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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 (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 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.

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 (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 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 20.23 months or a cumulative dose of >15,330 mg. The risk reduction is mainly observed in patients aged

BackgroundThis study investigated the risk of prostate cancer in ever users and never users of rosiglitazone in diabetes patients in Taiwan.MethodsThe 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.ResultsAt 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.ConclusionRosiglitazone has a null effect on the risk of prostate cancer.

Abstract 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

Self-monitoring of blood glucose (SMBG) is common in patients with diabetes. The aim of this study was to explore how frequency/behavior of SMBG affect glucose control in patients with type 2 diabetes. This cross-sectional study was conducted at a regional teaching hospital in Taiwan. All participants completed a structured questionnaire about the frequency and behavior of SMBG, and hemoglobulin A1C (A1C) data were recorded from medical records. A total of 382 diabetes outpatients participated in the study. In the patients using insulin injections, A1C was better in patients with SMBG ≥ 28 times than in those with SMBG < 28 times per month (7.82 ± 1.86% vs. 8.33 ± 1.31%, p = 0.025). In the patients not using insulin, A1C was better in patients with SMBG > 14 times than those with SMBG ≤ 14 times per month (7.08 ± 0.23% vs. 7.55 ± 0.08%, p = 0.038). The patients who more frequently reviewed the causes of hypoglycemia and hyperglycemia had a better A1C level (p for linear trend 14 times could improve glycemic control for insulin-requiring and non-insulin-requiring type 2 diabetes patients, respectively. Further exploration of the cause of hyperglycemia or hypoglycemia shown by SMBG could also improve blood glucose control.

Metformin is the first-line oral antidiabetic drug that shows multiple pleiotropic effects of anti-inflamation, anti-cancer, antiaging, 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.

AimTo compare the risk of gingival and periodontal diseases (GPD) between ever users and never users of metformin in patients with type 2 diabetes mellitus.MethodsThe 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.ResultsGPD 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.ConclusionLong-term use of metformin is associated with a significantly reduced risk of GPD.

Abstract This retrospective cohort study used the nationwide database of Taiwan’s National Health Insurance to investigate whether metformin would reduce the risk of acute appendicitis in patients with type 2 diabetes mellitus. We first identified 423,949 patients newly diagnosed of diabetes from 1999 to 2005. After excluding patients having type 1 diabetes mellitus, missing data, previous history of acute appendicitis, aged 80 years and followed up for 50%. The benefit did not differ between different formulations of metformin, and the estimated hazard ratio for conventional/immediate-release metformin versus never users was 0.516 (0.441–0.603) and was 0.509 (0.421–0.615) for prolonged/slow-release metformin versus never users. It is concluded that metformin use is associated with a reduced risk of acute appendicitis in patients with type 2 diabetes mellitus.

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).

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.

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 (63.9 months) and cumulative dose (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.

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.

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 and aimsAnimal studies suggested that vildagliptin might exert a beneficial effect on cognitive function. The present study evaluated whether the use of vildagliptin in patients with type 2 diabetes mellitus might affect dementia risk.MethodsThe database of Taiwan’s National Health Insurance was used to enroll an unmatched cohort and a propensity score-matched-pair cohort of ever and never users of vildagliptin from patients with newly diagnosed diabetes mellitus during 2002-2014. The patients should be alive on January 1, 2015 and were followed up for dementia diagnosis until December 31, 2016. Unadjusted and multivariate-adjusted hazard ratios (HR) and their 95% confidence intervals (CI) were estimated for vildagliptin ever versus never users, for cumulative duration and cumulative dose of vildagliptin therapy categorized into tertiles versus never users, and for cumulative duration and cumulative dose treated as continuous variables.ResultsThere were 355610 never users and 43196 ever users in the unmatched cohort and 40489 never users and 40489 ever users in the matched cohort. In the unmatched cohort, unadjusted HR (95% CI) was 0.929 (0.683-1.264) and the multivariate-adjusted HR (95% CI) was 0.922 (0.620-1.372). In the matched cohort, the unadjusted HR (95% CI) was 0.930 (0.616-1.402) and the multivariate-adjusted HR (95% CI) was 0.825 (0.498-1.367). None of the analyses conducted for cumulative duration and cumulative dose was significant, either being treated as tertile cutoffs or as continuous variables, in either the unmatched cohort or the matched cohort.ConclusionsThis study showed a neutral effect of vildagliptin on dementia risk.

