Risk of Endometrial Cancer in Women with Diabetes: A Population-Based Retrospective Cohort Study.

The aim of this study was to examine the association between type 2 diabetes (T2DM), use of glucose-lowering medications and endometrial cancer (EC) risk. METHODS: The risk of EC incidence among women with T2DM in Lithuania was assessed using a retrospective cohort study design. Female patients who were registered with T2DM between 1 January 2000 and 31 December 2012 were identified in the National Health Insurance Fund database. EC cases (ICD-10 code C54) were identified from the Lithuanian Cancer Registry. Standardized incidence ratios (SIRs) were calculated by dividing the observed numbers of EC among patients with T2DM by the expected number of EC, calculated using national rates. RESULTS: A total of 77,708 diabetic women were included in the analysis, and 995 cases of EC were identified. A significantly increased EC risk in diabetic women was found as compared to the general population (SIR = 1.69, 95% CI 1.59-1.80). The greatest EC risk was found among younger patients at T2DM diagnosis, and the risk declined gradually with increasing age but persisted in being significantly increased among all age groups. The risk for EC increased with increasing duration of diabetes, and the highest EC risk was observed more than 10 years after T2DM diagnosis. A significantly higher EC risk than expected from the general population was found in all patient groups by glucose-lowering medication combinations. The lowest EC risk was observed in diabetic women who were users of "oral only" (without metformin) (SIR = 1.42, 95% CI 1.10-1.83) and "metformin only" (SIR = 1.69, 95% CI 1.49-1.92) medications. A two times greater EC risk was observed among the remaining glucose-lowering medication categories. In contrast, use of insulin only was not related to a higher EC incidence risk (SIR = 0.45, 95% CI 0.23-0.86); however, the risk estimation was based on nine cases. CONCLUSIONS: Our study shows a significantly increased EC risk in diabetic women as compared to the general population. In this study, a significantly higher EC risk was found in all patient groups by glucose-lowering medication combinations, except for insulin only users.

Increased Mortality Risk in People with Type 2 Diabetes Mellitus in Lithuania.

This retrospective cohort study aimed to analyze overall and cause-specific mortality risk in people with type 2 diabetes mellitus (T2DM) in Lithuania. Information on the diagnosis of T2DM and glucose-lowering medication was obtained from the National Health Insurance Fund database, causes of death-from death certificates. Sex, age, and calendar period-standardized mortality ratios (SMRs) were calculated. In addition, 89,512 patients were followed-up between 2010 and 2017, contributing to the observation period of 592,321 person-years. Overall mortality risk was increased for both sexes (overall SMR = 1.35, 95% confidence interval (CI) 1.34-1.37). Greatest mortality risk was in the age group of 40-49 years at diabetes diagnosis (SMR = 1.68, 95% CI 1.60-1.76) and among those who had died before the age of 50 (SMR = 22.04, 95% CI 18.82-25.81). Patients treated with insulin only had the highest SMR (2.43, 95% CI 2.32-2.55). Mortality risk increased with increasing diabetes duration and was higher in women in all these groups. The highest cause-specific SMRs were infection-related causes (SMR = 1.44), particularly septicemia (SMR = 1.78), diseases of the circulatory system (SMR = 1.42), especially ischemic heart (SMR = 1.46) and cerebrovascular diseases (SMR = 1.38), as well as diseases of the digestive system (SMR = 1.35). Cancer mortality risk was elevated for women (SMR = 1.13), but not for men (SMR = 0.93). In conclusion, people with T2DM had an excess mortality risk, which was higher in women compared to men, younger people, in those who were diagnosed with T2DM at a younger age, had longer diabetes duration, and who required treatment with insulin.

Preexisting diabetes, metformin use and long-term survival in patients with prostate cancer.

OBJECTIVE: To assess prostate cancer-specific and overall survival in prostate cancer patients with or without preexisting type 2 diabetes mellitus (T2DM) with regards to metformin use. METHODS: Patients diagnosed with prostate cancer in the Lithuanian population between 2001 and 2005 were identified through the Lithuanian Cancer Registry and followed until 2016, date of death, loss to follow-up or whichever came first. Information regarding the diagnosis of T2DM and antihyperglycemic medications were obtained from the National Health Insurance Fund database. Prostate cancer-specific and overall survival outcomes were analysed using univariate and multivariate Cox proportional hazard models. RESULTS: Out of 6689 men included, 254 (3.8%) had preexisting T2DM. There were 4807 deaths during follow-up, including 2084 from prostate cancer. No differences were found in prostate cancer-specific survival between men with or without T2DM. The risk of overall mortality was higher (HR = 1.24, 95% CI = 1.07-1.43) in diabetic men. Univariate analysis showed cancer stage at diagnosis and age to be significant predictors of survival. After adjustment for age and stage at diagnosis, there was no difference in prostate-specific survival between non-diabetic patients compared to metformin users or metformin non-users. However, overall survival was lower in T2DM patients, with a higher mortality risk for metformin non-users (HR = 1.63, 95% CI = 1.27-2.10). Prostate cancer-specific mortality risk was insignificantly lower in diabetic men on metformin (HR = 0.74, 95% CI = 0.54-1.02). CONCLUSION: There was no difference in long-term prostate cancer-specific survival in patients with or without T2DM. Overall survival was lower in T2DM patients not treated with metformin.

