Thiazolidinedione Use Is Associated with a Borderline Lower Risk of Multiple Myeloma and a Significantly Lower Risk of Death in Patients with Type 2 Diabetes Mellitus in Taiwan.

BACKGROUND: Thiazolidinedione (TZD) exerts anti-proliferative effects on multiple myeloma (MM) cells. However, there has not been any human study investigating the risk of MM associated with TZD use. METHODS: We used Taiwan's National Health Insurance database to identify 423,949 patients who had been newly diagnosed with diabetes mellitus between 1999 and 2005. After excluding ineligible patients, 86,999 pairs of patients with and without the use of TZD (rosiglitazone or pioglitazone) that had been matched based on propensity score were selected for a follow-up for MM until 31 December 2011. The hazard ratios for MM were estimated using Cox regression and weighted using a propensity score. RESULTS: After a median follow-up of 4.6 years and 4.7 years in ever users and never users of TZD, 32 and 47 cases were diagnosed with MM, respectively. A 35% lower risk (though not statistically significant) was observed among ever users (hazard ratio 0.652, 95% confidence interval: 0.416-1.023, p = 0.0625). When ever users were divided by the median (15 months) cumulative duration of TZD therapy, the hazard ratios (95% confidence interval) for the lower and upper medians were 0.706 (0.394-1.264) and 0.603 (0.346-1.051), respectively. When treated as a continuous variable, the hazard ratio for every 1-month increment of the cumulative duration was 0.980 (95% confidence interval: 0.963-0.997, p = 0.0185). In the age subgroup analysis, a significantly lower risk could be seen in the older age subgroup of ≥65 years (hazard ratio 0.550, 95% confidence interval: 0.305-0.992, p = 0.0468). Additional analyses suggested that there were no interactions between TZD and some medications and between TZD and some clinical diagnoses, and that the use of TZD as a preventive drug for MM might not be cost-effective because a number-needed-to-treat of 5800 was too large. Survival analyses suggested that ever users had a significantly lower risk of death when all patients were analyzed (hazard ratio: 0.84, 95% confidence interval: 0.81-0.87, p < 0.0001 via a log-rank test) or when patients who developed MM were analyzed (hazard ratio: 0.40, 95% confidence interval: 0.19-0.86, p = 0.0153 via a log-rank test). CONCLUSIONS: In Taiwanese patients with type 2 diabetes mellitus, TZD use is associated with a borderline lower risk of MM, which is more remarkable in patients aged ≥65 years. Because of the low incidence of MM, the use of TZD for the prevention of MM may not be cost-effective. Patients who have been treated with TZD may have a survival advantage. Future research is required to confirm the findings.

Rosiglitazone has a null association with the risk of prostate cancer in type 2 diabetes patients.

Background: This study investigated the risk of prostate cancer in ever users and never users of rosiglitazone in diabetes patients in Taiwan. Methods: The nationwide database of the National Health Insurance was used to enroll male patients who had a new diagnosis of type 2 diabetes mellitus at an age ≥ 25 years from 1999 to 2005. A total of 11,495 ever users and 11,495 never users of rosiglitazone matched on propensity score were selected and they were followed up for the incidence of prostate cancer from January 1, 2006 until December 31, 2011. Cox proportional hazard model incorporated with the inverse probability of treatment weighting using the propensity score was used to estimate hazard ratios. Results: At the end of follow-up, incident cases of prostate cancer were found in 84 never users and 90 ever users of rosiglitazone. The calculated incidence was 173.20 per 100,000 person-years in never users and was 187.59 per 100,000 person-years in ever users. The overall hazard ratio (95% confidence intervals) for ever versus never users was 1.089 (0.808-1.466). The hazard ratios were 0.999 (0.643-1.552) for the first tertile (< 672 mg), 1.147 (0.770-1.709) for the second tertile (672-3584 mg) and 1.116 (0.735-1.695) for the third tertile (> 3584 mg) of cumulative dose. Sensitivity analyses consistently showed a null association between rosiglitazone and prostate cancer risk. Conclusion: Rosiglitazone has a null effect on the risk of prostate cancer.

The Risk of Age-Related Macular Degeneration Is Reduced in Type 2 Diabetes Patients Who Use Metformin.

