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替尔泊肽和司美格鲁肽在肥胖或2型糖尿病患者中的减重疗效、HbA1c改善、安全性、停药后体重反弹和适用人群有什么差异？请按RCT、真实世界研究和系统综述整理关键证据，并说明药企市场推广表达的合规边界。
替尔泊肽（Tirzepatide）和司美格鲁肽（Semaglutide）都是在肥胖或2型糖尿病患者管理中表现出显著疗效的药物，它们通过不同的作用机制，在减重、糖化血红蛋白（HbA1c）改善和安全性方面呈现出一些差异。以下将根据随机对照试验（RCT）、真实世界研究和系统综述中的关键证据，详细阐述这两种药物的差异，并探讨药企市场推广的合规边界。
替尔泊肽和司美格鲁肽在肥胖或2型糖尿病患者中的差异
1. 减重疗效
随机对照试验 (RCT) 证据：
-
替尔泊肽：
- 在SURMOUNT-1试验中，针对肥胖或超重且无糖尿病的成人，每周一次皮下注射替尔泊肽在72周内实现了显著且持续的体重减轻。5 mg、10 mg和15 mg剂量的替尔泊肽分别使平均体重减轻了-15.0%、-19.5%和-20.9%，而安慰剂组仅为-3.1% 。
- SURMOUNT-4试验进一步评估了替尔泊肽维持减重效果的能力。在36周的开放标签导入期后，参与者平均体重减轻了20.9%。在随后的52周双盲、安慰剂对照期，继续接受替尔泊肽治疗的患者体重平均变化为-5.5%，而转用安慰剂的患者体重增加了14.0%，两组差异达到-19.4% 。这表明持续治疗能维持并增强初始减重效果，而停药则会导致体重显著反弹 。
- 一项为期176周的SURMOUNT-1扩展分析显示，在肥胖和糖尿病前期患者中，替尔泊肽治疗三年后，5 mg、10 mg和15 mg剂量组的平均体重变化分别为-12.3%、-18.7%和-19.7%，而安慰剂组为-1.3% 。
- 在2型糖尿病患者中，SURPASS-2试验显示，替尔泊肽在减重方面优于司美格鲁肽1 mg。5 mg、10 mg和15 mg替尔泊肽组的平均减重差异分别为-1.9 kg、-3.6 kg和-5.5 kg，均显著优于司美格鲁肽组 。
- 一项系统综述和网络荟萃分析指出，替尔泊肽对2型糖尿病患者的减重效果更为显著，其中替尔泊肽15 mg组的减重范围为9.57 kg，而司美格鲁肽2.0 mg组的减重范围为4.97 kg。所有剂量的替尔泊肽均比司美格鲁肽2.0 mg、1.0 mg和0.5 mg表现出更高的减重疗效 。另一项网络荟萃分析也指出，替尔泊肽（-8.47 kg）是减重效果最好的GLP-1RA药物之一，仅次于CagriSema（一种司美格鲁肽与卡格利肽的组合，-14.03 kg）。
-
司美格鲁肽：
- STEP 1试验中，每周一次皮下注射2.4 mg司美格鲁肽辅以生活方式干预，在68周内使超重或肥胖成人平均体重减轻了17.3%，而安慰剂组为2.0% 。
- STEP 4试验进一步评估了司美格鲁肽维持减重效果的潜力。在20周的导入期后，患者平均体重减轻了10.6%。在随后的48周内，继续使用司美格鲁肽的患者体重平均变化为-7.9%，而转用安慰剂的患者体重增加了6.9%，两组差异为-14.8个百分点 。这表明持续使用司美格鲁肽能维持减重效果，而停药会导致体重反弹 。
真实世界研究证据：
- 一项在孟加拉国进行的回顾性观察研究显示，替尔泊肽和司美格鲁肽均能显著减重，但替尔泊肽的减重幅度更大（8.53±4.10 kg vs 6.85±3.38 kg；p=0.033）。当结合生活方式干预时，替尔泊肽的减重效果尤为显著 。
- 一项针对袖状胃切除术后体重反弹患者的回顾性队列研究发现，司美格鲁肽和替尔泊肽在6个月内分别导致平均体重减轻10.3%和15.5%。替尔泊肽组的减重效果在6个月时显著优于司美格鲁肽组（p < 0.02）。
- 一项评估非糖尿病肥胖患者心血管结局的真实世界研究显示，替尔泊肽与司美格鲁肽相比，平均减重更多（-9.8 kg vs -8.0 kg；p < 0.001）。
系统综述证据：
- 一项网络荟萃分析指出，替尔泊肽在降低HbA1c和体重的效果方面，优于每周一次1.0 mg的司美格鲁肽，以及滴定基础胰岛素 。
- 另一项系统综述和网络荟萃分析明确指出，替尔泊肽在2型糖尿病患者的HbA1c和体重减轻方面比司美格鲁肽具有更显著的效果 。
- 对于日本2型糖尿病患者，替尔泊肽15 mg在降低HbA1c水平和体重方面显示出最显著的效果，优于皮下注射司美格鲁肽1.0 mg和口服司美格鲁肽14 mg 。
