Metformin, Sulfonylureas, or Other Antidiabetes Drugs and the Risk of Lactic Acidosis or Hypoglycemia

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.Merck SA, Lyon, Franc

Use of depot medroxyprogesterone acetate and fracture risk

Depot medroxyprogesterone acetate (DMPA), which has a high rate of use among teenagers in Europe and the United States, has been associated with impaired bone mineral acquisition during adolescence and accelerated bone loss in later life. Studies on the association between DMPA use and fracture risk are limited.; We aimed at evaluating the relationship between use of hormonal contraceptives, specifically DMPA, and fracture risk.; We conducted a case-control analysis using the United Kingdom-based General Practice Research Database.; Participants were females aged 20-44 yr with an incident fracture diagnosis between 1995 and 2008.; Odds ratios (OR) with 95% confidence intervals (CI) of incident fracture in relation to exposure to DMPA or combined oral contraceptives were assessed. Adjustments were made for smoking, body mass index, and additional potential confounders.; We identified 17,527 incident fracture cases and 70,130 control patients (DMPA exposure: 11 and 8%, respectively). Compared with nonuse, current use of one to two, three to nine, or 10 or more DMPA prescriptions yielded adjusted OR for fractures of 1.18 (95% CI = 0.93-1.49), 1.36 (95% CI = 1.15-1.60), and 1.54 (95% CI = 1.33-1.78), respectively. Fracture risk was highest after longer treatment duration (<2-3 yr), and there was no difference in patients below and above the age of 30 yr. For users of combined estrogen-containing oral contraceptives, the OR were around 1.; This population-based study suggests that use of DMPA is associated with a slightly increased risk of fractures

Chronic obstructive pulmonary disease and the risk of cardiovascular diseases

Previous large epidemiological studies reporting on the association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases mainly focussed on prevalent diseases rather than on the incidence of newly diagnosed cardiovascular outcomes. We used the UK-based General Practice Research Database (GPRD) to assess the prevalence and incidence of cardiovascular diseases in COPD patients aged 40-79 between 1995 and 2005, and we randomly matched COPD-free comparison patients to COPD patients. In nested-case control analyses, we compared the risks of developing an incident diagnosis of cardiac arrhythmias, venous thromboembolism, myocardial infarction, or stroke between patients with and without COPD, stratifying the analyses by COPD-severity, using COPD-treatment as proxy for disease severity. We identified 35,772 patients with COPD and the same number of COPD-free patients. Most cardiovascular diseases were more prevalent among COPD patients than among the comparison group of COPD-free patients. The relative risk estimates of developing an incident diagnosis of cardiac arrhythmia (OR 1.19, 95% CI 0.98-1.43), deep vein thrombosis (OR 1.35, 95% CI 0.97-1.89), pulmonary embolism (OR 2.51, 95% CI 1.62-3.87), myocardial infarction (OR 1.40, 95% CI 1.13-1.73), or stroke (OR 1.13, 95% CI 0.92-1.38), tended to be increased for patients with COPD as compared to COPD-free controls. The findings of this large observational study provide further evidence that patients with COPD are at increased risk for most cardiovascular disease

The Risk of Venous Thromboembolism (VTE) in Men with Benign Prostatic Hyperplasia Treated with 5-Alpha Reductase Inhibitors (5ARIs)

