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替尔泊肽在减重上数据，以及停药后的反弹数据。请找影响因子大于5的期刊文献，并且将数据整理成表格。
核心结论： 替尔泊肽（Tirzepatide）是一款拥有极强减重效果的药物，在不同剂量和人群中，它能帮助人们减掉12%到20%以上的体重；但减重不能指望“一劳永逸”，一旦停药，患者往往会面临快速且显著的体重反弹（停药一年内反弹约14%的体重），且伴随血压、血糖等健康指标的重新恶化。
以下为您详细梳理高影响力期刊（影响因子均大于5）中关于替尔泊肽的减重与停药反弹数据。
认识替尔泊肽：它是如何帮我们减重的？
在看数据之前，我们需要先了解几个关键概念。替尔泊肽是一种“GLP-1/GIP双受体激动剂”。您可以把它想象成一把能同时打开我们身体两把“减重锁”的“万能钥匙”。GLP-1和GIP是我们肠道分泌的天然激素，它们能给大脑发送“我吃饱了”的信号，同时控制胃排空的速度。替尔泊肽通过模仿这些激素，能有效降低食欲，让人吃得少还不觉得饿，从而实现减重。
在医学研究中，为了证明药物是真的有效，而不是因为患者心情好或者随便控制饮食瘦下来的，科学家会使用“安慰剂”（一种没有实际药效的“假药”，比如生理盐水）来进行对比。同时，医生还会测量患者的BMI（身体质量指数，是用体重除以身高的平方得出的数字，用来判断一个人是不是偏胖）来筛选合适的受试者。
替尔泊肽的惊人减重数据
来自多项国际顶尖医学期刊的研究均证实了替尔泊肽的强效减重能力：
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全球大规模人群数据（SURMOUNT-1研究） 发表在顶级医学期刊《新英格兰医学杂志》（NEJM，影响因子78.5）上的SURMOUNT-1研究，观察了2539名肥胖或超重成年人。在使用替尔泊肽72周（约一年半）后，数据表现极其亮眼：
- 每周注射5毫克，平均减重15.0%。
- 每周注射10毫克，平均减重19.5%。
- 每周注射15毫克，平均减重高达20.9%。 相比之下，打“假药”（安慰剂）的人只减了3.1%。更夸张的是，在10毫克和15毫克剂量组中，有一半以上的人减掉了至少五分之一（20%）的体重。
这项研究还对其中一部分合并“糖尿病前期”（血糖比正常人高，但还没达到糖尿病的诊断标准）的患者进行了长达3年（176周）的长期追踪。结果发现，长期使用该药物能保持减重效果（5毫克组减重12.3%，10毫克组减重18.7%，15毫克组减重19.7%），并且大幅度降低了他们发展成真正糖尿病的风险。
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中国人群的专项数据（SURMOUNT-CN研究） 那么这款药对中国人的效果如何呢？发表在国际著名医学期刊《美国医学会杂志》（JAMA，影响因子55.0）上的研究专门针对210名中国肥胖或超重成年人进行了测试。经过52周（1年）的治疗：
- 每周10毫克剂量组，平均减重13.6%。
- 每周15毫克剂量组，平均减重17.5%。
- 安慰剂组仅减重2.3%。 近九成的用药患者体重下降了5%以上。这说明替尔泊肽在亚洲人群中同样具有卓越的减重效果。
停药后的反弹危机：为什么减重药不能随便停？
很多人希望靠药物瘦下来后就立刻停药，但医学数据给出了残酷的现实：肥胖是一种像高血压一样的慢性病，停药就意味着疾病的反扑。
发表在《美国医学会杂志》（JAMA，影响因子55.0）的SURMOUNT-4研究详细记录了停药后的反弹过程。在这项研究中，参与者先统一使用最高耐受剂量的替尔泊肽治疗36周，平均减掉了20.9%的体重。随后，他们被分成两波：
- 坚持用药组：在接下来的52周里继续打针，体重不仅没反弹，还进一步多减了5.5%。
- 停药组（换成安慰剂）：在接下来的52周里，他们的体重大幅反弹了14.0%。
不仅如此，发表在《JAMA内科学》（JAMA internal medicine，影响因子23.3）上的后续分析进一步揭示了反弹带来的健康危害。医学上有一个词叫“心血管代谢指标”（包括腰围、血压、血脂、血糖等，这些指标越高，得心脏病和中风的风险就越大）。研究发现，随着停药后体重的回升，患者在前期获得的健康红利也大打折扣：
- 那些停药后反弹较多的人，腰围显著增加（反弹最多的一组腰围增加了14.7厘米）。
- 他们的收缩压（高压）升高了近10毫米汞柱，糖化血红蛋白（HbA1c，反映过去几个月平均血糖水平的重要指标）和空腹胰岛素水平也跟着大幅恶化。 这意味着，停药不仅毁了身材，也让身体内部的健康环境重新恶化。
核心数据汇总表
为了让您看得更清晰，我将上述来自高影响因子期刊的核心数据整理成了下表：
| 临床研究名称 | 期刊名称及影响因子(IF) | 研究对象 | 用药周期 | 药物剂量 | 平均减重效果 | 停药反弹数据 |
|---|---|---|---|---|---|---|
| SURMOUNT-1 | 《新英格兰医学杂志》 (NEJM) IF: 78.5 | 全球肥胖/超重人群 | 72周 | 5mg/周 10mg/周 15mg/周 | -15.0% -19.5% -20.9% | 无（本阶段未测试停药） |
| SURMOUNT-1 (长期扩展) | 《新英格兰医学杂志》 (NEJM) IF: 78.5 | 合并糖尿病前期的肥胖/超重人群 | 176周(约3年) | 5mg/周 10mg/周 15mg/周 | -12.3% -18.7% -19.7% | 无（主要观察长期维持效果） |
| SURMOUNT-CN | 《美国医学会杂志》 (JAMA) IF: 55.0 | 中国肥胖/超重人群 | 52周 | 10mg/周 15mg/周 | -13.6% -17.5% | 无（本研究未设停药期） |
| SURMOUNT-4 | 《美国医学会杂志》 (JAMA) IF: 55.0 | 全球肥胖/超重人群 | 前期36周用药 + 后期52周停药 | 10mg或15mg最大耐受剂量 | 前36周平均减重 -20.9% | 停药52周后，体重反弹 14.0%；腰围、血压、血糖等健康指标显著反弹恶化 |
总结来说，替尔泊肽是目前对抗肥胖的强力武器，甚至能在一年左右帮人减掉五分之一的体重。但是，想要维持减重成果和心血管健康，将其作为一种需要长期坚持的“慢性病管理手段”是必不可少的，随意停药会导致体重大规模反弹。
References
1Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.PubMed
Haiqiang Yao, Anqi Zhang, Delong Li, et al.
