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Cited by 62Pharmacology and Obesity TreatmentBariatric Surgery and OutcomesObesity, Physical Activity, Diet

Safety and effects of anti-obesity medications on weight loss, cardiometabolic, and psychological outcomes in people living with overweight or obesity: a systematic review and meta-analysis

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Liu, Leiling, Li, Zhiqi, Ye, Wenrui, Peng, Pu, Wang, Yurong, Wan, Luqing, Li, Jiangnan, Zhang, Mei +4 more·2025·eClinicalMedicine
DOI 10.1016/j.eclinm.2024.103020PMC PMC11743856
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Abstract

Background Overweight and obesity pose serious health challenges for individuals and societies. This study aims to facilitate personalised treatment of obesity by summarising recent research on weight-loss pharmacotherapies, with a focus on their effects on weight reduction, cardiometabolic health, psychological outcomes, and adverse events. Methods This systematic review and meta-analysis included searches of Web of Science, PubMed, and Cochrane Central Register of Controlled Trials from inception to June 8, 2024. Randomised controlled trials evaluating weight-loss pharmacotherapies approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMA) for treating overweight or obesity were included. Primary outcomes included changes in body weight, cardiometabolic indicators, psychological outcomes, and adverse events. Summary data was extracted from published reports. Random-effects meta-analyses were used to calculate weighted mean differences (WMDs), risk ratios (RRs), and 95% confidence intervals (CI). The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system was used to assess the certainty of evidence for each pooled analysis. PROSPERO registration: CRD42024547905. Findings A total of 154 randomised controlled trials (n = 112,515 participants) were included. Tirzepatide had the greatest weight-loss effect (WMD −11.69, 95% CI −19.22 to −4.15; P = 0.0024; I 2 = 100.0%; moderate certainty), followed by semaglutide (−8.48, −12.68 to −4.27; P < 0.0001; I 2 = 100.0%; moderate certainty). Tirzepatide had the strongest antihypertensive effect on both systolic (WMD −5.74, −9.00 to −2.48; P = 0.0006; I 2 = 99.8%; moderate certainty) and diastolic blood pressure (WMD −2.91, −4.97 to −0.85; P = 0.0056; I 2 = 99.8%; moderate certainty) and best reduced triglycerides (WMD −0.77, −0.85 to −0.69; P < 0.0001; I 2 = 3.2%; high certainty), fasting glucose (WMD −3.06, −5.53 to −0.59; P = 0.015; I 2 = 100.0%; moderate certainty), insulin (WMD −4.91, −8.15 to −1.68; P = 0.0029; I 2 = 97.0%; moderate certainty), and glycated haemoglobin levels (WMD −1.27, −1.82 to −0.73; P < 0.0001; I 2 = 100.0%; moderate certainty). Semaglutide (RR 0.83, 0.74–0.92; P < 0.0001; I 2 = 0.0%; high certainty) and liraglutide (0.87, 0.79–0.96; P = 0.0059; I 2 = 0.0%; high certainty) reduced the risk of major adverse cardiovascular events (MACEs). However, all three medications were associated with adverse gastrointestinal effects. Naltrexone/bupropion increased the risk of elevated blood pressure (RR 1.72, 1.04–2.85; P = 0.036; I 2 = 0.0%; high certainty). Topiramate increased depression risk (RR 1.62, 1.14 to 2.30; P = 0.0077; I 2 = 0.0%; high certainty), and phentermine/topiramate raised concerns about anxiety (RR 1.91, 1.09 to 3.35; P = 0.025; I 2 = 29.5%; high certainty), sleep disorders (RR 1.55, 1.24–1.93; P < 0.0001; I 2 = 0.0%; high certainty), and irritability (RR 3.31, 1.69–6.47; P < 0.0001; I 2 = 0.0%; high certainty). No medication increased the risk of serious adverse events. Interpretation For weight reduction, tirzepatide is the top choice, followed by semaglutide. Considering cardiometabolic risk factors, tirzepatide shows the best blood pressure- and glucose-lowering benefits, while semaglutide and liraglutide reduce the risk of MACEs. Naltrexone/bupropion carries a risk of increased blood pressure. Phentermine/topiramate should be used with caution due to its higher risk of psychological side effects. Despite limitations related to study heterogeneity, these findings provide valuable insights for weight management strategies across diverse individuals. Funding National Natural Science Foundation of China, Leading Talents Program of Hunan Province, and Fundamental Research Funds for the Central Universities of Central South University.

