Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial (original) (raw)
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Diabetes, Obesity and Metabolism, 2011
To evaluate the efficacy and safety of saxagliptin vs. placebo in patients with type 2 diabetes mellitus (T2DM) and renal impairment. Methods: In this multicentre, randomized, parallel-group, double-blind, placebo-controlled study, patients with glycated haemoglobin (HbA1c) 7-11% and creatinine clearance <50 ml/min were stratified by baseline renal impairment (moderate, severe or end-stage on haemodialysis), and randomized (1 : 1) to saxagliptin 2.5 mg once daily or placebo for 12 weeks. Oral antihyperglycaemic drugs and insulin therapy present at enrolment were continued throughout the study. The absolute change in HbA1c from baseline to week 12 (primary efficacy end-point) was analysed using an analysis of covariance model with last observation carried forward methodology.
Diabetes and Vascular Disease Research, 2011
To assess the long-term efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus inadequately controlled on sulphonylurea monotherapy, 768 patients were randomised to saxagliptin 2.5 or 5 mg in combination with glyburide 7.5 mg versus placebo added to up-titrated glyburide over 76 weeks (24 weeks plus 52-week extension) in this phase 3, double-blind, placebo-controlled trial; 557 patients completed the study, 142 without being rescued. At 76 weeks, adjusted mean changes from baseline HbA1C (repeated measures model) (95% confidence interval) for saxagliptin 2.5 mg, saxagliptin 5 mg, and up-titrated glyburide were 0.11% (-0.05, 0.27), 0.03% (-0.14, 0.19), and 0.69% (0.47, 0.92), respectively (post hoc and nominal p < 0.0001 for saxagliptin 2.5 and 5 mg vs. up-titrated glyburide). Adverse event frequency was similar in all treatment groups; reported hypoglycaemia event rates were 24.2%, 22.9%, and 20.6% with saxagliptin 2.5 mg, saxagliptin 5 mg, and up-titrated g...
Diabetes Obesity & Metabolism, 2009
Aim: The study aim was to evaluate the efficacy and safety of initial combination therapy with saxagliptin + metformin vs. saxagliptin or metformin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycaemic control.Methods: In this multicentre, randomized, double-blind, active-controlled phase 3 trial, 1306 treatment-naïve patients with T2D ≥18 to ≤77 years, glycosylated haemoglobin (HbA1c) ≥8 to ≤12%, fasting C-peptide concentration ≥1.0 ng/ml, body mass index ≤40 kg/m2 were randomized to receive saxagliptin 5 mg + metformin 500 mg, saxagliptin 10 mg + metformin 500 mg, saxagliptin 10 mg + placebo or metformin 500 mg + placebo for 24 weeks. From weeks 1–5, metformin was uptitrated in 500-mg/day increments to 2000 mg/day maximum in the saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin and metformin + placebo treatment groups. The main outcome measure was HbA1c change from baseline to week 24. Selected secondary outcomes included change from baseline to week 24 in fasting plasma glucose (FPG), proportion of patients achieving HbA1c <7% and postprandial glucose area under the curve (PPG-AUC).Results: At 24 weeks, saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin demonstrated statistically significant adjusted mean decreases vs. saxagliptin 10 mg and metformin monotherapies in HbA1c (−2.5 and −2.5% vs. −1.7 and −2.0%, all p < 0.0001 vs. monotherapy) and FPG (−60 and −62 mg/dl vs. −31 and −47 mg/dl, both p < 0.0001 vs. saxagliptin 10 mg; p = 0.0002 saxagliptin 5 mg + metformin vs. metformin; p < 0.0001 saxagliptin 10 mg + metformin vs. metformin). Proportion of patients achieving an HbA1c <7% was 60.3 and 59.7%, respectively, for saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin (all p < 0.0001 vs. monotherapy). PPG-AUC was significantly reduced [−21 080 mg·min/dl (saxagliptin 5 mg + metformin) and −21 336 mg·min/dl (saxagliptin 10 mg + metformin) vs. −16 054 mg·min/dl (saxagliptin 10 mg) and −15 005 mg·min/dl (metformin), all p < 0.0001 vs. monotherapy]. Adverse event occurrence was similar across all groups. Hypoglycaemic events were infrequent.Conclusion: Saxagliptin + metformin as initial therapy led to statistically significant improvements compared with either treatment alone across key glycaemic parameters with a tolerability profile similar to the monotherapy components.
