Advances in weight-loss medications for cardiovascular-kidney-metabolic syndrome_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Yuan ¹ , ZHANG Zhongyang ² , SUN Qin ² , YU Zhenghang ² , LIANG Dianyuan ² , XIE Sijun ² ,  REN Yixing ^1,2

1. Department of Gastrointestinal Surgery, Affiliated Hospital, North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
2. Institute of Hepatobiliary, Pancreatic and Gastroenterology, North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;

Corresponding author：

REN Yixing, Email: cra0009@163.com

Keywords：

weight-loss medication; semaglutide; tirzepatide; glucagon-like peptide 1; glucose-dependent insulinotropic peptide; cardiovascular-kidney-metabolic syndrome

DOI：

10.7507/1007-9424.202506092

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To explore therapeutic mechanisms and clinical application prospects of novel weight-loss medications in patients with obesity complicated by cardiovascular-kidney-metabolic (CKM) syndrome, aiming to provide theoretical support and therapeutic strategies for personalized precision management of CKM syndrome. Methods Recent domestic and international studies were retrospectively reviewed, focusing on the mechanisms of action, clinical research outcomes, and application progress of novel weight-loss medications, including glucagon-like peptide 1 (GLP-1) receptor agonists, dual glucose-dependent insulinotropic peptide (GIP)/GLP-1 receptor agonists, triple GIP/GLP-1/glucagon receptor agonists, and amylin analogues. Special emphasis was placed on their comprehensive effects on cardiovascular, renal, and metabolic parameters. Results Novel weight-loss medications have demonstrated significant weight reduction and multisystem benefits through precise regulation of central appetite pathways, insulin sensitivity, and lipid metabolism. Among these medications, GLP-1 receptor agonists (e.g., semaglutide) and dual receptor agonists (e.g., tirzepatide) have been confirmed in phase Ⅲ clinical trials to effectively reduce cardiovascular event risks, slow renal function deterioration, and markedly improve glycemic control in obese patients with CKM syndrome. Triple receptor agonists (e.g., retatrutide) and combination medication regimen (e.g., CagriSema regimen) have further enhanced weight-loss efficacy, providing novel therapeutic avenues for obesity-related diseases. Additionally, these medications usually require combined application with traditional chronic disease medications, such as sodium-glucose linked transporter 2 inhibitors and renin-angiotensin-aldosterone system blockers, to achieve comprehensive therapeutic outcomes in CKM syndrome patients. However, further studies are needed to address long-term safety in real-world settings, optimization of drug formulations, and application in precision medicine. Conclusions Novel weight-loss medications offer promising strategies for personalized precision treatment of obesity with CKM syndrome due to their significant weight-loss efficacy and multisystem synergistic effects. Although current clinical trials demonstrate substantial therapeutic potential, the complexity of CKM syndrome and individual patient variability necessitate additional in-depth research to facilitate broader clinical adoption and optimization of these medications.

Citation： ZHANG Yuan, ZHANG Zhongyang, SUN Qin, YU Zhenghang, LIANG Dianyuan, XIE Sijun, REN Yixing. Advances in weight-loss medications for cardiovascular-kidney-metabolic syndrome. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2025, 32(9): 1130-1140. doi: 10.7507/1007-9424.202506092 Copy