BACKGROUND: Whether metformin may reduce the risk of age-related macular degeneration (AMD) requires confirmation. This study compared the risk of AMD between ever users and never users of metformin matched on propensity score (PS) in Taiwanese patients with type 2 diabetes mellitus. METHODS: We enrolled study subjects from Taiwan's National Health Insurance. A total of 423,949 patients with new onset diabetes from 1999 to 2005 were identified. After excluding ineligible patients and enrolling only patients aged between 50 and 79 years, we created 13,303 pairs of ever users and never users of metformin matched on PS. The patients were followed from 1 January 2006 to 31 December 2011. We estimated hazard ratios by Cox regression. RESULTS: AMD was newly diagnosed in 506 ever users and 639 never users. The respective incidence rates (per 100,000 person-years) were 778.72 and 1016.62. The hazard ratio (HR) and 95% confidence interval (CI) for ever versus never users was 0.756 (0.673-0.850). While ever users were categorized by tertiles of cumulative duration (<31.8, 31.8-63.9 and >63.9 months) and cumulative dose (<947.1, 947.1-2193.5 and >2193.5 g) of metformin, a dose-response pattern was observed. For the respective tertiles of cumulative duration, the HRs (95% CIs) were 1.131 (0.961-1.330), 0.821 (0.697-0.967) and 0.464 (0.384-0.561), while compared to never users. For the respective tertiles of cumulative dose, the HRs (95% CIs) were 1.131 (0.962-1.329), 0.739 (0.624-0.876) and 0.525 (0.438-0.629). A risk reduction among ever users was observed for all tertiles of defined daily dose but was most remarkable for the third tertile with a defined daily dose of >0.64. Subgroup analyses suggested that the benefit of metformin could be similarly observed among men and women and for age subgroups of 50-64 and 65-79 years. However, patients with diabetic retinopathy would not be significantly benefited and metformin did not seem to be preventive for exudative AMD. CONCLUSION: In general, metformin significantly reduces the risk of AMD.

Rosiglitazone Does Not Affect the Risk of Inflammatory Bowel Disease: A Retrospective Cohort Study in Taiwanese Type 2 Diabetes Patients.

Human studies on the effect of rosiglitazone on inflammatory bowel disease (IBD) are still lacking. We investigated whether rosiglitazone might affect IBD risk by using the reimbursement database of Taiwan's National Health Insurance to enroll a propensity-score-matched cohort of ever users and never users of rosiglitazone. The patients should have been newly diagnosed with diabetes mellitus between 1999 and 2006 and should have been alive on 1 January 2007. We then started to follow the patients from 1 January 2007 until 31 December 2011 for a new diagnosis of IBD. Propensity-score-weighted hazard ratios were estimated with regards to rosiglitazone exposure in terms of ever users versus never users and in terms of cumulative duration and cumulative dose of rosiglitazone therapy for dose-response analyses. The joint effects and interactions between rosiglitazone and risk factors of psoriasis/arthropathies, dorsopathies, and chronic obstructive pulmonary disease/tobacco abuse and the use of metformin were estimated by Cox regression after adjustment for all covariates. A total of 6226 ever users and 6226 never users were identified and the respective numbers of incident IBD were 95 and 111. When we compared the risk of IBD in ever users to that of the never users, the estimated hazard ratio (0.870, 95% confidence interval: 0.661-1.144) was not statistically significant. When cumulative duration and cumulative dose of rosiglitazone therapy were categorized by tertiles and hazard ratios were estimated by comparing the tertiles of rosiglitazone exposure to the never users, none of the hazard ratios reached statistical significance. In secondary analyses, rosiglitazone has a null association with Crohn's disease, but a potential benefit on ulcerative colitis (UC) could not be excluded. However, because of the low incidence of UC, we were not able to perform detailed dose-response analyses for UC. In the joint effect analyses, only the subgroup of psoriasis/arthropathies (-)/rosiglitazone (-) showed a significantly lower risk in comparison to the subgroup of psoriasis/arthropathies (+)/rosiglitazone (-). No interactions between rosiglitazone and the major risk factors or metformin use were observed. We concluded that rosiglitazone has a null effect on the risk of IBD, but the potential benefit on UC awaits further investigation.