Background: Many men receive 5-alpha reductase inhibitors (5ARIs) for ongoing treatment of benign prostatic hyperplasia (BPH). The increased risk of cardiovascular complications with 5ARIs has been documented in BPH studies and the occurrence of cerebral venous thrombosis, presumably due to increased estrogen level following 5ARI use, was described in multiple case reports. The objective of this study was to determine if 5ARIs with or without alpha blockers (AB) were associated with an increased risk of venous thromboembolism (VTE) in males with BPH. Methods: We conducted a nested case-control study among a population of men ages 40-79 who received at least one 5ARI or AB prescription for treatment of BPH between 1995 and 2015 in the UK-based Clinical Practice Research Datalink GOLD. Cases of incident VTE (pulmonary embolism [PE] or deep venous thrombosis [DVT]) and matched controls were identified from this population. We used descriptive analyses and conditional logistic regression to evaluate the risk of VTE in users of 5ARIs compared to users of ABs. Results: For 5ARI only users, the adjusted odds ratios (aORs), (95% CI) for VTE were 1.51 (0.98-2.32) in current 5ARI users and 1.23 (0.70-2.17) in recent/distant past, compared to AB only users. However, the aOR (95% CI) in men who had 50 or more current 5ARI prescriptions compared to users of ABs only was higher: 2.29 (1.14-4.63). For 5ARI with AB use, the aORs, (95% CI) for VTE were 1.16 (0.64-2.10) in current 5ARI+AB users and 1.93 (0.71-5.25) in recent/distant past, compared to AB only users. The aOR (95% CI) in men who had 50 or more current 5ARI+AB prescriptions compared to users of ABs only was 1.65 (0.64-4.26). Conclusion: Current use of 5ARI, particularly long-term use, is associated with an increased risk of incident idiopathic VTE compared to patients treated with AB use only

The association between thyroid disorders and incident gout: population-based case-control study

Thyroid hormones influence kidney function and thereby might alter serum urate levels, a major risk factor for gouty arthritis.; To assess the risk of developing incident gout in association with hypothyroidism or hyperthyroidism.; Retrospective population-based case-control analysis.; UK-based Clinical Practice Research Datalink, a primary care research database.; We identified adult patients with a diagnosis of incident gout between 1990 and 2014. We matched one control to each gout case in terms of age, sex, general practice, calendar time, and years of active history in the database.; We used conditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for developing gout in association with hypo- or hyperthyroidism and adjusted for potential confounders.; The study population encompassed 68,159 incident gout cases, of whom 78.8% were male, and the same number of matched controls. There was no increased risk of gout in patients with hypothyroidism: adjusted OR of gout of 1.12 (95% CI 1.05-1.20) compared with no hypothyroidism. Current short-term treatment of thyroid hormone replacement therapy was associated with an adjusted OR of gout of 1.54 (95% CI 1.24-1.92), compared with no treatment. Neither hyperthyroidism nor current treatment with thyroid suppression therapy was associated with gout (adjusted OR, 1.08 [95% CI 0.95-1.22] and 0.82 [95% CI 0.57-1.17], respectively).; This large observational study does not provide evidence that hypothyroidism or hyperthyroidism, irrespective of treatment, is associated with a clinically relevant increased risk of developing incident gout. There may be an exception among patients with newly diagnosed and treated hypothyroidism

Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database

Objective To examine the risk of non-fatal idiopathic venous thromboembolism in current users of a combined oral contraceptive containing drospirenone, relative to current users of preparations containing levonorgestrel

Częstość chorób wątroby u chorych na cukrzycę typu 2 leczonych doustnymi lekami przeciwcukrzycowymi

