ADOPT ("A Diabetes Outcome Progression Trial") is a double-blind, controlled clinical trial that aims at assessing the efficacy of rosiglitazone, as compared to metformin or glibenclamide, in maintaining long-term glycaemic control in patients with recently diagnosed type 2 diabetes. It randomized 4,360 patients who were followed for a median of 4.0 years. The cumulative incidence of monotherapy failure (defined as a confirmed level of fasting plasma glucose level of more than 180 mg/dl) averaged at 5 years 15% with rosiglitazone, 21% with metformin, and 34% with glibenclamide. This represents a risk reduction for rosiglitazone of 32% as compared to metformin and 63% as compared to glibenclamide (P
Over the years, drug products, including those indicated for diabetes, have been withdrawn from the marketplace because of quality concerns and/or severe adverse drug reactions. While the drug regulatory process is designed to detect, among other things, adverse drug reactions before a drug receives marketing authorization, for various reasons, premarket detection of all potential adverse reactions associated with a drug may not be possible. As such, regulatory authorities must also react to and manage adverse reactions identified at the postmarket stage. In this article, we provide a general overview of drug regulation in Canada and the United States and consider an example of a drug indicated for the treatment of diabetes and how newly identified potential safety concerns were managed in the postmarket environment.
Cites: N Engl J Med. 2007 Jun 14;356(24):2457-7117517853
Cites: J Am Board Fam Pract. 2001 Sep-Oct;14(5):362-711572541
Diabetic men have lowered overall prostate cancer (PCa) risk, while their risk of high-grade disease may be elevated. The antidiabetic drug metformin may reduce the risk. This study evaluated PCa incidence among users of metformin and other antidiabetic drugs in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC).
The study population (78,615 men) was linked to the national prescription database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for PCa were estimated using Cox regression, with medication use as a time-dependent variable. The effect of diabetes was estimated by comparing antidiabetic drug users to non-users, while drug-specific effects were evaluated within antidiabetic drug users. Analyses were performed in both study arms of FinRSPC.
Compared to non-users, men using antidiabetic drugs had lowered overall PCa risk (HR 0.85, 95% CI 0.79-0.92), and this association was not affected by PCa screening. However, the risk of metastatic PCa was increased (HR 1.44, 95% CI 1.09-1.91). Among antidiabetic drug users, metformin decreased overall PCa risk (HR 0.81, 95% CI 0.69-0.95) in a dose-dependent manner. When stratified by FinRSPC study arm, the risk reduction was observed only in the screening arm. Sulphonylureas increased the risk of metastatic PCa (HR 2.04, 95% CI 1.11-3.77). Use of thiazoledenediones or insulin was not associated with PCa risk.
Among antidiabetic drug users, metformin lowered the overall PCa risk, while the risk of metastatic disease was elevated in sulphonylurea users. As sulphonylureas stimulate insulin secretion, the results suggest that hyperinsulinemia may be a risk factor for PCa.
*School of Pharmacy, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador †Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD) ‡School of Public Health §Department of Medicine, Division of General Internal Medicine, University of Alberta ?Mazankowski Alberta Heart Institute ¶Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
The aim of this study was to assess the impact of removing prior-authorization restrictions on the use of thiazolidinediones (TZDs) and outcomes.
In a controlled interrupted time-series analysis, whereby new users of antidiabetic agents over 65 years of age in adjacent Canadian provinces with different TZD-related policies [Alberta (n = 16,653) and Saskatchewan (n = 6682)] were followed from January 2001 to December 2006. Prior authorization for TZDs was removed in Alberta (intervention province) in December 2003 (rosiglitazone) and February 2004 (pioglitazone); no policy changes occurred in Saskatchewan (control province). Adjusted differences in percent change between intervention and control provinces were used to estimate policy-attributable effects (PAE) on TZD use within 30 days and 1 year and patient outcomes (composite of all-cause mortality or hospitalization for acute coronary events or heart failure) within 1 year.
