Ujjwala Vijapurkar

Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone

The efficacy and safety of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and pioglitazone.

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 HbA1c (-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 HbA1c, body weight, and systolic blood pressure were examined in the stage 3a and 3b CKD subgroups, with greater decreases in HbA1c, -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 HbA1c, body weight, and blood pressure, and was generally well tolerated.

Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus.

Hyperuricaemia is associated with an increased risk of gout, kidney stones and cardiovascular disease. The present post hoc analysis of pooled data from four placebo‐controlled phase III studies assessed the effect of canagliflozin, a sodium‐glucose co‐transporter 2 inhibitor, on serum uric acid levels in patients with type 2 diabetes mellitus (T2DM) and in a subset of patients with hyperuricaemia [defined as baseline serum uric acid ≥475 µmol/l (∼8 mg/dl)]. At week 26, canagliflozin 100 and 300 mg were associated with a ∼13% reduction in serum uric acid compared with placebo. In the subset of patients with hyperuricaemia, placebo‐subtracted percent reductions in serum uric acid were similar to those in the overall cohort. More patients in the hyperuricaemic group achieved a serum uric acid level of <360 µmol/l (∼6 mg/dl) with both canagliflozin 100 mg (23.5%) and 300 mg (32.4%) compared with placebo (3.1%). Incidences of gout and kidney stones were low and similar across groups. In conclusion, canagliflozin treatment decreased serum uric acid in patients with T2DM, including those with baseline hyperuricaemia.

Effect of Canagliflozin on Blood Pressure and Adverse Events Related to Osmotic Diuresis and Reduced Intravascular Volume in Patients With Type 2 Diabetes Mellitus

The effects of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, on blood pressure (BP) and osmotic diuresis– and intravascular volume reduction–related adverse events (AEs) were evaluated using pooled data from four placebo‐controlled, phase 3 studies in patients with type 2 diabetes mellitus (T2DM; N=2313). At baseline, 1332 (57.6%) patients were taking an antihypertensive medication. Canagliflozin 100 mg and 300 mg provided reductions (95% confidence interval [CI]) from baseline in systolic BP (SBP) compared with placebo (−4.3 mm Hg [−5.0 to −3.5], −5.0 mm Hg [−5.8 to −4.2], and −0.3 mm Hg [−1.2 to 0.5], respectively) and in diastolic BP (DBP; −2.5 mm Hg [−2.9 to −2.0], −2.4 mm Hg [−2.9 to −1.9], and −0.6 mm Hg [−1.1 to −0.02], respectively). Placebo‐subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were −4.0 mm Hg (−5.1 to −2.8) and −4.7 mm Hg (−5.8 to −3.5) and reductions in DBP were −1.9 mm Hg (−2.6 to −1.2) and −1.9 mm Hg (−2.6 to –1.1), respectively. Compared with the overall population, patients with elevated baseline SBP (≥140 mm Hg) had numerically greater absolute SBP reductions (95% CI) with canagliflozin 100 mg and 300 mg and placebo (−12.8 mm Hg [−15.2 to −10.5], −14.2 mm Hg [−16.4 to −12.0], and −6.8 mm Hg [−9.1 to −4.5], respectively). Numerically greater DBP reductions were seen in patients with DBP ≥90 mm Hg at baseline (−5.9 mm Hg [−8.2 to −3.6], −9.0 mm Hg [−11.1 to −6.9], and −7.4 mm Hg [−9.6 to −5.1], respectively). In patients with elevated SBP at baseline, placebo‐subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were −6.0 mm Hg (−9.1 to −2.9) and −7.4 mm Hg (−10.4 to −4.4), respectively. Placebo‐subtracted changes in DBP were 1.5 mm Hg (−1.6 to 4.5) and −1.6 mm Hg (−4.5 to 1.2), respectively, in those with elevated DBP at baseline. Canagliflozin 100 mg and 300 mg were associated with increased incidence of osmotic diuresis–related AEs (eg, pollakiuria [increased urine volume] and polyuria [increased urine frequency]) vs placebo (6.7%, 5.6%, and 0.8%). The incidence of intravascular volume reduction–related AEs (eg, orthostatic hypotension and postural dizziness) was low across groups (1.2%, 1.3%, and 1.1%). In summary, canagliflozin was associated with reduced BP in patients with T2DM across a range of baseline BPs, with increased incidence of AEs related to osmotic diuresis but not intravascular volume reduction.

