Metformin Did Not Prevent Metabolic Syndrome During ADT but Improved Weight, Waist and HbA1c: Findings from the PRIME Phase 3 Trial

Highlight

– The PRIME randomized phase 3 trial found no statistically significant reduction in metabolic syndrome (MS) incidence at 18 months with metformin versus placebo in men initiating androgen deprivation therapy (ADT) for prostate cancer.

– Metformin produced modest but statistically significant improvements in body weight, waist circumference (at several time points), and hemoglobin A1c compared with placebo.

– The trial closed early for drug supply cessation after enrolling 166 of the planned 300 participants, limiting statistical power and interpretability of the negative primary outcome.

Background

Androgen deprivation therapy (ADT) is a cornerstone treatment for advanced and locally advanced prostate cancer. While effective for disease control, ADT produces a well-characterized metabolic phenotype including increased central adiposity, insulin resistance, dyslipidemia, and increases in the incidence of diabetes and cardiovascular events. These changes overlap with criteria for metabolic syndrome (MS), a cluster of risk factors associated with higher cardiovascular and metabolic morbidity.

Metformin, a first-line antihyperglycemic agent, improves insulin sensitivity and reduces hepatic gluconeogenesis; it also promotes modest weight loss or weight stabilization and has an acceptable safety profile in non‑insulin‑treated patients. These properties make metformin an attractive candidate to mitigate ADT-associated metabolic complications. The PRIME (Prevention and Intervention of Metabolic Syndrome) study was designed to test whether metformin started at ADT initiation reduces MS incidence at 18 months in normoglycemic men with prostate cancer.

Study design

The PRIME trial (Eigl et al., J Urol. 2025) was a multicenter, double-blind, randomized phase 3 trial. Key features:

• Population: Normoglycemic men with prostate cancer scheduled to start at least 9 months of ADT.
• Intervention: Metformin 850 mg orally twice daily for 18 months versus matched placebo.
• Randomization: 2:1 allocation in favor of metformin.
• Primary endpoint: Proportion of participants meeting criteria for metabolic syndrome at 18 months.
• Follow-up: Median 24 months (IQR 19.5–36 months) for the cohort analyzed.

The trial originally planned to enroll 300 patients but closed prematurely on November 24, 2023 because of drug supply cessation; 166 patients were randomized and included in the final analysis (90 metformin, 45 placebo analyzed per description; numbers reflect available evaluable participants across time points).

Key findings

This section summarizes the principal results reported by the PRIME investigators with emphasis on the primary endpoint, prespecified metabolic secondary outcomes, and temporal patterns.

Primary endpoint: metabolic syndrome at 18 months

At baseline, proportions meeting MS criteria were 38/90 (42%) in the metformin arm versus 26/45 (58%) in the placebo arm (P = .09), indicating a higher baseline prevalence in the placebo group though the difference was not statistically significant. At 18 months, the proportions were 40/73 (55%) with metformin versus 23/34 (68%) with placebo (P = .20). The primary outcome therefore did not demonstrate a statistically significant reduction in MS incidence with metformin.

Body weight

Metformin-treated participants experienced statistically significant reductions in mean body weight compared with placebo at intermediate time points. Reported between-arm differences were:

• At 9 months: mean change −0.9 kg (SD 4) with metformin versus +1.8 kg (SD 3.8) with placebo (P < .001).
• At 12 months: mean change −0.33 kg (SD 3.9) with metformin versus +1.8 kg (SD 3.9) with placebo (P = .004).

These results suggest metformin prevented the typical ADT-associated weight gain and produced modest weight reduction in some patients.

Waist circumference

Waist circumference, a proxy for central adiposity, showed smaller increases with metformin than placebo at several time points:

• At 9 months: +0.8 cm (SD 4.3) with metformin vs +2.9 cm (SD 5.7) with placebo (P = .03).
• At 12 months: +1.9 cm (SD 5.1) with metformin vs +3.3 cm (SD 6.0) with placebo (P = .15) — not statistically significant.
• At 18 months: +1.8 cm (SD 3.8) with metformin vs +3.8 cm (SD 6.1) with placebo (P = .03).

These differences indicate metformin attenuated accumulation of central adiposity associated with ADT at several measured intervals.

Glycemic control (Hemoglobin A1c)

Mean hemoglobin A1c changes were small but significantly favored metformin at intermediate time points:

• At 9 months: change −0.02% (SD 0.23) with metformin vs +0.08% (SD 0.26) with placebo (P = .02).
• At 12 months: change +0.03% (SD 0.27) with metformin vs +0.08% (SD 0.27) with placebo (P = .03).

Absolute HbA1c differences were numerically modest but consistent with metformin’s known glycemic effects and may be clinically relevant in the prevention of progression to diabetes in at‑risk individuals.

Other outcomes and safety

The summary provided does not include detailed adverse event rates, cardiovascular events, or diabetes incidence. The published paper (Eigl et al., J Urol. 2025) should be consulted for comprehensive safety data, adherence metrics, and subgroup analyses. In general, metformin is associated with gastrointestinal adverse effects and very low risk of lactic acidosis when used in appropriate populations; these general considerations remain applicable when evaluating metformin in men on ADT.

