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OBJECTIVE: Semaglutide, a glucagon-like peptide 1 receptor agonist, reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D) at high risk of cardiovascular disease (CVD) in a post hoc analysis of pooled data from Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN) 6 and Peptide Innovation for Early Diabetes Treatment (PIONEER) 6. We estimated the benefit of adding semaglutide to standard of care (SoC) on life-years free of new/recurrent CVD events in people with T2D at high risk of CVD. RESEARCH DESIGN AND METHODS: The Diabetes Lifetime-perspective prediction (DIAL) competing risk–adjusted lifetime CVD risk model for people with T2D was developed previously. Baseline characteristics of the pooled cohort from SUSTAIN 6 and PIONEER 6 (POOLED cohort) (N = 6,480) were used to estimate individual life expectancy free of CVD for patients in the POOLED cohort. The hazard ratio of MACE from adding semaglutide to SoC was derived from the POOLED cohort (hazard ratio [HR] 0.76 [95% CI 0.62–0.92]) and combined with an individual's risk to estimate their CVD benefit. RESULTS: Adding semaglutide to SoC was associated with a wide distribution in life-years free of CVD gained, with a mean increase of 1.7 (95% CI 0.5–2.9) life-years. Estimated life-years free of CVD gained with semaglutide was dependent on baseline risk (life-years free of CVD gained in individuals with established CVD vs. those with cardiovascular risk factors only: 2.0 vs. 0.2) and age at treatment initiation. CONCLUSIONS: Adding semaglutide to SoC was associated with a gain in life-years free of CVD events that was dependent on baseline CVD risk and age at treatment initiation. This study helps contextualize the results of semaglutide clinical trials. [ABSTRACT FROM AUTHOR]

Aims: The LIRA‐ADD2SGLT2i trial demonstrated that liraglutide + sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) ± metformin significantly improved glycaemic control (not body weight) versus placebo in adults with type 2 diabetes (T2D). This post‐hoc analysis assessed whether baseline characteristics influenced these findings. Materials and methods: LIRA‐ADD2SGLT2i (NCT02964247) was a placebo‐controlled, double‐blind, multinational trial, wherein participants received liraglutide (≤1.8 mg/day) or placebo (randomized 2:1). Changes from baseline to week 26 in haemoglobin A1c (HbA1c), body weight and waist circumference stratified by HbA1c, body mass index (BMI), diabetes duration, duration of pre‐trial SGLT2i use and Homeostatic Model Assessment of Insulin Resistance (HOMA‐IR) were analysed. These five baseline characteristics were divided into tertiles, and the treatment effect was evaluated using the trial product estimand. Results: Data from all 303 participants were analysed. There was a significant interaction between baseline HbA1c tertiles (7.0%‐<7.6%; 7.6%‐8.1%; ≥8.2%‐9.5%) and glycaemic control at week 26 (p[interaction] =.011), with the lowest HbA1c estimated treatment difference (95% confidence interval) observed in patients with lowest baseline HbA1c [−0.20% (−0.59, 0.19); −0.68% (−1.03, −0.33); −0.98% (−1.33, −0.64), respectively]. There were no significant interactions in glycaemic control across baseline BMI, diabetes duration, insulin resistance determined by HOMA‐IR or SGLT2i use duration (p[interaction] >.05, all). Across the five characteristics assessed, no significant interactions were found for body weight or waist circumference changes from baseline (p[interaction] >.05, all). Conclusion: For individuals with T2D and inadequate glycaemic control despite therapy with SGLT2is ± metformin, liraglutide 1.8 mg would provide an effective treatment intensification option, irrespective of HbA1c, BMI, diabetes duration, insulin resistance determined by HOMA‐IR and SGLT2i use duration. [ABSTRACT FROM AUTHOR]

In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes in both the "established CV disease" (CVD) and "CV risk factor" subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD from those used in REWIND. The present post hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re‐categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re‐categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P‐interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum. [ABSTRACT FROM AUTHOR]

Aim: To compare the effect of liraglutide or placebo added on to sodium‐glucose co‐transporter‐2 inhibitor (SGLT2i) ± metformin on glycaemic control in patients with type 2 diabetes. Materials and Methods: Patients with type 2 diabetes on a stable SGLT2i dose ± metformin (with HbA1c 7.0%–9.5% and body mass index [BMI] ≥ 20 kg/m2) were randomized 2:1 to add‐on liraglutide 1.8 mg/day or placebo in this parallel, double‐blind, multinational trial. Primary and confirmatory secondary endpoints were changes in HbA1c and body weight from baseline to week 26, respectively. The proportions of patients achieving HbA1c (<7.0%) targets and safety events after week 26 were also assessed. Results: Of 303 patients randomized (one in error), 280 completed treatment. Mean changes in HbA1c from baseline to week 26 with liraglutide (n = 202) and placebo (n = 100) were − 0.98% and − 0.30%, respectively (estimated treatment difference [ETD]: −0.68% [95% CI: −0.89, −0.48]; P < 0.001). Mean body weight changes from baseline were − 2.81 versus −1.99 kg, respectively (ETD: −0.82 kg [95% CI: −1.73, 0.09]; P = 0.077); 51.8% of liraglutide‐treated patients achieved HbA1c < 7.0% versus 23.2% receiving placebo (odds ratio: 5.1 [95% CI: 2.67, 9.87]; P < 0.001). More patients treated with liraglutide reported ≥1 treatment‐emergent adverse events (66.3%) versus placebo (47.0%). Conclusions: Liraglutide significantly improved glycaemic control compared with placebo in patients with type 2 diabetes, insufficiently controlled with SGLT2is with/without metformin, with no unexpected safety findings. [ABSTRACT FROM AUTHOR]

Background: Metformin is the regulatory-approved treatment of choice for most youth with type 2 diabetes early in the disease. However, early loss of glycemic control has been observed with metformin monotherapy. Whether liraglutide added to metformin (with or without basal insulin treatment) is safe and effective in youth with type 2 diabetes is unknown.Methods: Patients who were 10 to less than 17 years of age were randomly assigned, in a 1:1 ratio, to receive subcutaneous liraglutide (up to 1.8 mg per day) or placebo for a 26-week double-blind period, followed by a 26-week open-label extension period. Inclusion criteria were a body-mass index greater than the 85th percentile and a glycated hemoglobin level between 7.0 and 11.0% if the patients were being treated with diet and exercise alone or between 6.5 and 11.0% if they were being treated with metformin (with or without insulin). All the patients received metformin during the trial. The primary end point was the change from baseline in the glycated hemoglobin level after 26 weeks. Secondary end points included the change in fasting plasma glucose level. Safety was assessed throughout the course of the trial.Results: Of 135 patients who underwent randomization, 134 received at least one dose of liraglutide (66 patients) or placebo (68 patients). Demographic characteristics were similar in the two groups (mean age, 14.6 years). At the 26-week analysis of the primary efficacy end point, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of -1.06 percentage points (P<0.001); the difference increased to -1.30 percentage points by 52 weeks. The fasting plasma glucose level had decreased at both time points in the liraglutide group but had increased in the placebo group. The number of patients who reported adverse events was similar in the two groups (56 [84.8%] with liraglutide and 55 [80.9%] with placebo), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.Conclusions: In children and adolescents with type 2 diabetes, liraglutide, at a dose of up to 1.8 mg per day (added to metformin, with or without basal insulin), was efficacious in improving glycemic control over 52 weeks. This efficacy came at the cost of an increased frequency of gastrointestinal adverse events. (Funded by Novo Nordisk; Ellipse ClinicalTrials.gov number, NCT01541215.). [ABSTRACT FROM AUTHOR]