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GLP-1受体激动剂与替尔泊肽减重效果、停药反弹和安全性比较
GLP-1受体激动剂（GLP-1RAs）和替尔泊肽（Tirzepatide）在减重效果、停药反弹和安全性方面存在相似之处，但也表现出显著差异。替尔泊肽作为一种双重GIP/GLP-1受体激动剂，在减重效果上通常优于单一GLP-1RAs，但两者都存在停药后体重反弹的风险，并共享相似的胃肠道不良事件。
1. 减重效果比较
1.1 替尔泊肽的减重效果
替尔泊肽在多项临床试验中显示出显著的减重效果。
- 在SURMOUNT-1试验中，针对肥胖或超重且不伴有糖尿病的成年人，72周治疗后，替尔泊肽不同剂量组的平均体重百分比变化分别为：5毫克组-15.0%，10毫克组-19.5%，15毫克组-20.9% 。与安慰剂组的-3.1%相比，这些减重效果显著优异 。其中，10毫克和15毫克组有50%和57%的参与者体重减轻达到或超过20% 。
- 在SURMOUNT-2试验中，针对肥胖或超重且伴有2型糖尿病的成年人，72周治疗后，替尔泊肽10毫克和15毫克组的平均体重百分比变化分别为-12.8%和-14.7% 。与安慰剂组的-3.2%相比，替尔泊肽组的减重效果有显著统计学意义 。
- 一项对成人肥胖或超重患者的荟萃分析发现，替尔泊肽（5毫克、10毫克和15毫克）在体重减轻方面优于安慰剂和GLP-1RAs 。
- 另一项针对2型糖尿病患者的系统评价和网络荟萃分析显示，替尔泊肽在体重管理方面表现出强大的益处，平均体重减轻8.47公斤（95% CI -9.68至-7.26），且证据可信度高 。
- 与司美格鲁肽（一种GLP-1RA）的头对头比较研究显示，替尔泊肽在3个月、6个月和12个月时均表现出更大的体重变化（差异分别为-2.4%、-4.3%和-6.9%）。服用替尔泊肽的患者更有可能实现≥5%、≥10%和≥15%的体重减轻目标（风险比分别为1.76、2.54和3.24）。
- 一项更新的系统评价和网络荟萃分析指出，在所有GLP-1受体激动剂和多激动剂中，替尔泊肽15毫克组是减重效果排名前三的治疗方式之一，平均体重减轻16.53% 。
1.2 GLP-1受体激动剂的减重效果
GLP-1受体激动剂也被证明能够有效减轻体重。
- 司美格鲁肽2.4毫克每周一次皮下注射，在肥胖或超重且伴有2型糖尿病的成人中，68周后平均体重减轻9.6% 。与安慰剂组的-3.4%相比，司美格鲁肽2.4毫克组的减重效果具有临床意义 。
- 多项研究表明，GLP-1RAs可有效促进体重减轻，并改善高血糖、胰岛素敏感性、血压和心血管代谢保护等指标 。
- 网络荟萃分析发现，所有15种GLP-1RA都对体重管理有显著益处 。其中，CagriSema（司美格鲁肽联合cagrilintide）的减重效果最佳，平均体重减轻14.03公斤 。
1.3 替尔泊肽与GLP-1RAs的对比总结
总体而言，替尔泊肽的减重效果通常优于单一GLP-1受体激动剂。
- 一项比较研究表明，替尔泊肽在降低糖化血红蛋白水平和诱导体重减轻方面，比皮下注射司美格鲁肽1.0毫克和口服司美格鲁肽14毫克更显著 。
- 在治疗2型糖尿病患者的SURPASS-2试验中，替尔泊肽（5毫克、10毫克和15毫克）相较于司美格鲁肽1毫克，在体重减轻方面表现出更大的优势，平均治疗差异分别为-1.9公斤、-3.6公斤和-5.5公斤 。
- 替尔泊肽的这种优势可能与其作为双重GIP/GLP-1受体激动剂的作用机制有关 。GIP和GLP-1通过刺激大脑饱食中枢的神经元来调节食物摄入 。GIP直接刺激脂肪生成，而GLP-1间接促进脂肪分解，共同维持健康的脂肪细胞并减少异位脂肪分布 。这些协同作用可能导致了替尔泊肽在减重方面的更优表现。
