.92%) vs GLP-1 RAs, and −7.66 mmol/mol (−0.70%) to −12.02 mmol/mol (−1.09%) vs basal insulin regimens. Tirzepatide was more efficacious in reducing body weight; reductions vs GLP-1 RAs ranged from 1.68 kg with tirzepatide 5 mg to 7.16 kg with tirzepatide 15 mg. Incidence of hypoglycaemia with tirzepatide was similar vs placebo and lower vs basal insulin. Nausea was more frequent with tirzepatide vs placebo, especially with tirzepatide 15 mg (OR 5.60 [95% CI 3.12, 10.06]), associated with higher incidence of vomiting (OR 5.50 [95% CI 2.40, 12.59]) and diarrhoea (OR 3.31 [95% CI 1.40, 7.85]). Odds of gastrointestinal events were similar between tirzepatide and GLP-1 RAs, except for diarrhoea with tirzepatide 10 mg (OR 1.51 [95% CI 1.07, 2.15]). Tirzepatide 15 mg led to higher discontinuation rate of study medication due to adverse events regardless of comparator, while all tirzepatide doses were safe in terms of serious adverse events and mortality. Conclusions/interpretation: A dose-dependent superiority on glycaemic efficacy and body weight reduction was evident with tirzepatide vs placebo, GLP-1 RAs and basal insulin. Tirzepatide did not increase the odds of hypoglycaemia but was associated with increased incidence of gastrointestinal adverse events. Study limitations include presence of statistical heterogeneity in the meta-analyses for change in HbA_1c and body weight, assessment of risk of bias solely for the primary outcome, and generalisation of findings mainly to individuals who are overweight or obese and already on metformin-based background therapy. PROSPERO registration no. CRD42021283449. Graphical