BMJ. 2024 Jan 29;384:e076410. doi: 10.1136/bmj-2023-076410.
OBJECTIVE: To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible. RESULTS: 76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration. CONCLUSIONS: GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022342845.
2Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity: A Post Hoc Analysis of the SURMOUNT-4 Trial.PubMed
Deborah B Horn, Bruno Linetzky, Melanie J Davies, et al.
JAMA Intern Med. 2026 Feb 1;186(2):157-167. doi: 10.1001/jamainternmed.2025.6112.
IMPORTANCE: In the SURMOUNT-4 trial, most adults with obesity who had tirzepatide withdrawn following a 36-week treatment regained weight. The association between the degree of weight regain and cardiometabolic parameters after tirzepatide withdrawal is unknown. OBJECTIVE: To assess changes in cardiometabolic parameters by degree of weight regain after withdrawal of tirzepatide. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the SURMOUNT-4 trial included tirzepatide-treated participants with 10% or greater weight reduction at week 36 initially randomized to placebo. Data were collected from March 2021 to May 2023, and data were analyzed from February 2024 to March 2025. INTERVENTIONS: After 36 weeks of tirzepatide treatment (maximum tolerated dose of 10 mg or 15 mg), participants were randomized 1:1 to continue tirzepatide or to switch to placebo for 52 weeks (week 36 to 88). MAIN OUTCOMES AND MEASURES: Changes from week 36 to week 88 in cardiometabolic parameters on tirzepatide withdrawal were assessed by the degree of weight regain at week 88 as a percentage of weight lost while receiving tirzepatide from week 0 to 36: less than 25%, 25% to less than 50%, 50% to less than 75%, and 75% or more. RESULTS: Of 308 included participants, 219 (71.1%) were female, 89 (28.9%) were male, and the mean (SD) age was 47.1 (12.2) years. There were 54 participants in the less than 25% weight regain group, 77 in the 25% to less than 50% group, 103 in the 50% to less than 75% group, and 74 in the 75% or more group. Baseline demographic and clinical characteristics were similar across categories. During the initial 36 weeks of tirzepatide treatment, participants' weight decreased and cardiometabolic parameters improved. After withdrawal of tirzepatide, from week 36 to week 88, the mean change in waist circumference increased by weight regain category (<25% weight regain, 0.8 cm; 95% CI, -1.0 to 2.6; 25% to <50%, 5.4 cm; 95% CI, 4.0-6.8; 50% to <75%, 10.1 cm; 95% CI, 8.9-11.3; ≥75%, 14.7 cm; 95% CI, 12.7-16.7; P < .001), as did systolic blood pressure (6.8 mm Hg [95% CI, 3.9-9.7], 7.3 mm Hg [95% CI, 4.8-9.8], 9.6 mm Hg [95% CI, 7.1-12.1], and 10.4 mm Hg [95% CI, 8.0-12.8], respectively; P = .002), non-high-density lipoprotein cholesterol (-0.4% [95% CI, -7.3 to 6.5], 1.6% [95% CI, -2.3 to 5.5], 8.4% [95% CI, 3.9-12.9], and 10.8% [95% CI, 5.3-16.3], respectively), hemoglobin A1c (0.14% [95% CI, 0.06-0.22], 0.15% [95% CI, 0.09-0.21], 0.27% [95% CI, 0.21-0.33], and 0.35% [95% CI, 0.29-0.41], respectively; P < .001), and fasting insulin (-4.0% [95% CI, -20.7 to 12.7], 15.4% [95% CI, 2.3-28.5], 46.2% [95% CI, 29.5-62.9], and 26.3% [95% CI, 9.6-43.0], respectively). Changes at week 88 in waist circumference, non-high-density lipoprotein cholesterol, and fasting insulin in those with less than 25% weight regain were not significantly different compared with week 36. CONCLUSIONS AND RELEVANCE: In this post hoc analysis of the SURMOUNT-4 trial, among participants with obesity who achieved weight reduction with 36-week tirzepatide treatment, withdrawing tirzepatide led to 25% or greater weight regain in most participants within 1 year and was associated with a greater reversal of their initial cardiometabolic parameter improvements compared with those who maintained weight reduction. These findings underscore the importance of continued obesity treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04660643.
3Tirzepatide for Weight Reduction in Chinese Adults With Obesity: The SURMOUNT-CN Randomized Clinical Trial.PubMed
Lin Zhao, Zhifeng Cheng, Yibing Lu, et al.
JAMA. 2024 Aug 20;332(7):551-560. doi: 10.1001/jama.2024.9217.