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2. Koliaki C, Liatis S, Kokkinos A. Obesity and cardiovascular disease: revisiting an old relationship. Metabolism, 2019, 92: 98-107.
3. Pálsson R, Patel UD. Cardiovascular complications of diabetic kidney disease. Adv Chronic Kidney Dis, 2014, 21(3): 273-280.
4. Yu L, Bao S, Zhu F, et al. Serum lactate dehydrogenase is a novel predictor for the severity in the patients with MAFLD: a cross-sectional study in Hefei, China. Diabetes Metab Syndr Obes, 2025, 18: 345-361.
5. Rubino F, Puhl RM, Cummings DE, et al. Joint international consensus statement for ending stigma of obesity. Nat Med, 2020, 26(4): 485-497.
6. Melson E, Ashraf U, Papamargaritis D, et al. What is the pipeline for future medications for obesity?. Int J Obes (Lond), 2025, 49(3): 433-451.
7. Jalleh RJ, Rayner CK, Hausken T, et al. Gastrointestinal effects of GLP-1 receptor agonists: mechanisms, management, and future directions. Lancet Gastroenterol Hepatol, 2024, 9(10): 957-964.
8. Drucker DJ. Efficacy and safety of GLP-1 medicines for type 2 diabetes and obesity. Diabetes Care, 2024, 47(11): 1873-1888.
9. Kumar S, Blaha MJ. GLP-1 RA for cardiometabolic risk reduction in obesity—how do we best describe benefit and value?. Am J Prev Cardiol, 2024, 18: 100682. doi: 10.1016/j.ajpc.2024.100682.
10. 何丽云, 张化冰, 李玉秀. 全面评估, 合理决策: 基于胰高血糖素样肽1受体激动剂用药风险的最新发现. 协和医学杂志, 2022, 13(6): 948-952.
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15. von Scholten BJ, Kreiner FF, Rasmussen S, et al. The potential of GLP-1 receptor agonists in type 2 diabetes and chronic kidney disease: from randomised trials to clinical practice. Ther Adv Endocrinol Metab, 2022, 13: 20420188221112490. doi: 10.1177/20420188221112490.
16. Nashwan AJ, Abukhadijah HJ, Karavadi V, et al. Exploring glucagon-like peptide-1 receptor agonists usage among non-diabetic healthcare providers: a cross-sectional multi-country study. Health Sci Rep, 2025, 8(4): e70638. doi: 10.1002/hsr2.70638.
17. Pillarisetti L, Agrawal DK. Semaglutide: double-edged sword with risks and benefits. Arch Intern Med Res, 2025, 8(1): 1-13.
18. Yin Y, Zhang M, Cao Q, et al. Efficacy of GLP-1 receptor agonist-based therapies on cardiovascular events and cardiometabolic parameters in obese individuals without diabetes: a meta-analysis of randomized controlled trials. J Diabetes, 2025, 17(4): e70082. doi: 10.1111/1753-0407.70082.
19. Górriz JL, Romera I, Cobo A, et al. Glucagon-like peptide-1 receptor agonist use in people living with type 2 diabetes mellitus and chronic kidney disease: a narrative review of the key evidence with practical considerations. Diabetes Ther, 2022, 13(3): 389-421.
20. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol, 2018, 6(8): 605-617.
21. Alqifari SF, Alkomi O, Esmail A, et al. Practical guide: glucagon-like peptide-1 and dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus. World J Diabetes, 2024, 15(3): 331-347.
22. Michos ED, Bakris GL, Rodbard HW, et al. Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: a review of their kidney and heart protection. Am J Prev Cardiol, 2023, 14: 100502. doi: 10.1016/j.ajpc.2023.100502.
23. Rodbard HW, Lingvay I, Reed J, et al. Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomized, controlled trial. J Clin Endocrinol Metab, 2018, 103(6): 2291-2301.
24. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med, 2022, 387(3): 205-216.
25. Paddu NU, Lawrence B, Wong S, et al. Weight maintenance on cost-effective antiobesity medications after 1 year of GLP-1 receptor agonist therapy: a real-world study. Obesity (Silver Spring), 2024, 32(12): 2255-2263.
26. Chen X, Zhang X, Xiang X, et al. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular outcomes in high-risk type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetol Metab Syndr, 2024, 16(1): 251. doi: 10.1186/s13098-024-01497-4.
27. Véniant MM, Lu SC, Atangan L, et al. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat Metab, 2024, 6(2): 290-303.
28. Jiang Y, Zhu H, Gong F. Why does GLP-1 agonist combined with GIP and/or GCG agonist have greater weight loss effect than GLP-1 agonist alone in obese adults without type 2 diabetes?. Diabetes Obes Metab, 2025, 27(3): 1079-1095.
29. Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2A trial. Nat Med, 2024, 30(7): 2037-2048.
30. Liu L, Shi H, Xie M, et al. Efficacy and safety of tirzepatide versus placebo in overweight or obese adults without diabetes: a systematic review and meta-analysis of randomized controlled trials. Int J Clin Pharm, 2024, 46(6): 1268-1280.
31. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity—a phase 2 trial. N Engl J Med, 2023, 389(6): 514-526.
32. Patti ME. Triple G agonists—a home run for obesity?. N Engl J Med, 2023, 389(6): 562-563.
33. Mikhail N, Wali S. Cagrilintide combined with semaglutide: a new approach for treatment of obesity and type 2 diabetes. Clin Trials Clin Res, 2023, 2(5). doi: 10.31579/2834-5126/043.
34. Frias JP, Deenadayalan S, Erichsen L, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet, 2023, 402(10403): 720-730.
35. Liu L, Liu W, Deng W. Amylin inhibits gastric cancer progression by targeting CCN1 and affecting the PI3K/AKT signalling pathway. Ann Med, 2025, 57(1): 2480754. doi: 10.1080/07853890.2025.2480754.
36. Hankir MK, Le Foll C. Central nervous system pathways targeted by amylin in the regulation of food intake. Biochimie, 2025, 229: 95-104.
37. Panou T, Gouveri E, Popovic DS, et al. Amylin analogs for the treatment of obesity without diabetes: present and future. Expert Rev Clin Pharmacol, 2024 Sep 30: 1-9. doi: 10.1080/17512433.2024.2409403.
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