2. 停药反弹比较
GLP-1受体激动剂和替尔泊肽的治疗效果需要持续维持，停药后普遍存在体重反弹的风险。
- 一项系统综述和荟萃分析评估了GLP-1RAs停药后体重的可持续性，结果显示停药后体重会显著反弹，且反弹的体重与最初减轻的体重成比例 。
- 服用利拉鲁肽的参与者平均体重反弹2.20公斤，而服用司美格鲁肽/替尔泊肽的参与者平均体重反弹9.69公斤 。这表明替尔泊肽停药后的体重反弹可能更为显著，这与其最初更强的减重效果相对应 。
- 另一项叙述性综述也强调，无论是GLP-1 RA还是GIP/GLP-1 RA（如替尔泊肽），停止治疗后体重会迅速反弹，这可能会大大抵消通过减重获得的代谢益处 。
- SURMOUNT-1试验的一项最新分析报告指出，在肥胖和糖尿病前期患者中，经过176周的替尔泊肽治疗后，患者体重得到显著且持续的减轻 。但在停药17周后，替尔泊肽组仍有2.4%的参与者患有2型糖尿病，而安慰剂组为13.7%，尽管替尔泊肽组的发病率显著降低，但其长期停药后的效果仍需进一步关注 。
- 因此，建议将GLP-1RA治疗视为一种慢性疗法，以防止体重反弹和相关肥胖带来的不良后果 。未来的研究需要关注这些治疗的最佳持续时间，或探索涉及减少剂量的方案以防止体重反弹 。
3. 安全性比较
GLP-1受体激动剂和替尔泊肽的安全性特征相似，主要表现为胃肠道不良事件。
3.1 替尔泊肽的安全性
- 在SURPASS-2试验中，替尔泊肽和司美格鲁肽组最常见的不良事件是胃肠道问题，主要为轻度至中度。替尔泊肽组的恶心发生率为17%至22%，腹泻为13%至16%，呕吐为6%至10% 。司美格鲁肽组的相应数据分别为恶心18%，腹泻12%，呕吐8% 。
- 低血糖事件（血糖水平低于54毫克/分升）在替尔泊肽组的发生率分别为0.6%（5毫克组）、0.2%（10毫克组）和1.7%（15毫克组），而司美格鲁肽组为0.4% 。
- 严重不良事件在替尔泊肽组的发生率为5%至7%，司美格鲁肽组为3% 。
- 在SURMOUNT-1试验中，替尔泊肽最常见的不良事件也是胃肠道问题，大多数为轻度至中度，主要发生在剂量递增期间 。因不良事件导致治疗中断的比例在替尔泊肽不同剂量组为4.3%、7.1%和6.2%，安慰剂组为2.6% 。
- SURMOUNT-2试验也报告了相似的胃肠道不良事件发生率（恶心、腹泻和呕吐），且多为轻中度，导致治疗中断的事件较少（<5%）。
- 一项关于替尔泊肽与司美格鲁肽头对头比较的研究发现，两组的胃肠道不良事件发生率相似 。
- 替尔泊肽在心血管事件方面表现出安全性，荟萃分析发现MACE-4（非致死性心肌梗死、非致死性卒中、心血管死亡和因心绞痛住院）事件在最长达2年的随访期内呈减少趋势，且所有分析的心血管事件（MACE-4或其组成部分）的风险比均未超过1.0 。
3.2 GLP-1受体激动剂的安全性
- GLP-1RAs通常会引起胃肠道不良事件，如恶心、呕吐、腹泻和便秘，这些事件通常是轻度至中度且短暂的 。
- 司美格鲁肽2.4毫克组的胃肠道不良事件发生率为63.5%，司美格鲁肽1.0毫克组为57.5%，安慰剂组为34.3% 。
- 高剂量GLP-1RAs的使用尤其需要关注胃肠道不良事件的安全问题 。
- 司美格鲁肽还可能增加胆道疾病（胆石症）的风险 。
- 鉴于司美格鲁肽强效的降血糖作用，对于存在糖尿病视网膜病变恶化风险的患者，尤其是在同时使用胰岛素的情况下，应密切监测 。
3.3 安全性总结
- 替尔泊肽和GLP-1受体激动剂都以胃肠道不良事件为主要副作用，这些事件通常是轻度到中度，并主要发生在剂量递增期间 。