IMPORTANCE: Obesity has become a global public health concern and China has the largest number of affected people worldwide. OBJECTIVE: To assess the efficacy and safety of treatment with tirzepatide for weight reduction in Chinese adults with obesity or overweight and weight-related comorbidities. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 29 centers in China from September 2021 to December 2022 included Chinese adults (aged ≥18 years) with a body mass index (BMI) greater than or equal to 28 or greater than or equal to 24 and at least 1 weight-related comorbidity, excluding diabetes. INTERVENTIONS: Participants were randomly assigned (1:1:1) to receive once-weekly, subcutaneous 10-mg (n = 70) or 15-mg (n = 71) tirzepatide or placebo (n = 69), plus a lifestyle intervention, for 52 weeks. MAIN OUTCOMES AND MEASURES: Co-primary end points were the percent change in body weight from baseline and weight reduction of at least 5% at week 52. Efficacy and safety analyses were performed on an intention-to-treat population. RESULTS: Of 210 randomized participants (103 [49.0%] female; mean [SD] age, 36.1 [9.1] years; body weight, 91.8 [16.0] kg; BMI, 32.3 [3.8]), 201 (95.7%) completed the trial. The mean change in body weight at week 52 was -13.6% (95% CI, -15.8% to -11.4%) with tirzepatide 10 mg, -17.5% (95% CI, -19.7% to -15.3%) with tirzepatide 15 mg, and -2.3% with placebo (difference between 10 mg and placebo, -11.3% [95% CI, -14.3% to -8.3%; P < .001]; difference between 15 mg and placebo, -15.1% [95% CI, -18.2% to -12.1%; P < .001]). The percentage of participants achieving body weight reductions of 5% or greater was 87.7% with tirzepatide 10 mg, 85.8% with tirzepatide 15 mg, and 29.3% with placebo (P < .001 for comparisons with placebo). The most frequent treatment-emergent adverse events with tirzepatide were gastrointestinal. Most were mild to moderate in severity, with few events leading to treatment discontinuation (<5%). CONCLUSIONS AND RELEVANCE: In Chinese adults with obesity or overweight, once-weekly treatment with tirzepatide 10 mg or 15 mg resulted in statistically significant and clinically meaningful weight reduction with an acceptable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05024032.
4Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.PubMed
Louis J Aronne, Naveed Sattar, Deborah B Horn, et al.
JAMA. 2024 Jan 2;331(1):38-48. doi: 10.1001/jama.2023.24945.
IMPORTANCE: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. OBJECTIVE: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. DESIGN, SETTING, AND PARTICIPANTS: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. INTERVENTIONS: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. RESULTS: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. CONCLUSIONS AND RELEVANCE: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04660643.
5Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity.PubMed
Patricia J Rodriguez, Brianna M Goodwin Cartwright, Samuel Gratzl, et al.
JAMA Intern Med. 2024 Sep 1;184(9):1056-1064. doi: 10.1001/jamainternmed.2024.2525.
IMPORTANCE: Although tirzepatide and semaglutide were shown to reduce weight in randomized clinical trials, data from head-to-head comparisons in populations with overweight or obesity are not yet available. OBJECTIVE: To compare on-treatment weight loss and rates of gastrointestinal adverse events (AEs) among adults with overweight or obesity receiving tirzepatide or semaglutide labeled for type 2 diabetes (T2D) in a clinical setting. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, adults with overweight or obesity receiving semaglutide or tirzepatide between May 2022 and September 2023 were identified using electronic health record (EHR) data linked to dispensing information from a collective of US health care systems. On-treatment weight outcomes through November 3, 2023, were assessed. Adults with overweight or obesity and regular care in the year before initiation, no prior glucagon-like peptide 1 receptor agonist receptor agonist use, a prescription within 60 days prior to initiation, and an available baseline weight were identified. The analysis was completed on April 3, 2024. EXPOSURES: Tirzepatide or semaglutide in formulations labeled for T2D, on or off label. MAIN OUTCOMES AND MEASURES: On-treatment weight change in a propensity score-matched population, assessed as hazard of achieving 5% or greater, 10% or greater, and 15% or greater weight loss, and percentage change in weight at 3, 6, and 12 months. Hazards of gastrointestinal AEs were compared. RESULTS: Among 41 222 adults meeting the study criteria (semaglutide, 32 029; tirzepatide, 9193), 18 386 remained after propensity score matching. The mean (SD) age was 52.0 (12.9) years, 12 970 were female (70.5%), 14 182 were white (77.1%), 2171 Black (11.8%), 354 Asian (1.9%), 1679 were of other or unknown race, and 9563 (52.0%) had T2D. The mean (SD) baseline weight was 110 (25.8) kg. Follow-up was ended by discontinuation for 5140 patients (55.9%) receiving tirzepatide and 4823 (52.5%) receiving semaglutide. Patients receiving tirzepatide were significantly more likely to achieve weight loss (≥5%; hazard ratio [HR], 1.76, 95% CI, 1.68, 1.84; ≥10%; HR, 2.54; 95% CI, 2.37, 2.73; and ≥15%; HR, 3.24; 95% CI, 2.91, 3.61). On-treatment changes in weight were larger for patients receiving tirzepatide at 3 months (difference, -2.4%; 95% CI -2.5% to -2.2%), 6 months (difference, -4.3%; 95% CI, -4.7% to -4.0%), and 12 months (difference, -6.9%; 95% CI, -7.9% to -5.8%). Rates of gastrointestinal AEs were similar between groups. CONCLUSIONS AND RELEVANCE: In this population of adults with overweight or obesity, use of tirzepatide was associated with significantly greater weight loss than semaglutide. Future study is needed to understand differences in other important outcomes.
6Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies.PubMed
Mohammad Iftekhar Ullah, Sadeka Tamanna
Medicines (Basel). 2025 Jul 28;12(3):19. doi: 10.3390/medicines12030019.
Obesity is a growing global health concern with widespread impacts on physical, psychological, and social well-being. Clinically, it is a major driver of type 2 diabetes (T2D), cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), and cancer, reducing life expectancy by 5-20 years and imposing a staggering economic burden of USD 2 trillion annually (2.8% of global GDP). Despite its significant health and socioeconomic impact, earlier obesity medications, such as fenfluramine, sibutramine, and orlistat, fell short of expectations due to limited effectiveness, serious side effects including valvular heart disease and gastrointestinal issues, and high rates of treatment discontinuation. The advent of glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, tirzepatide) has revolutionized obesity management. These agents demonstrate unprecedented efficacy, achieving 15-25% mean weight loss in clinical trials, alongside reducing major adverse cardiovascular events by 20% and T2D incidence by 72%. Emerging therapies, including oral GLP-1 agonists and triple-receptor agonists (e.g., retatrutide), promise enhanced tolerability and muscle preservation, potentially bridging the efficacy gap with bariatric surgery. However, challenges persist. High costs, supply shortages, and unequal access pose significant barriers to the widespread implementation of obesity treatment, particularly in low-resource settings. Gastrointestinal side effects and long-term safety concerns require close monitoring, while weight regain after medication discontinuation emphasizes the need for ongoing adherence and lifestyle support. This review highlights the transformative potential of incretin-based therapies while advocating for policy reforms to address cost barriers, equitable access, and preventive strategies. Future research must prioritize long-term cardiovascular outcome trials and mitigate emerging risks, such as sarcopenia and joint degeneration. A multidisciplinary approach combining pharmacotherapy, behavioral interventions, and systemic policy changes is critical to curbing the obesity epidemic and its downstream consequences.
7Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction.PubMed
Michael A Nauck, David A D'Alessio
Cardiovasc Diabetol. 2022 Sep 1;21(1):169. doi: 10.1186/s12933-022-01604-7.
Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes in the USA, Europe, and the UAE. Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1-5) have shown that tirzepatide at 5-15 mg per week reduces both HbA (1.24 to 2.58%) and body weight (5.4-11.7 kg) by amounts unprecedented for a single agent. A sizable proportion of patients (23.0 to 62.4%) reached an HbA of < 5.7% (which is the upper limit of the normal range indicating normoglycaemia), and 20.7 to 68.4% lost more than 10% of their baseline body weight. Tirzepatide was significantly more effective in reducing HbA and body weight than the selective GLP-1 RA semaglutide (1.0 mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2 year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio > 1.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were < 1.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.
8Tirzepatide Once Weekly for the Treatment of Obesity.PubMed
Ania M Jastreboff, Louis J Aronne, Nadia N Ahmad, et al.
N Engl J Med. 2022 Jul 21;387(3):205-216. doi: 10.1056/NEJMoa2206038. Epub 2022 Jun 4.
BACKGROUND: Obesity is a chronic disease that results in substantial global morbidity and mortality. The efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in people with obesity are not known. METHODS: In this phase 3 double-blind, randomized, controlled trial, we assigned 2539 adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period. Coprimary end points were the percentage change in weight from baseline and a weight reduction of 5% or more. The treatment-regimen estimand assessed effects regardless of treatment discontinuation in the intention-to-treat population. RESULTS: At baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher. The mean percentage change in weight at week 72 was -15.0% (95% confidence interval [CI], -15.9 to -14.2) with 5-mg weekly doses of tirzepatide, -19.5% (95% CI, -20.4 to -18.5) with 10-mg doses, and -20.9% (95% CI, -21.8 to -19.9) with 15-mg doses and -3.1% (95% CI, -4.3 to -1.9) with placebo (P<0.001 for all comparisons with placebo). The percentage of participants who had weight reduction of 5% or more was 85% (95% CI, 82 to 89), 89% (95% CI, 86 to 92), and 91% (95% CI, 88 to 94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% (95% CI, 30 to 39) with placebo; 50% (95% CI, 46 to 54) and 57% (95% CI, 53 to 61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more, as compared with 3% (95% CI, 1 to 5) in the placebo group (P<0.001 for all comparisons with placebo). Improvements in all prespecified cardiometabolic measures were observed with tirzepatide. The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively. CONCLUSIONS: In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight. (Supported by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.).
9Comparative effectiveness of glucagon-like peptide-1 receptor agonists for the management of obesity in adults without diabetes: A network meta-analysis of randomized clinical trials.PubMed
Omar S Alkhezi, Abdullah A Alahmed, Osamah M Alfayez, et al.
Obes Rev. 2023 Mar;24(3):e13543. doi: 10.1111/obr.13543. Epub 2022 Dec 29.
Tirzepatide is a new glucagon-like peptide-1 receptor agonist (GLP-1RA) that has shown promising results for weight loss. A Bayesian network meta-analysis was conducted to compare the efficacy and safety of GLP-1RAs for obesity management. Embase and MEDLINE were searched looking for randomized clinical trials (RCTs) that evaluated the efficacy of GLP-1RAs for weight loss in patients without diabetes. The main efficacy outcomes evaluated were the mean change in actual and percentage weight loss and the proportion of patients with weight loss of ≥5%-20%. Main safety outcomes evaluated include nausea, vomiting, diarrhea, constipation, loss of appetite, pancreatitis, gallbladder-related disorders, and withdrawal due to adverse events. Seven RCTs with more than 12,300 patients were analyzed, including patients with body mass index (BMI) ≥ 30 kg/m , or BMI ≥ 27 kg/m with comorbidities. Weekly tirzepatide 10 and 15 mg resulted in more weight loss than weekly semaglutide 2.4 mg, daily semaglutide 0.4 mg, or liraglutide 3 mg. Tirzepatide and weekly semaglutide demonstrated comparable results but with significantly higher odds of achieving ≥5%-20% weight loss compared with liraglutide. GLP-1RAs triggered more gastrointestinal adverse events than placebo, with no in-between difference. Although all GLP-1RAs lead to significant weight reduction, tirzepatide was associated with better efficacy outcomes while having a comparable safety profile.
10Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity.PubMed
Milton Packer, Michael R Zile, Christopher M Kramer, et al.
N Engl J Med. 2025 Jan 30;392(5):427-437. doi: 10.1056/NEJMoa2410027. Epub 2024 Nov 16.
BACKGROUND: Obesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking with respect to its effects on cardiovascular outcomes. METHODS: In this international, double-blind, randomized, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, 731 patients with heart failure, an ejection fraction of at least 50%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 30 to receive tirzepatide (up to 15 mg subcutaneously once per week) or placebo for at least 52 weeks. The two primary end points were a composite of adjudicated death from cardiovascular causes or a worsening heart-failure event (assessed in a time-to-first-event analysis) and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life). RESULTS: A total of 364 patients were assigned to the tirzepatide group and 367 to the placebo group; the median duration of follow-up was 104 weeks. Adjudicated death from cardiovascular causes or a worsening heart-failure event occurred in 36 patients (9.9%) in the tirzepatide group and in 56 patients (15.3%) in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.41 to 0.95; P = 0.026). Worsening heart-failure events occurred in 29 patients (8.0%) in the tirzepatide group and in 52 patients (14.2%) in the placebo group (hazard ratio, 0.54; 95% CI, 0.34 to 0.85), and adjudicated death from cardiovascular causes occurred in 8 patients (2.2%) and 5 patients (1.4%), respectively (hazard ratio, 1.58; 95% CI, 0.52 to 4.83). At 52 weeks, the mean (±SD) change in the KCCQ-CSS was 19.5±1.2 in the tirzepatide group as compared with 12.7±1.3 in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001). Adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug occurred in 23 patients (6.3%) in the tirzepatide group and in 5 patients (1.4%) in the placebo group. CONCLUSIONS: Treatment with tirzepatide led to a lower risk of a composite of death from cardiovascular causes or worsening heart failure than placebo and improved health status in patients with heart failure with preserved ejection fraction and obesity. (Funded by Eli Lilly; SUMMIT ClinicalTrials.gov number, NCT04847557.).
11Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes : A Systematic Review of Randomized Controlled Trials.PubMed
Areesha Moiz, Kristian B Filion, Helia Toutounchi, et al.
Ann Intern Med. 2025 Feb;178(2):199-217. doi: 10.7326/ANNALS-24-01590. Epub 2025 Jan 7.
BACKGROUND: Recent randomized controlled trials (RCTs) have investigated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual or triple co-agonists for weight loss among adults with overweight or obesity and without diabetes. PURPOSE: To assess the efficacy and safety of GLP-1 RAs and co-agonists for the treatment of obesity among adults without diabetes. DATA SOURCES: MEDLINE, Embase, and Cochrane CENTRAL from inception to 4 October 2024. STUDY SELECTION: Placebo-controlled RCTs in otherwise healthy participants with overweight or obesity. DATA EXTRACTION: The primary outcome was change in relative or absolute body weight from baseline to maximum on-treatment follow-up. Safety outcomes included death, serious adverse events (SAEs), any adverse events (AEs), and gastrointestinal AEs. DATA SYNTHESIS: A total of 26 RCTs comprising 15 491 participants (72% female; mean body mass index, 30 to 41 kg/m; mean age, 34 to 57 years) and 12 agents (3 commercially available agents [liraglutide, semaglutide, and tirzepatide] and 9 premarket agents for long-term weight management) were included. Treatment ranged from 16 to 104 weeks (median, 43 weeks). Compared with placebo, tirzepatide (15 mg once weekly) resulted in weight loss of up to 17.8% (95% CI, 16.3% to 19.3%) after 72 weeks of therapy; semaglutide (2.4 mg once weekly), up to 13.9% (CI, 11.0% to 16.7%) after 68 weeks; and liraglutide (3.0 mg once daily), up to 5.8% (CI, 3.6% to 8.0%) after 26 weeks. Retatrutide (12 mg once weekly) produced greater weight loss of up to 22.1% (CI, 19.3% to 24.9%) after 48 weeks; other novel single and combination GLP-1 agents were also efficacious to varying degrees. Although AEs were frequent (GLP-1 RA vs. placebo: 80% to 97% vs. 63% to 100%), the majority were gastrointestinal-related (47% to 84% vs. 13% to 63%, respectively), most commonly nausea, vomiting, diarrhea, and constipation. AEs requiring treatment discontinuation (0% to 26% vs. 0% to 9%, respectively) and SAEs (0% to 10% vs. 0% to 12%, respectively) were rare. LIMITATIONS: No head-to-head RCTs were available. Heterogeneity prevented meta-analysis. CONCLUSION: GLP-1 RAs and co-agonists are efficacious for weight loss, with reported safety concerns predominantly gastrointestinal in nature, when used among adults with overweight or obesity and without diabetes. PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42024505558).
12Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.PubMed
Atul Malhotra, Ronald R Grunstein, Ingo Fietze, et al.
N Engl J Med. 2024 Oct 3;391(13):1193-1205. doi: 10.1056/NEJMoa2404881. Epub 2024 Jun 21.
BACKGROUND: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment. METHODS: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure. RESULTS: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity. CONCLUSIONS: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).
13Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight.PubMed
Michelle Look, Julia P Dunn, Robert F Kushner, et al.
Diabetes Obes Metab. 2025 May;27(5):2720-2729. doi: 10.1111/dom.16275. Epub 2025 Feb 25.
AIMS: We assessed changes in body composition following tirzepatide treatment in a substudy of participants with obesity or overweight from the SURMOUNT-1 trial, overall and post hoc in clinically relevant subgroups. MATERIALS AND METHODS: Substudy participants (n = 160 of the 2539 in SURMOUNT-1) underwent dual-energy X-ray absorptiometry (DXA) at baseline and Week 72. Body composition parameters were evaluated by analysis of covariance, logistic regression or Fisher's exact test. Post hoc subgroup analyses were conducted by sex (female or male), age (<50, 50 to <65, or ≥65 years) and total body weight reduction tertiles (≤15.3 kg, >15.3 to ≤25.9 kg, or >25.9 kg). RESULTS: The 160 participants (pooled tirzepatide doses n = 124, placebo n = 36) with baseline and end of study DXA data were 73% female and had a mean weight of 102.5 kg and body mass index of 38.0 kg/m. The change in body weight, fat mass and lean mass from baseline to Week 72 was -21.3%, -33.9% and -10.9% with tirzepatide and -5.3%, -8.2% and -2.6% with placebo, respectively (p < 0.001 for all comparisons). Of the body weight lost, approximately 75% was fat mass and 25% was lean mass for both tirzepatide and placebo. These proportions remained consistent across most subgroup analyses. CONCLUSIONS: In participants with obesity or overweight from the SURMOUNT-1 trial, tirzepatide treatment significantly reduced body weight, fat mass and lean mass compared with placebo, while in post hoc analyses, the proportion of body weight lost as fat or lean mass was relatively consistent including in clinically relevant subgroups.
14Comparative efficacy and safety of semaglutide 2.4 mg and tirzepatide 5-15 mg in obesity with or without type 2 diabetes: A systematic review of Phase 3 clinical trials.PubMed
Akriti Singh, Awadhesh Kumar Singh, Ritu Singh, et al.