Cohort Study of Antihyperglycemic Medication and Pancreatic Cancer Patients Survival.

BACKGROUND: We assessed the association between the use of metformin and other antihyperglycemic medications on overall survival in diabetic patients with pancreatic cancer. METHODS: Patients with pancreatic cancer and diabetes between 2000 and 2015 were identified from the Lithuanian Cancer Registry and the National Health Insurance Fund database. Cohort members were classified into six groups according to type 2 diabetes mellitus treatment: sulfonylurea monotherapy; metformin monotherapy; insulin monotherapy; metformin and sulfonylurea combination; metformin and other antihyperglycemic medications; all other combinations of oral antihyperglycemic medications. Survival was calculated from the date of cancer diagnosis to the date of death or the end of follow-up (31 December 2018). RESULTS: Study group included 454 diabetic patients with pancreatic cancer. We found no statistically significant differences in overall survival between patients by glucose-lowering therapy. However, highest mortality risk was observed in patients on insulin monotherapy, and better survival was observed in the groups of patients using antihyperglycemic medication combinations, metformin alone, and metformin in combination with sulfonylurea. Analysis by cumulative dose of metformin showed significantly lower mortality risk in the highest cumulative dose category (HR 0.76, 95% CI 0.58-0.99). CONCLUSIONS: Our study showed that metformin might have a survival benefit for pancreatic cancer patients, suggesting a potentially available option for the treatment.

Reduced risk of prostate cancer in a cohort of Lithuanian diabetes mellitus patients.

BACKGROUND: During the past decade, a huge interest was devoted to the type-2 diabetes mellitus and their associations with prostate cancer development. OBJECTIVES: The aim of this study was to determine whether type 2 diabetes mellitus and treatment with metformin is associated with prostate cancer risk. MATERIALS AND METHODS: The cohort was composed of diabetic male patients identified in the National Health Insurance Fund database during 2000-2016 and cancer cases in national Cancer Registry. We calculated standardized incidence ratios (SIR) for prostate cancers as a ratio of observed number of cancer case in people with diagnosis of diabetes to the expected number of cancer cases in the underlying general population. RESULTS: 2754 prostate cancers were observed versus 3111.26 expected within the period of observation entailing an SIR of 0.89 (95% CI: 0.85-0.92). Significantly lower risk of prostate cancer was found in diabetes patients in all age groups, also was in metformin-users and never-users' groups, with higher risk reduction in metformin-users (SIR 0.71, 95% CI: 0.68-0.75) than in diabetes patients never-users (SIR 0.88, 95% CI: 0.80-0.96). CONCLUSION: In this large population-based study, we found a significantly decreased risk of prostate cancer among men with diabetes and metformin-users.

Increased kidney cancer risk in diabetes mellitus patients: a population-based cohort study in Lithuania.

BACKGROUND: Diabetes is associated with increased risk of various cancers but its association with kidney cancer is unclear. The objective of this study was to evaluate the association between T2DM with or without metformin use and the risk of kidney cancer in a population-based national cohort in Lithuania. METHODS: The cohort was composed of diabetic patients identified in the NHIF database during 2000-2012. Cancer cases were identified by record linkage with the national Cancer Registry. Standardized incidence ratios (SIRs) for kidney cancer as a ratio of observed number of cancer cases in diabetic patients to the expected number of cancer cases in the underlying general population were calculated. RESULTS: T2DM patients (11,592) between 2000 and 2012 were identified. Overall, 598 cases of primary kidney cancer were identified versus 393.95 expected yielding an overall SIR of 1.52 (95% CI: 1.40-1.64). Significantly higher risk was found in males and females. Significantly higher risk of kidney cancer was also found in both metformin users and never-users' groups (SIRs 1.45, 95% CI: 1.33-1.60 and 1.78 95% CI: 1.50-2.12, respectively). CONCLUSIONS: The patients with T2DM have higher risk for kidney cancer compared with the general Lithuanian population.

