Michael Bodmer

Long-Term Metformin Use Is Associated With Decreased Risk of Breast Cancer

OBJECTIVE To evaluate whether use of oral hypoglycemic agents is associated with an altered breast cancer risk in women. RESEARCH DESIGN AND METHODS Using the U.K.-based General Practice Research Database, we conducted a nested case-control analysis among 22,621 female users of oral antidiabetes drugs with type 2 diabetes. We evaluated whether they had an altered risk of breast cancer in relation to use of various types of oral hypoglycemic agents. Case and control patients with a recorded diagnosis of type 2 diabetes were matched on age, calendar time, and general practice, and the multivariate conditional logistic regression analyses were further adjusted for use of oral antidiabetes drugs, insulin, estrogens, smoking BMI, diabetes duration, and HbA1c (A1C). RESULTS We identified 305 case patients with a recorded incident diagnosis of breast cancer. The mean ± SD age was 67.5 ± 10.5 years at the time of the cancer diagnosis. Long-term use of ≥40 prescriptions (>5 years) of metformin, based on 17 exposed case patients and 120 exposed control patients, was associated with an adjusted odds ratio of 0.44 (95% CI 0.24–0.82) for developing breast cancer compared with no use of metformin. Neither short-term metformin use nor use of sulfonylureas or other antidiabetes drugs was associated with a materially altered risk for breast cancer. CONCLUSIONS A decreased risk of breast cancer was observed in female patients with type 2 diabetes using metformin on a long-term basis.

Use of Thiazolidinediones and Fracture Risk

BACKGROUND Thiazolidinediones may adversely affect the skeleton owing to decreased bone formation and accelerated bone loss. METHODS This study examines the association between the use of thiazolidinediones or other oral antidiabetic drugs and the risk of fracture. This nested case-control analysis uses the UK General Practice Research Database, including case patients with fracture aged 30 to 89 years with an incident fracture diagnosis between January 1994 and December 2005 and control subjects who were matched to case patients on age, sex, calendar time, and general practice attended. We assessed the odds ratios (ORs) of having a fracture associated with the use of rosiglitazone maleate, pioglitazone hydrochloride, other oral antidiabetic agents, or insulin. RESULTS There were 1020 case patients with an incident low-trauma fracture and 3728 matched controls. After adjustment for age, body mass index, other antidiabetic drugs, comedication, and comorbidities, the ORs for users of 8 or more thiazolidinedione prescriptions (corresponding to approximately 12-18 months of therapy) compared with nonuse was 2.43 (95% confidence interval [CI], 1.49-3.95). Rosiglitazone (OR, 2.38; 95% CI, 1.39-4.09) and pioglitazone (OR, 2.59; 95% CI, 0.96-7.01) were used more frequently by case patients with fracture (predominantly hip and wrist fractures) than by controls. The association was independent of patient age and sex and tended to increase with thiazolidinedione dose. No materially altered relative fracture risk was found in association with the use of other oral antidiabetic drugs. CONCLUSION This analysis provides further evidence of a possible association between long-term use of thiazolidinediones and fractures, particularly of the hip and wrist, in patients with diabetes mellitus.

Metformin, Sulfonylureas, or Other Antidiabetes Drugs and the Risk of Lactic Acidosis or Hypoglycemia: A nested case-control analysis

OBJECTIVE—Lactic acidosis has been associated with use of metformin. Hypoglycemia is a major concern using sulfonylureas. The aim of this study was to compare the risk of lactic acidosis and hypoglycemia among patients with type 2 diabetes using oral antidiabetes drugs. RESEARCH DESIGN AND METHODS—This study is a nested case-control analysis using the U.K.-based General Practice Research Database to identify patients with type 2 diabetes who used oral antidiabetes drugs. Within the study population, all incident cases of lactic acidosis and hypoglycemia were identified, and hypoglycemia case subjects were matched to up to four control patients based on age, sex, practice, and calendar time. RESULTS—Among the study population of 50,048 type 2 diabetic subjects, six cases of lactic acidosis during current use of oral antidiabetes drugs were identified, yielding a crude incidence rate of 3.3 cases per 100,000 person-years among metformin users and 4.8 cases per 100,000 person-years among users of sulfonylureas. Relevant comorbidities known as risk factors for lactic acidosis could be identified in all case subjects. A total of 2,025 case subjects with hypoglycemia and 7,278 matched control subjects were identified. Use of sulfonylureas was associated with a materially elevated risk of hypoglycemia. The adjusted odds ratio for current use of sulfonylureas was 2.79 (95% CI 2.23–3.50) compared with current metformin use. CONCLUSIONS—Lactic acidosis during current use of oral antidiabetes drugs was very rare and was associated with concurrent comorbidity. Hypoglycemic episodes were substantially more common among sulfonylurea users than among users of metformin.

Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: The REDUCE randomized clinical trial

IMPORTANCE International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown. OBJECTIVE To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids. DESIGN, SETTING, AND PATIENTS REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011. INTERVENTIONS Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%. MAIN OUTCOME AND MEASURE Time to next exacerbation within 180 days. RESULTS Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently. CONCLUSIONS AND RELEVANCE In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN19646069.

Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study.

To explore the risk of developing Alzheimers disease (AD) in individuals with diabetes mellitus treated with metformin or other antidiabetic drugs.

Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis.

OBJECTIVES:The objective of this study was to explore the association between use of metformin or other antidiabetic drugs, diabetes, and the risk of pancreatic cancer.METHODS:We conducted a case–control study using the UK-based General Practice Research Database (GPRD). Cases had a first-time diagnosis of pancreatic cancer, and six controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the GPRD before the index date. Results were further adjusted in multivariate logistic regression analyses for potential confounders such as body mass index, smoking, alcohol consumption, and diabetes duration.RESULTS:In all, 2,763 case patients with a recorded diagnosis of pancreatic cancer were identified. Mean age±s.d. was 69.5±11.0 years. Long-term use (≥30 prescriptions) of metformin was not associated with a materially altered risk of pancreatic cancer (adjusted odds ratio (adj. OR): 0.87, 95% confidence interval (CI): 0.59–1.29), but there was a suggestion of effect modification by gender, as long-term use of metformin was linked to a decreased risk in women (adj. OR: 0.43, 95% CI: 0.23–0.80). Both use of sulfonylureas (≥30 prescriptions, adj. OR: 1.90, 95% CI: 1.32–2.74) and of insulin (≥40 prescriptions, adj. OR: 2.29, 95% CI: 1.34–3.92) were associated with an increased risk of pancreatic cancer.CONCLUSIONS:Use of metformin was associated with a decreased risk of pancreatic cancer in women only, whereas use of sulfonylureas and of insulin was associated with an increased risk of pancreatic cancer.

Use of metformin and the risk of ovarian cancer: A case–control analysis

OBJECTIVE To explore the association between use of metformin or other antidiabetic drugs and the risk of ovarian cancer. METHODS Using the UK-based General Practice Research Database, we conducted a case-control analysis to evaluate whether users of metformin or other antidiabetic drugs had an altered risk of ovarian cancer. Cases had an incident diagnosis of ovarian cancer, and up to 6 controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the GPRD prior to the index date. Results were further adjusted by multivariate logistic regression analyses for BMI, polycystic ovaries, endometriosis, use of estrogens or oral contraceptives, a history of hysterectomy, and smoking. RESULTS We identified 1611 case patients with a recorded diagnosis of ovarian cancer. Mean age ± SD was 61.2 ± 13.1 years at the time of cancer diagnosis. Long-term use (≥ 30 prescriptions) of metformin, but not of sulfonylureas, was associated with a tendency towards a reduced risk of ovarian cancer (OR 0.61, 95% CI 0.30-1.25 for metformin and 1.26, 95% CI 0.65-2.44 for sulfonylureas). Long-term use of insulin (≥ 40 prescriptions) was associated with a slightly increased risk for ovarian cancer (OR 2.29, 95% CI 1.13-4.65). CONCLUSION In this large epidemiological study long-term use of metformin, but not of sulfonylureas, was associated with a tendency towards a decreased risk of ovarian cancer. Long-term use of insulin was associated with an increased risk of ovarian cancer.