Background: The effect of metformin on the risk of atrial fibrillation (AF) requires confirmation. This retrospective cohort study compared the incidence of hospitalization for AF in ever and never users of metformin.Methods: Patients with newly diagnosed type 2 diabetes mellitus during 1999–2005 were enrolled from Taiwan's National Health Insurance database. Analyses were conducted in both an unmatched cohort of 173,398 ever users and 21,666 never users and in a propensity score-matched cohort of 21,662 pairs of ever and never users. They were free from a diagnosis of AF before January 1, 2006 and were followed up until December 31, 2011. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the propensity score.Results: A total of 303 ever users and 86 never users in the unmatched cohort and 56 ever users and 86 never users in the matched cohort developed hospitalization for AF during follow-up. The respective incidence rates were 37.72 and 92.45 per 100,000 person-years in the unmatched cohort and were 56.98 and 92.46 per 100,000 person-years in the matched cohort. The hazard ratio for ever vs. never users was 0.405 (95% confidence interval: 0.319–0.515) in the unmatched cohort and 0.617 (0.441–0.864) in the matched cohort. Hazard ratios for the tertiles of cumulative duration of metformin therapy vs. never users showed a dose-response effect. The findings were consistent in sensitivity analyses.Conclusion: Metformin use is associated with a lower risk of hospitalization for AF in patients with type 2 diabetes mellitus.

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.

BackgroundDiabetic sensory neuropathy has rarely been studied in the Asian populations. This study investigated the prevalence and risk factors of sensory symptoms (SS) in the Taiwanese diabetes patients.MethodsA total of 1,400 diabetes patients received a health examination together with a structured questionnaire interview for three categories of abnormal sensation of numbness or tingling pain, electric shock, and skin thickness sensation on seven anatomical sites on upper limbs and six sites on lower limbs. Prevalence of SS was defined using nine different criteria, with the least stringent criterion of “any positive symptom on at least 1 site” and the most stringent criterion of “any positive symptom on at least bilateral and symmetrical 2 sites involving the lower limb.” Logistic regression was used to estimate the odds ratios and their 95% confidence interval for SS by the different definitions. Fasting plasma glucose and hemoglobin A1c were entered in separate models to avoid hypercollinearity.ResultsThe prevalence of SS was 14.4 and 54.0% when using the most stringent and least stringent criterion, respectively. Women consistently had a significantly higher prevalence than men did. Among the three categories of symptoms, numbness or tingling pain was the most common, and fingers and toes were the most commonly involved anatomical sites. For any symptoms, 37.1% of the patients had any symptoms on the upper limbs and 41.7% had any symptoms on the lower limbs. Female sex, diabetes duration, hemoglobin A1c, and hypertension were associated with SS in all models.ConclusionsTaiwanese diabetes patients may have a high prevalence of SS if a structured questionnaire is used for screening. Female sex, diabetes duration, hemoglobin A1c, and hypertension are associated with SS.

Aims/Introduction To investigate the clinical outcomes of patients with type 2 diabetes mellitus (T2DM) who initiated dapagliflozin in real-world practice in Taiwan. Materials and Methods In this multicenter retrospective study, adult patients with T2DM who initiated dapagliflozin after May 1st 2016 either as add-on or switch therapy were included. Changes in clinical and laboratory parameters were evaluated at 3 and 6 months. Baseline factors associated with dapagliflozin response in glycated hemoglobin (HbA1c) were analyzed by univariate and multivariate logistic regression. Results A total of 1,960 patients were eligible. At 6 months, significant changes were observed: HbA1c by −0.73% (95% confidence interval [CI] −0.80, −0.67), body weight was -1.61 kg (95% CI −1.79, −1.42), and systolic/diastolic blood pressure by −3.6/−1.4 mmHg. Add-on dapagliflozin showed significantly greater HbA1c reduction (−0.82%) than switched therapy (−0.66%) (p = 0.002). The proportion of patients achieving HbA1c