Diabetology & Metabolic Syndrome, 2010
Saxagliptin is a potent, selective DPP4 inhibitor. Highlights from abstracts presented at the 2010 meetings of the European Association for the Study of Diabetes and the American Diabetes Association include studies and analyses that shed light on the promising role for saxagliptin within the management of type 2 diabetes mellitus. Data show that saxagliptin combination therapy improves HbA 1c levels compared with placebo, particularly in patients with high HbA 1c at baseline, long duration of disease, low baseline creatinine clearance, and low homeostasis model assessment 2 β-cell function at baseline. These efficacy benefits are achieved without any increase in hypoglycemia or other adverse events. The study results also show that the saxagliptin plus metformin combination is a good candidate for initial therapy in drug-naïve patients treated for as long as 72 weeks. Survey data presented confirm that hypoglycemia (and fear of hypoglycemia) is a barrier to patients' acceptance of diabetes treatment, limiting its efficacy. Therefore, therapies such as saxagliptin that have a low risk of hypoglycemia may be more acceptable to patients in helping them to achieve glycemic control and to optimize their quality of life. In patients with renal impairment, for whom metformin is contraindicated, saxagliptin monotherapy is a promising option for antidiabetic management as, when given at a reduced dose, it is well-tolerated with a safety profile similar to that of placebo.
Diabetes, Obesity and Metabolism, 2011
Aim: To assess the efficacy and safety of saxagliptin + metformin initial combination therapy compared with saxagliptin or metformin alone over 76 weeks (24-week short-term + 52-week long-term extension) in treatment-naïve type 2 diabetes mellitus patients with inadequate glycaemic control. Methods: In this phase 3, parallel-group, double-blind, active-controlled study, 1306 patients 18-77 years of age (HbA1c 8.0-12.0%) were randomized to saxagliptin 5 mg + 500 mg metformin, saxagliptin 10 mg + 500 mg metformin, saxagliptin 10 mg + placebo or 500 mg metformin + placebo. Blinded metformin was titrated during weeks 1-5 of the short-term treatment period in 500 mg/day increments to 2000 mg/day maximum in the metformin-based treatment groups. No titration of metformin was permitted during the long-term treatment period. A total of 888 patients completed the study (76 weeks), 613 without being rescued. Changes in HbA1c, fasting plasma glucose, 120-min postprandial glucose (PPG) and PPG-area under the curve (AUC) from baseline to week 76 were analysed using a repeated-measures model. Results: At 76 weeks, adjusted mean changes from baseline HbA1c (95% CI) for saxagliptin 5 mg + metformin, saxagliptin 10 mg +
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...
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.
BMC Endocrine Disorders, 2014
Background: To compare the safety and efficacy of saxagliptin 2.5 mg twice daily (BID) versus placebo add-on therapy to metformin immediate release (IR) in patients with type 2 diabetes and inadequate glycemic control with metformin alone. Methods: This multicenter, 12-week, double-blind, parallel-group trial enrolled adult outpatients with type 2 diabetes (glycated hemoglobin [HbA 1c ] 7.0%-10.0%) on stable metformin IR monotherapy (≥1500 mg, BID for ≥8 weeks). Patients were randomized to double-blind saxagliptin 2.5 mg BID or placebo added on to metformin IR following a 2-week, single-blind, placebo add-on therapy lead-in period. The primary end point was the change from baseline to week 12 in HbA 1c . Key secondary end points included change from baseline to week 12 in fasting plasma glucose (FPG) and the proportion of patients achieving HbA 1c <7.0% or HbA 1c ≤ 6.5% at week 12. Efficacy was analyzed in all patients who received randomized study drug with ≥1 postbaseline assessment. Safety was assessed in all treated patients.