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In this phase 3b, open-label, randomized, controlled trial involving adults with obesity without type 2 diabetes, tirzepatide was superior to semaglutide in reducing body weight and waist circumference.

In patients with heart failure with preserved ejection fraction and obesity, treatment with tirzepatide led to a lower risk of death from cardiovascular causes or worsening heart-failure events than placebo.

A 3-year study of tirzepatide in participants with obesity and prediabetes showed substantial and sustained weight reduction and decreased risk of progression to diabetes with tirzepatide, as compared with placebo.

Tirzepatide, a dual incretin agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, has favorable effects on glycemic control and body weight. The effects on cardiovascular outcomes are uncertain. We conducted an active-comparator-controlled, double-blind, noninferiority trial in which patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned in a 1:1 ratio to receive a weekly subcutaneous injection of tirzepatide (up to 15 mg) or dulaglutide (1.5 mg), an agent that has been shown to reduce the incidence of cardiovascular events. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke and was tested for noninferiority of tirzepatide to dulaglutide with a margin of 1.05 for the upper limit of the 95.3% confidence interval for the hazard ratio. An upper limit of less than 1.00 was considered to indicate superiority of tirzepatide to dulaglutide. A total of 13,299 patients underwent randomization; 134 were subsequently excluded because they did not meet inclusion criteria. The modified intention-to-treat population thus included 6586 patients in the tirzepatide group and 6579 in the dulaglutide group. The mean (±SD) age of the patients was 64.1±8.8 years, 29.0% were women, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 32.6±5.5, the mean glycated hemoglobin level was 8.4±0.9%, and the mean duration of diabetes was 14.7±8.8 years. A primary end-point event occurred in 801 patients (12.2%) in the tirzepatide group and 862 (13.1%) in the dulaglutide group (hazard ratio, 0.92; 95.3% confidence interval, 0.83 to 1.01; P = 0.003 for noninferiority; P = 0.09 for superiority). The incidence of adverse events appeared to be similar in the two groups, although more gastrointestinal adverse events were observed in the tirzepatide group. Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was noninferior to dulaglutide with respect to a composite of death from cardiovascular causes, myocardial infarction, or stroke. (Funded by Eli Lilly; SURPASS-CVOT ClinicalTrials.gov number, NCT04255433.).

Current treatment options for youth-onset type 2 diabetes are limited and have demonstrated lower glycaemic efficacy than those for adult-onset type 2 diabetes. We aimed to assess the safety and efficacy of tirzepatide, a glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, compared with placebo in youth-onset type 2 diabetes. We conducted a phase 3, double-blind, placebo-controlled, multicentre (39 sites), multinational (eight countries) trial over 30 weeks, followed by an open-label extension for 22 weeks in which all participants received tirzepatide. Participants aged 10 to <18 years with youth-onset type 2 diabetes inadequately controlled with metformin and/or basal insulin were randomly assigned (1:1:1) to receive tirzepatide 5 mg, 10 mg, or placebo administered by subcutaneous injection with a single-dose pen. Randomisation was stratified by age group (≤14 years or >14 years) and antihyperglycaemic medication use (metformin, basal insulin, or both). All participants, investigators, and the sponsor were masked to treatment assignment during the 30-week double-blind period. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to week 30. Data from all participants who received at least one dose of study drug were used to analyse efficacy and safety. This completed trial is registered with ClinicalTrials.gov (NCT05260021). Between April 12, 2022, and Dec 27, 2023, 146 participants were screened, of whom 99 (60 [61%] female, 39 [39%] male; mean age 14·7 years [SD 1·8]; mean baseline HbA1c 8·04% [1·23]) were randomly assigned to tirzepatide 5 mg (n=32), tirzepatide 10 mg (n=33), or placebo (n=34). At week 30, tirzepatide was superior to placebo in reducing HbA1c, with a mean reduction of 2·23% in the pooled tirzepatide group versus an increase of 0·05% in the placebo group (estimated treatment difference −2·28%; 95% CI −2·87 to −1·69; p<0·0001). Glycaemic efficacy was sustained up to 52 weeks with tirzepatide treatment. Tirzepatide also resulted in significant reductions in BMI of 7·4% and 11·2% for the 5 mg and 10 mg groups, respectively, compared with 0·4% in the placebo group at 30 weeks. The most common adverse events with tirzepatide treatment were gastrointestinal, all mild to moderate in severity, and decreased over time. Two (6%) patients in the tirzepatide 5 mg group discontinued study drug due to an adverse event. The safety profile of tirzepatide was consistent with that reported in adults. No deaths were reported during the study period. Tirzepatide demonstrated significant improvements in glycaemic control and BMI compared with placebo. These effects were sustained over 1 year. Eli Lilly and Company.

Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, which was approved in 2023 by the US Food and Drug Administration for weight management in adults with obesity or overweight. The purpose of this study was to conduct qualitative exit interviews with participants who had participated in the SURMOUNT-4 clinical trial, to better understand the patient experience of tirzepatide. Online exit interviews were conducted with adults from the USA who had participated in the SURMOUNT-4 clinical trial for weight management, recruited from 16 US-based SURMOUNT-4 clinical sites. Interviews utilized a semi-structured interview guide, and included questions related to receiving tirzepatide, using a single-use injection pen device, and the overall trial experience. Interviews were audio recorded and transcribed, and analyzed using a content analysis. Eighty-six adults (83% female; mean age 49.9 years) participated in the interviews. All participants shared at least one perceived benefit of tirzepatide experienced during the open-label phase of SURMOUNT-4, including improved appetite control, increased energy, or improved clothing fit. Despite the gastrointestinal side effects experienced, many participants liked the efficacy of tirzepatide, and reported that the single-use injection pen device for administering the study medication was easy to use. Most participants were willing to continue taking tirzepatide. Study findings showed that beyond the direct pharmacological effects of treatment with tirzepatide, participants reported a wide range of perceived improvements across several aspects of their lives. Participants also reported a few negative experiences, including side effects. It is possible that the participants who had a more positive experience were more inclined to participate in the exit interviews. This study highlights the value of exit interviews, which can provide more learning about patient experiences during a clinical trial.

In this phase 2 trial in patients with metabolic dysfunction–associated steatohepatitis and moderate or severe fibrosis, tirzepatide was more effective than placebo with respect to resolution of MASH without worsening of fibrosis.

Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used therapies for cardiovascular risk reduction in type 2 diabetes (T2D). With the emergence of the SURPASS-CVOT trial, tirzepatide (a dual GIP/GLP-1 receptor agonist) has entered the therapeutic landscape; however, its comparative effect on cardiovascular outcomes compared to placebo and individual GLP-1RAs remains undefined. Methods We conducted a systematic review and frequentist network meta-analysis (NMA) of RCTs enrolling adults with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular (CV) risk. Eligible RCTs evaluated tirzepatide or GLP-1RAs and reported major adverse cardiovascular events (MACE), CV mortality, all-cause mortality, non-fatal myocardial infarction (MI) or non-fatal stroke. A class-level NMA was conducted to estimate the incremental benefit of tirzepatide and GLP-1RAs over placebo, and an agent-level NMA was conducted to explore differences between tirzepatide and individual GLP-1RA agents. Subgroup analyses, including established cardiovascular disease populations, and leave-one-out sensitivity analyses were performed. Results Eleven trials met inclusion criteria (10 GLP-1RA trials and 1 tirzepatide trial [SURPASS-CVOT]). In the class-level analysis, tirzepatide significantly reduced MACE (HR 0.79, 95% CI 0.69–0.91), CV mortality (HR 0.77, 95% CI 0.66–0.90), all-cause mortality (HR 0.74, 95% CI 0.65–0.83), non-fatal MI (HR 0.77, 95% CI 0.61–0.97), and non-fatal stroke (HR 0.79, 95% CI 0.64–0.97) compared to placebo. Formal statistical comparisons between tirzepatide and the GLP-1RA class could not be performed within the constraints of the NMA; however, point estimates across outcomes numerically favored tirzepatide compared with placebo. In the agent-level analysis, tirzepatide reduced MACE compared to placebo (HR 0.81, 95% CI 0.70–0.94) and lixisenatide (HR 0.79, 95% CI 0.65–0.97). Subgroup and sensitivity analyses did not substantially change point estimates. Conclusion Among adults with T2D and established ASCVD or high CV risk, class-level analysis demonstrated that tirzepatide significantly reduced the risk of cardiovascular events compared to placebo; at the agent-level, tirzepatide demonstrated comparable efficacy to individual GLP-1RAs. These findings suggest that tirzepatide provides cardiovascular benefit at least comparable to established GLP-1RAs, supporting its emerging role in cardiovascular risk reduction in T2D. Graphical abstract