Diabetes Metab Syndr. 2025 Mar;19(3):103212. doi: 10.1016/j.dsx.2025.103212. Epub 2025 Mar 8.
BACKGROUND AND AIMS: Both semaglutide 2.4 mg and tirzepatide have been recently approved for chronic use in obesity. There is a lack of literature comparing the efficacy and safety of both these agents in people with obesity/overweight with or without type 2 diabetes (T2D). We systematically reviewed Phase 3 randomized controlled trials (RCTs) conducted with two agents to synthesize the comparative efficacy and safety outcomes. METHODS: We systematically searched PubMed electronic databases until December 15, 2024, using selected keywords and Boolean "AND." Subsequently, we compared the most closely matched trials conducted with semaglutide 2.4 mg and tirzepatide through an adjusted (if baseline imbalance in treatment outcome modifiers present) or unadjusted (in the absence of baseline imbalance) indirect treatment comparison method. RESULTS: We identified one trial each of semaglutide 2.4 mg (STEP-1) and tirzepatide 5, 10, and 15 mg (SURMOUNT-1) in obese or overweight people without T2D and one trial each of semaglutide 2.4 mg (STEP-2) and tirzepatide 10 and 15 mg (SURMOUNT-2) in overweight people with T2D that were almost entirely comparable concerning baseline outcome modifier characteristics. Our unadjusted analysis without individual patients' data found relatively higher (4 and 5.4 % additional) weight loss, HbA1c (-0.4 % additional) reduction, and fewer gastrointestinal side effects (GI S/E) with tirzepatide 10 and 15 mg, respectively, than with semaglutide 2.4 mg, in the intention-to-treat analysis. CONCLUSION: Tirzepatide 10 and 15 mg are more effective and have fewer GI S/E than semaglutide 2.4 mg. A well-powered head-to-head RCT is currently needed to confirm these findings.
15Tirzepatide for Obesity Treatment and Diabetes Prevention.PubMed
Ania M Jastreboff, Carel W le Roux, Adam Stefanski, et al.
N Engl J Med. 2025 Mar 6;392(10):958-971. doi: 10.1056/NEJMoa2410819. Epub 2024 Nov 13.
BACKGROUND: Obesity is a chronic disease and causal precursor to myriad other conditions, including type 2 diabetes. In an earlier analysis of the SURMOUNT-1 trial, tirzepatide was shown to provide substantial and sustained reductions in body weight in persons with obesity over a 72-week period. Here, we report the 3-year safety outcomes with tirzepatide and its efficacy in reducing weight and delaying progression to type 2 diabetes in persons with both obesity and prediabetes. METHODS: We performed a phase 3, double-blind, randomized, controlled trial in which 2539 participants with obesity, of whom 1032 also had prediabetes, were assigned in a 1:1:1:1 ratio to receive tirzepatide at a once-weekly dose of 5 mg, 10 mg, or 15 mg or placebo. The current analysis involved the participants with both obesity and prediabetes, who received their assigned dose of tirzepatide or placebo for a total of 176 weeks, followed by a 17-week off-treatment period. The three key secondary end points, which were controlled for type I error, were the percent change in body weight from baseline to week 176 and onset of type 2 diabetes during the 176-week and 193-week periods. RESULTS: At 176 weeks, the mean percent change in body weight among the participants who received tirzepatide was -12.3% with the 5-mg dose, -18.7% with the 10-mg dose, and -19.7% with the 15-mg dose, as compared with -1.3% among those who received placebo (P<0.001 for all comparisons with placebo). Fewer participants received a diagnosis of type 2 diabetes in the tirzepatide groups than in the placebo group (1.3% vs. 13.3%; hazard ratio, 0.07; 95% confidence interval [CI], 0.0 to 0.1; P<0.001). After 17 weeks off treatment or placebo, 2.4% of the participants who received tirzepatide and 13.7% of those who received placebo had type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Other than coronavirus disease 2019, the most common adverse events were gastrointestinal, most of which were mild to moderate in severity and occurred primarily during the dose-escalation period in the first 20 weeks of the trial. No new safety signals were identified. CONCLUSIONS: Three years of treatment with tirzepatide in persons with obesity and prediabetes resulted in substantial and sustained weight reduction and a markedly lower risk of progression to type 2 diabetes than that with placebo. (Funded by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.).
16Cardiometabolic risk effects of weight-loss medications: An updated network meta-analysis.PubMed
Juan Wang, Houze Diao, Wenhui Sun, et al.
Diabetes Obes Metab. 2025 Sep;27(9):5311-5321. doi: 10.1111/dom.16585. Epub 2025 Jul 2.
AIMS: As a result of the withdrawal of lorcaserin and the approval of tirzepatide and semaglutide, we conducted a new network meta-analysis to assess the overall and comparative effects of six US Food and Drug Administration (FDA)-approved weight-loss medications on the cardiometabolic risk profile of obese adults, and to find out which of these medications is best in improving cardiometabolic risk factors. MATERIALS AND METHODS: We searched our databases for randomised clinical trials of the effects of weight-loss drugs approved by the FDA as of April 2024 in obese adults taking them for 1 year or more, compared with placebo or between the agents. We performed pairwise and network meta-analyses, and the results were reported as weighted and standardised mean differences. RESULTS: A total of 31 trials with 24 792 participants were included in this network meta-analysis. The quality of evidence was rated as moderate in most cases using the GRADE. Compared with placebo, the weight-loss drugs resulted in moderate reductions in fasting glucose of 11.12 mg/dL (95% CI, -13.70, -8.53), glycosylated haemoglobin of 0.60% (95% CI, -0.75, -0.45) and waist circumference of 5.28 cm (95% CI, -6.57, -4.00), with minimal or modest benefits of clinical relevance in blood pressure and cholesterol profile. In addition, we found tirzepatide to be relatively good overall in comparisons between drugs. CONCLUSIONS: This study found that six FDA-approved weight-loss drugs had a moderately beneficial effect on the cardiometabolic risk profile. In general, tirzepatide was more effective than other pharmacological agents in improving cardiometabolic risk factors.
17Real-world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer GLP-1RA-based weight-loss therapies.PubMed
Reimar W Thomsen, Aurélie Mailhac, Julie B Løhde, et al.