总结减重疗效： 综合来看，替尔泊肽在减重方面通常表现出优于司美格鲁肽的疗效，尤其是在较高剂量下。这在无糖尿病的肥胖或超重人群以及2型糖尿病患者中均有体现。替尔泊肽作为双重GIP/GLP-1受体激动剂，其独特的双重作用机制可能解释了其在减重方面的优势 。
2. HbA1c 改善
随机对照试验 (RCT) 证据：
-
替尔泊肽：
- 在SURPASS-2试验中，针对2型糖尿病患者，替尔泊肽所有剂量（5 mg、10 mg、15 mg）在降低HbA1c方面均非劣效且优于司美格鲁肽1 mg。与基线相比，5 mg、10 mg和15 mg替尔泊肽组的HbA1c平均变化分别为-2.01、-2.24和-2.30个百分点，而司美格鲁肽组为-1.86个百分点 。
- 一项系统综述和网络荟萃分析显示，替尔泊肽15 mg是降低HbA1c最有效的治疗方法（平均差异-21.61 mmol/mol [-1.96%]），其次是替尔泊肽10 mg（-20.19 mmol/mol [-1.84%]），优于司美格鲁肽2.0 mg（-17.74 mmol/mol [-1.59%]）。
- 另一项网络荟萃分析也得出结论，替尔泊肽是血糖控制最有效的GLP-1RA药物，能最大程度地降低HbA1c浓度（平均差异-2.10%）和空腹血糖浓度（-3.12 mmol/L）。
- SURMOUNT-1试验的扩展分析显示，在肥胖和糖尿病前期患者中，替尔泊肽显著降低了进展为2型糖尿病的风险，替尔泊肽组的诊断率为1.3%，而安慰剂组为13.3% 。
-
司美格鲁肽：
- SURPASS-2试验中，司美格鲁肽1 mg在40周内使HbA1c平均降低了-1.86个百分点 。
- 系统综述和网络荟萃分析显示，司美格鲁肽2.0 mg、1.0 mg和0.5 mg分别使HbA1c平均降低-1.59%、-1.39%和-1.09% 。
真实世界研究证据： 相关真实世界研究主要关注减重，未直接提供HbA1c改善的具体数据。
系统综述证据：
- 一项系统综述指出，替尔泊肽在HbA1c和体重减轻方面具有比司美格鲁肽更显著的效果 。
- 对于日本患者，替尔泊肽15 mg在降低HbA1c水平方面表现出最显著的效果，优于皮下和口服司美格鲁肽 。
总结HbA1c改善： 与减重疗效类似，替尔泊肽在改善HbA1c水平方面也显示出优于司美格鲁肽的疗效 。其双重作用机制可能使其在血糖控制方面更为强大。
3. 安全性
随机对照试验 (RCT) 证据：
-
替尔泊肽：
- 在SURPASS-2、SURMOUNT-1和SURMOUNT-4试验中，替尔泊肽最常见的不良事件是胃肠道事件，主要为轻度至中度，并主要发生在剂量递增期间。这些事件包括恶心（17-22%）、腹泻（13-16%）和呕吐（6-10%）。
- 低血糖事件在替尔泊肽组中报告发生率较低（0.6% [5mg], 0.2% [10mg], 1.7% [15mg]），与司美格鲁肽组（0.4%）相似 。
- 严重不良事件在替尔泊肽组中报告率为5-7%，而司美格鲁肽组为3% 。
- SURMOUNT-1试验中，不良事件导致的治疗中断率在替尔泊肽5mg、10mg、15mg组分别为4.3%、7.1%、6.2%，安慰剂组为2.6% 。
- 一项关于替尔泊肽的综述指出，心血管事件（MACE-4）在整个临床试验项目中倾向于减少，且心血管安全性符合常规定义（MACE的置信区间上限小于1.3）。
- 替尔泊肽三年治疗期内，除了COVID-19，最常见的不良事件仍是胃肠道事件，大部分为轻度至中度，主要发生在试验前20周的剂量递增期，未发现新的安全信号 。
-
司美格鲁肽：
- 在SURPASS-2试验中，司美格鲁肽组常见的胃肠道不良事件包括恶心（18%）、腹泻（12%）和呕吐（8%）。
- 低血糖事件报告率为0.4% 。
- 严重不良事件报告率为3% 。
- STEP 4试验中，继续使用司美格鲁肽的患者中有49.1%报告胃肠道事件，而安慰剂组为26.1% 。
真实世界研究证据：
- 孟加拉国的一项真实世界研究显示，胃肠道不良事件是司美格鲁肽和替尔泊肽最常见的，替尔泊肽组发生频率更高，但严重事件罕见 。
- 在袖状胃切除术后体重反弹患者的研究中，两种治疗均未报告严重不良事件 。
- 一项针对非糖尿病肥胖患者心血管结局的真实世界研究显示，替尔泊肽和司美格鲁肽的不良事件发生率相当，没有发现新的安全信号 。
- 一项全球药物警戒研究发现，司美格鲁肽与缺血性视神经病变（ION）和糖尿病视网膜病变（DR）等眼部不良事件的风险显著相关，而替尔泊肽仅在FAERS数据库中与DR显著相关 。这提示司美格鲁肽可能存在更高的眼部不良事件风险，需要全球药物警戒和上市后监测 。
