Safety Of Canagliflozin In Patients Research Articles

Cardiovascular protection with sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: Does it apply to all patients?

Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease (CVD). Cardiovascular risk in these patients should be considered as a continuum, and comprehensive treatment strategies should aim to target multiple disease risk factors. Large‐scale clinical trials of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have shown an impact on cardiovascular outcomes, including heart failure hospitalization and cardiovascular death, which appears to be independent of their glucose‐lowering efficacy. Reductions in major cardiovascular events appear to be greatest in patients with established CVD, particularly those with prior myocardial infarction, but are independent of heart failure or renal risk. Most large‐scale trials of SGLT2 inhibitors predominantly include patients with T2D with pre‐existing CVD and high cardiovascular risk at baseline, limiting their applicability to patients typically observed in clinical practice. Real‐world evidence from observational studies suggests that there might also be beneficial effects of SGLT2 inhibitors on heart failure hospitalization and all‐cause mortality in various cohorts of lower risk patients. The most common adverse events reported in clinical and observational studies are genital infections; however, the overall risk of these events appears to be low and easily managed. Similar safety profiles have been reported for elderly and younger patients. There is still some debate regarding the safety of canagliflozin in patients at high risk of fracture and amputation. Outstanding questions include specific patterns of cardiovascular protection according to baseline risk.

Beneficials Effects of Canagliflozin in a Weight-Centered Management in Patients with Type 2 Diabetes Mellitus in Real Practice

Objective: Evaluate the real-world efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus (T2DM), associated to a weight-loss intensive lifestyle intervention program (WLIP), to achieve weight loss greater than 5% at 12 months. Methods: Retrospective review of patients with T2DM included in a WLIP, who were prescribed canagliflozin from June 2015 to December 2016 at four endocrinology clinics in the south of Spain within routine clinical practice context. Changes during 12 months in anthropometric variables, HbA1c, uric acid and adverse events were assessed. Results: 201 patients with T2DM (45.8% women, 60.3 ± 9.4 years old and BMI: 34.9 ± 8.7 kg/m2) were studied. Patients treated with canagliflozin lost an average weight and reduced an average of waist circumference of -4.0 ± 4.2 kg and -3.2 ± 8.4 cm, -5.4 ± 5.7 kg and -4.9 ± 9.9 cm and -5.3 ± 8.0 kg and -7.0 ± 14.6 cm, achieving weight loss greater than 5%: 29.0%, 47.9% and 42.7% of patients at 3, 6 and 12 months, respectively. HbA1c levels were average reduced by -1.2%, -1.3% and -1.3% and 68.8% reached an HbA1c level ≤ 7% at 12 months. 17.9% (36 patients) experienced mild adverse events and canagliflozin treatment was suspended in 23 patients (11.4%). Conclusion: The addition of canagliflozin to the treatment of overweight or obese patients with T2DM, as a complement of a weight-loss intensive lifestyle intervention, was associated with improvement in body weight and glycemic control with relative mild adverse events.

Efficacy and safety of canagliflozin in patients with type 2 diabetes based on history of cardiovascular disease or cardiovascular risk factors: a post hoc analysis of pooled data

BackgroundTreatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and the use of concomitant medications. The sodium glucose co-transporter 2 inhibitor, canagliflozin, has been shown to improve glycaemic control and reduce body weight and blood pressure (BP) with a favourable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of canagliflozin in patients with T2DM based on CV disease history or CV risk factors.MethodsAnalyses were based on pooled data from four 26-week, placebo-controlled, Phase 3 studies that evaluated canagliflozin 100 and 300 mg in patients with T2DM (N = 2313; mean HbA1c, 8.0%; body weight, 89 kg; systolic BP, 128 mmHg). Changes from baseline to week 26 in HbA1c, body weight, and systolic BP were assessed based on history of CV disease, history of hypertension, baseline statin use, and number of CV risk factors. Safety was assessed based on adverse event (AE) reports.ResultsAt week 26, both canagliflozin doses lowered HbA1c, body weight, and systolic BP compared with placebo in patients with and without CV disease history or risk factors. Placebo-subtracted HbA1c reductions with canagliflozin 100 and 300 mg were similar in patients with a history of CV disease (−0.95 and −1.07%) versus no history of CV disease (−0.71 and −0.90%), history of hypertension (−0.72 and −0.89%) versus no history of hypertension (−0.73 and −0.95%), baseline statin use (−0.77 and −0.99%) versus no statin use (−0.69 and −0.85%), and 0–1 CV risk factor (−0.72 and −0.87%) versus ≥2 CV risk factors (−0.74 and −1.02%). Similar body weight and systolic BP reductions were seen with canagliflozin versus placebo across subgroups. The incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups.ConclusionsThe efficacy and safety of canagliflozin were generally consistent across subgroups of patients with T2DM and varying degrees of CV disease history or risk factors.Trial registration numbers and dates ClinicalTrials.gov: NCT01081834, 4 March 2010; NCT01106625, 1 April 2010; NCT01106677, 1 April 2010; NCT01106690, 1 April 2010

