整理 | GLP1减重宝典内容团队 近年来，GLP-1受体激动剂（GLP-1RA）显著改变了肥胖管理格局，但"停药即反弹"的现实挑战同样显著。来自丹麦的一项随机对照研 究延伸随访显示：与单用药物相比，将监督运动纳入治疗与停药过渡期，能在一年后显著改善体重与体成分维持。这一发现为临床决策 与患者长期管理提供了更具操作性的路径。 ▍ 研究设计与方法概览 试验纳入18–65岁肥胖成人（BMI 32–43 kg/m²），整体分三阶段推进： 停治随访（52–104周）：全部干预在第52周终止，于第104周评估体重、体脂等结局。 主要终点为从随机化（第0周）至停药后一年（第104周）的体重变化，次要终点为体脂百分比变化。共有109名完成治疗者参加了停药 一年后的评估。 ▍ 主要发现与证据 联合方案的持久优势：与单用利拉鲁肽相比，"监督运动+利拉鲁肽"在停药一年后体重更低（约−5.1 kg，具有统计学意义），体脂百分 比亦显著下降（约−2.3 个百分点）。达成并维持≥10%初始体重减轻的比例，联合组显著高于单药与安慰剂。 运动带来的"后劲"：停药后一年，单用利拉鲁肽的体重回升幅度高于监督运动组（约+6.0 kg的差异），也 ...

Core Viewpoint - Eli Lilly Canada has launched ZEPBOUND™ KwikPen® (tirzepatide injection) in Canada, providing a new chronic weight management solution for adults with obesity or overweight [2][5]. Group 1: Product Overview - ZEPBOUND™ is a once-weekly injection approved for long-term weight control in conjunction with a healthy diet and regular exercise [2]. - It is suitable for adults with a Body Mass Index (BMI) of 30 or higher, or those with a BMI between 27 and 30 who have weight-related conditions such as hypertension, dyslipidemia, type 2 diabetes, sleep apnea, or cardiovascular diseases [2]. Group 2: Mechanism of Action - ZEPBOUND™ regulates appetite and metabolism by simultaneously activating two hormone receptors: GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) [3]. - It is the first and only dual receptor agonist approved in Canada for long-term weight management, offering both weight loss and weight maintenance effects [3]. Group 3: Clinical Evidence - The approval of ZEPBOUND™ is based on results from four global SURMOUNT phase 3 clinical trials (SURMOUNT-1 to SURMOUNT-4) [5]. - In the SURMOUNT-1 study, 2,539 adults without diabetes but with obesity or overweight and related conditions participated. After 72 weeks, participants using the maximum dose (15 mg) lost an average of 21.8 kg (48 lbs), while those using the minimum dose (5 mg) lost an average of 15.4 kg (34 lbs). The placebo group lost an average of only 3.2 kg (7 lbs) [5]. Group 4: Health Challenges and Economic Impact - Obesity is a serious chronic disease affecting one in three Canadians, linked to over 200 diseases, including heart disease and type 2 diabetes [6]. - The annual economic loss related to obesity in Canada has reached CAD 27.6 billion, which is 20% higher than previous estimates [6]. Group 5: Reception and Advocacy - Medical professionals and patient organizations have welcomed the launch of ZEPBOUND™, highlighting it as an important advancement in obesity treatment [8]. - Experts emphasize the need for equitable access to treatment and recognition of the challenges faced by individuals with obesity, advocating for societal change and support [8].