A Cohort Study of Exposure to Antihyperglycemic Therapy and Survival in Patients with Lung Cancer.

We evaluated the effect of antihyperglycemic therapy on the survival of patients with lung cancer (LC). The analysis included patients with LC and concomitant type 2 diabetes. 15,929 patients were classified into five groups: metformin users, insulin users, metformin and insulin users, sulphonylurea users and non-diabetic group. A multivariate analysis showed that exposure to either metformin or to insulin was associated with a lower risk of LC-specific mortality, and this approached statistical significance (HR 0.82, 95% CI 0.72-92 for metformin and HR 0.65, 95% CI 0.44-95 for insulin). When deaths from all causes were considered, only metformin exposure was associated with a significantly lower risk of death (HR 0.82, 95% CI 0.73-0.92). Users of sulphonylurea were at a higher risk of LC-specific and overall mortality (HRs 1.19, 95% CI 0.99-1.43 and 1.22, 95% CI 1.03-1.45). Our study shows a positive effect of metformin on the survival of patients with LC. Moreover, our results show that exposure to insulin was associated with a lower risk of LC-specific mortality, but not with deaths from all causes. The study results suggested that users of sulphonylurea may be at a higher risk of LC-specific and overall mortality.

A Cohort Study of Antihyperglycemic Medication Exposure and Gastric Cancer Risk.

We assessed gastric cancer risk in type 2 diabetes mellitus patients. Gastric cancer patients with diabetes between 2001-2012 were identified. Four groups were analysed: combination therapy with metformin users; insulin and other medication users; metformin and insulin users; and sulfonylurea users. Standardised incidence ratios (SIRs) for gastric cancers as a ratio of the observed number of cancer cases in people with diabetes to the expected number of cancer cases in the underlying general population were calculated. A total of 99,992 patients with diabetes were analysed and 337 gastric cancer cases in patients with diabetes were observed when compared to the expected number of 400.54 gastric cancer cases, according to the cancer rates of the general population (SIR 0.84, 95% confidence interval (CI): 0.76-0.94). Lower risk of gastric cancer was found both in male and female patients with diabetes, however, risk among females was insignificantly lower. Higher gastric cancer risk was found in the group of diabetic patients treated with sulfonylureas (SIR 1.31, 95% CI: 1.04-1.65) and significantly lower risk than expected from the general population was found in the group of metformin users (SIR 0.75, 95% CI: 0.66-0.86). Type 2 diabetes mellitus was not associated with increased risk of gastric cancer. Metformin might decrease the risk of gastric cancer in patients with diabetes, while sulfonylureas may increase gastric cancer risk.

Positive effect of metformin treatment in colorectal cancer patients with type 2 diabetes: national cohort study.

We aimed to estimate colorectal cancer risk in patients with type 2 diabetes mellitus (T2DM) using metformin. Patients with colorectal cancer and diabetes from 2000 to 2012 were identified form Lithuanian Cancer Registry and the National Health Insurance Fund database. Standardized incidence ratios (SIRs) for colorectal cancers as a ratio of observed number of cancer cases in people with diabetes to the expected number of cancer cases in the underlying general population was calculated. We analysed 111 109 patients with diabetes. Overall, 1213 colorectal cancers were observed versus 954.91 expected within a period of observation entailing an SIR of 1.27 [95% confidence interval (CI): 1.20-1.34]. Significantly higher risk of colorectal cancer was found both in male and female patients with diabetes in all age groups. Higher risk was found for both colon and rectum cancers 1.36 (95% CI: 1.27-1.46) and 1.11 (95% CI: 1.01-1.22), respectively. There were no differences in risk over time since initial diabetes diagnosis. Never-users of metformin had twice higher risk of colorectal cancer compared to general population (SIR: 2.14, 95% CI: 1.95-2.35). Among metformin users, risk was lover (SIR: 1.47, 95% CI: 1.36-1.58) and colorectal cancer risk decreased with increasing cumulative dose of metformin (P < 0.001). Patients with T2DM had increased risk of colorectal cancer compared with the general Lithuanian population. Decreasing colorectal cancer risk with increasing cumulative dose of metformin indicates that metformin may be a protective agent for colorectal cancer development.

A cohort study of antihyperglycemic medication exposure and survival in patients with gastric cancer.