- 一项药物警戒研究发现，司美格鲁肽与抑郁症的报告失衡信号（SDR）具有统计学意义，而利拉鲁肽和替尔泊肽则没有。这表明司美格鲁肽可能与抑郁症存在特定药物关联，而非GLP-1RA药物类效应，提示需要进行药物特异性安全监测 。
- 一项药理警戒研究分析了FDA不良事件报告系统（FAERS）数据，指出司美格鲁肽与“药物滥用”、“药物戒断综合征”、“未经处方使用处方药”和“故意产品使用问题”等不良事件的报告失衡率（PRR）显著高于其他GLP-1受体激动剂。这可能是首个记录司美格鲁肽与其他GLP-1类似物相比具有滥用/误用潜力的研究，但需要进一步的实证调查来确认 。
系统综述证据：
- 系统综述普遍指出，GLP-1RA，包括替尔泊肽和司美格鲁肽，最常见的不良事件是胃肠道症状，且在高剂量下更常见 。
- 一项网络荟萃分析显示，替尔泊肽和司美格鲁肽与安慰剂相比，胃肠道不良事件发生率增加，但两种药物均未增加严重不良事件或严重低血糖的风险 。
- 一项关于GLP-1RA管理胃肠道症状的膳食建议研究强调，这些药物会减缓胃排空，导致胃肠道症状，因此需要饮食调整以改善患者依从性 。
总结安全性： 两种药物的主要不良事件均是轻度至中度的胃肠道反应，且在高剂量递增期更为常见 。替尔泊肽和司美格鲁肽的严重低血糖和严重不良事件发生率较低且相似 。然而，司美格鲁肽在某些特定不良事件方面可能存在更高的风险信号，例如眼部不良事件（缺血性视神经病变、糖尿病视网膜病变）、抑郁症 和潜在的滥用/误用风险 。替尔泊肽在心血管安全性方面表现良好，并可能对降低心血管事件风险有益 。
4. 停药后体重反弹
随机对照试验 (RCT) 证据：
-
替尔泊肽：
- SURMOUNT-4试验明确指出，停用替尔泊肽会导致已减轻体重的显著反弹，而持续治疗则能维持并增强初始减重效果 。在36周导入期后平均减重20.9%的患者中，继续治疗组体重仅进一步下降5.5%，而转用安慰剂组体重增加了14.0% 。
- 一项SURMOUNT-1的扩展研究也显示，在17周的停药期后，替尔泊肽组的2型糖尿病诊断率从1.3%上升到2.4%，这间接提示了代谢益处可能随停药而减弱 。
-
司美格鲁肽：
- STEP 1试验的扩展分析显示，在停用每周一次皮下注射2.4 mg司美格鲁肽和生活方式干预一年后，参与者恢复了此前体重减轻的三分之二，心血管代谢指标也向基线水平逆转 。这证实了肥胖的慢性性质，并表明需要持续治疗来维持体重和健康改善 。
- STEP 4试验也表明，从司美格鲁肽切换到安慰剂会导致体重反弹，而继续治疗则能维持减重效果 。
系统综述证据：
- 一项对GLP-1RA停药后体重反弹的系统综述和荟萃分析发现，停用GLP-1RA治疗后，体重反弹与初始体重减轻的量成正比 。服用利拉鲁肽的患者平均反弹2.20 kg，而服用司美格鲁肽/替尔泊肽的患者平均反弹9.69 kg 。
- 该综述强调，GLP-1RA停药后体重显著反弹，无论是否进行生活方式干预，因此应将其视为一种慢性治疗，以防止体重反弹及与肥胖相关的不良后果 。
- 另一项综述分析了停用GLP-1RA或替尔泊肽对体重的影响，结果显示，无论治疗持续时间长短，停药后体重均迅速反弹。这种反弹可能会显著抵消通过减重获得的代谢益处 。
总结停药后体重反弹： 替尔泊肽和司美格鲁肽停药后均会导致显著的体重反弹 。这强调了肥胖是一种需要长期管理的慢性疾病，并且为了维持减重效果和相关的代谢益处，可能需要持续的药物治疗 。
5. 适用人群
随机对照试验 (RCT) 证据：
-
替尔泊肽：
- 已获批用于2型糖尿病的治疗 。
- 已在肥胖或超重且至少有一种体重相关并发症（不包括糖尿病）的成人中进行了广泛研究并显示出疗效 。
- 对肥胖合并糖尿病前期的患者，替尔泊肽能显著降低进展为2型糖尿病的风险 。
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司美格鲁肽：
- 已获批用于2型糖尿病的治疗 。
- 已在超重或肥胖且至少有一种体重相关合并症（不包括糖尿病）的成人中显示出减重疗效 。
真实世界研究证据：
- 研究表明，替尔泊肽和司美格鲁肽均可用于袖状胃切除术后体重反弹的患者 。
- 两种药物在非糖尿病肥胖个体中的心血管结局也得到了评估 。
- 孟加拉国的真实世界研究也证实了两种药物对肥胖成人的减重效果 。
系统综述证据：
- GLP-1RA类药物（包括司美格鲁肽和替尔泊肽）总体上被认为是治疗成人2型糖尿病的有效方法 。