Metformin Reduces the Risk of Hearing Loss: A Retrospective Cohort Study.

OBJECTIVE: To compare the risk of hearing loss with regard to metformin exposure. STUDY DESIGN: Retrospective cohort. SETTING: Taiwan's National Health Insurance database. METHODS: We enrolled 292,071 ever users and 18,200 never users of metformin with new-onset diabetes mellitus from 1999 to 2005 and followed them for hearing loss from January 1, 2006, to December 31, 2011. Hazard ratios (HRs) weighted by propensity score were estimated. RESULTS: Hearing loss was newly diagnosed in 10,085 ever users and 1072 never users. Their respective incidence rates (per 100,000 person-years) were 738.09 and 1366.83. The HR comparing ever-to-never users was 0.534 (95% confidence interval [CI]: 0.501-0.569]. The HR (95% CI) for the first (<27.07 months), second (27.07-59.13 months), and third (>59.13 months) tertiles of cumulative duration of metformin therapy were 0.912 (0.852-0.975), 0.544 (0.508-0.582), and 0.275 (0.255-0.295), respectively; and were 0.900 (0.841-0.962), 0.531 (0.496-0.569), and 0.293 (0.273-0.315), respectively, for the first (<796.70 g), second (796.70-2020.15 g), and third (>2020.15 g) tertiles of cumulative dose. The magnitude of risk reduction became more remarkable in corresponding to the increasing tertiles of the defined daily dose prescribed. Subtype analyses suggested that the risk reduction was more significant for sensorineural than conductive hearing loss. Findings derived from a propensity score-matched cohort did not substantially change the conclusions, and the risk reduction for mixed hearing loss was not statistically significant in the matched cohort as significantly observed in the unmatched cohort. CONCLUSION: The risk of hearing loss is reduced in a dose-response pattern in patients who use metformin.

Differential Effects of Metformin on Immune-Mediated and Androgen-Mediated Non-Cancer Skin Diseases in Diabetes Patients: A Retrospective Cohort Study.

BACKGROUND: Metformin's effects on non-cancer skin diseases are rarely investigated. OBJECTIVE: The aim of the study was to investigate immune-mediated (urticaria, allergic contact dermatitis, and psoriasis) and androgen-mediated (acanthosis nigricans, hidradenitis suppurativa, and acne) skin diseases associated with metformin use. METHODS: Metformin initiators (n = 234,585) and non-metformin initiators (n = 125,921) within the initial 12 months of antidiabetic drug prescription during 1999-2009 were followed up until December 31, 2011. Cox regression weighted for propensity score was used to estimate hazard ratios for metformin initiators versus non-metformin initiators in intention-to-treat (ITT) and per-protocol (PP) analyses. RESULTS: For immune-mediated skin diseases, hazard ratios were 0.930 (95% confidence interval: 0.920-0.940) and 0.930 (0.918-0.943) in ITT and PP analyses, respectively, and the hazard ratios for each specific outcome were all significantly below unity. For androgen-mediated skin diseases, the ITT and PP hazard ratios were 1.110 (1.060-1.162) and 0.990 (0.935-1.048), respectively, and all hazard ratios were not significant for each specific outcome except for acne in the ITT analysis (hazard ratio: 1.116, 95% confidence interval: 1.064-1.170). CONCLUSION: Metformin use is associated with a significantly lower risk of immune-mediated skin diseases but lacks a preventive effect on androgen-mediated skin diseases.

Effect of Metformin on Lower Urinary Tract Symptoms in Male Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study in Taiwan.