Core Viewpoint - China has the highest number of overweight and obese individuals globally, with over half of the adult population affected, leading to significant health and economic implications [2] Group 1: Obesity Statistics - As of 2021, 16.4% of adults in China are classified as obese, and 34.3% as overweight, totaling approximately 532 million individuals, with nearly 100 million being obese [2] - By 2030, projections indicate that the number of overweight adults in China will reach 540 million, and the obese population will increase to 150 million, representing growth of 2.8 times and 7.5 times since 2000, respectively [2] - By 2035, it is estimated that one-quarter of the global population will be classified as obese, up from 14% in 2020 [2] Group 2: GLP-1 Drug Usage and Compliance - The introduction of GLP-1 drugs like semaglutide has transformed the weight loss market, although many users discontinue the medication after a period [3][5] - A study published in the journal "Obesity" found that 44% of patients remained on weight loss medication after three months, 33% after six months, and only 19% after one year [5] - For semaglutide users, the retention rates were higher, with 63% after three months, 56% after six months, and 40% after one year [5] Group 3: Effects of Discontinuation - A clinical trial indicated that participants who used semaglutide for 20 weeks lost an average of 10.6% of their body weight, but those who switched to a placebo regained an average of 6.9% of their weight [6] - Participants who continued semaglutide and lifestyle interventions maintained an average weight loss of 17.3% over 68 weeks, while those who stopped regained about two-thirds of their lost weight within a year [6] Group 4: Reasons for Discontinuation - Common side effects of GLP-1RA drugs include nausea, diarrhea, vomiting, constipation, abdominal pain, and gastroesophageal reflux, which may lead to discontinuation [8] - Approximately 17% of patients reported nausea even at low doses of semaglutide, with diarrhea and vomiting rates at 12.2% and 6.4%, respectively [8] - Drug supply issues have also been a concern since 2022, leading to shortages of semaglutide [9] Group 5: Recommendations for Discontinuation - It is advised to gradually reduce the dosage of GLP-1 drugs rather than stopping abruptly to mitigate increased hunger sensations [12][14] - Patients should monitor their appetite and weight closely after discontinuation, and if weight begins to increase, they may consider resuming medication at a lower dose [14] - Maintaining healthy eating habits and regular exercise is crucial to prevent weight regain after stopping medication [14][15] Group 6: Importance of Continued Medication - Long-term management of obesity is essential, as it is considered a chronic disease, similar to hypertension or heart disease [19] - In the STEP 5 trial, participants using semaglutide for two years lost an average of 15.2% of their body weight, with 77.1% of patients achieving at least a 5% weight loss [19] - The SELECT trial showed that patients who continued semaglutide for four years maintained an average weight loss of about 10% without rebound [19]

Core Viewpoint - The SURMOUNT-5 study demonstrates that Tirzepatide significantly outperforms Semaglutide in weight loss and waist circumference reduction among overweight adults with obesity-related comorbidities but without diabetes [2][4]. Summary by Sections Study Results - Tirzepatide achieved an average weight loss of 20.2% compared to Semaglutide's 13.7% over 72 weeks, with a relative weight loss effect of 1.47 times greater than Semaglutide [2][3]. - Participants in the Tirzepatide group lost an average of 22.8 kg, while those in the Semaglutide group lost 15.0 kg [2]. - In key secondary endpoints, 64.6% of Tirzepatide participants lost at least 15% of their body weight, compared to 40.1% for Semaglutide [3]. Expert Commentary - Dr. Louis J. Aronne highlighted the significant weight loss effects of Tirzepatide, reinforcing its position as an effective option for obesity management [4]. - Dr. Leonard C. Glass emphasized the leading role of Tirzepatide in obesity treatment, providing valuable guidance for clinicians [4]. - Derrick Hirsh pointed out the public health implications of obesity in China, noting that obesity-related healthcare spending is expected to account for about 22% of total healthcare expenditures by 2030 [4]. Safety and Mechanism - The overall safety profile of Tirzepatide was consistent with previous studies, with gastrointestinal issues being the most common adverse events [6]. - Tirzepatide activates both GIP and GLP-1 receptors, giving it a natural advantage over Semaglutide, which only targets GLP-1 receptors [6]. Market Competition - Both Tirzepatide and Semaglutide face production bottlenecks, prompting expansions in manufacturing capacity by both companies [7]. - In Q1 2025, Semaglutide's weight loss version generated approximately $2.448 billion in revenue, while Tirzepatide generated about $2.31 billion, with Tirzepatide's sales growing at a faster rate [7]. - Novo Nordisk and Eli Lilly are competing in the oral weight loss drug market, with Eli Lilly planning to submit its oral GLP-1 drug Orforglipron for regulatory approval by the end of 2025 [7].