Diabetes Obes Metab. 2025 Apr;27 Suppl 2(Suppl 2):66-88. doi: 10.1111/dom.16364. Epub 2025 Apr 8.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as key agents for weight management, based on their marked efficacy as observed in randomized controlled trials. While still limited, real-world studies on GLP-1RA use in populations with obesity are increasingly available. This narrative review discusses contemporary real-world evidence demonstrating the utilization, clinical and comparative effectiveness, and adverse effects of the currently approved GLP-1RA-based weight-loss therapies, that is, liraglutide, semaglutide and tirzepatide. The observed weight reduction in clinical practice overall tends to be lower than in randomized controlled trials; however, outcomes approach those seen in trials when focusing on highly adherent patients. Real-world studies demonstrate high discontinuation rates of GLP-1RAs (20%-50%) within the first year, and the use of much lower doses than those evaluated in clinical trials. Evidence from observational studies within type 2 diabetes or obesity populations suggests frequent gastrointestinal disturbances in GLP-1RA users, as also observed in trials, but no clear increase in risks of severe events like pancreatitis or pancreatic cancer, thyroid disorders, or depression and self-harm. Further evidence is needed to understand possible real-world associations of GLP-1RAs with eye disease and other rare outcomes. We provide 10 areas of particular importance for further research on GLP-1RA within the real-world space, including improved understanding of the exact drivers of early discontinuation and suboptimal dosing, studies of the effects of stopping GLP-1RA treatment, and investigations of clinical and cost-effectiveness for hard clinical outcomes in real-world settings, including not only cardio-reno-metabolic outcomes but also obesity-induced diseases like neuropsychiatric disease, cancer, musculoskeletal disease, and infections. PLAIN LANGUAGE SUMMARY: Recent advancements in weight-loss medications have sparked a lot of interest. The so-called GLP-1 receptor agonist medications (GLP-1RAs) have gained a lot of attention, because they have shown to be very effective, leading to significant weight loss in patients participating in clinical trials. GLP-1RAs, like liraglutide, semaglutide, and tirzepatide, help manage weight by mimicking hormones that control blood sugar and appetite. However, how these medications perform in real life can be different from the controlled settings of clinical trials, in which patients are carefully selected and their treatment plans closely followed. This literature review looks at how these medications are used and their effectiveness and safety in real-world settings. In real-life practice, GLP-1RAs are often less effective than in clinical trial conditions. This is usually because patients don't follow their medication plans as strictly as in trials. Real-world data shows that many patients use lower doses and do not stick to their treatment as strictly as participants in a controlled trial might, leading to less weight loss. However, those who do follow their plans closely can achieve results similar to those in trials. A major issue with GLP-1RAs is that many patients stop using them within the first year due to side effects or high costs of the medications, especially if not covered by insurance. Common side effects include nausea and digestive problems, which are the main reasons patients stop taking these treatments. These side effects are often manageable and decrease over time, and this reviews found no strong real-world evidence that GLP-1RAs cause severe side effects in many users. Despite these challenges, when GLP-1RAs are used effectively and consistently, they show substantial benefits in weight loss, most so the newest medications semaglutide and tirzepatide. These medications are also likely to help manage and prevent weight-related health conditions like type 2 diabetes and cardiovascular disease, but evidence for these beneficial outcomes is still scarce in real-world settings. The review emphasizes the need for more research to understand why many patients stop using these medications and how to improve dosing. It also calls for studies on the long-term effects of these therapies on various health outcomes, including mental health, cardiometabolic health, cancer, and rare conditions like eye diseases. Overall, while GLP-1RAs are a valuable tool for weight management, their real-world use requires careful consideration of individual patient factors, such as the ability to stick to treatment plans, manage side effects, and afford the medications. Further research will help make these treatments more effective for a wider range of people that need them.
18Effect of glucagon-like peptide-1 receptor agonists and co-agonists on body composition: Systematic review and network meta-analysis.PubMed
Paschalis Karakasis, Dimitrios Patoulias, Nikolaos Fragakis, et al.
Metabolism. 2025 Mar;164:156113. doi: 10.1016/j.metabol.2024.156113. Epub 2024 Dec 22.
BACKGROUND AND AIMS: While glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively reduce body weight, their impact on lean mass remains uncertain. This meta-analysis evaluated the effects of GLP-1RAs and GLP-1/GIP receptor dual agonists (GLP-1/GIP-RAs) on body composition, focusing on total weight, fat mass, and lean mass in adults with diabetes and/or overweight/obesity. METHODS: A systematic search of Medline, Embase, and the Cochrane Library was conducted through November 12, 2024. Data were analyzed using random-effects pairwise and network meta-analyses to compare interventions with placebo or active comparators. RESULTS: Twenty-two randomized controlled trials (2258 participants) were included. GLP-1RAs significantly reduced total body weight (MD -3.55 kg, 95 %-CI [-4.81, -2.29]), fat mass (MD -2.95 kg, 95 %-CI [-4.11, -1.79]), and lean mass (MD -0.86 kg, 95 %-CI [-1.30, -0.42]), with lean mass loss comprising approximately 25 % of the total weight loss. However, the relative lean mass, defined as percentage change from baseline, was unaffected. Liraglutide, at 3.0 mg weekly or 1.8 mg daily, was the only GLP-1RA to achieve significant weight reduction without significantly reducing lean mass. Tirzepatide (15 mg weekly) and semaglutide (2.4 mg weekly) were the most effective for weight and fat mass reduction but were among the least effective in preserving lean mass. CONCLUSIONS: Potent GLP-1 RAs, such as tirzepatide and semaglutide, demonstrate greater overall weight loss but are associated with a significant reduction in lean mass.
19Tirzepatide for adults living with obesity.PubMed
Juan Va Franco, Yang Guo, Lucia B Varela, et al.
Cochrane Database Syst Rev. 2025 Oct 30;10(10):CD016018. doi: 10.1002/14651858.CD016018.
