Association of Metformin as treatment of Type 2 Diabetes and progression of Benign Prostate Hyperplasia. - For the 2009 naïve BPH patients of Republic of Korea -
2형 당뇨로 인한 메트포민 복용이 전립선 비대증 악화에 미치는 영향 - 한국의 2009년도 신규 전립선비대증 환자를 대상으로 -

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보건대학원 보건학과(보건학전공)
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서울대학교 대학원
학위논문 (석사)-- 서울대학교 대학원 : 보건대학원 보건학과(보건학전공), 2018. 8. 원성호.

Association of Metformin as treatment of Type 2 Diabetes and progression of

Benign Prostate Hyperplasia

- For the 2009 naïve BPH patients of Republic of Korea -


Department of Public Health

Graduate School of Public Health

Seoul National University

Background: As a prevalent and progressing disease, Benign Prostate Hyperplasia (BPH) comes along with proliferation of the periurethral and transition zones of the prostate and difficulty of voiding urine. BPH is a common disease in men over 40 years old and the prevalence of BPH increases as aging
men older than 70 years old show 80% of prevalence rate. A progressive condition of BPH causes symptoms which require treatment and the treatment option for BPH can be categorized into non-invasive treatment including watchful waiting and medical treatment and invasive treatment including prostatectomy. Surgical treatment is suggested as the last option for treating BPH patients since it can bring complications after surgery.

Type 2 Diabetes Mellitus (T2DM) is also prevalent and well known disease which leads complications in many organ systems. History of association of BPH and Diabetes dates back up to decades. Underline mechanism of association of BPH and diabetes is suggested that insulin resistance with secondary hyperinsulinemia and hyperglycemia is the key role for prostate enlargement. Hyperinsulinemia increases level of Insulin-like Growth Hormone 1(IGF-1) which predisposes to have higher risk of BPH. Hyperglycemia increases cytosolic-free calcium in smooth muscle cells and neural tissues, leading to sympathetic nervous system activation contributing in more severe LUTS independent of prostatic enlargement. While T2DM is a negative factor for progression of BPH, few studies discovered that metformin, commonly used drug to treat T2DM, inhibits proliferation of prostate. Though association of prevalence of BPH and T2DM has a few evidences, association of progression of BPH, T2DM and medication of T2DM
metformin, lack of data and evidence. More studies should be done to find out clearer association with T2DM and the progression of BPH by metformin intake.

Objective: The aim of this study is to analyze association of type 2 Diabetes Mellitus and Benign Prostate Hyperplasia with metformin by investigating patients who newly diagnosed BPH in 2009 and follow up occurrence of prostatectomy to measure progression of BPH until June 2017 with claims data of HIRA in Korea.

Method: This study used claims data of the Health Insurance Review and Assessment Service of BPH patients in 2009 in Korea. The registered analysis number of the data requested by the Health Insurance Review and Assessment Service is M20180205893, which is applied to the remote access system and granted access to data. Detailed medical data including diagnosis data, prescribed drugs including Metformin and drugs for treating BPH and surgery information were used to obtain general conclusion about associations between T2DM, Metformin and prostatectomy among BPH patients. Each patients information from different tables was joined by join key for each patient. Confounding variables were defined by literature review. Frequency analyses were performed to examine the characteristics of the data, and the incidence rate of prostatectomy of BPH patients was estimated by 10,000 person year. After Proportional Hazard assumption test, the cox proportional hazard model was used to estimate the hazard ratio for prostatectomy of BPH patients with T2DM-metformin, T2DM non-metformin and without T2DM was measured. Moreover, total drug dose of Metformin was calculated per each Metformin intake T2DM group during look back period to consider dose effect of Metformin.

Results: Among 211,648 patients diagnosed as naïve BPH in 2009 who requires medical treatment, 13,926 patients were BPH with T2DM and 197,722 patients were BPH without T2DM. Among BPH naïve patients with T2DM, 11,050 were metformin group and 2,872 were non-metformin group. From the baseline characteristics, those with T2DM were older than those without T2DM (P<0.0001) and had more hypertension (P<0.0001). Total 7,672 patients received prostatectomy until June 2017. Average age of patients who received prostatectomy is higher than those who didnt receive prostatectomy (P<0.0001). The overall incidence of prostatectomy per 10,000 men was estimated to be 52.899 (CI: 38.725 to 83.438), while the incidence of prostatectomy per 10,000 of BPH patients without T2DM was estimated to be 53.061 (CI: 33.919 to 85.724). Incidence of prostatectomy per 10,000 men with T2DM - metformin seems to be slightly lower than that of BPH patients without T2DM by reaching 48.606 (CI: 33.919 to 85.724) while T2DM patients without metformin incidence increases up to 57.497 (CI: 39.874 to 103.035). The hazard ratios according to T2DM-metformin were found to be 0.860 for prostatectomy (P value=0.007), which drives a conclusion of T2DM comorbid patients with Metformin are at lower risk of receiving prostatectomy. Among subject patients in age group under 65 years old, T2DM with Metformin group showed lower HR of prostatectomy with 0.758(P-value=0.006). When dose of Metformin was considered, Metformin-High group showed significantly low risk of prostatectomy with HR 0.756(P value=0.005)

Conclusion: From this study, although Diabetes is a risk factor of BPH, the characteristics of Diabetes patients
less likely to undergo surgeries due to complications and well managed diabetes can be helpful on managing BPH. Moreover Metformins underline mode of action might block the progression of BPH. Though Diabetes can raise risk of progression of BPH, emphasizing managing Diabetes in their earlier stage and maintaining compliance of medication can lessen the risk of progression of BPH including prostatectomy and intake of Metformin can bring helpful outcome in managing progression of BPH.

Keywords: Benign Hyper Plasia, Metformin, Type 2 Diabetes Mellitus, Prostatectomy, Cox proportional hazard model
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