PURPOSE: This study investigated the risk of lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) associated with metformin use. MATERIALS AND METHODS: We used the database of Taiwan's National Health Insurance to create 9,833 pairs of ever users and never users of metformin matched on propensity score. They were males with a new diagnosis of type 2 diabetes during 1999-2005. The incidence of LUTS/BPH was calculated from January 1, 2006 until December 31, 2011. We estimated hazard ratios by Cox regression weighted on propensity score. RESULTS: There were 515 incident cases in ever users after a median follow-up of 5.4 years (incidence rate: 11.24 per 1,000 person-years) and 682 cases in never users after 5.2 years (15.92 per 1,000 person-years). The hazard ratio (HR) that compared ever to never users was 0.69 (95% confidence interval [CI], 0.62-0.78). The HRs that compared ever users categorized into quartiles of cumulative duration (<19.33, 19.33-41.56, 41.57-67.17, and >67.17 mo) to never users were 1.02 (0.84-1.23), 1.01 (0.86-1.20), 0.57 (0.47-0.69), and 0.40 (0.32-0.49), respectively. For the quartiles of cumulative dose of <582.00, 582.00-1,361.00, 1,361.01-2,449.00, and >2,449.00 g, the respective HRs were 1.03 (0.85-1.24), 0.96 (0.81-1.13), 0.60 (0.49-0.72), and 0.40 (0.32-0.50). The lower risk was significant in all quartiles of defined daily dose. However, a larger daily dose was associated with a greater risk reduction. There were no significant interactions between metformin and other antidiabetic drugs. Patients who used rosiglitazone and/or pioglitazone without metformin had a significantly higher risk (HR, 1.33; 95% CI, 1.09-1.63) and a combination with metformin attenuated such an adverse impact (HR, 0.78; 95% CI, 0.66-0.91). CONCLUSIONS: A significantly lower risk of LUTS/BPH is observed in males with type 2 diabetes who use metformin.

Pioglitazone and Prostate Cancer Risk in Taiwanese Male Patients with Type 2 Diabetes: A Retrospective Cohort Study.

PURPOSE: This study investigated prostate cancer risk associated with pioglitazone use. MATERIALS AND METHODS: The Taiwan's National Health Insurance database was used to create a propensity score-matched cohort of male patients with type 2 diabetes mellitus newly diagnosed in 1999-2005 and aged ≥25 years at baseline. The matched cohort included 20437 ever users and 20437 never users of pioglitazone. The patients were followed up for the incidence of prostate cancer until December 31, 2011. Hazard ratios (HRs) were created from Cox regression weighted on propensity score. RESULTS: Prostate cancer was diagnosed in 121 ever users of pioglitazone (incidence: 175.84 per 100,000 person-years) and 143 never users of pioglitazone (incidence: 216.66 per 100,000 person-years). When ever users were compared to never users of pioglitazone, the HR was 0.815 (95% confidence interval [CI], 0.639-1.039; p=0.0987). When ever users were categorized into tertiles of cumulative duration of pioglitazone therapy (<6.83, 6.83-20.23, and >20.23 months), the HRs were 1.044 (95% CI, 0.741-1.471), 0.975 (95% CI, 0.690-1.377) and 0.539 (95% CI, 0.374-0.778), respectively. For the tertiles of cumulative dose of <5,040, 5,040-15,330, and >15,330 mg, the HRs were 1.008 (95% CI, 0.710-1.429), 1.090 (95% CI, 0.785-1.515) and 0.484 (95% CI, 0.330-0.711), respectively. A significantly lower risk associated with pioglitazone use could only be seen in patients aged <65 years (HR, 0.578; 95% CI, 0.360-0.927) but not in patients aged ≥65 years. CONCLUSIONS: A significantly lower risk of prostate cancer is observed after a cumulative duration of pioglitazone therapy for >20.23 months or a cumulative dose of >15,330 mg. The risk reduction is mainly observed in patients aged <65 years.

Pioglitazone Has a Null Association with Inflammatory Bowel Disease in Patients with Type 2 Diabetes Mellitus.

Pioglitazone shows potential benefits in inflammatory bowel disease (IBD) in preclinical studies, but its effect in humans has not been researched. We used a nationwide database of Taiwan's National Health Insurance to investigate whether pioglitazone might affect IBD risk. We enrolled 12,763 ever users and 12,763 never users matched on a propensity score from patients who had a new diagnosis of type 2 diabetes mellitus between 1999 and 2008. The patients were alive on 1 January 2009, and they were followed up for a new diagnosis of IBD until 31 December 2011. Propensity score-weighted hazard ratios were estimated, and the interactions between pioglitazone and major risk factors of IBD (i.e., psoriasis, arthropathies, dorsopathies, chronic obstructive pulmonary disease/tobacco abuse, and any of the above) and metformin were investigated. At the end of the follow-up, 113 ever users and 139 never users were diagnosed with IBD. When compared to never users, the hazard ratio for ever users was 0.809 (95% confidence interval: 0.631-1.037); and none of the hazard ratios for ever users categorized by tertiles of cumulative duration and cumulative dose reached statistical significance. No interactions with major risk factors or metformin were observed. Our findings suggested a null effect of pioglitazone on IBD.