Efficacy and safety of canagliflozin in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

Canagliflozin is a new SGLT2 inhibitor which has been approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes (T2D) mellitus in more than 30 countries. To evaluate the efficacy and safety of canagliflozin in patients with T2D, we carried out a meta-analysis of phase III clinical trials to offer an additional evidence of the efficacy and safety of canagliflozin for evidence-based clinical practice, strictly restricting the treatment durations to 26 weeks (core period) and 52 weeks (extension period). Randomized controlled trials (RCTs) published in English were searched in PubMed, Embase, and the Cochrane Library database (before April 2016). The studies reporting the efficacy and safety of canagliflozin in patients with T2DM were considered. Two authors separately performed data extraction. The differences were discussed and resolved. Pooled weighted mean differences (WMDs) or relative risks and 95% confidence intervals (CIs) were computed by using either fixed- or random-effects models. At the end of the selection process, 7 RCTs were collected and included in the present analysis. Placebo-subtracted WMDs (%) of glycosylated hemoglobin (HbA1c) were -0.63 (95% CI: -0.77, -0.49) and -0.80 (95% CI: -0.98, -0.62) for canagliflozin 100 and 300 mg, respectively, from baseline to week 26. At week 26, canagliflozin 100 and 300 mg significantly reduced the body weight from baseline when compared with that of placebo, with a WMD of -2.23 and -3.00 in percent changes (P < 0.001 for both). The fasting and postmeal glucose, blood pressure (BP), and triglycerides were also reduced. These reductions were sustained over 52 weeks but had no significant differences between the 100 and 300 mg doses. The overall safety of canagliflozin was good, with the exception of high incidence of genital mycotic infections and osmotic diuresis-related adverse events. Canagliflozin was found to reduce HbA1c, fasting and postmeal glucose, body weight, BP, and triglycerides, and it was generally well tolerated in patients with T2DM.

Abstract 12482: Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Based on History of Cardiovascular Disease or Cardiovascular Risk Factors

Introduction: Treatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and use of concomitant medications. Canagliflozin (CANA), an SGLT2 inhibitor, has been shown to improve glycemic control, body weight, and blood pressure (BP) with a favorable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of CANA in patients with T2DM based on CV disease history/risk factors. Methods: These analyses were based on pooled data from four 26-week, placebo (PBO)-controlled, Phase 3 studies that evaluated CANA 100 and 300 mg in patients with T2DM (N = 2313; mean A1C, 8.0%; body weight, 89 kg; systolic BP [SBP], 128 mmHg). Changes from baseline in A1C, body weight, and SBP at Week 26 were assessed in subgroups of patients based on history of CV disease (Y/N), history of hypertension (Y/N), baseline statin use (Y/N), and number of CV risk factors (0/1 vs ≥2). Safety was based on adverse event (AE) reports. Results: CANA 100 and 300 mg lowered A1C, body weight, and SBP versus PBO in patients with or without CV disease history/risk factors ( Table ). At Week 26, A1C reductions with CANA 100 and 300 mg relative to PBO were generally similar in patients with history of CV disease (–0.95% and –1.07%) versus no CV disease (–0.71% and –0.90%), history of hypertension (–0.72% and –0.89%) versus no hypertension (–0.73% and –0.95%), baseline statin use (–0.77% and –0.99%) versus no statin use (–0.69% and –0.85%), and ≥2 CV risk factors (–0.74% and –1.02%) versus 0/1 CV risk factor (–0.72% and –0.87%). Similar body weight and SBP reductions were also seen with CANA versus PBO across subgroups. Incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups. Conclusions: CANA was efficacious and generally well tolerated in patients with T2DM regardless of CV disease history/risk factors.

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus living in hot climates.