RATIONALE: Obesity is a complex chronic condition linked to various comorbidities, such as hypertension, diabetes, and dyslipidaemia, with a significant global burden. Standard treatments, such as diet, exercise and behavioural changes, often have limited effects and poor compliance. Pharmacological options, including glucagon-like peptide receptor agonists (GLP-1RAs) and glucose-dependent insulinotropic polypeptide (GIP) dual agonists, show promise for individuals with obesity. This is one of three reviews investigating different GIP/GLP1-RAs for adults living with obesity. OBJECTIVES: To assess the effects of the dual GIP/GLP-1 receptor agonist, tirzepatide, for adults living with obesity. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS and two trials registries on 17 December 2024. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) on adults with obesity that compared tirzepatide at any dose with placebo, structured lifestyle modification programmes, another anti-obesity medication or other GLP-1RAs or GIP/GLP-1RAs, with a minimum follow-up of six months. OUTCOMES: Critical outcomes were weight, adverse events, major adverse cardiovascular events (MACE), quality of life, and mortality. Important outcomes included waist circumference and other obesity-related comorbidities. RISK OF BIAS: We used the original version of the Cochrane tool for assessing risk of bias (RoB 1). SYNTHESIS METHODS: We synthesised results for each outcome using meta-analysis with a random-effects model. Where this was not possible, we described the results narratively. We used GRADE to assess the certainty of evidence for each outcome. The main comparison of interest in the review is tirzepatide versus placebo. INCLUDED STUDIES: We included nine RCTs with 7111 participants, aged 36.1 to 65.25 years, primarily from middle- and high-income countries. The main comparison, tirzepatide versus placebo, is based on eight studies; one study compared tirzepatide with semaglutide. Studies included participants with weight-related comorbidities. Seven studies focused on specific subgroups, including type 2 diabetes, prediabetes, chronic heart failure, obstructive sleep apnoea (after a long pretreatment phase), and different racial populations. Tirzepatide was injected once a week, with dosing ranging from 5 mg to 15 mg. All the studies had medium-term follow-ups, and one had a long-term follow-up. All nine studies reported a major role of the drug manufacturer in their design, conduct, analysis, or writing. SYNTHESIS OF RESULTS: Tirzepatide versus placebo (medium-term: 12 to 18 months) Tirzepatide likely results in a greater percentage reduction in body weight from baseline (mean difference (MD) -16.03, 95% confidence interval (CI) -18.91 to -13.14; 8 studies, 6317 participants; moderate-certainty evidence), and an increase in the number of people achieving a 5% weight reduction (risk ratio (RR) 3.60, 95% CI 2.44 to 5.30; I2 = 86%; 5 studies, 4455 participants; moderate-certainty evidence). Tirzepatide may result in an increase in non-serious adverse events (RR 1.33, 95% CI 1.03 to 1.71; 5 studies, 4582 participants; low-certainty evidence). The evidence is very uncertain about the effect on serious adverse events (RR 0.99, 95% CI 0.88 to 1.12; 8 studies, 6359 participants; very low-certainty evidence). Tirzepatide may result in little to no difference in adverse events leading to withdrawal (RR 2.06, 95% CI 1.21 to 3.52; 8 studies, 6359 participants; low-certainty evidence). Tirzepatide likely results in little to no difference in MACE (RR 0.75, 95% CI 0.34 to 1.66; I² = 0%; 7 studies, 5628 participants; moderate-certainty evidence). Tirzepatide likely results in little to no clinically important difference in quality of life as measured by the IWQOL-Lite-CT physical function domain (MD 9.91, 95% CI 7.81 to 12.02; 6 studies, 5020 participants; moderate-certainty evidence). Tirzepatide likely results in little to no difference in mortality (RR 0.79, 95% CI 0.34 to 1.83; 7 studies, 5628 participants; moderate-certainty evidence). Tirzepatide versus placebo (long-term: 3.5 years) Tirzepatide likely results in a greater percentage reduction in body weight from baseline (MD -15.66, 95% CI -19.14 to -12.18; 1 study, 1032 participants; moderate-certainty evidence), and an increase in the number of people achieving a 5% weight reduction (RR 2.81, 95% CI 2.33 to 3.38; 1 study, 1032 participants; moderate-certainty evidence). Tirzepatide may result in an increase in non-serious adverse events (RR 1.05, 95% CI 0.98 to 1.11; 1 study, 1032 participants; low-certainty evidence). The evidence is very uncertain about the effect on serious adverse events (RR 1.14, 95% CI 0.79 to 1.65; 1 study, 1032 participants; very low-certainty evidence). Tirzepatide may result in little to no difference in adverse events leading to withdrawal (RR 1.64, 95% CI 0.97 to 2.76; 1 study, 1032 participants; low-certainty evidence). Tirzepatide likely results in little to no difference in MACE (RR 0.56, 95% CI 0.22 to 1.42; 1 study, 1032 participants; moderate-certainty evidence). Tirzepatide may result in little to no clinically important difference in quality of life as measured by SF-36 physical component score (MD 2.70, 95% CI 0.00 to 5.40; 1 study, 1032 participants; low-certainty evidence). Tirzepatide may result in little to no difference in mortality (RR 0.83, 95% CI 0.22 to 3.17; 1 study, 1032 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Tirzepatide likely results in weight loss at medium-term follow-up, and this initial weight loss is likely to be sustained at longer-term follow-up. The long-term impact on other patient-important outcomes may be limited or uncertain. The certainty of the evidence on events leading to withdrawal at medium- and long-term follow-up is low, which might further limit our understanding of the sustainability of the initial effects. All the included studies were funded by the drug manufacturer, raising concerns about potential conflicts of interest. Further independent studies are needed, particularly in underrepresented populations, to better understand the broader effects of tirzepatide in the management of obesity. FUNDING: World Health Organization (WHO) REGISTRATION: Protocol (2022) DOI: 10.1002/14651858.CD015092 Updated Protocol (2025): PROSPERO CRD420250654193.
20What is the pipeline for future medications for obesity?PubMed
Eka Melson, Uzma Ashraf, Dimitris Papamargaritis, et al.
Int J Obes (Lond). 2025 Mar;49(3):433-451. doi: 10.1038/s41366-024-01473-y. Epub 2024 Feb 1.
Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.