- 替尔泊肽作为双重GIP/GLP-1受体激动剂，是第一个获批用于2型糖尿病的药物，并在肥胖管理中显示出优异的效果 。
总结适用人群： 替尔泊肽和司美格鲁肽都适用于2型糖尿病患者，用于改善血糖控制和体重管理 。同时，两者也广泛应用于肥胖或超重且伴有相关并发症（不包括糖尿病）的成人，以实现减重目的 。值得注意的是，替尔泊肽已被证明在肥胖合并糖尿病前期的患者中有效，可以显著延缓或预防2型糖尿病的发生 。在某些特定情况下，如代谢和减重手术后体重反弹，这两种药物也可能作为治疗选择 。
药企市场推广表达的合规边界
鉴于替尔泊肽和司美格鲁肽在疗效和安全性方面的差异，以及停药后体重反弹的普遍现象，药企在市场推广时需要严格遵守合规边界，确保信息的准确性、完整性和非误导性。
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准确表述疗效差异：
- 减重疗效：如果替尔泊肽在减重方面表现出统计学上的优越性（如多项RCT和真实世界研究所示），药企可以在推广中明确指出这一优势，但必须基于已批准的适应症和临床数据 。例如，可以表述“替尔泊肽在多项研究中显示出比司美格鲁肽更显著的体重减轻效果”。
- HbA1c改善：同样，替尔泊肽在HbA1c改善方面的优势也可以被提及，但需确保措辞准确，避免过度宣传，并与临床数据保持一致 。
- 避免绝对化或夸大：例如，不应声称某种药物是“最好的”或“彻底治愈”某种疾病，而应使用“更有效”、“显著改善”等客观词汇。
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全面披露安全性信息：
- 常见不良反应：胃肠道不良事件是两种药物的共同特征，药企必须如实告知，包括其性质（通常轻度至中度）和发生时机（主要在剂量递增期）。
- 特定风险警示：对于司美格鲁肽可能存在的眼部不良事件 、抑郁症信号 和潜在滥用/误用风险 ，药企在推广时必须谨慎，并在产品说明书和专业宣传材料中充分披露，提醒医生和患者关注。即使这些是药物警戒信号，而非确定的因果关系，也应进行风险提示。
- 心血管安全性：可以提及两款药物在心血管安全性方面的研究结果，如替尔泊肽在MACE-4事件中未发现风险增加甚至有潜在益处 。
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强调持续治疗的重要性与停药后反弹风险：
- 慢性疾病管理：药企应明确指出肥胖和2型糖尿病是慢性疾病，需要长期管理 。
- 停药反弹风险：必须强调停用这两种药物后体重会显著反弹，并且代谢益处也会逆转 。这对于患者的长期依从性和治疗预期管理至关重要。推广时应避免制造“短期用药即可”的印象。例如，可以表述为“为维持体重减轻和相关健康益处，建议长期持续治疗。停药可能导致体重反弹。”
-
明确适应症和适用人群：
- 药企的推广内容必须严格限定在药品监管机构批准的适应症范围内。例如，如果替尔泊肽和司美格鲁肽均被批准用于2型糖尿病和肥胖/超重管理，则应明确说明。
- 不能在未获批的适应症上进行宣传。
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避免虚假宣传和误导性对比：
- 引用可靠证据：所有宣传内容必须有充分的临床证据支持，且应注明出处，如RCT、真实世界研究或系统综述 。
- 平衡利弊：推广时应平衡地呈现药物的益处和风险，避免片面强调益处而忽略风险。
- 不得暗示非处方药性质：这些药物均为处方药，需要医生处方和指导使用，不能暗示可以随意购买或使用。
-
对公众和医疗专业人士区别对待：
- 对公众：推广内容应使用通俗易懂的语言，避免专业术语，并侧重于疾病认知和治疗选择的教育，同时突出风险提示。
- 对医疗专业人士：可以提供更详细的临床数据、药理机制和不良事件发生率等专业信息，但仍需确保信息的准确性和完整性。
通过严格遵守这些合规边界，药企可以负责任地推广替尔泊肽和司美格鲁肽，确保医生和患者获得准确、全面的信息，从而做出明智的治疗决策。
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.).
2Continued 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.
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.