- 替尔泊肽和司美格鲁肽在胃肠道不良事件的发生率上表现相似 。
- 严重的低血糖事件在两类药物中都相对罕见，但在替尔泊肽高剂量组的发生率略高 。
- 目前未发现替尔泊肽或司美格鲁肽有新的安全信号，其整体风险/效益比对2型糖尿病患者有利 。然而，对于胰腺癌和甲状腺癌的明确结论，由于这些疾病的低发生率，目前尚无法得出 。
4. 作用机制差异
替尔泊肽和GLP-1受体激动剂在作用机制上的差异，是导致其减重效果不同的关键因素。
- GLP-1受体激动剂（如司美格鲁肽）是选择性GLP-1受体激动剂 。GLP-1是一种肠促胰素分子，通过激活GLP-1受体，具有降低体重、保护胰岛β细胞、促进胰岛β细胞增殖、抑制食欲和延缓胃排空等多种生物学效应 。它还能在血糖过高时抑制胰高血糖素的产生 。
- 替尔泊肽是首个被批准用于治疗2型糖尿病的双重GIP/GLP-1受体激动剂 。它是一种酰化肽，旨在激活GIP和GLP-1受体，这两种受体都是胰岛素分泌的关键介质，并在调节食物摄入的大脑区域表达 。
- GIP和GLP-1在调节食物摄入、刺激胰岛素分泌方面都有作用 。但它们对胰高血糖素产生的影响不同，GIP在低血糖时具有促胰高血糖素作用，而GLP-1在高血糖时具有抑制胰高血糖素作用 。此外，GIP直接刺激脂肪生成，而GLP-1间接促进脂肪分解，共同维持健康的脂肪细胞，减少异位脂肪分布 。
- 替尔泊肽通过双重激活GIP和GLP-1受体，能够更大程度地改善胰岛素敏感性和胰岛素分泌反应，这与较低的餐后胰岛素和胰高血糖素浓度相关 。尽管两种药物在抑制食欲方面作用相似，但替尔泊肽导致了更大的体重减轻 。这种双重作用机制被认为是替尔泊肽在减重和血糖控制方面表现出更高疗效的原因 。
5. 结论
综合来看，替尔泊肽在减重效果上通常优于单一GLP-1受体激动剂，这主要得益于其双重GIP/GLP-1受体激动剂的作用机制。两者在安全性方面相似，主要的不良事件是轻度至中度的胃肠道反应。然而，两者都面临停药后体重显著反弹的问题，因此需要考虑将其作为长期慢性治疗。在临床应用中，医生应根据患者的具体情况（包括是否有2型糖尿病、基线体重、对治疗的耐受性等）权衡替尔泊肽和GLP-1受体激动剂的利弊，并充分告知患者停药反弹的风险。
References
1Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.PubMed
Juan P Frías, Melanie J Davies, Julio Rosenstock, et al.
BACKGROUND: Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown. METHODS: In an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks. RESULTS: The estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide. CONCLUSIONS: In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 ClinicalTrials.gov number, NCT03987919.).
2Discontinuing glucagon-like peptide-1 receptor agonists and body habitus: A systematic review and meta-analysis.PubMed
Sara Berg, Hannah Stickle, Suzanne J Rose, et al.