SummaryAimsPatients with type 2 diabetes mellitus (T2DM) have increased risk of adverse events (AEs; e.g. dehydration, hypoglycaemia) in hot weather. This analysis assessed the efficacy and safety of canagliflozin, a sodium glucose co‐transporter 2 (SGLT2) inhibitor, in patients with T2DM who live in hot climates.MethodsThis post hoc analysis evaluated patients with T2DM using pooled data from four 26‐week, placebo‐controlled studies (N=2,313) and data from a 104‐week, active‐controlled study (add‐on to metformin vs glimepiride; N=1,450). Changes in HbA1c, fasting plasma glucose (FPG), body weight and blood pressure (BP) were assessed in subsets of patients living in hot climates (pooled, placebo‐controlled studies, n=611; active‐controlled study, n=307) and those living in other climates (i.e. other climate subset; pooled, placebo‐controlled studies, n=1,702; active‐controlled study, n=1,143). Safety was assessed based on AE reports.ResultsCanagliflozin 100 and 300 mg lowered HbA1c, FPG, body weight and BP vs placebo over 26 weeks and glimepiride over 104 weeks in the hot climate subsets. Canagliflozin was generally well tolerated in the hot climate subsets, with a higher incidence of AEs related to the mechanism of SGLT2 inhibition (i.e. genital mycotic infections). Volume depletion–related AEs were low across groups.ConclusionCanagliflozin improved glycaemic control, lowered body weight and BP, and was generally well tolerated in patients with T2DM living in hot climates compared with placebo over 26 weeks or glimepiride over 104 weeks.Clinical Trials registration: ClinicalTrials.gov NCT01081834, NCT01106677, NCT01106625, NCT01106690, NCT00968812.

Efficacy and Safety of Canagliflozin in Type 2 Diabetes Patients of Different Ethnicity.

To assess the efficacy and safety of the sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin in patients of different ethnicities. Post hoc analysis of data pooled from four randomized, placebo-controlled, phase 3 studies of adults with inadequately controlled type 2 diabetes mellitus (T2DM). Once daily oral canagliflozin 100 mg or 300 mg, or placebo. Efficacy endpoints included change from baseline in HbA1c, body weight (BW), systolic blood pressure (SBP), and lipids at week 26; safety and tolerability were assessed by adverse event reports. Of the 2,313 patients included in this pooled analysis, 609 self-identified as Hispanic/Latino. Hispanic/Latino patients had a mean age of 54 years, mean duration of T2DM of 7 years, mean HbA1c of 8.1%, mean body mass index of 31.2 kg/m(2), and mean SBP of 126.1 mm Hg. There were more women in the non-Hispanic/Latino cohort (63%) compared with the Hispanic/Latino cohort. Placebo-subtracted changes in HbA1c were -.82% with canagliflozin 100 mg and -.94% with canagliflozin 300 mg in the Hispanic/Latino cohort, which were similar to reductions observed in the non-Hispanic/Latino cohort. Significantly greater dose-related reductions in HbA1c, BW, and SBP were observed with both canagliflozin doses compared with placebo. Canagliflozin was generally well-tolerated. Genital mycotic infections were less frequent in Hispanic/Latino women than in non-Hispanic/Latino women. The SGLT2 inhibitor canagliflozin was generally well-tolerated and was associated with clinically meaningful reductions in HbA1c, BW, and SBP in both Hispanic/Latino and non-Hispanic/Latino patients with T2DM.

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from Latin America

Objective:This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America.Research design and methods:Analyses were performed in subgroups of patients from Latin America based on data from three individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus sulfonylurea [n = 76/469]) and three individual, 52-week, active-controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n = 240/1101], add-on to metformin versus glimepiride [n = 155/1450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]).Main outcome measures:Changes from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (i.e., sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports.Results:Canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis–related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America.Conclusion:Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America.Clinical trial registration:NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from India.

Background:This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from India.Methods:Changes from baseline in HbA1c, fasting plasma glucose (FPG), body weight, and blood pressure (BP) with canagliflozin 100 and 300 mg were evaluated in a subgroup of patients from India (n = 124) from 4 randomized, double-blind, placebo- and active-controlled, Phase 3 studies (N = 2313; Population 1). Safety was assessed based on adverse event (AE) reports in these patients and in a broader subgroup of patients from India (n = 1038) from 8 randomized, double-blind, placebo- and active-controlled, Phase 3 studies (N = 9439; Population 2).Results:Reductions in HbA1c with canagliflozin 100 and 300 mg were −0.74% and −0.88%, respectively, in patients from India, and −0.81% and −1.00%, respectively, in the 4 pooled Phase 3 studies. In the Indian subgroup, both canagliflozin doses provided reductions in FPG, body weight, and BP that were consistent with findings in the overall population. The incidence of overall AEs in patients from India was generally similar with canagliflozin 100 and 300 mg and noncanagliflozin. The AE profile in patients from India was generally similar to the overall population, with higher rates of genital mycotic infections and osmotic diuresis–related and volume depletion–related AEs with canagliflozin versus noncanagliflozin.Conclusion:Canagliflozin provided glycemic control, body weight reduction, and was generally well tolerated in patients with T2DM from India.

Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes.

There are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin. The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined. Individuals receiving insulin at baseline were randomized to receive placebo (n = 690), canagliflozin 100 mg (n = 692), or canagliflozin 300 mg (n = 690). These individuals were 66% male and had a median age of 63 years, mean HbA1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m(2), estimated glomerular filtration rate of 75 mL/min/1.73 m(2), fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were -0.62% (95% CI -0.69, -0.54; -6.8 mmol/mol [95% CI -7.5, -5.9]; P < 0.001) and -0.73% (95% CI -0.81, -0.65; -8.0 mmol/mol [95% CI -8.9, -7.1]; P < 0.001) at 18 weeks and -0.58% (95% CI -0.68, -0.48; -6.3 mmol/mol [95% CI -7.4, -5.2]) and -0.73% (95% CI -0.83, -0.63; -8.0 mmol/mol [95% CI -9.1, -6.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses. Canagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.

Efficacy and Safety of Canagliflozin in Patients with Type 2 Diabetes and Stage 3 Nephropathy

Background/Aims: Some sodium glucose co-transporter 2 (SGLT2) inhibitors are approved for the treatment of patients with type 2 diabetes mellitus (T2DM) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m². The efficacy and safety of canagliflozin, an approved SGLT2 inhibitor, was evaluated in patients with stage 3 chronic kidney disease (CKD; eGFR ≥30 to <60 ml/min/1.73 m²). Methods: This analysis used integrated data from four randomized, placebo-controlled, phase 3 studies that enrolled patients with T2DM and stage 3 CKD. Results are presented for the overall population as well as subgroups with stage 3a CKD (eGFR ≥45 and <60 ml/min/1.73 m²) and stage 3b CKD (eGFR ≥30 and <45 ml/min/1.73 m²). Results: Among all subjects studied with stage 3 CKD, placebo-subtracted reductions in HbA_1c (-0.38 and -0.47%; p < 0.001), body weight (-1.6 and -1.9%; p < 0.001), and systolic blood pressure (-2.8 and -4.4 mm Hg; p < 0.01) were seen with canagliflozin 100 and 300 mg, respectively. Decreases in HbA_1c, body weight, and systolic blood pressure were examined in the stage 3a and 3b CKD subgroups, with greater decreases in HbA_1c, -0.47% (-0.61, -0.32) and body weight in subjects in stage 3a CKD, -1.8% (-2.3, -1.2) with canagliflozin 100 mg. Initial declines in eGFR were seen early following treatment initiation with canagliflozin, but trended towards baseline over time. The most common adverse events with canagliflozin included genital mycotic infections and adverse events related to reduced intravascular volume likely secondary to osmotic diuresis. Conclusion: In subjects with T2DM and stage 3 CKD, canagliflozin reduced HbA_1c, body weight, and blood pressure, and was generally well tolerated.

Safety of Canagliflozin in Patients with Type 2 Diabetes

Canagliflozin is a newly approved drug for the treatment of type 2 diabetes. This agent lowers blood glucose mainly by increasing urinary glucose excretion through inhibition of sodium glucose co-transporter 2 (SGLT2) in the kidneys. Data derived from randomized clinical trials lasting up to 52 weeks suggest that canagliflozin is generally well tolerated. The most common adverse effects are genital mycotic infections occurring in 11-15% of women exposed to canagliflozin versus 2-4% of those randomized to glimepiride or sitagliptin. In men, corresponding proportions are 8-9% versus 0.5-1%. Urinary tract infections (UTI) are slightly increased (5-7%) with the use of canagliflozin compared with placebo (4%). The risk of hypoglycemia associated with canagliflozin is marginally higher than placebo, but markedly increases when the drug is used in conjunction of insulin or sulfonylureas (SU), in patients with chronic kidney disease (CKD), and in the elderly. Worsening renal function and hyperkalemia may occur in patients using canagliflozin, particularly in patients with underlying CKD. Mild weight loss (mean 2-4 kg) and lowering of blood pressure represent 2 advantages of canagliflozin owing to its osmotic diuretic effect. However, the latter action may lead to postural hypotension and dizziness in susceptible subjects. Another concerning adverse effect of canagliflozin is an average 8% increase in plasma levels of low-density lipoprotein cholesterol (LDL-C) compared with placebo. Overall, canagliflozin is a useful addition for treatment of type 2 diabetes, but its safety needs to be established in long-term clinical trials.