To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in subjects with type 2 diabetes (T2DM). Electronic databases were searched from inception to 2nd October 2024 for randomised controlled trials comparing GLP-1RAs treating T2DM. Bayesian network meta-analyses were conducted to analyze metabolic and safety outcomes. 64 trials comprising of 25,572 participants were identified. Compared to placebo, tirzepatide showed the greatest reduction in HbA1-c (MD: -2.3%) and FPG (MD: -3.1mmol/L); semaglutide was second (HbA1-c: MD: -1.5%; FPG: MD: -2mmol/L); liraglutide was third (HbA1-c: MD: -1.2% FPG: MD: -1.6mmol/L) ( P <0.05). All treatments showed no statistically significant differences in BMI, SBP, DBP, TC, HDL-C and LDL-C compared to placebo. Tirzepatide (MD: -9.1 kg), semaglutide (MD: -2.8 kg) and liraglutide (MD: -1.2 kg) ( P <0.05) had significant reduction in body weight compared to placebo. GLP-1 RAs had higher risk of gastrointestinal symptoms. Semaglutide increased the risk of hypoglycemia compared to placebo while liraglutide reduced the risk of hypoglycemia compared to traditional antidiabetic drugs. GLP-1RAs improve glycaemic control, with tirzepatide, semaglutide and liraglutide exhibiting the most significant improvements. Tirzepatide is more suitable for treating T2DM with obesity. For individuals with normal weight, both semaglutide and liraglutide are generally more effective for treating T2DM. However, considering the potential for semaglutide to cause hypoglycemia, liraglutide may be the optimal choice for T2DM treatment to minimize the risk of hypoglycemia.

IntroductionThe increasing prevalence of overweight and obesity among individuals with type 1 diabetes (T1D) complicates glycaemic management and escalates insulin resistance, necessitating innovative therapeutic strategies. Tirzepatide, a dual agonist for glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, shows promise in managing weight and glycaemic control in type 2 diabetes but is unexplored in the context of T1D. This double-blind, placebo-controlled randomised trial will evaluate the efficacy of tirzepatide in adults with T1D and overweight/obesity over 32 weeks.Methods and analysis60 participants (aged 18–70 years) with a body mass index ≥27 kg/m2 and HbA1c≤10% will be randomised 1:1 to receive either tirzepatide or a placebo, alongside standard insulin therapy. The primary outcome is the change in body weight (%). Secondary measures include change in HbA1c (%), proportion of body weight lost (>5%, >10%, >15% and >20%), changes in insulin dosage, time in range by continuous glucose monitoring (CGM) criteria and severity of comorbidities. Compliance, adverse events and medication interactions will be closely monitored, with adjustments made for tolerability. Patient-reported outcomes and experiences will be measured to capture the benefits of glycaemic management, weight management and quality of life. To compare the means of body weight reduction (%) between the tirzepatide and control groups, an independent samples t-test will be employed under the assumption that data are normally distributed. Secondary outcome measures will be analysed by Student’s t-test. All data will be reported as group means with confidence intervals, with default statistical significance assumed at p<0.05.Ethics and disseminationEthical approval has been obtained from the Northern Sydney Local Health District’s Human Research Ethics Committee (approval ID #2024/ETH00180).Trial registration numberNCT06180616.