The Risk of Multiple Myeloma Is Reduced in Metformin Initiators: A Retrospective Cohort Study in Taiwanese Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Whether metformin might reduce the risk of multiple myeloma (MM) has not been extensively researched in humans. METHODS: The study subjects were enrolled from the reimbursement database of Taiwan's National Health Insurance. A total of 739,553 patients who had a new diagnosis of type 2 diabetes mellitus during 1999-2009 were identified. They were categorized as metformin initiators (metformin (+)) and non-metformin initiators (metformin (-)) based on the prescriptions of antidiabetic drugs that included metformin and did not include metformin within the initial 12 months, respectively. MM incidence was calculated after the initial 12 months of treatment group assignment until 31 December 2011. Hazard ratios based on intention-to-treat (ITT) and per-protocol (PP) approaches were estimated by Cox regression weighted by propensity scores. RESULTS: In the ITT analyses, the respective incidence rates for 497,248 metformin (+) and 242,305 metformin (-) were 9.97 and 14.33 per 100,000 person-years. The hazard ratio that compared metformin (+) to metformin (-) in the ITT analysis was 0.710 (95% confidence interval 0.593-0.850). In the PP analysis, the respective incidence rates were 5.14 and 13.98 per 100,000 person-years, and the hazard ratio was 0.355 (95% confidence interval, 0.270-0.466). The lower risk of MM among metformin (+) was supported by subgroup and sensitivity analyses. CONCLUSIONS: Type 2 diabetes patients who are initiated with metformin treatment have a significantly lower risk of MM, especially when they adhere to metformin treatment.

Metformin and risk of gingival/periodontal diseases in diabetes patients: A retrospective cohort study.

Aim: To compare the risk of gingival and periodontal diseases (GPD) between ever users and never users of metformin in patients with type 2 diabetes mellitus. Methods: The Taiwan's National Health Insurance database was used to enroll 423,949 patients with new onset diabetes mellitus from 1999 to 2005. After excluding ineligible patients, 60,309 ever users and 5578 never users were followed up for the incidence of GPD from January 1, 2006 until December 31, 2011. Propensity score-weighted hazard ratios were estimated by Cox regression. Results: GPD was newly diagnosed in 18,528 ever users (incidence: 7746.51 per 100,000 person-years) and 2283 never users (incidence: 12158.59 per 100,000 person-years). The hazard ratio that compared ever users to never users was 0.627 (95% confidence interval: 0.600-0.655). When metformin use was categorized by tertiles of cumulative duration and cumulative dose, the risk significantly reduced in a dose-response pattern when the cumulative duration reached approximately 2 years or the cumulative dose reached 670 grams. Analyses on the tertiles of defined daily dose of metformin showed that the reduction of GPD risk could be seen in all three subgroups but the benefit would be greater when the daily dose increased. Conclusion: Long-term use of metformin is associated with a significantly reduced risk of GPD.

Metformin's effects on varicocele, erectile dysfunction, infertility and prostate-related diseases: A retrospective cohort study.

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).

Pioglitazone and breast cancer risk in female patients with type 2 diabetes mellitus: a retrospective cohort analysis.

