Prospective Postmarketing Surveillance of Acute Myocardial Infarction in New Users of Saxagliptin: A Population-Based Study (original) (raw)
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Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data
Cardiovascular Diabetology, 2012
Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular (CV) disease; however, conclusive evidence that glycemic control leads to improved cardiovascular outcomes is lacking. Saxagliptin is a potent, selective dipeptidyl peptidase-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Saxagliptin was evaluated in a series of phase III trials as monotherapy; add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione; and as initial therapy in combination with metformin. Saxagliptin consistently improved glycemic control (as reflected by significant decreases in glycated hemoglobin, fasting plasma glucose, and postprandial glucose compared with controls) and was generally well tolerated. In these analyses, saxagliptin had clinically neutral effects on body weight, blood pressure, lipid levels, and other markers of CV risk compared with controls. A retrospective meta-analysis of 8 phase II and phase III trials found no evidence that saxagliptin increases CV risk in patients with T2DM (Cox proportional hazard ratio, 0.43; 95% CI, 0.23-0.80 for major adverse cardiovascular events retrospectively adjudicated). Instead, it raised the hypothesis that saxagliptin may reduce the risk of major adverse CV events. A long-term CV outcome trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-THrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) is currently ongoing to determine whether saxagliptin reduces CV risk in T2DM.
Safety of saxagliptin: rationale for and design of a series of postmarketing observational studies
Pharmacoepidemiology and Drug Safety, 2012
Purpose To describe the design and rationale of a series of postmarketing studies to examine the safety of saxagliptin, an oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus, in real-world settings. Methods We are conducting a series of retrospective cohort studies using two UK (General Practice Research Database, and The Health Improvement Network) and two US (Medicare, HealthCore Integrated Research Database SM) data sources. The primary outcomes of interest will include (i) hospitalization with acute liver failure, (ii) hospitalization for acute kidney injury, (iii) hospitalization for severe hypersensitivity reactions, (iv) hospitalization for severe infections, (v) hospitalization with infections associated with T-lymphocyte dysfunction (i.e., herpes zoster, tuberculosis, or nontuberculous mycobacteria), and (vi) major cardiovascular events. Diagnosis codes for the outcomes of interest will be validated by medical record review within each data source. Projected use and estimated incidence rates of outcomes of interest suggest there will be at least 80% statistical power to detect a minimum hazard ratio of 1.5 for major cardiovascular events, 2.0 for acute kidney injury and severe infections, 2.4 for acute liver failure, and 4.0 for severe hypersensitivity reactions. Results Forthcoming. Conclusions This postmarketing safety assessment will provide important information regarding the safety of saxagliptin and could potentially identify important dipeptidyl peptidase-4 inhibitor class effects. The methods described may be useful to others planning similar evaluations.
Diabetes Care, 2014
The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with few treatment options. We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial according to baseline renal function. RESEARCH DESIGN AND METHODS Patients with T2DM at risk for cardiovascular events were stratified as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m 2 ; n = 13,916), moderate renal impairment (eGFR 30-50 mL/min/1.73 m 2 ; n = 2,240), or severe renal impairment (eGFR <30 mL/min/1.73 m 2 ; n = 336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ‡0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95-2.91], P < 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28-6.28], P < 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50 mL/min/1.73 m 2 (HR 1.23 [95% CI 0.99-1.55]), eGFR 30-50 mL/min/1.73 m 2 (HR 1.46 [95% CI 1.07-2.00]), and in patients with eGFR <30 (HR 0.94 [95% CI 0.52-1.71]). Patients with renal impairment achieved reductions in microalbuminuria with saxagliptin (P = 0.041) that were similar to those of the overall trial population. CONCLUSIONS Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function.
Annals of Internal Medicine, 2016
Food and Drug Administration during the conduct of the study. Mr. Hamilton reports grants from the U.S. Food and Drug Administration during the conduct of the study. Dr. Lendle reports grants from the U.S. Food and Drug Administration during the conduct of the study. Dr. Iyer reports grants from the U.S. Food and Drug Administration during the conduct of the study. Mr. Rucker reports grants from the U.S. Food and Drug Administration during the conduct of the study. Ms. Pimentel reports grants from the U.S. Food and Drug Administration during the conduct of the study. Ms. Nathwani reports grants from the U.S. Food and Drug Administration during the conduct of the study. Dr. Griffin reports grants from the U.S. Food and Drug Administration and Harvard Pilgrim Health Care during the conduct of the study. Dr. Brown reports personal fees from Novartis Pharmaceuticals outside the submitted work. Mr. Fireman reports grants from the U.S. Food and Drug Administration during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2568.
The Use of Saxagliptin in People with Type 2 Diabetes in France: The Diapazon Epidemiological Study
Diabetes Therapy, 2017
Introduction: Saxagliptin is a potent, reversible inhibitor of dipeptidyl peptidase-4 that is indicated for the treatment of type 2 diabetes. The DIAPAZON study was a multicenter observational study intended to document the effectiveness, safety and patterns of saxagliptin use in France, including the saxagliptin retention rate, over 2 years of follow-up. Methods: A geographically representative sample of 304 French physicians (general practitioners and specialist endocrinologists or
Diabetology and Metabolic Syndrome
BACKGROUND: The aim of this study was to assess efficacy and safety of saxagliptin monotherapy for up to 76 weeks in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control, with main efficacy assessment at 24 weeks. METHODS: 365 treatment-naive patients with T2DM (HbA1c 7.0%-10.0%) were treated with saxagliptin 2.5 mg q.A.M., saxagliptin 2.5 mg q.A.M. with possible titration to saxagliptin 5 mg, saxagliptin 5 mg q.A.M., saxagliptin 5 mg q.P.M., or placebo. After week 24, patients in all groups were eligible for titration to saxagliptin 10 mg based on HbA1c [greater than or equal to]7%, and all unrescued placebo patients began blinded metformin 500 mg/day. Rescue with open-label metformin was available for patients with inadequate glycemic control. RESULTS: At week 24, placebo-subtracted mean HbA1c reduction from baseline (LOCF) was significantly greater in the saxagliptin treatment groups vs placebo, and remained greater through week 76. Serious adverse events...
Journal of managed care pharmacy : JMCP, 2014
Oral antihyperglycemic drugs used to treat type 2 diabetes mellitus (T2DM) vary in safety and tolerability. Treatment-related hypoglycemia and weight gain can exacerbate underlying disease. To evaluate the tolerability of saxagliptin using data from phase III clinical trials. Six 24-week randomized studies in 4,214 patients with T2DM were assessed. Saxagliptin 2.5 mg or 5 mg was compared with placebo in 2 trials of monotherapy in treatment-naïve patients and in 3 trials of add-on therapy to metformin, glyburide, or a thiazolidinedione; initial combination therapy with saxagliptin 5 mg plus metformin was compared with metformin monotherapy in treatment-naïve patients. Data from the monotherapy and add-on studies were pooled; data from the initial combination study were analyzed separately. No statistical analyses of between-group comparisons across studies were conducted for these safety analyses because of multiplicity of end points and relative lack of statistical power and becau...