Diabetes, obesity & metabolism

This indirect treatment comparison (ITC) compared the efficacy and safety of tirzepatide with semaglutide for managing obesity or overweight in participants with type 2 diabetes (T2D), informed by the pivotal trials SURMOUNT-2 and STEP 2. Participants had body mass index (BMI) ≥ 27 kg/m 2 , with ≥1 unsuccessful prior dietary weight reduction effort and glycated haemoglobin (HbA1c) 7%-10% on stable therapy. A heterogeneity assessment confirmed that study and patient baseline characteristics were similar. Bucher ITCs compared tirzepatide 10 and 15 mg once-weekly (QW) to semaglutide 2.4 mg QW via placebo, all adjunct to a reduced-calorie diet and increased physical activity. Tirzepatide 10 and 15 mg were associated with statistically significant greater reductions in weight, BMI and HbA1c versus semaglutide. Tirzepatide 15 mg was associated with statistically significant greater odds versus semaglutide of ≥5% and ≥15% weight reduction and statistically significant improvements in several cardiometabolic risk factors, including waist circumference, fasting plasma glucose and triglycerides. Both tirzepatide doses showed non-significant trends of greater improvements in high-density lipoprotein, low-density lipoprotein, systolic blood pressure and diastolic blood pressure versus semaglutide as well as a generally comparable safety profile to semaglutide. In this ITC versus semaglutide 2.4 mg, tirzepatide 10 and 15 mg were associated with statistically significant greater weight, BMI and HbA1c reduction and tirzepatide 15 mg with statistically significant improvements in multiple cardiometabolic risk factors crucial in managing obesity or overweight among patients with T2D. Both tirzepatide doses also had a generally similar safety profile to semaglutide. What is the context and purpose of this research study? Excess weight and type 2 diabetes (T2D) are strongly connected, where most patients with T2D have obesity or overweight. Weight management is crucial for improving T2D outcomes and preventing its progression. Weight management comprises behavioural interventions, psychological support, dietary changes and physical activity programmes. Medications may also be prescribed or surgical options may also be considered. Two such medications for weight management are tirzepatide (up to 15 mg) and semaglutide (up to 2.4 mg), which are injected subcutaneously once per week to help control appetite by prolonging patients' feeling of fullness. These medications are also used at different doses to treat T2D. Because there were no clinical trials directly comparing tirzepatide and semaglutide, particularly in patients with both T2D and either obesity or overweight, this study aimed to indirectly compare the effectiveness and safety of tirzepatide and semaglutide for weight management in patients with overweight or obesity and T2D. What was done? We indirectly compared the efficacy and safety of two doses of tirzepatide (10 and 15 mg per week) versus semaglutide 2.4 mg per week for weight management in adults with both T2D and either obesity or overweight. We used data from two large clinical trials, SURMOUNT-2 and STEP 2, which tested tirzepatide and semaglutide, respectively, against a placebo, all adjunct to diet and exercise. An indirect treatment comparison of tirzepatide and semaglutide was then possible via the placebo arm acting as the common comparator. The similarity of study design and patient populations in the two trials was evaluated and found to be sufficiently close to allow meaningful comparisons. Appropriate statistical methodology was used to facilitate comparisons of the two trials. What were the main results? Compared to semaglutide 2.4 mg, the higher dose of tirzepatide (15 mg) was associated with a statistically significant improvement in several outcomes such as weight reduction, glycaemic outcomes and triglycerides, while the lower dose of tirzepatide (10 mg) was associated with some statistically significant improvements (e.g., weight reduction and HbA1c) and had otherwise comparable outcomes to semaglutide. However, both doses of tirzepatide were associated with statistically significant greater reductions in glycated haemoglobin A1c (HbA1c) compared to semaglutide, which is a key target of T2D treatment. Both doses of tirzepatide had a generally similar safety profile compared to semaglutide. What is the originality and relevance of this study? Currently, there are no clinical trials that compare tirzepatide and semaglutide directly for the management of obesity and overweight in patients with T2D. Previous studies have compared tirzepatide and semaglutide results from different clinical trials for weight management in patients without T2D, not specifically focusing on patients with T2D. This is the first study to indirectly compare tirzepatide and semaglutide for weight management in people with T2D who also have obesity or overweight. The findings of this study suggest that higher doses of tirzepatide may be more effective than semaglutide for weight reduction and improving other health-related outcomes in these patients.