Mean age was 75 years, 51% were female, and 206,055 antidiabetic prescriptions were dispensed during follow-up. TZD use within 30 days among new users of antidiabetic agents increased almost >10% in Alberta compared with Saskatchewan controls immediately following the policy change: PAE = 9.4%, 95% confidence interval, 7.3%-11.6%. Other less expensive antidiabetic drug use decreased to exactly the same extent, suggesting TZD substitution. Compared with the controls, in Alberta there were no changes in the primary (clinical) composite outcome at 1 year (PAE = 0.31%, 95% confidence interval, -2.8% to +3.4%).
The removal of a prior-authorization policy for TZDs was associated with an immediate increase in TZD use but did not impact patient outcomes. In this case, the policy removal shifted drug use to a more expensive drug with less certain clinical benefit.
The purpose of this study was to identify reproductive risk factors associated with dysglycemia (diabetes, impaired glucose tolerance, and impaired fasting glucose) in a contemporary multiethnic population.
We studied 14,661 women screened with an oral glucose tolerance test for the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial. Reproductive risk factors were compared in normoglycemic and dysglycemic women.
Dysglycemia was significantly associated with the number of children born (odds ratio 1.03 per child [95% CI 1.01-1.05]), age (1.05 per year [1.04-1.05]), non-European ancestry (1.09 [1.01-1.17]), preeclampsia/eclampsia (1.14 [1.02-1.27]), irregular periods (1.21 [1.07-1.36]), and gestational diabetes mellitus (GDM) (1.53 [1.35-1.74]). The relationship between GDM and dysglycemia did not differ across BMI tertiles (P = 0.84) nor did the relationships of other risk factors.
Reproductive factors, particularly GDM, are associated with dysglycemia in middle-aged women from many ethnicities. Reproductive factors can be used to counsel young women about their future risk of dysglycemia, whereas in middle age they may help screen for dysglycemia.
OBJECTIVE: To thoroughly examine the mechanisms for insulin resistance in polycystic ovary syndrome (PCOS) and to evaluate the effects of pioglitazone treatment on insulin resistance, beta-cell function, LH secretion, and glucose metabolism. DESIGN: Randomized, blinded, placebo-controlled study. SETTING: Outpatient clinic, at a university hospital in Denmark. PATIENT(S): Thirty obese women with PCOS and 14 weight-matched healthy females. INTERVENTION(S): Sixteen weeks of blinded treatment with pioglitazone (30 mg/d) or placebo. MAIN OUTCOME MEASURE(S): Fasting blood samples, 24-hour 20-minute integrated blood sampling (LH, insulin, and C-peptide), euglycemic hyperinsulinemic clamps including 3-(3)H glucose, and indirect calorimetry were performed before and after the intervention period. RESULT(S): Patients with PCOS had significantly lower insulin sensitivity compared with controls, including significantly decreased insulin-stimulated oxidative and nonoxidative glucose metabolism. Pioglitazone treatment resulted in significantly lower levels of fasting insulin and significantly higher insulin sensitivity, increased insulin-stimulated glucose oxidation, and increased insulin-stimulated inhibition of lipid oxidation. During 24-hour blood sampling, significantly lower area under-the-curve insulin and lower median insulin levels were observed. Secretion profiles of LH and E(2) and T levels did not change significantly. CONCLUSION(S): Insulin resistance in PCOS was characterized by hyperinsulinemia, impaired insulin-stimulated oxidative and nonoxidative glucose metabolism, which was partly reversed by pioglitazone treatment.