PDB2 - Bayesian Network Meta-Analysis to Assess the Relative Efficacy and Safety of Canagliflozin in Patients with Type 2 Diabetes Mellitus (T2DM) Inadequately Controlled on Metformin and Sulphonylurea (MET+SU)

To assess the relative efficacy and safety of canagliflozin (CANA), a sodium-glucose co-transporter inhibitor, as an add-on to MET+SU, versus DPP-4 inhibitors, GLP-1 agonists and insulin, using Bayesian network meta-analysis (NMA). A systematic literature review was conducted according to NICE guidelines. Outcomes of interest included HbA1c, weight and hypoglycaemia. A Bayesian NMA using non-informative priors was conducted, based on linking trials with treatment and dose-specific common treatment arms. Assessment of model fit and selection of fixed versus random effects was based on the Deviance Information Criterion (DIC). Sensitivity analyses assessed the impact of individual trials and definition of priors. Consistency between direct and indirect evidence was assessed. Ten studies reporting results at 26 weeks +/- 4 weeks were identified. HbA1c-reduction (D) for CANA 100mg was comparable to DPP-4s (D between 0.05 and -0.14 versus sitagliptin and linagliptin respectively, with pairwise probabilities (P) of being more effective between 33-88%), and higher for CANA 300mg, which was comparable to GLP-1s (D=0.08;P=31% and 0.01;P=53%) versus liraglutide 1.8mg and exenatide 10µg respectively) and biphasic insulin (D=0.03;P=43%). CANA 300mg had the highest weight reduction with changes between 0.14kg;P=93% (vs. exenatide 10µg) and 5.13kg;P=100% (vs. biphasic insulin). The odds ratio for hypoglycaemia versus long-acting insulin were 0.31 and 0.39 for CANA 100mg and 300mg respectively, compared to 0.20-0.41 for other classes. NMA of add-on therapies to MET+SU suggests that glycaemic reductions for CANA at 26 weeks are at least as large for CANA 100 mg and greater for CANA 300 mg compared to DPP-4s. CANA 300mg was found to be comparable to liraglutide 1.8mg and biphasic insulin. Weight reduction was similar to GLP-1s and substantially higher compared to all other classes. All classes showed significantly lower hypoglycaemic event rates compared to insulin.

PRM193 - Bayesian Network Meta-Analysis to Assess Relative Efficacy and Safety of Canagliflozin in Patients with Type 2 Diabetes Mellitus (T2DM) Inadequately Controlled with Metformin

PRM193 - Bayesian Network Meta-Analysis to Assess Relative Efficacy and Safety of Canagliflozin in Patients with Type 2 Diabetes Mellitus (T2DM) Inadequately Controlled with Metformin

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial

AimsCanagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus (T2DM). This randomised, double-blind, placebo-controlled, Phase 3 study evaluated the efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2DM.MethodsPatients (N = 469) received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period and a 26-week extension. Prespecified primary end-point was change in HbA1c at 26 weeks. Secondary end-points included change in HbA1c at week 52 as well as proportion of patients achieving HbA1c < 7.0%, change in fasting plasma glucose (FPG) and systolic blood pressure, and per cent change in body weight, high-density lipoprotein cholesterol, and triglycerides (weeks 26 and 52).ResultsHbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (–0.85%, –1.06%, and –0.13%; p < 0.001); these reductions were maintained at week 52 (–0.74%, –0.96%, and 0.01%). Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 (p < 0.001) and week 52. Overall adverse event (AE) rates were similar across groups over 52 weeks, with higher rates of genital mycotic infections and osmotic diuresis-related AEs seen with canagliflozin vs. placebo; these led to few discontinuations. Increased incidence of documented, but not severe, hypoglycaemia episodes was seen with canagliflozin vs. placebo.ConclusionsCanagliflozin improved glycaemic control, reduced body weight, and was generally well tolerated in T2DM patients on metformin plus sulphonylurea over 52 weeks.