Research on Glucagon-like peptide 1 receptor agonist (GLP-1RA) has mainly focused on the efficacy of weight loss and not the long-term efficacy of weight loss maintenance. This systematic review and meta-analysis aims to evaluate the sustainability of weight loss of patients taking GLP-1RAs following the discontinuation of the drug. EBSCOhost was used to simultaneously search Academic Search Premier, CINHAL Ultimate, Cochrane Central Register of Controlled Trials, MEDLINE with full text, Cochrane Database of Systematic Reviews, and separate PubMed search was systematically investigated using a predetermined search strategy from inception to February 1st, 2024. The authors extracted data regarding body weight change from baseline on treatment and off treatment, change in waist circumference from baseline on and off treatment, and change in BMI from baseline on and off treatment. Meta-analysis was conducted using RevMan (version 5.4) to calculate pooled mean differences using a Der Simonian-Laird Random Effects model. ResultsThe initial search yielded 497 relevant articles and, after screening, retained 8 randomized controlled trials comprised of 2372 participants, all with a BMI ≥ 27 kg/m. After discontinuing GLP-1RA therapy, weight regain was proportional to the original weight loss. Participants who took liraglutide regained 2.20 kg (95% CI 1.69 to 2.70, P < 0.00001), and participants taking semaglutide/tirzepatide regained 9.69 kg (95% CI 5.78 to 13.60, P < 0.00001). This systematic review and meta-analysis show that significant weight is regained after discontinuing GLP-1RA treatment, which should be discussed when stopping therapy. PRACTITIONER POINTS: Question: Does discontinuation of Glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment lead to significant weight gain? Findings: In this systematic review and meta-analysis, discontinuing GLP-1RA treatment led to a pooled overall mean weight regain of 2.20 kg in participants taking liraglutide and 9.69 kg in those patients prescribed semaglutide/tirzepatide. The proportion of weight regained was proportional to the amount originally lost. Meaning: Discontinuation of GLP-1RA treatment leads to weight regain, regardless of lifestyle interventions, and should therefore be considered a chronic therapy to prevent weight regain and associated undesirable outcomes related to obesity.
3Weight Loss Efficacy of Tirzepatide Compared to Placebo or GLP-1 Receptor Agonists in Adults With Obesity or Overweight: A Meta-Analysis of Randomized Controlled Trials With ≥ 20 Weeks Treatment Duration.PubMed
Alhussain Khawaji, Abdulaziz A Jaly, Hanan A Bakri, et al.
Tirzepatide, a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like Peptide 1 (GLP-1) analogue, is a novel medication with comparable pharmacological characteristics and has demonstrated promising weight reduction outcomes in its antidiabetic trials following the approval of liraglutide and semaglutide for long-term weight control. Nonetheless, this efficacy has not been fully explored, so this meta-analysis was aimed to measure the weight loss efficacy and safety of tirzepatide in adults with overweight or obesity. We searched the PubMed, Cochrane, and Embase databases for RCTs of once-weekly tirzepatide vs. placebo or GLP-1 receptor agonists. We included studies involving adult participants who were overweight or obese despite T2DM or OHA use, with a trial duration of at least 20 weeks. The primary outcomes accounted for the mean difference in weight from baseline in the three doses of tirzepatide compared to placebo and GLP-1 receptor agonists, separately. The secondary outcomes included safety profiles and achievement of categorical weight loss of 5%, 10% and 15%. We performed the statistical analysis on RevMan 5.4, GRADE assessment using GRADEpro GDT and the quality of the included studies assessed using the Cochrane risk-of-bias (Version 2) tool. We identified six RCTs in which the data of 6266 subjects were analysed. Once-weekly doses (5, 10 and 15 mg) of tirzepatide were more effective than placebo and GLP-1 RAs. Also, the proportion of patients achieving categorical weight loss goals was higher in the tirzepatide groups than in others. GRADE assessment also indicated high-certainty evidence for ≥ 15% weight loss with tirzepatide and moderate-to-low certainty for lower thresholds. Gastrointestinal side effects appeared similar between the three doses of tirzepatide and GLP-1 RAs, but they were significantly higher than placebo might impact tolerability for certain patients. A dose-dependent tirzepatide was superior to placebo and GLP-1 RAs in weight reduction. However, the lean mass reduction and tolerability require further investigation. ClinicalTrials.gov identifier: NCT04255433.
4Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists.PubMed
Qiyuan Keith Liu
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.
5Comparative 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.
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.
6Weight Regain After Liraglutide, Semaglutide or Tirzepatide Interruption: A Narrative Review of Randomized Studies.PubMed
Massimo Quarenghi, Silvia Capelli, Giulia Galligani, et al.
The primary objective of this review is to analyze the effects on body weight of discontinuing therapy with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or tirzepatide in patients treated for obesity. In recent months, there has been a considerable increase in the utilization of GLP-1 RAs and GIP/GLP-1 RAs. However, the paucity of available data regarding their medium- to long-term safety remains a salient concern. Of particular significance is the observation of the weight curve following their suspension, a subject that has received scant attention to date. : For this, a bibliographic search was carried out in three electronic databases: PubMed, Cochrane Library and Google Scholar. The following filters were applied: A total of 427 references were identified, 178 articles were read in full, and 13 articles were included in the analysis. : The analysis showed a rapid regain of weight after cessation of therapy, regardless of the duration of the treatment with GLP-1 RA or GIP/GLP-1 RA. This rebound is likely to substantially mitigate the metabolic benefits attained through weight loss. Given the efficacy of these drugs, it is essential for future research to focus on elucidating the optimal duration of these treatments or identifying techniques or schemes that involve a reduction in dosages to prevent weight regain.
7Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial.PubMed
Melanie Davies, Louise Færch, Ole K Jeppesen, et al.
BACKGROUND: This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes. METHODS: This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m and glycated haemoglobin 7-10% (53-86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants. FINDINGS: From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was -9·6% (SE 0·4) with semaglutide 2·4 mg vs -3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was -6·2 percentage points (95% CI -7·3 to -5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo. INTERPRETATION: In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo. FUNDING: Novo Nordisk.
8GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects.PubMed
Xin Zhao, Minghe Wang, Zhitong Wen, et al.
Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.
9Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity.PubMed
Patricia J Rodriguez, Brianna M Goodwin Cartwright, Samuel Gratzl, et al.
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.
10Safety of Semaglutide.PubMed
Mark M Smits, Daniël H Van Raalte
The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.
11Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials.PubMed
Mihaela-Simona Popoviciu, Lorena Păduraru, Galal Yahya, et al.
Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies. This review summarizes numerous studies conducted on the main drugs in the GLP-1 agonists class, outlining the maximum achievable weight loss. Our aim is to emphasize the active role and main outcomes of GLP-1 agonists in promoting weight loss, as well as in improving hyperglycemia, insulin sensitivity, blood pressure, cardio-metabolic, and renal protection. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies.
12Tirzepatide, 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
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.
13Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials.PubMed
Zeyu Xie, Guimei Zheng, Zhuoru Liang, et al.
PURPOSE: This study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis. METHODS: Relevant randomized controlled trials (RCTs) with an intervention duration of at least 16 weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5 mg; retatrutide, 12 or 8 mg; tirzepatide, 15 or 10 mg; liraglutide, 3.0 mg; semaglutide, 2.4 mg; orforglipron, 45 or 36 mg; and beinaglutide, 0.2 mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software. RESULTS: Twenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12 mg (-22.10 % in body weight and - 17.00 cm in waist circumference), retatrutide 8 mg (-20.70 % and - 15.90 cm), and tirzepatide 15 mg (-16.53 % and - 13.23 cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (˂54 mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable. CONCLUSION: Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists.
14Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.PubMed
W Timothy Garvey, Juan P Frias, Ania M Jastreboff, et al.