Reductions in Mean 24-Hour Ambulatory Blood Pressure After 6-Week Treatment With Canagliflozin in Patients With Type 2 Diabetes Mellitus and Hypertension

This randomized, double‐blind, placebo‐controlled study evaluated the early effects of canagliflozin on blood pressure (BP) in patients with type 2 diabetes mellitus (T2DM) and hypertension. Patients were randomized to canagliflozin 300 mg, canagliflozin 100 mg, or placebo for 6 weeks and underwent 24‐hour ambulatory BP monitoring before randomization, on day 1 of treatment, and after 6 weeks. The primary endpoint was change in mean 24‐hour systolic BP (SBP) from baseline to week 6. Overall, 169 patients were included (mean age, 58.6 years; glycated hemoglobin, 8.1%; seated BP 138.5/82.7 mm Hg). At week 6, canagliflozin 300 mg provided greater reductions in mean 24‐hour SBP than placebo (least squares mean −6.2 vs −1.2 mm Hg, respectively; P=.006). Numerical reductions in SBP were observed with canagliflozin 100 mg. Canagliflozin was generally well tolerated, with side effects similar to those reported in previous studies. These results suggest that canagliflozin rapidly reduces BP in patients with T2DM and hypertension.

Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea

To evaluate the efficacy and safety of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin or metformin in combination with sulphonylurea.

Efficacy and Safety of Canagliflozin in Individuals Aged 75 and Older with Type 2 Diabetes Mellitus: A Pooled Analysis

To compare the efficacy and safety of canagliflozin, a sodium glucose co‐transporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM), in individuals younger than 75 and those aged 75 and older.

Renal effects of canagliflozin in type 2 diabetes mellitus

Abstract Background: Chronic kidney disease is commonly associated with type 2 diabetes mellitus (T2DM) and may impact the efficacy and safety of glucose-lowering therapies. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces blood glucose levels in patients with T2DM by lowering the renal threshold for glucose, thereby promoting urinary glucose excretion. This review describes the pharmacology, efficacy and safety of canagliflozin according to kidney function in participants with T2DM. Methods: Published articles that reported efficacy, safety and pharmacokinetics/pharmacodynamics data for canagliflozin in patients with T2DM and impaired renal function, and renal safety data with canagliflozin in various populations of patients with T2DM through May 2015 were included. Results: Early transient reductions in estimated glomerular filtration rate were observed with canagliflozin; these changes generally stabilized or attenuated over time and reversed after discontinuation, suggesting no renal (glomerular or tubular) damage with canagliflozin treatment. Urinary albumin-to-creatinine ratios were reduced with canagliflozin. Canagliflozin was generally well tolerated in patients with normal or mild to moderately impaired renal function, with a modestly higher incidence of renal-related adverse events and volume depletion–related adverse events in patients with moderate renal impairment. Adverse events related to potassium elevations were infrequent with canagliflozin 100 mg regardless of kidney function status; however, patients with moderately impaired kidney function experienced hyperkalemia more frequently with canagliflozin 300 mg compared with patients treated with either canagliflozin 100 mg or placebo. Canagliflozin was not associated with increased cardiovascular risk across studies; however, relatively few events among patients with impaired renal function meant that the analysis was not adequately powered to examine this outcome, and results from separate trials are awaited. Conclusions: Overall, canagliflozin is associated with small, transient changes in kidney function, and is well tolerated in patients with T2DM with varying kidney function status.

The efficacy and safety of canagliflozin across racial groups in patients with type 2 diabetes mellitus.