AimThis retrospective cohort study evaluated whether metformin use in patients with type 2 diabetes mellitus might reduce the risk of biliary tract cancer (BTC); and explored whether metformin use might affect the overall survival in patients who developed BTC.MethodsNew-onset type 2 diabetes patients aged 25–75 years during 1999–2005 were enrolled from the Taiwan’s National Health Insurance and followed up until December 31, 2011. A total of 287,995 ever users and 16,229 never users were identified (unmatched original cohort) and a 1:1 matched pairs of 16,229 ever users and 16,229 never users based on propensity score (PS) were created (matched cohort). Hazard ratios were estimated by three Cox regression models: 1) adjusted for PS; 2) incorporated with the inverse probability of treatment weighting using PS; and 3) all covariates treated as independent variables. Overall survival was compared between ever users and never users of metformin who developed BTC.ResultsIn the unmatched cohort, 73 never users and 523 ever users developed BTC, with respective incidence of 100.36 and 38.06 per 100,000 person-years. An overall risk reduction was observed in metformin users in all three regression models with respective hazard ratio (95% confidence interval) of 0.442 (0.344-0.568), 0.377 (0.295-0.481), and 0.477 (0.370-0.615). The tertile analyses showed a dose-response pattern with a neutral effect in the first tertile when metformin use was

BackgroundThe effect of metformin on leukemia risk remains unknown.MethodsThe Taiwan’s National Health Insurance database was used to enroll 610,089 newly diagnosed type 2 diabetes patients on at least 2 anti-diabetic prescriptions during 1999–2009. We followed-up these patients until 31 December 2011, in order to determine the incidence of leukemia. We used Cox regression model (incorporated with the inverse probability of treatment-weighting using propensity scores) to estimate hazard ratios in both intention-to-treat and per-protocol analyses.ResultsWe enrolled 414,783 metformin initiators and 195,306 non-metformin initiators. Among them, 598 and 372 patients developed new-onset leukemia after a median follow-up period of 5.08 years and 6.79 years, respectively. The respective incidence rates were 26.52 and 28.40 per 100,000 person-years. The hazard ratio for metformin initiators versus non-metformin initiators was 0.943 (95% confidence interval 0.828–1.074) in the intention-to-treat analysis and 0.852 (95% confidence interval 0.705–1.031) in the per-protocol analysis. Sensitivity analyses after excluding patients using the exclusion criteria (a follow-up duration < 24 and < 36 months, respectively, patients with incretin-based therapies during follow-up, and patients enrolled during 2 different periods of 1999–2003 and 2004–2009) consistently showed a neutral effect. However, metformin initiators had a significantly higher risk of leukemia in the per-protocol analyses when censoring patients at a time without regular follow-up.ConclusionMetformin use has an overall neutral effect on leukemia but we cannot exclude a significantly higher risk in patients who persistently use the drug.

Background: Whether metformin may reduce the risk of uterine leiomyoma in type 2 diabetes patients has not been investigated. This retrospective cohort study compared the risk of uterine leiomyoma in ever versus never users of metformin. Methods: Female patients with new-onset type 2 diabetes during 1999–2005 were enrolled from the reimbursement database of Taiwan’s National Health Insurance and followed up from 1 January 2006 until 31 December 2011. Analyses were conducted in a propensity score (PS) matched-pair cohort of 10,998 ever users and 10,998 never users of metformin. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the PS. Results: A total of 321 never users and 162 ever users developed uterine leiomyoma during follow up, with respective incidence of 704.65 and 329.82 per 100,000 person-years. The overall hazard ratio was 0.467 (95% confidence interval: 0.387–0.564). The hazard ratios for the first (53.1 months) tertiles of cumulative duration were 0.881 (0.685–1.132), 0.485 (0.367–0.642), and 0.198 (0.134–0.291), respectively; and were 0.751 (0.576–0.980), 0.477 (0.360–0.632), and 0.277 (0.198–0.386), respectively, for the first (1,725,500) tertiles of cumulative dose. Sensitivity analyses after excluding users of sulfonylurea, users of estrogen, users of insulin, users of incretin-based therapies during follow up, patients with irregular drug refills, patients who discontinued the use of metformin, patients who received metformin prescription less than four times, or redefining uterine leiomyoma by using ‘diagnostic code’ plus ‘procedure codes’ consistently supported a lower risk of uterine leiomyoma in ever users of metformin. Conclusion: Metformin use is associated with a lower risk of uterine leiomyoma.

