Objective To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.Design Systematic review with meta-analyses.Data sources Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011).Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin.Data extraction Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors.Results 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference −2.9 kg, 95% confidence interval –3.6 to –2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (–3.2 kg, –4.3 to –2.1; three trials) as well as patients with diabetes (–2.8 kg, –3.4 to –2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia.Conclusions The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.

Liraglutide is a long-acting human glucagon-like peptide-1 (GLP-1) analog (1–4), and the current study was undertaken to evaluate efficacy and safety after 14 weeks' treatment with liraglutide in patients with type 2 diabetes. Main inclusion criteria were patients aged ≥18 years with type 2 diabetes and A1C ≥7.5 and ≤10.0% (diet) or ≥7.0 and ≤9.5% (mono–oral antidiabetes drug); previous therapy was discontinued. Fasting plasma glucose (FPG) at randomization was 7–13 mmol/l. If FPG was >15 mmol/l during the study, the patient was withdrawn. The study was conducted in accordance with the Declaration of Helsinki (5). The study was double-blind, randomized (1:1:1:1), and placebo-controlled using three doses of liraglutide (0.65, 1.25, or 1.90 mg). The following main efficacy parameters were assessed: A1C, insulin, proinsulin, glucagon, fructosamine, lipids, home-measured seven-point plasma glucose profiles, and body weight. Safety parameters (adverse events, hypoglycemic episodes, clinical laboratory parameters, antibodies against liraglutide, vital signs, electrocardiogram, and thyroid (including ultrasonography) and parathyroid parameters were assessed. Liraglutide or placebo was administered in the evening (as in the most recently completed phase 2 study) (6) as once-daily subcutaneous injections in the abdomen or thigh. Baseline characteristics are given in Table 1. The placebo group accounted for almost one-half of the patient withdrawals, primarily due to ineffective therapy. Withdrawals due to adverse events were infrequent and occurred at a comparable level in all groups (Table 1). After 14 weeks of treatment, estimated change in A1C for placebo, 1.90, 1.25, or 0.65 mg was +0.29, −1.45, −1.40, and −0.98%, respectively (change for 1.90 mg vs. placebo: −1.74% [95% CI −2.18 to −1.29], P < 0.0001; 1.25 mg vs. placebo: −1.69% [−2.13 to −1.24], P < 0.0001; and 0.65 mg vs. placebo: −1.27% [−1.72 to −0.82], P < 0.0001). The …

Aims: To evaluate diabetic retinopathy (DR) data from across the SUSTAIN clinical trial programme. Materials and methods: The SUSTAIN clinical trial programme evaluated the efficacy and safety of semaglutide, a glucagon‐like peptide‐1 analogue, for the treatment of type 2 diabetes (T2D). In SUSTAIN 6, a 2‐year, pre‐approval cardiovascular outcomes trial, semaglutide was associated with a significant increase in the risk of DR complications (DRC) vs placebo. DR data from across the SUSTAIN trials were evaluated, and post hoc analyses of the SUSTAIN 6 data were conducted. These included subgroup analyses to identify at‐risk patients and a mediation analysis with initial change in glycated haemoglobin (HbA1c; percentage‐points at week 16) as a covariate, to examine the role of the magnitude of reduction in HbA1c as an intermediate factor affecting risk of DRC. Results: There was no imbalance in DR adverse events across the SUSTAIN 1 to 5 and Japanese trials. The majority of the effect with semaglutide vs placebo in SUSTAIN 6 may be attributed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients who had pre‐existing DR and poor glycaemic control at baseline, and who were treated with insulin. Conclusions: Early worsening of DR is a known phenomenon associated with the rapidity and magnitude of improvement in glycaemic control with insulin; the DRC findings in SUSTAIN 6 are consistent with this. Guidance regarding the early worsening of DR is recommended with insulin. Similar recommendations may be appropriate for semaglutide.

Aim To investigate the effects of semaglutide versus comparators on major adverse cardiovascular events (MACE: cardiovascular [CV] death, nonfatal myocardial infarction [MI], and nonfatal stroke) and hospitalization for heart failure (HF) in the SUSTAIN (subcutaneous semaglutide) and PIONEER (oral semaglutide) trials across subgroups of varying CV risk. Methods Post hoc analyses of individual patient‐level data combined from SUSTAIN 6 and PIONEER 6 were performed to assess MACE and HF. MACE were analyzed in subjects with and without: established CV disease and/or chronic kidney disease; prior MI or stroke; and prior HF. MACE in the SUSTAIN and PIONEER glycaemic efficacy trials were also assessed. Results In SUSTAIN 6 and PIONEER 6 combined, the hazard ratio (HR) for effect of semaglutide versus placebo on overall MACE was 0.76 (95% CI 0.62, 0.92), which was mainly driven by the effect on nonfatal stroke (HR 0.65 (95% CI 0.43, 0.97)). The HR for hospitalization for HF was 1.03 (95% CI 0.75, 1.40). The HRs for MACE were 0.05, except for HF (0.046). In the combined glycaemic efficacy trials, the HR for effect of semaglutide versus comparators on MACE was 0.85 (95% CI 0.55, 1.33). Conclusions In SUSTAIN and PIONEER combined, glucagon‐like peptide‐1 analogue semaglutide showed consistent effects on MACE versus comparators across varying CV risk. No effect of semaglutide on MACE was observed in subjects with prior HF.

Aims  To assess the effect of liraglutide, a once‐daily human glucagon‐like peptide‐1 analogue on pancreatic B‐cell function.Methods  Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First‐ and second‐phase insulin release were measured by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Arginine‐stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin‐modified frequently sampled intravenous glucose tolerance test.Results  The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first‐phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second‐phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine‐stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity.Conclusions  Fourteen weeks of treatment with liraglutide showed improvements in first‐ and second‐phase insulin secretion, together with improvements in arginine‐stimulated insulin secretion during hyperglycaemia.