BACKGROUND: Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes. METHODS: This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m or higher and glycated haemoglobin (HbA) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003. FINDINGS: Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years [SD 10·6], 476 [51%] were female, 710 [76%] were White, and 561 [60%] were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m (SD 6·6), and HbA 8·02% (SD 0·89; 64·1 mmol/mol [SD 9·7]). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was -12·8% (SE 0·6) and -14·7% (0·5), respectively, and -3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of -9·6% percentage points (95% CI -11·1 to -8·1) with tirzepatide 10 mg and -11·6% percentage points (-13·0 to -10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79-83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator. INTERPRETATION: In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management. FUNDING: Eli Lilly and Company.
15GLP-1-based medications: Mechanisms involved in obesity treatment.PubMed
Javier Salvador
Thanks to biochemical engineering, the glucagon-like peptide-1 (GLP-1) molecule has emerged as an essential element in the development of diverse agonists and multiagonists, based in the GLP-1 structure for obesity treatment. These new antiobesity medications can reach up to 24% weight loss, which makes possible an effective management of obesity and its complications. GLP-1 agonists affect diverse obesity etiopathogenic processes such as abnormal food intake regulation, adipocyte dysfunction, insulin resistance, adipokine production, inflammation, endothelial dysfunction, lipid metabolism, and oxidative stress. All these factors are significantly involved in the pathophysiology of multiple obesity-related complications, including diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, heart failure, and atherosclerosis, among others. Potentiation and complementation of GLP-1 effects by co-stimulation of GIP (glucose-dependent insulinotropic peptide), glucagon, or amylin and other receptors contribute to additional benefits, opening new horizons in the therapeutic individualization for persons living with obesity.
16Tirzepatide Once Weekly for the Treatment of Obesity.PubMed
Ania M Jastreboff, Louis J Aronne, Nadia N Ahmad, et al.
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.).
17Effect of tirzepatide on glycaemic control and weight loss compared with other glucagon-like peptide-1 receptor agonists in Japanese patients with type 2 diabetes mellitus.PubMed
Shunichiro Tsukamoto, Shohei Tanaka, Takayuki Yamada, et al.
AIM: To compare the therapeutic effects of glucose-dependent insulinotropic polypeptide (GIP)/ glucagon-like peptide-1 receptor agonists (GLP-1RAs) or GLP-1RAs in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library up to July 2023. Randomized controlled trials (RCTs) that compared GLP-1RAs or GIP/GLP-1RAs in Japanese patients with T2D were selected. A network meta-analysis was conducted to indirectly compare the treatments, focusing on efficacy in reducing glycated haemoglobin (HbA1c) levels and body weight (BW). RESULTS: A total of 18 RCTs were included in this analysis. Tirzepatide 15 mg showed the most significant reduction in HbA1c levels and BW compared with subcutaneous semaglutide 1.0 mg and oral semaglutide 14 mg (HbA1c: mean difference [95% confidence interval] -0.52 [-0.96; -0.08] and - 1.23 [-1.64; -0.81]; BW: -5.07 [-8.28; -1.86] and -6.84 [-8.97; -4.71], respectively). Subcutaneous semaglutide showed a superior reduction in HbA1c compared with oral semaglutide. Both subcutaneous and oral semaglutide were more effective than conventional GLP-1RAs, such as dulaglutide, liraglutide and lixisenatide. CONCLUSIONS: Among Japanese patients with T2D, tirzepatide showed the greatest effectiveness in reducing HbA1c levels and inducing weight loss. The study provides evidence to guide GLP-1RA treatment strategies in Japanese patients with T2D.
18Comparative 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.
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.
19Tirzepatide for Obesity Treatment and Diabetes Prevention.PubMed
Ania M Jastreboff, Carel W le Roux, Adam Stefanski, et al.
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.).
20Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.PubMed
Ania M Jastreboff, Lee M Kaplan, Juan P Frías, et al.
BACKGROUND: Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known. METHODS: We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed. RESULTS: We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter. CONCLUSIONS: In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04881760.).