Background A beneficial effect of metformin on heart failure requires confirmation. Methods and Results Patients with new‐onset type 2 diabetes mellitus during 1999 to 2005 were enrolled from Taiwan's National Health Insurance database and followed up from January 1, 2006, until December 31, 2011. Main analyses were conducted in an unmatched cohort (172 542 metformin ever users and 43 744 never users) and a propensity score matched‐pair cohort (matched cohort I, 41 714 ever users and 41 714 never users). Hazard ratios were estimated by Cox hazard regression incorporated with the inverse probability of treatment weighting using the propensity score in the unmatched cohort and by naïve method in the matched cohort I. Results showed that the respective incidence rates of heart failure hospitalization in ever users and never users were 304.25 and 864.31 per 100 000 person‐years in the unmatched cohort (hazard ratio, 0.350; 95% CI, 0.329–0.373) and were 469.66 and 817.01 per 100 000 person‐years in the matched cohort I (hazard ratio, 0.571; 95% CI, 0.526–0.620). A dose‐response pattern was consistently observed while estimating hazard ratios for the tertiles of cumulative duration of metformin therapy. Findings were supported by another propensity score–matched cohort created after excluding 10 potential instrumental variables in the estimation of propensity score (matched cohort II). An approximately 40% lower risk was consistently observed among ever users in different models derived from the matched cohorts I and II, but models from the matched cohort II were less subject to model misspecification. Conclusions Metformin use is associated with a lower risk of heart failure hospitalization.

Background: Whether human insulin may affect lung cancer risk requires investigation.Methods: All patients with a diagnosis of diabetes mellitus from 1996 to 2009 were enrolled from Taiwan's National Health Insurance. An entry date was set on January 1, 2004, and 1,007,617 patients with type 2 diabetes mellitus diagnosed before 2004 were followed up for new-onset lung cancer until December 31, 2009. Incidence rates of lung cancer for never-users, ever-users, and tertiles of three dose-response exposure parameters (i.e., time since starting insulin, cumulative dose, and cumulative duration) were calculated. Adjusted hazard ratios were estimated by Cox proportional hazards models. The joint effect of insulin and chronic obstructive pulmonary disease was also evaluated.Results: There were 156,720 ever-users and 850,897 never-users. The respective case numbers of incident lung cancer were 3,007 (1.92%) and 13,677 (1.61%), and the respective incidence rates were 424.45 and 313.60 per 100,000 person-years. The adjusted hazard ratio comparing ever-users vs. never-users was 1.545 (95% confidence interval: 1.478–1.614). The hazard ratios for the different subgroups of the three dose–response parameters all suggested a significantly higher risk of lung cancer associated with insulin use (P trend < 0.0001). Compared to patients without insulin use and without chronic obstructive pulmonary disease, insulin users who also had chronic obstructive pulmonary disease had the highest risk of lung cancer (adjusted hazard ratio: 1.891, 95% confidence interval: 1.767–2.024).Conclusions: This study suggests a significant association between human insulin use and lung cancer risk 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: 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.

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 (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.

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.

Background Whether metformin use may reduce hypertension risk has not been studied. This study investigated such possibility in patients with type 2 diabetes mellitus. Methods and Results Newly diagnosed patients with type 2 diabetes mellitus during 1999–2005 were enrolled from the reimbursement database of the Taiwan's National Health Insurance and followed to December 31, 2011. Hypertension was defined either by a diagnosis or by a diagnosis plus the use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers and/or calcium channel blockers. Analyses were conducted in a propensity score matched‐pair cohort of 4810 ever users and 4810 never users. Cox proportional hazards regression model was used to estimate the hazard ratios. Results showed that when hypertension was defined by a diagnosis, 2261 never users and 1908 ever users developed hypertension. The overall hazard ratio was 0.724 (0.681–0.769) and the hazard ratios for the first (13.0 months) tertiles of cumulative duration were 0.820 (0.745–0.903), 0.692 (0.634–0.756), and 0.687 (0.630–0.749), respectively. When cumulative duration of metformin therapy was treated as a continuous variable, the hazard ratio was 0.991 (0.989–0.994) for every 1‐month increment of metformin use. When hypertension was defined by a diagnosis plus the use of antihypertensive drugs, the overall hazard ratio was 0.831 (0.771–0.895), the hazard ratios for the respective tertiles were 0.868 (0.769–0.980), 0.852 (0.767–0.946), and 0.787 (0.709–0.874), and the hazard ratio was 0.994 (0.991–0.997) for every 1‐month increment of metformin use. Conclusions A reduced risk of hypertension is observed in metformin users in a dose‐response pattern.

