Effects of Incretin-Based Therapies on Testosterone Levels and Incretin Response in Men with Hypogonadism: A Systematic Literature Review Following PRISMA 2020 Guidelines.
Level 1 - systematic review of randomized trials
Systematic review of randomized controlled trials and observational studies
PubMed 42653816 · doi:10.3390/ph19081321
What was done
This systematic literature review followed PRISMA 2020 guidelines to examine the effects of incretin-based therapies (GLP-1 and GIP receptor agonists) on testosterone levels and evaluate whether baseline hypogonadism alters therapeutic response. Searches were conducted across PubMed/MEDLINE, Scopus, and Web of Science through December 31, 2024. Eligible human studies (RCTs, observational studies, cohort studies, cross-sectional studies, and systematic reviews) in adult men were screened independently in duplicate. Risk of bias was evaluated using RoB 2 for RCTs, the Newcastle-Ottawa Scale (NOS) for observational studies, and AMSTAR-2 for systematic reviews. Due to substantial clinical and methodological heterogeneity, findings were synthesized narratively.
What was found
A total of 29 studies were included (14 primary studies, 5 systematic reviews/meta-analyses, and 10 narrative reviews/expert opinions). Primary evidence from RCTs and observational studies showed that GLP-1 receptor agonists (specifically semaglutide and liraglutide) and the dual GIP/GLP-1 receptor agonist tirzepatide significantly increased total testosterone levels in men with obesity-related functional hypogonadism, with mean increases ranging from 2.5 to 5.2 nmol/L. This improvement was largely mediated by weight loss and reduced insulin resistance rather than direct androgenic action. No adequately powered comparative trials stratified by baseline testosterone status were identified to determine if baseline hypogonadism impairs glycemic or weight-loss response.
Why it matters
It demonstrates that incretin mimetics can partially restore testosterone levels in men with obesity-associated functional hypogonadism through weight reduction and metabolic improvement. It also clarifies that direct evidence is currently lacking on whether baseline androgen deficiency impairs clinical response to incretin drugs.
Limits
Primary randomized trials had very small sample sizes (n = 12–42) and short follow-up durations (12–24 weeks), creating moderate-to-high overall risk of bias and limited statistical power. Included systematic reviews were rated low-to-moderate confidence by AMSTAR-2, and observational studies were subject to confounding. Quantitative meta-analysis could not be performed due to heterogeneity, and direct comparative data stratified by baseline testosterone levels were missing entirely.
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