3Semaglutide and Tirzepatide for the Management of Weight Recurrence After Sleeve Gastrectomy: A Retrospective Cohort Study.PubMed
Mohammad Jamal, Mohsen Alhashemi, Carol Dsouza, et al.
BACKGROUND: Metabolic and bariatric surgery (MBS) is the most effective treatment for obesity and improvement of obesity-associated comorbidities. However, a proportion of these patients may suffer from weight recurrence and recurrence of obesity-associated comorbidities. METHOD: A retrospective cohort study of patients who underwent SG between January 2008 and August 2022 and sought treatment for weight recurrence with semaglutide or tirzepetide from January 2022 onwards. RESULT: A total of 115 patients were included, of which 70 had SG and treated for weight recurrence with semaglutide and 45 had SG and treated with tirzepatide. The mean age of patients was 38.8 (10.4) and 80.9% of patients were female. The mean pre-treatment weight and BMI was 94.0 (23.8) kg and 35.1 (6.0) kg/m. Following treatment with semaglutide and tirzepatide, the mean post-treatment weight at 6 months was 81.0 (19.0) kg from 90.1 (19.6) kg and 87.6 (28.3) kg from 100.2 (28.5) kg respectively, corresponding to a clinically significant mean weight loss from baseline to 6 months of 10.3 (5.9)% (p < 0.05) and 15.5 (6.3)% (p < 0.05). Weight loss in tirzepatide patients was significantly greater than the semaglutide patients at 6 months (p < 0.02). There were no reported severe adverse events to the treatment. CONCLUSION: Short-term outcomes show that semaglutide and tirzepatide can be an effective treatment for managing weight recurrence after SG. Studies with longer follow-up are needed to determine the durability, as weight regain after discontinuation of the medication is highly likely, and the high cost of these medications can limit their use.
4Efficacy and Safety of Tirzepatide and Semaglutide for Obesity Management: A Real-World Comparison.PubMed
Kishore Kumar Shil, Ananda D Hira, Sudipta Bakchi, et al.