This article reviews human observations on pioglitazone and bladder cancer risk. The PROspective pioglitAzone Clinical Trial In macroVascular Events trial showed an imbalance in bladder cancer between users of pioglitazone and placebo (14 versus six cases, p = 0.069). However, after excluding bladder cancer probably ascribed to other etiology, a blind assessment concluded that the imbalance might not be related to pioglitazone. Epidemiologic studies conducted in the United States and France using insurance databases independently suggested that pioglitazone use for >2 years might confer a 20%–40% higher risk. Another study evaluating bladder cancer risk in diabetic patients using the National Health Insurance in Taiwan did not find any incident bladder cancer case among 422 pioglitazone users for a follow-up of up to 3 years. Because observational studies may suffer from selection and information bias, and inadequate adjustment for confounders may inflate the estimated risk, causal inference from these studies should be interpreted with caution. While investigating cancer risk associated with a medication, indication bias should also be attended, especially when the medication is used at a late stage of the disease. Because pioglitazone is usually a second or third line antidiabetic agent, the users are always characterized by older age, longer diabetes duration, poorer glycemic control, and higher rates of complications and comorbidities. Biased estimates will also result if these differences are not appropriately addressed in the analyses. Current evidence neither concludes nor excludes a causal role of pioglitazone on bladder cancer. Clinical trials aiming at evaluating the risk of cancer associated with a medication is not ethical and may not be expected to provide an answer on the issue of pioglitazone-related bladder cancer. However, a meta-analysis using all available clinical trials to compare the bladder cancer risk between pioglitazone and comparators will be helpful. Well-conducted epidemiologic observational studies are probably other options. Because bladder cancer incidence and their risk factors may differ significantly among different ethnicities, a clarification of such a link in different ethnicities is needed, better by using long-term databases with large and representative sample size and appropriate adjustment for confounders. Furthermore, the interactions with other comorbidities and concomitant medications should be addressed.

A previous 12-year follow-up of a large diabetes cohort in Taiwan suggested a survival advantage in the patients with obesity. The present study further investigated additional determinants for cancer and non-cancer death in the cohort after a follow-up of 17 years.A cohort of 92546 diabetes patients recruited since 1995 was followed for vital status by matching the National Death Certificate Database until 2011. Cox regression estimated the hazard ratios for the following variables: age at baseline, sex, diabetes type, screen-detected diabetes (diabetes diagnosed accidentally through epidemiological screening programs or during visits to medical settings without a history of diabetes), diabetes duration, body mass index, insulin use, hypertension, smoking, and living region. Fasting glucose and history of dyslipidemia were available for additional adjustment in a subcohort of the patients (n = 14559).A total of 40229 diabetes patients (43.5% of the cohort) died during follow-up and 10.9% died under the age of 60. Insulin use and smoking significantly predicted cancer and non-cancer death. The adjusted hazard ratio (95% confidence interval) associated with insulin use was 1.161 (1.052-1.281) for cancer death and 1.469 (1.413-1.526) for non-cancer death. Screen-detected diabetes and body mass index were consistently associated with a lower risk, but diabetes duration a higher risk, for non-cancer death, with adjusted hazard ratio of 0.683 (0.666-0.702), 0.955 (0.951-0.958) and 1.018 (1.017-1.020), respectively. Diabetes type had a null association disregarding the causes of death and living in rural areas was significantly associated with a higher mortality from non-cancer death. Hypertension, fasting glucose and dyslipidemia showed differential impacts on cancer and non-cancer death, and were significantly predictive for non-cancer death.Screen-detected diabetes and a higher body mass index provide a survival advantage, especially for non-cancer death. However, insulin use is associated with a significantly higher risk of either cancer or non-cancer death.

To evaluate the association between incidence of any kidney cancer and type 2 diabetes mellitus.A random sample of 1,000,000 subjects covered by the National Health Insurance was recruited. A total of 998728 people (115655 diabetes and 883073 non-diabetes) without kidney cancer at recruitment were followed from 2003 to 2005. The cumulative incidence of kidney cancer from 2003 to 2005 in diabetic patients and non-diabetic people in all ages and in age

Background. To evaluate whether insulin use was predictive for mortality from breast cancer in Taiwanese women with diabetes mellitus. Methods. A total of 48,880 diabetic women were followed up to determine the mortality from breast cancer during 1995–2006. Cox models were used, considering the following independent variables: age, sex, diabetes type, diabetes duration, body mass index, smoking, insulin use, and area of residence. Insulin use was also considered for its duration of use at cutoffs of 3 years and 5 years. Results. Age was a significant predictor in all analyses. The multivariable-adjusted hazard ratio (95% confidence interval, P value) for insulin use without considering the duration of use was not statistically significant (1.339 [0.782–2.293, P=0.2878]). Compared with nonusers, insulin users showed the following adjusted hazard ratios for insulin use