BACKGROUND: Whether pioglitazone may affect breast cancer risk in female diabetes patients is not conclusive and has not been investigated in the Asian populations. METHODS: The reimbursement database of Taiwan's National Health Insurance was used to enroll an unmatched cohort and a propensity score-matched cohort of ever users and never users of pioglitazone in female patients with newly diagnosed type 2 diabetes during 1999-2008. The patients were alive on January 1, 2009 and were followed up for breast cancer incidence until December 31, 2011. Cox regression was used to estimate hazard ratios for ever users and tertiles of cumulative duration of pioglitazone therapy versus never users, and for cumulative duration of pioglitazone therapy treated as a continuous variable. Three models were created for the unmatched cohort and the matched cohort, respectively: 1) without adjustment for covariates; 2) after adjustment for covariates that differed with statistical significance (P-value < 0.05) between ever users and never users; and 3) after adjustment for all covariates. RESULTS: There were 174,233 never users and 6926 ever users in the unmatched cohort; and 6926 never users and 6926 ever users in the matched cohort. After a median follow-up of 2.8 years, the numbers of incident breast cancer were 1044 in never users and 35 in ever users in the unmatched cohort and were 41 and 35, respectively, in the matched cohort. Hazard ratios suggested a null association between pioglitazone and breast cancer in all three models in either the unmatched cohort or the matched cohort. The overall hazard ratio after adjustment for all covariates was 0.758 (95% confidence interval: 0.539-1.065) in the unmatched cohort and was 0.824 (95% confidence interval: 0.524-1.296) in the matched cohort. None of the hazard ratios for the tertiles of cumulative duration of pioglitazone therapy and for the cumulative duration being treated as a continuous variable were statistically significant. CONCLUSIONS: This study suggests a null association between pioglitazone and breast cancer risk in female patients with type 2 diabetes mellitus. However, because of the small breast cancer cases and the limited follow-up time, further studies are warranted to confirm our findings.

Pioglitazone and Risk of Chronic Obstructive Pulmonary Disease in Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study.

BACKGROUND: Pioglitazone's effect on chronic obstructive pulmonary disease (COPD) has rarely been studied. PURPOSE: This retrospective observational study investigated whether the use of pioglitazone would affect the risk of COPD in patients with type 2 diabetes mellitus. PATIENTS AND METHODS: The Taiwan's National Health Insurance database was used to enroll 9487 matched pairs of ever users and never users of pioglitazone based on propensity score from a cohort of 350,536 patients. The enrolled patients had a new diagnosis of type 2 diabetes mellitus between 1999 and 2008 and were not having a diagnosis of COPD before January 1, 2009. They were then followed up for COPD, starting from January 1, 2009 until December 31, 2011. Diagnosis of COPD was based on the codes of 491 for chronic bronchitis and 492 for emphysema based on the International Classification of Diseases, Ninth Revision, Clinical Modification. Cox regression was used to estimate hazard ratios. The interactions between pioglitazone and COPD risk factors including pneumonia, pulmonary tuberculosis and tobacco abuse were also investigated. RESULTS: In 9487 never users and 9487 ever users of pioglitazone, the case numbers of incident COPD were 359 and 295, respectively. The respective incidence rates of COPD were 1484.73 and 1167.61 per 100,000 person-years. The overall hazard ratio (95% confidence interval) for COPD that compared ever to never users was 0.778 (0.667-0.908). The hazard ratios for the tertiles of cumulative duration of pioglitazone therapy (cutoffs: <11.0, 11.0-19.6 and >19.6 months) to never users were 0.904 (0.729-1.121), 0.727 (0.578-0.914) and 0.715 (0.570-0.896), respectively. No interactions between pioglitazone and COPD risk factors including pneumonia, pulmonary tuberculosis and tobacco abuse were noted. CONCLUSION: Pioglitazone use is associated with a significantly lower risk of COPD.

The Effect of Metformin on Male Reproductive Function and Prostate: An Updated Review.

Metformin is the first-line oral antidiabetic drug that shows multiple pleiotropic effects of anti-inflamation, anti-cancer, anti-aging, anti-microbia, anti-atherosclerosis, and immune modulation. Metformin's effects on men's related health are reviewed here, focusing on reproductive health under subtitles of erectile dysfunction (ED), steroidogenesis and spermatogenesis; and on prostate-related health under subtitles of prostate specific antigen (PSA), prostatitis, benign prostate hyperplasia (BPH), and prostate cancer (PCa). Updated literature suggests a potential role of metformin on arteriogenic ED but controversial and contradictory effects (either protective or harmful) on testicular functions of testosterone synthesis and spermatogenesis. With regards to prostate-related health, metformin use may be associated with lower levels of PSA in humans, but its clinical implications require more research. Although there is a lack of research on metform's effect on prostatitis, it may have potential benefits through its anti-microbial and anti-inflammatory properties. Metformin may reduce the risk of BPH by inhibiting the insulin-like growth factor 1 pathway and some but not all studies suggest a protective role of metformin on the risk of PCa. Many clinical trials are being conducted to investigate the use of metformin as an adjuvant therapy for PCa but results currently available are not conclusive. While some trials suggest a benefit in reducing the metastasis and recurrence of PCa, others do not show any benefit. More research works are warranted to illuminate the potential usefulness of metformin in the promotion of men's health.