Background Incretin-based therapies have emerged as effective strategies for obesity and type 2 diabetes mellitus (T2DM) management. Semaglutide and tirzepatide are among the most promising agents. Real-world data in Bangladesh on their efficacy, lifestyle interactions, and safety profiles remain limited. The objective of the study is to evaluate the associations of tirzepatide and semaglutide with weight reduction and safety in adults with obesity, and to assess the influence of lifestyle factors on treatment outcomes. Methods This retrospective observational study analyzed the electronic medical records of 100 adults with obesity from three tertiary centers in Bangladesh (58 patients treated with tirzepatide, 42 patients treated with semaglutide) over one year. Participants had completed at least three months of therapy. Demographics, clinical parameters, comorbidities, lifestyle adherence, weight change, and adverse events were collected using a structured questionnaire. Results A total of 100 participants (58 tirzepatide, 42 semaglutide; median age 27 years) were included, with 87 (87%) being female. Baseline BMI was higher in the tirzepatide group (36.6±4.77 vs. 32.3±3.55 kg/m²; p<0.001). Both drugs produced significant weight loss, with tirzepatide achieving greater reductions than semaglutide (8.53±4.10 vs. 6.85±3.38 kg; p=0.033). Clinically meaningful weight loss (≥5%) was observed in 89 (89%) of participants, and ≥10% loss in 33 (33%), with higher proportions in the tirzepatide group. Lifestyle interventions further enhanced weight reduction, most notably with tirzepatide. Gastrointestinal adverse events were the most common, occurring more frequently with tirzepatide, while serious events were rare. Overall, tirzepatide was associated with greater weight reduction, especially when combined with lifestyle modification. Conclusion Tirzepatide and semaglutide were both associated with weight reduction in obesity, with greater reductions observed with tirzepatide, particularly when combined with lifestyle interventions, underscoring the importance of combining behavioral and pharmacological strategies.
5Burden of 375 diseases and injuries, risk-attributable burden of 88 risk factors, and healthy life expectancy in 204 countries and territories, including 660 subnational locations, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023.PubMed
BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.
6Comparative 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.
7Tirzepatide 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.).
8Weight 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.
9Is There a Risk for Semaglutide Misuse? Focus on the Food and Drug Administration's FDA Adverse Events Reporting System (FAERS) Pharmacovigilance Dataset.PubMed
Stefania Chiappini, Rachel Vickers-Smith, Daniel Harris, et al.
Recent media reports commented about a possible issue of the misuse of antidiabetics related to molecules promoted as a weight-loss treatment in non-obese people. We evaluated here available pharmacovigilance misuse/abuse signals related to , a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (, , , , , and ) and the - combination. To acheieve that aim, we analyzed the Food and Drug Administration's FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AERs) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AERs involving the selected molecules were submitted to FAERS; most involved dulaglutide (n = 11,858; 37.6%) and semaglutide (n = 8249; 26.1%). In comparing semaglutide vs. the remaining molecules, the respective PRR values of the AERs 'drug abuse', 'drug withdrawal syndrome', 'prescription drug used without a prescription', and 'intentional product use issue' were 4.05, 4.05, 3.60, and 1.80 (all < 0.01). The same comparisons of semaglutide vs. the phentermine-topiramate combination were not associated with any significant differences. To the best of our knowledge, this is the first study documenting the misuse/abuse potential of semaglutide in comparison with other GLP1 analogues and the phentermine-topiramate combination. The current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.
10Association of Glucagon-Like Peptide-1 Receptor Agonists With Optic Nerve and Retinal Adverse Events: A Population-Based Observational Study Across 180 Countries.PubMed
Moiz Lakhani, Angela T H Kwan, Andrew Mihalache, et al.