Statin Use and Risk of Gallstone Disease Followed by Cholecystectomy

CONTEXT Gallstone disease is a leading cause of morbidity in western countries and carries a high economic burden. Statins decrease hepatic cholesterol biosynthesis and may therefore lower the risk of cholesterol gallstones by reducing the cholesterol concentration in the bile. Data on this association in humans are scarce. OBJECTIVE To study the association between the use of statins, fibrates, or other lipid-lowering agents and the risk of incident gallstone disease followed by cholecystectomy. DESIGN, SETTING, AND PARTICIPANTS Case-control analysis using the UK-based General Practice Research Database. Incident patients between 1994 and 2008 and 4 controls per each patient were identified and matched on age, sex, general practice, calendar time, and years of history in the database. The study population was 76% women and the mean (SD) age was 53.4 (15.0) years at the index date. Conditional logistic regression was used to estimate the odds ratio (OR) of developing gallstones followed by cholecystectomy in relation to exposure to lipid-lowering agents, stratified by exposure timing and duration. The ORs and 95% confidence intervals (CIs) were adjusted for smoking, body mass index, ischemic heart disease, stroke, and estrogen use. MAIN OUTCOME MEASURE The adjusted OR (AOR) for developing gallstone disease followed by cholecystectomy in relation to exposure to lipid-lowering agents. RESULTS A total of 27,035 patients with cholecystectomy and 106,531 matched controls were identified, including 2396 patients and 8868 controls who had statin use. Compared with nonuse, current statin use (last prescription recorded within 90 days before the first-time diagnosis of the disease) was 1.0% for patients and 0.8% for controls (AOR, 1.10; 95% CI, 0.95-1.27) for 1 to 4 prescriptions; 2.6% vs 2.4% (AOR, 0.85; 95% CI, 0.77-0.93) for 5 to 19 prescriptions, and 3.2% vs 3.7% (AOR, 0.64; 95% CI, 0.59-0.70) for 20 or more prescriptions. The AORs for current use of statins defined as 20 or more prescriptions were similar (around 0.6) across age, sex, and body mass index categories, and across the statin class. CONCLUSION Long-term use of statins was associated with a decreased risk of gallstones followed by cholecystectomy.

Use of metformin is not associated with a decreased risk of colorectal cancer: a case-control analysis

Background: To explore the association between use of metformin or other antidiabetic drugs and the risk of colorectal cancer. Methods: Using the United Kingdom–based General Practice Research Database (GPRD), we conducted a nested case–control analysis in patients with diabetes mellitus. Cases had an incident diagnosis of colorectal cancer, and up to 6 controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the GPRD prior to the index date. Results were adjusted for multiple potential confounders. Results: We identified 920 diabetic patients with colorectal cancer. Mean age ± SD was 70.2 ± 8.6 years and 63.3% were male. Extensive use (≥50 prescriptions) of metformin was associated with a slightly increased risk of colorectal cancer (adjusted OR = 1.43, 95% CI: 1.08–1.90) as compared with non use, with an adjustment of OR = 1.81 (95% CI: 1.25–2.62) in men and of 1.00 (95% CI: 0.63–1.58) in women. Neither extensive use of sulfonylureas (adjusted OR = 0.79, 95% CI: 0.60–1.03) nor insulin (adjusted OR = 0.90, 95% CI: 0.63–1.28) were associated with an increased risk of colorectal cancer. A long-term history of diabetes (>10 years) was not associated with a materially increased risk of colorectal cancer compared with short-term diabetes duration (<2 years; adjusted OR = 1.14, 95% CI: 0.90–1.46). Conclusion: Use of metformin was linked to an increased risk of colorectal cancer in men. Use of sulfonylureas or insulin was not associated with an altered risk of colorectal cancer. Impact: Metformin does not prevent colorectal cancer. Cancer Epidemiol Biomarkers Prev; 21(2); 280–6. ©2011 AACR.

Seizures in patients with Alzheimer’s disease or vascular dementia: A population-based nested case–control analysis

Purpose:  Patients with Alzheimer’s disease (AD) have an increased risk of developing seizures or epilepsy. Little is known about the role of risk factors and about the risk of developing seizures/epilepsy in patients with vascular dementia (VD). The aim of this study was to assess incidence rates (IRs) of seizures/epilepsy in patients with AD, VD, or without dementia, and to identify potential risk factors of seizures or epilepsy.