OBJECTIVE. We evaluated liver disease in conventionally treated type 2 diabetic patients to provide a reference against which reports of liver disease related to novel oral antidiabetic treatments could be compared. RESEARCH DESIGN AND METHODS. In this follow-up study, patients with type 2 diabetes who were treated with oral antidiabetic agents were identified from the U.K.-based General Practice Research Database and were followed to determine whether they developed liver disease. The specific types and etiologies of liver disorders were determined. Incidence rates were calculated based on the accumulated exposure time to oral antidiabetic agents. RESULTS. Among 44,406 type 2 diabetic patients, 605 had a computer diagnosis of liver disease with an incidence rate of 53.2/10,000 person-years (95% CI 49.2&#150;57.6). Of the 605 subjects, 186 had nonsympWSTĘP. W badaniu oceniane były przypadki uszkodzenia wątroby u chorych na cukrzycę typu 2 leczonych tradycyjnymi doustnymi środkami przeciwcukrzycowymi. Celem próby była ponowna analiza danych dotyczących zależności uszkodzeń wątroby od stosowania doustnych leków przeciwcukrzycowych. MATERIAŁ I METODY. Do badania zakwalifikowano chorych na cukrzycę typu 2 leczonych doustnymi lekami przeciwcukrzycowymi. Korzystano z Brytyjskiej Bazy Danych. Chorzy byli obserwowani w kierunku ewentualnego rozwoju chorób wątroby. Określono typ i etiologię rozpoznanych schorzeń, a ich częstość obliczano na podstawie skumulowanego czasu trwania terapii doustnej. WYNIKI. Spośród 44 406 chorych na cukrzycę typu 2 u 605 potwierdzono po przeprowadzeniu badania komputerowego występowanie choroby wątroby, wskaźnik zapadalności wynosił 53,2/10 000 osobolat (95% CI 49,2&#8211;57,6). U 186 z nich choroba miała postać łagodnych, przejściowych, bezobjawowych epizodów, u 249 występowały czynniki predysponujące, natomiast u 113 stwierdzono istnienie innych przyczyn uszkodzenia wątroby. Oceniono, że u 57 pacjentów uszkodzenie wątroby było prawdopodobnie spowodowane stosowaniem leków, wskaźnik zapadalności wynosił 5,0/10 000 osobolat (3,9&#8211;6,5). Rozpoznanie to potwierdzono w 11 przypadkach, u 8 chorych stwierdzono stłuszczenie wątroby spowodowane cukrzycą, u pozostałych chorych przyczyna pozostała nierozpoznana. Terapię doustnymi środkami przeciwcukrzycowymi kontynuowało 51 z 57 chorych, u 2 nie potwierdzono, że przyjmowane leki wywołały uszkodzenie wątroby, przy wskaźniku zapadalności wynoszącym 0,2/10 000 osobolat (< 0,1&#8211;0,6). WNIOSKI. W badanej populacji choroby wątroby występowały często. U wielu chorych dodatkowo występowały inne schorzenia, które mogą powodować uszkodzenie wątroby

Case-control analysis on metformin and cancer of the esophagus

Purpose: Metformin use has been associated with decreased cancer risks, though data on esophageal cancer are scarce. We explored the relation between use of metformin or other anti-diabetic drugs and the risk of esophageal cancer. Methods: We conducted a case-control analysis in the UK-based general practice research database (GPRD, now clinical practice research datalink, CPRD). Cases were individuals with an incident diagnosis of esophageal cancer between 1994 and 2010 at age 40-89years. Ten 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. Various potential confounders including diabetes mellitus, gastro-esophageal reflux, and use of proton-pump inhibitors were evaluated in univariate models, and the final results were adjusted for BMI and smoking. Results are presented as odds ratios (ORs) with 95% confidence intervals (CI). Results: Long-term use (≥30 prescriptions) of metformin was not associated with a materially altered risk of esophageal cancer (adj. OR 1.23, 95% CI 0.92-1.65), nor was long-term use of sulfonylureas (adj. OR 0.93, 95% CI 0.70-1.23), insulin (adj. OR 0.87, 95% CI 0.60-1.25), or of thiazolidinediones (adj. OR 0.71, 95% CI 0.37-1.36). Conclusion: In our population-based study, use of metformin was not associated with an altered risk of esophageal cance

Helping everyone do better: a call for validation studies of routinely recorded health data.

There has been a surge of availability and use for research of routinely collected electronic health data, such as electronic health records, health administrative data, and disease registries. Symptomatic of this surge, in 2012, Pharmacoepidemiology and Drug Safety (PDS) published a supplemental issue containing several reviews of validated methods for identifying health outcomes using routine health data,1 focusing on databases feeding the US Mini-Sentinel Program