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  • GLP-1 RAs have primarily been associated with gastrointestinal side effects and have demonstrated more favorable psychiatric and cardiovascular safety profiles than alternative anti-obesity medications.

    “In contrast, GLP-1 RAs have primarily been associated with gastrointestinal side effects and have demonstrated more favorable psychiatric and cardiovascular safety profiles.13,14”

    From The expanding role of GLP-1 receptor agonists: a narrative review of current evidence and future directions (2025) · cites this paper as [13]

    The Results and Discussion (pages not available) identify gastrointestinal disorders as common with GLP-1 receptor agonists and report cardiovascular benefits for semaglutide and liraglutide, particularly in people with weight-related complications. The broad claim of a more favorable psychiatric safety profile is qualified by the Results finding that liraglutide increased sleep-disorder incidence; cardiovascular protection was not established for every GLP-1–based medication. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Phentermine-topiramate is linked to psychiatric and cognitive effects, including irritability (RR 3.31), anxiety (RR 1.91), and sleep disorders (RR 1.55).

    “Phentermine-topiramate has been linked to psychiatric and cognitive effects, including irritability (relative risk [RR] vs. placebo: 3.31, 95% confidence interval [CI] 1.69, 6.47), anxiety (RR: 1.91, 95% CI 1.09, 3.35), and sleep disorders (RR: 1.55, 95% CI 1.24, 1.93).13”

    From The expanding role of GLP-1 receptor agonists: a narrative review of current evidence and future directions (2025) · cites this paper as [13]

    The Results table reports the stated relative risks and confidence intervals for irritability, anxiety, and sleep disorders with phentermine/topiramate. The Discussion describes these as adverse psychological effects, but the passages found do not establish a separate cognitive effect; that part of the characterization is unsupported. Page numbers were not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Naltrexone-bupropion is associated with anxiety (RR 2.44) and elevated blood pressure (RR 1.72).

    “Naltrexone-bupropion is associated with anxiety (RR vs. placebo: 2.44, 95% CI 1.29, 4.63) and elevated blood pressure (RR: 1.72, 95% CI 1.04, 2.85).13”

    From The expanding role of GLP-1 receptor agonists: a narrative review of current evidence and future directions (2025) · cites this paper as [13]

  • Previous NMAs and a traditional meta-analysis on therapeutic options for overweight and obesity did not include more recently available OMMs such as tirzepatide, or included medications not approved for overweight/obesity, or adopted different inclusion criteria.

    “Several NMAs20–23 and a traditional meta-analysis24 on different therapeutic options for overweight and obesity were published in the last few years, but they did not include more recently available OMMs, such as tirzepatide20–22, or they included medications not approved for the treatment of overweight/obesity (for example, metformin, SGLT2 inhibitors or GLP-1 agonists, such as dulaglutide)22, or”

    From A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults (2025) · cites this paper as [24]

  • The results of this NMA are in line with those reported in previous NMA and meta-analysis.

    “These results are in line with those reported in previous NMA and meta-analysis20–22,24”

    From A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults (2025) · cites this paper as [24]

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Authors
Liu, L., Li, Z., Ye, W., Peng, P., Wang, Y., Wan, L., Li, J., Zhang, M., Wang, Y., Liu, R., Xu, D., & Zhang, J.
Affiliations
  • Second Xiangya Hospital of Central South University (CN)
  • Xiangya Hospital Central South University (CN)
  • University College London (GB)
Corresponding author
  • Xu, Danyan
  • Zhang, Jingjing
ORCID
Venue
eClinicalMedicine
Publisher
Elsevier BV
Published
2025-01
Volume
79
Pages
103020
ISSN
2589-5370 (ISSN-L)
DOI
10.1016/j.eclinm.2024.103020
PMC
PMC11743856
OpenAlex
W4405844467
Cited by
62
References
57
Citations by year
2026: 29 · 2025: 33
FWCI
3.88
Type
journal article
Language
en
Open access
Licence
Locations
  • EClinicalMedicine (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fundamental Research Funds for Central Universities of the Central South University (2024ZZTS0166)
  • Leading Talents Program of Guangdong Province
  • National Natural Science Foundation of China (82370807, 81871858, 82172550)
Topics
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
  • Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Obesity, Physical Activity, Diet
Keywords
anti-obesity drugs, pharmacological weight loss, obesity, overweight, tirzepatide, semaglutide, GLP-1 receptor agonists, GIP receptor agonist, weight loss, cardiometabolic outcomes, blood pressure, triglycerides, adverse events, psychological outcomes, anxiety, sleep disorders, personalized treatment

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