Metformin Is Associated with a Lower Incidence of Benign Brain Tumors: A Retrospective Cohort Study in Patients with Type 2 Diabetes Mellitus.

Background: The risk of benign brain tumors (BBT) associated with metformin use has not received much attention. Therefore, a retrospective cohort study was designed to investigate such an association in patients with type 2 diabetes mellitus (T2DM). Methods: We used the database of Taiwan's National Health Insurance to enroll 152,176 ever users and 16,120 never users of metformin for the follow-up of incidence of BBT and a more specific outcome of cerebral meningioma. The patients were newly diagnosed with T2DM between 1999 and 2005; and they were followed up from 1 January 2006 until 31 December 2011. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Results: During follow-up, 111 never users and 557 ever users were diagnosed with BBT. For BBT, the respective incidence rates for never users and ever users were 153.95 per 100,000 person-years and 77.61 per 100,000 person-years. While ever users were compared to never users, the hazard ratio was 0.502 (95% confidence interval: 0.409-0.615). A dose-response pattern was seen when ever users were categorized into tertiles of cumulative duration of metformin therapy (cutoffs: <27.10 months, 27.10-58.27 months and >58.27 months) with respective hazard ratios of 0.910 (0.728-1.138), 0.475 (0.375-0.602) and 0.243 (0.187-0.315). For cerebral meningioma, the overall hazard ratio was 0.506 (0.317-0.808); and the hazard ratios comparing the respective tertiles to never users were 0.895 (0.531-1.508), 0.585 (0.346-0.988) and 0.196 (0.104-0.369). Conclusions: A reduced risk of BBT and cerebral meningioma is observed in metformin users in patients with T2DM.

Metformin Reduces the Risk of Diverticula of Intestine in Taiwanese Patients with Type 2 Diabetes Mellitus.

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 (<27.37 months), second (27.37-59.70 months) and third (>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 <50, 50-64 and ≥65 years, but the magnitude of risk reduction attenuated with increasing age. Conclusion: Metformin treatment is associated with a significantly reduced risk of diverticula of intestine.

The Relationship between Diabetes Mellitus and Gastric Cancer and the Potential Benefits of Metformin: An Extensive Review of the Literature.

The objective of this review is to summarize the findings of published research that investigated the relationship between diabetes mellitus and gastric cancer (GCa) and the potential benefits of metformin on GCa. Related literature has been extensively reviewed, and findings from studies investigating the relationship between diabetes mellitus and GCa suggest that hyperglycemia, hyperinsulinemia and insulin resistance are closely related to the development of GCa. Although not supported by all, most observational studies suggest an increased risk of GCa in patients with type 2 diabetes mellitus, especially in women and in Asian populations. Incidence of second primary malignancy diagnosed after GCa is significantly higher in diabetes patients. Diabetes patients with GCa may have more complications after gastrectomy or chemotherapy and they may have a poorer prognosis than patients with GCa but without diabetes mellitus. However, glycemic control may improve in the diabetes patients with GCa after receiving gastrectomy, especially after procedures that bypass the duodenum and proximal jejunum, such as Roux-en-Y gastric bypass or Billroth II reconstruction. The potential links between diabetes mellitus and GCa may involve the interactions with shared risk factors (e.g., obesity, hyperglycemia, hyperinsulinemia, insulin resistance, high salt intake, smoking, etc.), Helicobacter pylori (HP) infection, medications (e.g., insulin, metformin, statins, aspirin, proton pump inhibitors, antibiotics, etc.) and comorbidities (e.g., hypertension, dyslipidemia, vascular complications, heart failure, renal failure, etc.). With regards to the potential benefits of metformin on GCa, results of most observational studies suggest a reduced risk of GCa associated with metformin use in patients with T2DM, which can be supported by evidence derived from many in vitro and animal studies. Metformin use may also reduce the risk of HP infection, an important risk factor of GCa. In patients with GCa, metformin users may have improved survival and reduced recurrence. More studies are required to clarify the pathological subtypes/anatomical sites of GCa associated with type 2 diabetes mellitus or prevented by metformin, to confirm whether GCa risk can also be increased in patients with type 1 diabetes mellitus and to explore the possible role of gastric microbiota in the development of GCa.