Expert commentary and interpretation

Clinical interpretation of the PRIME results requires integrating efficacy signals, trial limitations, and biological plausibility.

Why might the primary endpoint have been neutral?

• Underpowering due to early trial closure: The study stopped after 166 of 300 planned participants were randomized because of drug supply cessation. A smaller sample reduces power to detect modest differences in a binary composite endpoint such as MS.
• Baseline imbalance: A numerically higher baseline prevalence of MS in the placebo arm (58% vs 42%, P = .09) could bias outcomes toward the null or complicate interpretation, especially in a smaller sample.
• Outcome sensitivity: Metabolic syndrome is a dichotomous composite of several thresholds. Small but consistent improvements in continuous measures (weight, waist, A1c) may not translate into a statistically significant change in the composite categorical definition within the observation window.
• Population selection: Participants were normoglycemic at baseline. Metformin’s relative benefit is often greater in people with impaired glucose tolerance or insulin resistance; enrolling low‑risk participants may blunt observable effects on a categorical endpoint such as MS.
• ADT metabolic effects may be potent and multifactorial; a single agent may only partially mitigate these complex physiologic changes.

Clinical significance of secondary metabolic effects

Although the primary endpoint was negative, the observed reductions in weight gain, waist circumference, and small improvements in HbA1c are clinically meaningful. Central adiposity and modest rises in glycemia contribute to long‑term cardiovascular risk; interventions that attenuate these trajectories may have downstream benefits, especially when combined with lifestyle measures (diet, exercise) and broader cardiovascular risk management.

Implications for practice

Routine prescription of metformin for all men initiating ADT cannot be recommended on the basis of the PRIME trial’s primary result. However, considering metformin for selected patients—particularly those with elevated cardiometabolic risk, prediabetes, or progressive weight gain on ADT—may be reasonable, acknowledging the limited direct evidence for hard clinical endpoints. Shared decision-making should consider the magnitude of benefit observed, patient comorbidities, tolerance of metformin, and patient preferences.

Research recommendations

• Adequately powered randomized trials that reach planned sample sizes and include pre-specified high-risk subgroups (prediabetes, obesity) are needed to determine whether metformin prevents MS or reduces clinical cardiovascular or diabetes outcomes in ADT recipients.
• Trials combining metformin with structured lifestyle interventions could test additive or synergistic benefits on metabolic outcomes and patient‑centered endpoints.
• Longer follow-up to capture incident diabetes, cardiovascular events, and quality of life is essential to inform clinical decision making.

Limitations

Key limitations to keep in mind when interpreting PRIME include early termination with incomplete enrollment, baseline imbalance in MS prevalence, and lack of detailed safety and event data in the provided summary. The binary composite primary endpoint may be less sensitive than continuous measures for detecting modest but clinically useful metabolic changes.

Conclusion

The PRIME randomized phase 3 trial did not demonstrate that metformin reduces the incidence of metabolic syndrome at 18 months among normoglycemic men starting ADT for prostate cancer. Nonetheless, metformin produced modest and statistically significant improvements in body weight, waist circumference at several time points, and small reductions or attenuated increases in hemoglobin A1c. These findings suggest that metformin may mitigate some ADT-associated metabolic changes even if it does not prevent categorical metabolic syndrome in an unselected, normoglycemic population. Larger, adequately powered trials, ideally targeting higher‑risk patients and incorporating cardiovascular endpoints and lifestyle interventions, are needed to define the role of metformin in this setting.

Funding and clinicaltrials.gov

Funding sources and trial registration details are reported in the original publication: Eigl BJ et al., A Randomized Phase 3 Trial of Metformin in Patients Initiating Androgen Deprivation Therapy as Prevention and Intervention of Metabolic Syndrome: The PRIME Study. J Urol. 2025;214(5):496-508. Readers should consult the full paper for specific funding acknowledgements, conflict of interest disclosures, and registration identifiers.

References

1. Eigl BJ, Elangovan A, Ghosh S, Kim JO, Thoms J, Bouchard M, Peacock M, Fleshner N, Campbell H, Vigneault E, Vincent F, So A, Cury F, Quon H, Carlson R, Lambert C, Klotz L, Chi K, Brundage M, Pollak M, Rebane L, Chiu L, Courneya KS, Usmani N. A Randomized Phase 3 Trial of Metformin in Patients Initiating Androgen Deprivation Therapy as Prevention and Intervention of Metabolic Syndrome: The PRIME Study. J Urol. 2025 Nov;214(5):496-508. doi: 10.1097/JU.0000000000004695. Epub 2025 Jul 25. PMID: 40711960.

2. Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement. Circulation. 2009 Oct 20;120(16):1640-1645. doi:10.1161/CIRCULATIONAHA.109.192644.

(Consult the full PRIME publication for detailed methods, subgroup analyses, safety data, and supplementary materials.)