BACKGROUND: Whether metformin may affect thyroid cancer risk has not been studied. This study investigated the association between metformin use and thyroid cancer risk in Taiwanese patients with type 2 diabetes mellitus. METHODS: The reimbursement databases of all diabetic patients from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2006 and 1,414,723 patients with type 2 diabetes were followed for thyroid cancer incidence until the end of 2009. Incidences for ever-users, never-users and subgroups of metformin exposure using tertile cutoffs for cumulative duration of therapy and cumulative dose were calculated and adjusted hazard ratios were estimated by Cox regression. Additional sensitivity analyses were conducted. RESULTS: There were 795,321 ever-users and 619,402 never-users, with respective numbers of incident thyroid cancer of 683 (0.09%) and 1,614 (0.26%), and respective incidence of 24.09 and 87.33 per 100,000 person-years. The overall fully adjusted hazard ratio (95% confidence interval) was 0.683 (0.598-0.780), and all categories of the dose-response parameters showed significantly lower risk with P-trends < 0.0001. The protective effect of metformin on thyroid cancer incidence was also supported by sensitivity analyses, disregarding age (< 50 or ≥ 50 years) and sex; and was not affected by excluding users of insulin, sulfonylurea, and insulin and/or sulfonylurea respectively, by previous diagnosis of other cancers or by potential detection examinations that might lead to differential diagnosis of thyroid cancer. CONCLUSIONS: This study provides evidence for the first time that metformin use in patients with type 2 diabetes may reduce the risk of thyroid cancer.

BACKGROUND: Whether human insulin can induce bladder cancer is rarely studied. METHODS: The reimbursement databases of all Taiwanese diabetic patients from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2004 and a total of 785,234 patients with type 2 diabetes were followed up for bladder cancer incidence until the end of 2009. Users of pioglitazone were excluded and the period since the initiation of insulin glargine (marketed after the entry date in Taiwan) was not included in the calculation of follow-up. Incidences for ever-users, never-users and subgroups of human insulin exposure (using tertile cutoffs of time since starting insulin, duration of therapy and cumulative dose) were calculated and the hazard ratios were estimated by Cox regression. RESULTS: There were 87,940 ever-users and 697,294 never-users, with respective numbers of incident bladder cancer of 454 (0.52%) and 3,330 (0.48%), and respective incidence of 120.49 and 94.74 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) indicated a significant association with insulin in the age-sex-adjusted models [1.238 (1.122-1.366)], but not in the model adjusted for all covariates [1.063 (0.951-1.187)]. There was also a significant trend for the hazard ratios for the different categories of the dose-response parameters in the age-sex-adjusted models, which became insignificant when all covariates were adjusted. CONCLUSIONS: This study relieves the concern of a bladder cancer risk associated with human insulin. Appropriate adjustment for confounders is important in the evaluation of cancer risk associated with a medication.

BACKGROUND: The trend of lung cancer incidence in Taiwan is unknown, and the association between type 2 diabetes/insulin use and lung cancer is rarely studied. METHODS: The trends of lung cancer incidence in 1979-2007 in the Taiwanese general population were calculated. A random sample of 1,000,000 subjects covered by the National Health Insurance in 2005 was recruited. A total of 494,002 men and 502,948 women and without lung cancer were followed for the annual cumulative incidence of lung cancer in 2005, with calculation of the risk ratios between diabetic and non-diabetic subjects. Logistic regression estimated the adjusted odds ratios for risk factors. RESULTS: The trends increased significantly in both sexes (P

Risk of increasing breast and bladder cancer remains a safety issue of SGLT2 (sodium glucose cotransporter type 2) inhibitors, a novel class of antidiabetic agent. We reviewed related papers published before January 29, 2014, through Pubmed search. Dapagliflozin and canagliflozin are the first two approved SGLT2 inhibitors for diabetes therapy. Although preclinical animal toxicology did not suggest a cancer risk of dapagliflozin and overall tumor did not increase, excess numbers of female breast cancer and male bladder cancer were noted in preclinical trials (without statistical significance). This concern of cancer risk hindered its approval by the US FDA in January, 2012. New clinical data suggested that the imbalance of bladder and breast cancer might be due to early diagnosis rather than a real increase of cancer incidence. No increased risk of overall bladder or breast cancer was noted for canagliflozin. Therefore, the imbalance observed with dapagliflozin treatment should not be considered as a class effect of SGLT2 inhibitors and the relationship with cancer for each specific SGLT2 inhibitor should be examined individually. Relationship between SGLT2 inhibition and cancer formation is still inconclusive and studies with larger sample size, longer exposure duration, and different ethnicities are warranted.