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Objectives: To investigate the risk of varicocele, erectile dysfunction (ED), infertility, prostatitis, benign prostate hyperplasia (BPH) and prostate cancer associated with metformin use.Materials and methods: A total of 261,838 males, mean age 52.39 years (SD: 11.39), with a new-onset type 2 diabetes mellitus in 1999–2009 were identified from Taiwan’s National Health Insurance. Among them, 175,171 were metformin initiators [metformin (+)] and 86,667 were non-metformin initiators [metformin (−)] in the initial 12-month prescriptions of antidiabetic drugs. Follow-up started after the initial 12-month prescriptions. Outcomes were followed up until 31 December 2011. Intention-to-treat (ITT) and per-protocol (PP) hazard ratios comparing metformin (+) to metformin (−) were estimated by Cox regression incorporated with the inverse probability of treatment-weighting using propensity scores.Results: The median follow-up time ranged 5.55–6.82 years in metformin (−) and 4.36–5.17 years in metformin (+) for different outcomes in ITT analyses. The respective median follow-up time in PP analyses ranged 2.20–2.61 years in metformin (−) and ranged 3.99–4.65 years in metformin (+). In the ITT analyses, for metformin (−), the incidence rates (per 100,000 person-years) of varicocele, ED, infertility, prostatitis, BPH and prostate cancer were 26.42, 455.89, 22.82, 590.23, 4226.19, and 141.69, respectively; and the respective incidence rates for metformin (+) were 25.65, 488.10, 32.60, 510.30, 3685.66, and 116.57. The hazard ratios (95% confidence intervals) comparing metformin (+) to metformin (−) in the ITT analyses were 0.960 (0.784–1.174) for varicocele, 1.077 (1.026–1.130) for ED, 1.368 (1.116–1.676) for infertility, 0.887 (0.849–0.927) for prostatitis, 0.883 (0.868–0.899) for BPH and 0.878 (0.802–0.961) for prostate cancer. The hazard ratios for the respective outcomes in the PP analyses were 0.845 (0.662–1.078), 1.350 (1.264–1.441), 1.396 (1.078–1.808), 0.800 (0.756–0.846), 0.875 (0.855–0.895), and 0.613 (0.548–0.686).Conclusion: Metformin use in patients with type 2 diabetes mellitus is associated with a neutral effect on varicocele, a higher risk of sexual dysfunction (ED and infertility) and a reduced risk of prostate-related health (prostatitis, BPH and prostate cancer).

Aim: To investigate the risk of diverticula of intestine associated with metformin use.Methods: This retrospective cohort study used the Taiwan’s National Health Insurance database to enroll 307,548 ever users and 18,839 never users of metformin. The patients were followed up starting on January 1, 2006 and ending on a date up to December 31, 2011. To address confounding by indication, hazard ratios were derived from Cox regression based on the inverse probability of treatment weighting using propensity score.Results: During follow-up, newly diagnosed cases of diverticula were identified in 1,828 ever users (incidence rate: 125.59 per 100,000 person-years) and 223 never users (incidence rate: 268.17 per 100,000 person-years). Ever users had an approximately 54% lower risk, as shown by the overall hazard ratio of 0.464 (95% confidence interval 0.404–0.534). While patients categorized in each tertile of cumulative duration of metformin therapy were compared to never users, a dose-response pattern was observed with hazard ratios of 0.847 (0.730–0.983), 0.455 (0.391–0.531) and 0.216 (0.183–0.255) for the first (59.70 months) tertiles, respectively. The findings were similar when the diagnosis of diverticula was restricted to the small intestine or to the colon. Subgroup analyses suggested that the lower risk of diverticula of intestine associated with metformin use was significant in all age groups of

Background: Metformin has anti-inflammatory property and reduces the risk of varicose vein in our previous study.Aim: To investigate the risk of hemorrhoid, another common disease involving the hemorrhoidal venous plexus, in ever vs. never users of metformin in patients with type 2 diabetes mellitus.Methods: This is a population-based retrospective cohort study. Patients with new-onset type 2 diabetes mellitus during 1999–2005 were enrolled from Taiwan’s National Health Insurance. All patients who were alive on January 1, 2006 were followed up until December 31, 2011. Analyses were conducted in both an unmatched cohort of 152,347 ever users and 19,523 never users and in 19,498 propensity score (PS)-matched pairs of ever and never users. Traditional Cox regression and Cox regression incorporated with the inverse probability of treatment weighting (IPTW) using the PS were used to estimate hazard ratios.Results: New-onset hemorrhoid was diagnosed in 8,211 ever users and 2025 never users in the unmatched cohort and in 1,089 ever users and 2022 never users in the matched cohort. The hazard ratio for ever vs. never users derived from the traditional Cox regression was 0.464 (95% confidence interval: 0.440–0.488) in the unmatched cohort; and was 0.488 (0.453–0.525) in the matched cohort. In the IPTW models, the hazard ratio was 0.464 (0.442–0.487) in the unmatched cohort and was 0.492 (0.457–0.530) in the matched cohort. A dose-response pattern was observed while comparing the tertiles of cumulative duration, cumulative dose and defined daily dose of metformin therapy to never users in all analyses. A risk reduction of approximately 40–50% was consistently observed in various sensitivity analyses.Conclusion: Chronic therapy with metformin in patients with type 2 diabetes mellitus is associated with a lower risk of hemorrhoid.