OBJECTIVE: We aimed to estimate survival in gastric cancer patients with type 2 diabetes mellitus (T2DM) using different antihyperglycemic medication. METHODS: Patients with gastric cancer and diabetes between 2003-2013 were identified form The Lithuanian Cancer Registry and The National Health Insurance Fund database. Cohort members were classified into five groups: four groups of T2DM patients according to treatment: metformin users; metformin and other medication users; sulphonylurea users; insulin and other medication users; and non-diabetic group. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate gastric cancer-specific survival and overall survival. RESULTS: 8423 patients met eligibility criteria. Survival analysis showed no differences in gastric cancer-specific survival between non-diabetic and diabetic patient groups. Better survival was observed in the groups of patients using antihyperglycemic medication combinations with metformin, metformin alone or insulin. Lowest survival was observed in diabetic patients who were sulphonylurea users. Survival analysis comparing overall survival between non-diabetic and diabetic patients (p = 0.89) showed no evidence of survival difference between groups and survival differences between antihyperglycemic medication user groups were of borderline significance (p = 0.052). CONCLUSIONS: Antihyperglycemic medication use was not associated with a significant effect on survival in patients with gastric cancer and T2DM.

Metformin increases cancer specific survival in colorectal cancer patients-National cohort study.

PURPOSE: We aimed to assess oncological outcomes in colorectal cancer patients with type 2 diabetes mellitus (T2DM) using metformin. METHODS: Patients with colorectal cancer and T2DM during 2000-2012 period were identified form Lithuanian Cancer Registry and the National Health Insurance Fund database. Colorectal cancer-specific survival (CS) was the primary outcome. It was measured from date of colorectal cancer diagnosis to date of death due to colorectal cancer, or last known date alive. RESULTS: 15,052 people who met eligibility criteria for this analysis, including 1094 (7.27%) with pre-existing type 2 diabetes (271 metformin never users and 823 metformin users) and 13 958 people without diabetes assessed. During follow-up (mean follow-up time was 4.4 years, with range from 1 day to 17 years) there were 10,927 deaths including 8559 from colorectal cancer. Significantly lower risk in CS between diabetic and non-diabetic people with lower risk of cancer-specific mortality (HR 0.87, 95% CI 0.80-0.94) in diabetic patient population was seen. After adjustment for age, stage at diagnosis and metformin usage, significant difference in colorectal CS between metformin users in diabetic patient population compared to non-diabetics and metformin non-users in diabetic patient population was found (0.80 (0.72-0.89) vs 1.00 and vs 1.05 (0.91-1.23)). Overall survival (OS) was better for diabetic patients with significant difference in diabetic metformin users (HR 0.91, 95% CI 0.79-0.94). CONCLUSIONS: Colorectal cancer patients with T2DM treated with metformin as part of their diabetic therapy appear to have a superior OS and CS. However, prospective controlled studies are still needed to evaluate the efficacy of metformin as an anti-tumor agent.

Increased Risk of Site-Specific Cancer in People with Type 2 Diabetes: A National Cohort Study.

A retrospective cohort design was used with the objective to evaluate cancer risk among people with type 2 diabetes mellitus (T2DM) in Lithuania. The cohort was established by identifying all patients with the first diagnosis of T2DM in the National Health Insurance Fund database during 2000-2012. Cancer cases were identified by record linkage with the Lithuanian Cancer Registry. Standardized incidence ratios (SIRs) were calculated. Of the 127,290 people that were included, 5959 cases of cancer in men and 6661 cancer cases in women with T2DM were observed. A statistically significant increase in risk for all cancer sites was observed in women, SIR 1.16 (95% CI 1.14-1.19), but not in men, SIR 1.00 (95% CI 0.98-1.03). Among males, a significant increase of liver (SIR 2.11, 95% CI 1.79-2.49]), pancreas (SIR 1.77, 95% CI 1.57-1.99), kidney (SIR 1.46 95% CI 1.31-1.62), thyroid (SIR 1.83, 95% CI 1.32-2.54), colorectal (SIR 1.23, 95% CI 1.14-1.31]), skin melanoma (SIR 1.40, 95% CI 1.11-1.76), and non-melanoma skin (SIR 1.14, 95% CI 1.05-1.23) cancer was observed. For females with T2DM, a significant increase in risk of cancer of the liver (SIR 1.45, 95% CI 1.17-1.79), pancreas (SIR 1.74, 95% CI 1.56-1.93), kidney (SIR = 1.43, 95% CI 1.28-1.60), thyroid (SIR = 1.40, 95% CI 1.22-1.62), breast (SIR = 1.24, 95% CI 1.17-1.31), and corpus uteri (SIR 2.07, 95% CI 1.93-2.21) was observed. In conclusion, people with T2DM in Lithuania had an increased risk of site-specific cancer.