PURPOSE: To clarify whether endogenous peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligand, rosiglitazone, affect retinal leukostasis and the associated vascular leakage using an experimental diabetic model. METHODS: Diabetes was induced in heterozygous PPARgamma+/- mice and Brown Norway rats with an intraperitoneal streptozotocin (STZ) injection. Retinal leukostasis and leakage, quantified by concanavalin A (Con A) lectin perfusion labeling combined with a fluorophotometric dextran leakage assay, were investigated at 120 days in diabetic PPARgamma+/- and wild-type mice and at 21 days in diabetic rats receiving rosiglitazone or the vehicle. The retinal protein expression levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-alpha, and the intercellular adhesion molecule (ICAM)-1 were investigated by means of the ELISA assay. RESULTS: In the diabetic PPARgamma+/- mice, retinal leukostasis and leakage were greater than in the diabetic wild-type mice. In addition retinal leukostasis and leakage were suppressed by treatment with rosiglitazone in experimental diabetic rats. ELISA analysis revealed that the upregulated ICAM-1 expression in the diabetic rat retina was reduced by rosiglitazone treatment. CONCLUSIONS: An endogenous pathway involving PPARgamma provides protection against retinal leukostasis and retinal leakage in diabetes and treatment with PPARgamma specific ligands inhibits retinal leukostasis and retinal leakage in diabetic rats.
It is unclear whether diabetes mellitus or use of particular glucose-lowering agents is associated with increased risk of mortality after noncardiac surgery in patients with known cardiac disease.
We carried out a retrospective cohort study using 4 linked administrative databases in the province of Alberta, Canada from 1999-2006.
Of the 32,834 patients with known cardiac disease in our cohort, 9305 (28%) had diabetes. All-cause 30-day mortality after noncardiac surgery was 6.4% in patients with diabetes, and 6.1% in those without diabetes (multivariate adjusted odds ratio [aOR] 0.97, 95% confidence interval [CI], 0.87-1.08). In the 24,037 patients older than 65, mortality was 7.5% in individuals with diabetes and 7.5% in those without diabetes (5.7% in those taking insulin [aOR, 0.89; 95% CI, 0.70-1.13], 8.0% in those using oral agents only [aOR, 1.08; 95% CI, 0.95-1.22]). None of the glucose-lowering drug classes were associated with perioperative mortality in elderly cardiac patients (sulfonylureas aOR, 0.94; 95% CI, 0.76-1.16; metformin aOR, 0.92; 95% CI, 0.74-1.14; thiazolidinediones aOR, 0.64; 95% CI, 0.40-1.04; insulin aOR, 0.83; 95% CI, 0.65-1.08), but use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (aOR, 0.83; 95% CI, 0.75-0.93), ß-blockers (aOR, 0.82; 95% CI, 0.72-0.93), or statins (aOR, 0.65; 95% CI, 0.55-0.78) in the 100 days before surgery were associated with lower 30-day mortality.
Neither diabetes nor exposure to common classes of glucose-lowering drugs preoperatively were associated with increased perioperative mortality in cardiac patients undergoing noncardiac surgery. However, cardiac patients not using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, ß-blockers, or statins preoperatively exhibited higher mortality rates, emphasizing the importance of optimizing evidence-based therapy before elective surgery in these patients.
To establish the practice patterns of Canadian vitreoretinal (VR) specialists in the treatment of diabetic macular edema (DME).
A survey was mailed, faxed, e-mailed, and published online for access by all Canadian VR specialists.
All VR specialists identified from the Canadian Ophthalmology Society directory and the Canadian Retina and Vitreous Society directory.
A 19-item survey investigating treatment of DME was mailed to all VR specialists. A reminder fax and e-mail was sent with the survey attached. In all correspondence, physicians were given information regarding an available online version of the survey. The survey data was descriptively analyzed with the Statistical Package for the Social Sciences.
With clinically significant macular edema (CSME) that is either away from the foveal avascular zone (FAZ) or diffuse, the most common first-line treatment option was macular photocoagulation 48 (78.8%) and 33 (54.1%), respectively. For microaneurysms within the FAZ, 33 (54.1%) of respondents chose intravitreal antivascular endothelial growth factor agents as their first-line treatment. In all, 51 respondents (83.6%) felt that vitrectomy played a role in the management of treatment-resistant CSME. Before utilizing intravitreal triamcinolone acetonide (IVT) injections, 34 (55.7%) of respondents did use a topical steroid trial to look for raised intraocular pressure whereas 16 (26.2%) of respondents did not use IVT injections at all.
This survey provides valuable practical information on how DME is currently being treated in Canada and may serve as a baseline to assess how these patterns evolve over time.