Tirzepatide reduced weight significantly more than placebo in adults with obesity/overweight who had already achieved ≥5% weight reduction with a 12-week intensive lifestyle intervention (randomized population) in SURMOUNT-3, a phase 3, 72-week, randomized, double-blind clinical trial. This analysis evaluated health-related quality of life (HRQoL) with tirzepatide versus placebo treatment in the SURMOUNT-3 randomized population and selected subgroups. The randomized population received placebo (N = 292) or tirzepatide maximum tolerated dose (N = 287) for 72 weeks. HRQoL was assessed from randomization to week 72 using the Short Form-36 Version 2 Health Survey acute form, Impact of Weight on Quality of Life-Lite Clinical Trials Version, 5-level EQ-5D version Health State Index, EQ visual analogue scale and the Patient Global Impression of Status (PGIS) for Physical Activity. In tirzepatide recipients, changes in HRQoL scores from randomization to week 72 were descriptively summarized by achievement of weight reduction thresholds, and for those with versus without physical function limitations at randomization (identified with PGIS for Physical Activity). Tirzepatide was associated with significantly larger improvements than placebo in most HRQoL measures from randomization to 72 weeks. Improvements in tirzepatide recipients were generally numerically larger in those who met greater weight reduction thresholds. HRQoL score changes showed greater improvements for adults with versus without physical function limitations for all measures. Tirzepatide improved HRQoL in adults with obesity/overweight and was generally associated with larger improvements in adults meeting greater weight reduction thresholds and in adults with versus without reported physical function limitations at randomization. What is the context and purpose of this research study? In a clinical trial called SURMOUNT-3, tirzepatide was significantly better than placebo for reducing weight in adults with obesity/overweight who had already lost ≥5% weight following a 12-week intensive lifestyle programme. This analysis looked at the effects of tirzepatide compared with placebo for 72 weeks on quality of life (QoL) in SURMOUNT-3. In addition, among tirzepatide recipients, the relationship between meeting different weight reduction thresholds and changes in QoL was described as was the association of tirzepatide with QoL in study participants who had physical limitations at randomization. What was done? Eligible adults with obesity/overweight were enrolled in a 12-week intensive lifestyle programme. Those who lost ≥5% of initial weight at the end of the 12 weeks were invited to continue participating in the study and were randomly assigned to receive injections of either their maximum tolerated dose of tirzepatide (10 or 15 mg) or placebo for 72 weeks via single-dose pens. QoL was measured using a number of well-established surveys that assessed general health, the impact of weight on QoL and the impact of health on the level of physical ability in day-to-day life. These surveys were completed by the study participants when they were first assigned treatment with tirzepatide or placebo (randomization) and again after 72 weeks of treatment. The difference in scores from randomization to week 72 was then calculated to determine whether or not the QoL of participants had improved with treatment. In addition, in participants who took tirzepatide, changes in QoL scores from randomization to week 72 were summarized by weight reduction thresholds (≥5%, ≥10%, ≥15%, ≥20%, ≥25%), and for those with versus without physical limitations at randomization. What were the main results? Adults with obesity/overweight who had already lost ≥5% weight with a 12-week intensive lifestyle programme who then took tirzepatide for 72 weeks not only had significantly more weight loss compared with those taking placebo, but they also had significantly improved QoL. These improvements in QoL were generally larger with greater weight loss and in adults who reported physical limitations at randomization compared to those who reported no such limitations. The improvements in QoL were observed in physical function as well as in general mental health and weight-related psychological and social functions. What is the originality and relevance of this study? Findings of this study show that in addition to reducing weight in people who have already lost ≥5% weight after lifestyle interventions, tirzepatide improved QoL. This is important because other studies have shown that people with obesity have reduced QoL. Tirzepatide was generally associated with improved QoL the most in adults who had greater weight loss and in adults who reported physical limitations at randomization.

Retatrutide, a novel synthetic molecule, is a triple agonist activating the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and glucagon receptors. The TRIUMPH clinical development program evaluates its safety and efficacy concurrently for the treatment of obesity and two related complications-obstructive sleep apnea (OSA) and knee osteoarthritis (OA). A novel basket trial design simultaneously evaluates retatrutide treatment across these multiple adiposity-related disease states. TRIUMPH consists of four Phase 3, multicenter, randomized, double-blind studies assessing weekly subcutaneous retatrutide compared to placebo, in conjunction with healthy diet and physical activity in over 5800 participants. The four trials consist of two weight management basket trials (TRIUMPH-1 and TRIUMPH-2) with OSA and/or OA protocols nested within the weight management trial; one weight management trial in a population with CVD (TRIUMPH-3); and one stand-alone OA trial (TRIUMPH-4). The primary endpoint for weight management is percent change in body weight, for OSA is change in Apnea-Hypopnea Index and for knee OA includes change in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score. The basket trial permits independent analysis of weight management, OSA and OA studies with type I error rate controlled at α = 0.05, split between the overarching weight management and each basket trial. By recruiting participants with shared disease exposures, the TRIUMPH program will assess the safety and efficacy of retatrutide for the treatment of adults with obesity and two of its common complications-OSA and OA.