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Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin.

ABSTRACT: To evaluate the efficacy and safety of titrated canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin and sitagliptin.In this randomized, double-blind study, patients with T2DM (N = 218) on metformin ?1500 mg/day and sitagliptin 100 mg received canagliflozin 100 mg or placebo. After 6 weeks, the canagliflozin dose was increased from 100 to 300 mg (or from placebo to matching placebo) if all of the following criteria were met: baseline estimated glomerular filtration rate ?70 ml/min/1.73 m(2) ; fasting self-monitored blood glucose ?5.6 mmol/l (?100 mg/dl); and no volume depletion-related adverse events (AEs) within 2 weeks before dose increase. Endpoints included change in glycated haemoglobin (HbA1c) at week 26 (primary); proportion of patients achieving HbA1c <7.0%; and changes in fasting plasma glucose (FPG), body weight and systolic blood pressure (SBP). Safety was assessed using AE reports.Overall, 85.4% of patients were titrated to canagliflozin 300 mg or matching placebo (mean ± standard deviation time to titration 6.2 ± 0.8 weeks). At week 26, canagliflozin (pooled 100 and 300 mg) demonstrated superiority in HbA1c reduction versus placebo (-0.91% vs. -0.01%; p < 0.001). Canagliflozin provided significant reductions in FPG, body weight and SBP compared with placebo (p < 0.001). The overall AE incidence was 39.8 and 44.4% for canagliflozin and placebo, respectively. Canagliflozin was associated with an increased incidence of genital mycotic infections.Titrated canagliflozin significantly improved HbA1c, FPG, body weight and SBP, and was generally well tolerated over 26 weeks in patients with T2DM as add-on to metformin and sitagliptin.

SUBMITTER: Rodbard HW

PROVIDER: S-EPMC5089595 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin.

Rodbard H W HW Seufert J J Aggarwal N N Cao A A Fung A A Pfeifer M M Alba M M

Diabetes, obesity & metabolism 20160607 8

<h4>Aims</h4>To evaluate the efficacy and safety of titrated canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin and sitagliptin.<h4>Methods</h4>In this randomized, double-blind study, patients with T2DM (N = 218) on metformin ≥1500 mg/day and sitagliptin 100 mg received canagliflozin 100 mg or placebo. After 6 weeks, the canagliflozin dose was increased from 100 to 300 mg (or from placebo to matching p ...[more]

PMID: 27160639

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Project description:ObjectiveTo assess the effectiveness of sitagliptin compared to sulfonylureas as add-on to metformin in adults with type 2 diabetes mellitus from both randomised controlled trials (RCTs) and 'real-world' non-randomised studies.Methods and analysesWe conducted a systematic review of EMBASE, MEDLINE, CENTRAL and grey literature for RCTs and non-randomised studies. We reported outcomes relating to change in HbA1c, fasting glucose, weight, blood pressure and lipids from baseline and need for treatment change. No study investigating macrovascular and microvascular diabetes complications was found. Meta-analysis was used where studies were sufficiently homogenous.ResultsSeven RCTs and five non-randomised studies were eligible for inclusion from 1335 articles retrieved. Meta-analysis of three homogenous RCTs revealed a statistically significant decrease in weight with sitagliptin when compared to sulfonylureas (weighted mean difference (WMD) -2.05 kg; 95% CI -2.38 to -1.71); however, a similar change from baseline in HbA1c (WMD 0.05; 95% CI -0.03 to 0.12), fasting glucose (WMD 0.11; 95% CI -0.08 to -0.29), blood pressure, lipids and the proportion achieving HbA1c <7% by study end (OR 0.98; 95% CI 0.85 to 1.13) was observed.Non-randomised studies identified consisted of four prospective and one retrospective cohort study. Three of these five studies were of moderate/high quality, and results though less precise suggested similar real-world comparative glycaemic and weight effectiveness for both treatments. Data from two cohort studies suggested that treatment change (HR 0.65; 95% CI 0.57 to 0.73) and insulin initiation (HR 0.76; 95% CI 0.65 to 0.90) were less likely among those prescribed sitagliptin; however, inadequate reporting of HbA1c at time of treatment change made interpreting results challenging.ConclusionSitagliptin users experienced modest weight loss compared to gain with sulfonylureas; however, this difference was around 2 kg, which may not be of major clinical significance for most individuals. Similar change was observed across most other effectiveness outcomes reported. Further studies are needed to address longer-term effectiveness outcomes for sitagliptin compared to sulfonylureas as add-on to metformin.Prospero registration numberCRD42016033983.

Project description:Aims/hypothesisThe aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin.MethodsThis randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants (N = 1,284) with type 2 diabetes aged ≥ 18 and ≤ 80 years who had inadequate glycaemic control (HbA1c ≥ 7.0% [53 mmol/mol] and ≤10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo (n = 368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA1c at week 26; secondary endpoints included changes in HbA1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study.ResultsAt week 26, canagliflozin 100 mg and 300 mg reduced HbA1c vs placebo (-0.79%, -0.94%, -0.17%, respectively; p < 0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA1c (-0.73%, -0.88%,-0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (-0.12, 0.12) and -0.15% (-0.27, -0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: -3.7%, -4.2%, -1.2%, respectively; p < 0.001) and sitagliptin (week 52: -3.8%, -4.2%, -1.3%, respectively; p < 0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) (p < 0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin.Conclusions/interpretationCanagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin.Clinical trial registryClinicalTrials.gov NCT01106677 FUNDING: This study was supported by Janssen Research & Development, LLC.

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Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin.

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Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin.

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