PURPOSE: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are important therapeutic options for type 2 diabetes and obesity; however, concerns about ophthalmic safety persist. This study examined associations between GLP-1 RAs and ocular adverse events (AEs). DESIGN: Global observational pharmacovigilance study. METHODS: We searched the US FAERS database (via OpenVigil 2.1) and WHO's VigiBase (via VigiAccess) for optic nerve and retinal AEs associated with semaglutide and tirzepatide, covering the period from their respective approval dates-December 2017 for semaglutide and May 2022 for tirzepatide-through September 2024. In FAERS, all other drugs were compared, while in VigiBase, metformin, empagliflozin, dulaglutide, and insulin served as controls. Disproportionality metrics included reporting odds ratios (RORs) with 95% confidence intervals. RESULTS: Semaglutide and tirzepatide accounted for 76 444 cases (0.59%) in FAERS (n = 12 936 341) and 118 639 cases (0.34%) in VigiBase (n > 35 000 000). Semaglutide showed significantly higher odds of ischemic optic neuropathy (ION) (FAERS: ROR = 11.12, 95% CI = 8.15-15.16; VigiBase: ROR = 68.58, 95% CI = 16.75-280.67), diabetic retinopathy (DR) (FAERS: ROR = 17.28, 95% CI = 13.62-21.91; VigiBase: ROR = 7.81, 95% CI = 5.60-10.90), as well as retinal/vitreous detachment, retinal/vitreous hemorrhage, and retinal tear (FAERS: ROR = 2.44-5.89, 95% CI = 1.70-8.97, all P < .001, IC = 0.49, compared to all other drugs. VigiBase: ROR = 5.49-20.91, 95% CI = 2.71-90.11, all P ≤ .0001, IC ≥ 0.53, compared to metformin). Unique to VigiBase were macular edema (ROR = 3.87, 95% CI = 1.89-7.92), macular hole (ROR = 20.90, 95% CI = 2.65-165.01), and papilledema (ROR = 6.97, 95% CI = 2.53-19.17) (all P ≤ .004, IC ≥ 0.27, compared to metformin). Sensitivity analyses using empagliflozin and dulaglutide revealed significant associations with ION and DR, while vitreous detachment and hemorrhage were significant when compared to dulaglutide. Additionally, when insulin was used as a comparator, semaglutide showed a higher ROR for ION (ROR = 9.84, 95% CI = 4.25-22.81, P < .0001, IC = 0.42). However, tirzepatide was only significantly associated with DR in FAERS. CONCLUSIONS: Given the widespread use of semaglutide, its association with ocular AEs highlight the need for global pharmacovigilance and post-marketing surveillance.
11Tirzepatide, 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.
12Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension.PubMed
John P H Wilding, Rachel L Batterham, Melanie Davies, et al.
AIM: To explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension. MATERIALS AND METHODS: STEP 1 (NCT03548935) randomized 1961 adults with a body mass index ≥ 30 kg/m (or ≥ 27 kg/m with ≥ 1 weight-related co-morbidity) without diabetes to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. At week 68, treatments (including lifestyle intervention) were discontinued. An off-treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. This subset comprised all eligible participants from any site in Canada, Germany and the UK, and sites in the United States and Japan with the highest main phase recruitment. All analyses in the extension were exploratory. RESULTS: Extension analyses included 327 participants. From week 0 to week 68, mean weight loss was 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo. Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120. Cardiometabolic improvements seen from week 0 to week 68 with semaglutide reverted towards baseline at week 120 for most variables. CONCLUSIONS: One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.
13Real-World Cardiovascular Outcomes of Obesity Treatment With Tirzepatide Versus Semaglutide in Non-Diabetic Adults.PubMed
Mai Katsura, Yu Horiuchi, Kengo Tanabe, et al.
AIMS: Treatment of obesity with glucagon-like peptide-1 (GLP-1) receptor agonists improves cardiovascular outcomes. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, achieves greater weight loss than GLP-1 receptor agonists alone; however, direct real-world comparisons of clinical outcomes are limited. MATERIALS AND METHODS: We conducted a retrospective, active-comparator, new-user cohort study using the TriNetX global federated electronic health record database. Adults (≥ 18 years) without diabetes who initiated tirzepatide or semaglutide for the treatment of obesity between November 2023 and August 2024 were included. Patients with recent atherosclerotic events, prior heart failure (HF), or crossovers to the comparator were excluded. The primary outcome was major cardiovascular events including all-cause death, acute coronary syndrome, stroke, or new-onset HF at 12 months. RESULTS: One-to-one propensity score matching yielded 35 336 pairs. Tirzepatide was associated with a lower incidence of the composite outcome compared with semaglutide (1.90% vs. 2.18%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.97; p = 0.01), driven by reduced new-onset HF (1.04% vs. 1.29%; HR, 0.79; 95% CI, 0.68-0.92; p = 0.002), including both HF with reduced and preserved ejection fraction. No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke. Mean weight loss was greater with tirzepatide (-9.8 kg vs. -8.0 kg; p < 0.001). Adverse event rates were comparable, with no new safety signals. CONCLUSIONS: In obese individuals without diabetes, tirzepatide was associated with a lower risk of cardiovascular events, especially incident HF, compared with semaglutide, with a similar safety profile.