Metformin and Risk of Malignant Brain Tumors in Patients with Type 2 Diabetes Mellitus.

The risk of malignant brain tumors associated with metformin use has rarely been investigated in humans. This retrospective cohort study investigated such an association. Patients with new-onset type 2 diabetes mellitus diagnosed from 1999 to 2005 in the nationwide database of Taiwan's national health insurance were used to enroll study subjects. We first identified an unmatched cohort of 153,429 ever users and 16,222 never users of metformin. A cohort of 16,222 ever users and 16,222 never users matched on propensity score was then created from this unmatched cohort. All patients were followed up from 1 January 2006 until 31 December 2011. The incidence density was calculated and hazard ratios were derived from Cox regression incorporated with the inverse probability of treatment weighting using a propensity score. The results showed that 27 never users and 155 ever users developed malignant brain tumors in the unmatched cohort. The incidence rate was 37.11 per 100,000 person-years in never users and 21.39 per 100,000 person-years in ever users. The overall hazard ratio comparing ever users versus never users was 0.574 (95% confidence interval: 0.381-0.863). The respective hazard ratios comparing the first (<27.13 months), second (27.13-58.33 months), and third (>58.33 months) tertiles of cumulative duration of metformin therapy versus never users were 0.897 (0.567-1.421), 0.623 (0.395-0.984), and 0.316 (0.192-0.518). In the matched cohort, the overall hazard ratio was 0.317 (0.149-0.673) and the respective hazard ratios were 0.427 (0.129-1.412), 0.509 (0.196-1.322), and 0.087 (0.012-0.639) for the first, second, and third tertile of cumulative duration of metformin therapy. In conclusion, this study shows a risk reduction of malignant brain tumors associated with metformin use in a dose-response pattern. The risk reduction is more remarkable when metformin has been used for approximately 2-5 years.

Metformin and primary bone cancer risk in Taiwanese patients with type 2 diabetes mellitus.

BACKGROUND: The effect of metformin on primary bone cancer risk has not been researched. This retrospective cohort study investigated the risk of primary bone cancer between metformin initiators and non-metformin initiators in patients with type 2 diabetes mellitus. METHODS: A total of 673,532 patients with newly diagnosed type 2 diabetes mellitus and had been prescribed antidiabetic drugs for 2 or more times during 1999-2009 were enrolled from Taiwan's National Health Insurance. Metformin initiators and non-metformin initiators were defined according to the prescriptions of antidiabetic drugs within the initial 12 months. The patients were then followed up until December 31, 2011 for the incidence of primary bone cancer. Cox regression incorporated with the inverse probability of treatment-weighting using propensity scores was used to estimate hazard ratios in intention-to-treat and per-protocol analyses. RESULTS: In the intention-to-treat analysis, the respective incidence rates were 10.56 and 12.90 per 100,000 person-years in 453,532 metformin initiators and 220,000 non-metformin initiators and the hazard ratio for initiators versus non-initiators was 0.830 (95% confidence interval 0.686-1.004, P-value = 0.0551). In the per-protocol analysis, the incidence rates were 7.58 and 11.77 per 100,000 person-years, respectively, and the hazard ratio was 0.615 (95% confidence interval 0.468-0.808, P-value = 0.0005). Subgroup analyses with regards to sex and age (<60 and ≥60 years) showed that the significantly lower risk associated with metformin use was only observed in men aged ≥60 years in the per-protocol analysis. CONCLUSIONS: A significantly lower risk of primary bone cancer can be observed in patients with type 2 diabetes mellitus who adhere to metformin treatment. This benefit can only be observed in men aged ≥60 years.