AbstractObjective:Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, enhances urinary glucose excretion through an insulin-independent mode of action, and improves glycemic control in patients with type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of canagliflozin across racial groups.Methods:The efficacy of canagliflozin 100 mg and 300 mg was evaluated by racial group using data pooled from four placebo-controlled phase 3 studies and two placebo-controlled sub-studies of a population of patients with inadequately controlled T2DM (N = 4158). Least-squares mean changes from baseline were calculated for hemoglobin A1c (HbA1c), systolic blood pressure (SBP), body weight (BW), cholesterol, and triglycerides. Safety/tolerability evaluation included reporting of general and prespecified adverse events (AEs).Results:A total of 75% of patients were White, 13% were Asian, 4% were Black/African American, and 8% were ‘Other’ (American Indian, Alaskan Native, mixed race, Native Haw...Abstract Objective: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, enhances urinary glucose excretion through an insulin-independent mode of action, and improves glycemic control in patients with type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of canagliflozin across racial groups. Methods: The efficacy of canagliflozin 100 mg and 300 mg was evaluated by racial group using data pooled from four placebo-controlled phase 3 studies and two placebo-controlled sub-studies of a population of patients with inadequately controlled T2DM (N = 4158). Least-squares mean changes from baseline were calculated for hemoglobin A1c (HbA1c), systolic blood pressure (SBP), body weight (BW), cholesterol, and triglycerides. Safety/tolerability evaluation included reporting of general and prespecified adverse events (AEs). Results: A total of 75% of patients were White, 13% were Asian, 4% were Black/African American, and 8% were ‘Other’ (American Indian, Alaskan Native, mixed race, Native Hawaiian or other Pacific Islander, not reported, and unknown). Baseline demographics were similar for these groups. Dose-related reductions in HbA1c, BW, and SBP were observed with both canagliflozin doses in all racial groups. Canagliflozin was generally safe and well tolerated. Treatment with canagliflozin was associated with an increased rate of genital mycotic infections (GMIs) and urinary tract infections (UTIs) in all racial groups. GMIs were observed more often in Black/African American males and males from the ‘Other’ racial group, whereas UTIs and osmotic diuresis-related AEs were less common in Asians. Key study limitations include the high proportion of White patients compared with other racial groups and the fact that included studies were not powered to evaluate racial differences. Conclusion: Canagliflozin was generally well tolerated and consistently associated with reductions in HbA1c, BW, and SBP in patients with T2DM independent of racial background. (ClinicalTrials.gov numbers: NCT01081834; NCT01106677; NCT01106625; NCT01106690; and NCT01032629.)

Diabetes-Related Composite Quality End Point Attainment: Canagliflozin Versus Sitagliptin Based on a Pooled Analysis of 2 Clinical Trials.

PURPOSE This post hoc analysis evaluated attainment of diabetes-related composite quality measures (CQMs) with canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg in patients with type 2 diabetes mellitus (T2DM). We used pooled data from two 52-week Phase III clinical trials evaluating the efficacy of canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg. METHODS CQMs assessed included the combined attainment of glycosylated hemoglobin (HbA1c), blood pressure (BP), and LDL-C. To assess on-treatment differences at 52 weeks, odds ratios (ORs) and associated 95% CIs were calculated based on a logistic regression model. CQM attainment was assessed in the overall population and for patients with a body mass index ≥25 kg/m(2) at baseline. FINDINGS Overall, baseline demographic and disease characteristics were comparable across treatment groups. Proportions of patients with T2DM meeting the CQMs HbA1c <7.0%, BP <130/80 mm Hg, and LDL-C <100 mg/dL and HbA1c <8.0%, BP <140/90 mm Hg, and LDL-C <100 mg/dL were similar at baseline. After 52 weeks of treatment, the proportion of patients meeting both CQMs was similar for canagliflozin 100 mg and sitagliptin 100 mg, and favored canagliflozin 300 mg versus sitagliptin 100 mg. For canagliflozin 300 mg, the OR was 1.79 (95% CI, 1.25-2.58) for the CQM HbA1c <7.0%, BP <130/80 mm Hg, and LDL-C <100 mg/dL; the OR was 1.49 (95% CI, 1.15-1.92) for the CQM HbA1c <8.0%, BP <140/90 mm Hg, and LDL-C <100 mg/dL. CQM attainments for patients with a body mass index ≥25 kg/m(2) were similar to those for the overall population. IMPLICATIONS At 52 weeks of treatment, this analysis observed comparable CQM attainment for canagliflozin 100 mg, and superior CQM attainment for canagliflozin 300 mg, compared with sitagliptin 100 mg. ClinicalTrials.gov identifiers are NCT01106677 and NCT01137812.