14Exploring potential associations between GLP-1RAs and depressive disorders: a pharmacovigilance study based on FAERS and VigiBase data.PubMed
Min Wang, Xiaohong Chen, Zaiqiang Liu, et al.
BACKGROUND: GLP-1 receptor agonists (GLP-1RAs) are increasingly prescribed for diabetes and obesity management. Recent pharmacovigilance reports have raised concerns about potential neuropsychiatric adverse events, yet comprehensive safety assessments focusing on depressive disorders remain limited. This study investigated associations between specific GLP-1RAs and depressive disorders using real-world post-marketing surveillance data. METHODS: We analyzed individual case safety reports (ICSRs) for liraglutide, semaglutide, and tirzepatide from the FDA Adverse Event Reporting System (FAERS) and WHO VigiBase databases through December 2024. Disproportionality analysis using reporting odds ratio (ROR) and information component (IC) identified signals of disproportionate reporting (SDRs) for depressive disorders. Time-to-onset analysis, stratified analyses, active comparator assessments, and co-medication evaluations were conducted to characterize these associations. FINDINGS: Only semaglutide demonstrated statistically significant SDRs for depressive disorders in both databases (FAERS: ROR 1.26, 95% confidence interval (CI) 1.15-1.37; IC 0.33, 95% CI 0.20-0.45; VigiBase: ROR 1.38, 95% CI 1.27-1.49; IC 0.46, 95% CI 0.34-0.57), while liraglutide and tirzepatide showed no SDRs. Stratified analyses revealed increased disproportionality in females and healthcare professional reports. WSP analysis showed semaglutide-associated depression followed an early failure pattern, with no significant drug interactions identified with psychotropic medications. INTERPRETATION: This pharmacovigilance investigation identified a semaglutide-specific SDR for depressive disorders across both databases, while liraglutide and tirzepatide showed no SDRs. Although inconsistent with reported protective effects in existing studies of GLP-1RAs, these findings suggest drug-specific rather than class-wide safety monitoring is warranted. FUNDING: This work was supported by grants from the Foshan "Fourteen Five" Key Medical Specialty Construction Project (grant number FSZD145035) and Natural Science Foundation of Hunan Province (grant number 2023JJ60520).
15Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.PubMed
Thomas Karagiannis, Konstantinos Malandris, Ioannis Avgerinos, et al.
AIMS/HYPOTHESIS: We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus. METHODS: We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA and body weight from baseline. Secondary outcomes were achievement of HbA target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework. RESULTS: A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA (mean difference -21.61 mmol/mol [-1.96%]) followed by tirzepatide 10 mg (-20.19 mmol/mol [-1.84%]), semaglutide 2.0 mg (-17.74 mmol/mol [-1.59%]), tirzepatide 5 mg (-17.60 mmol/mol [-1.60%]), semaglutide 1.0 mg (-15.25 mmol/mol [-1.39%]) and semaglutide 0.5 mg (-12.00 mmol/mol [-1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia. CONCLUSIONS/INTERPRETATION: Our data show that s.c. tirzepatide had a more pronounced effect on HbA and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events. REGISTRATION: PROSPERO registration no. CRD42022382594.
16Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.PubMed
Domenica Rubino, Niclas Abrahamsson, Melanie Davies, et al.
IMPORTANCE: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. OBJECTIVE: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. INTERVENTIONS: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. MAIN OUTCOMES AND MEASURES: The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). RESULTS: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%). CONCLUSIONS AND RELEVANCE: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03548987.
17Discontinuing 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.
18Dietary Recommendations for the Management of Gastrointestinal Symptoms in Patients Treated with GLP-1 Receptor Agonist.PubMed
Silvia Gentinetta, Francesca Sottotetti, Matteo Manuelli, et al.
GLP-1 receptor agonist (GLP-1RA) have been developed to address the global burden of obesity and are renowned for their safety and efficacy. These medications influence hunger and satiety, reducing energy intake and promoting weight loss. Despite their benefits, GLP-1RAmay cause a slowed gastric emptying, leading to gastrointestinal symptoms. This study examines how food properties and meal composition affect these symptoms. Dietary recommendations are provided, particularly for evening meals, focusing on how different foods and nutrients can influence the rate of gastric emptying, to improve patient compliance and prevent interruption in weight loss.
19Effect 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.
20Tirzepatide 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.).