George Capuano

Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes.

OBJECTIVE To evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy. RESEARCH DESIGN AND METHODS This was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed. RESULTS Canagliflozin was associated with significant reductions in A1C from baseline (7.6–8.0%) to week 12: −0.79, −0.76, −0.70, −0.92, and −0.95% for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus −0.22% for placebo (all P < 0.001) and −0.74% for sitagliptin. FPG was reduced by −16 to −27 mg/dL, and body weight was reduced by −2.3 to −3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non–dose-dependent increase in symptomatic genital infections with canagliflozin (3–8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3–9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low. CONCLUSIONS Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females.

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

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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/m2, estimated glomerular filtration rate of 75 mL/min/1.73 m2, 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. CONCLUSIONS 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.

Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies

Abstract Objective: To characterize genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) using pooled data from Phase 3 studies. Research design and methods: Genital mycotic infections with canagliflozin 100 and 300 mg were evaluated in Population 1 (N = 2313; mean exposure [weeks]: canagliflozin, 24.3; placebo, 23.8), including patients from four placebo-controlled studies, and Population 2 (N = 9439; mean exposure [weeks]: canagliflozin, 68.1; control, 64.4), including patients from eight placebo/active-controlled studies (including older patients and those with renal impairment or high cardiovascular disease risk). Clinical trial registration: ClinicalTrials.gov identifier: NCT01081834. ClinicalTrials.gov identifier: NCT01106625. ClinicalTrials.gov identifier: NCT01106677. ClinicalTrials.gov identifier: NCT01106690. ClinicalTrials.gov identifier: NCT01032629. ClinicalTrials.gov identifier: NCT01064414. ClinicalTrials.gov identifier: NCT01106651. ClinicalTrials.gov identifier: NCT00968812. Main outcome measures: Adverse events suggestive of genital mycotic infections were recorded, with additional information collected using supplemental electronic case report forms. Results: In Population 1, genital mycotic infection incidence was higher with canagliflozin 100 and 300 mg than placebo (95% confidence intervals excluded zero) in females (10.4%, 11.4%, 3.2%) and males (4.2%, 3.7%, 0.6%). These were generally mild to moderate in intensity, none were serious, and few led to discontinuation. Most events with canagliflozin were treated with antifungal therapies, and median symptom duration following treatment initiation was similar across groups; few patients had >1 event (females, 2.3%; males, 0.9%). Findings with canagliflozin 100 and 300 mg versus control were similar in Population 2 (females: 14.7%, 13.9%, 3.1%; males: 7.3%, 9.3%, 1.6%); a low proportion of males underwent circumcision across groups. Most events with canagliflozin occurred within the first 4 months in females and first year in males; no consistent evidence of dose dependence was observed. Key limitations included lack of laboratory confirmation for most events and variable treatment methods. Conclusions: Genital mycotic infection incidences were higher with canagliflozin than control in patients with T2DM; events were generally mild to moderate in intensity and responded to standard treatments.

Urinary Tract Infection in Randomized Phase III Studies of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor

Abstract Background: Canaglifozin, a sodium glucose co–transporter 2 inhibitor, lowers plasma glucose in individuals with hyperglycemia by inhibiting renal glucose reabsorption and increasing glucosuria. Urinary tract infections (UTIs) were characterized in patients with type 2 diabetes mellitus enrolled in Phase III studies of canaglifozin. Methods: Analyses were performed in 2 pooled datasets: Population 1 (N = 2313; mean exposure [weeks]: canaglifozin, 24.3; placebo, 23.8) including patients from 4 placebo–controlled studies; Population 2 (N = 9439; mean exposure [weeks]: canaglifozin, 68.1; control, 64.4) including patients from 8 placebo– and active–controlled studies (including patients with renal impairment or high risk of cardiovascular disease, and older patients). Individual studies in special patient populations and 2 active–controlled studies were analyzed separately. Patients with a prior history of UTIs were not excluded from these studies. Urinary tract infection frequency and characteristics were systematically collected, with additional information for each event collected using supplemental electronic case report forms. Results: In Populations 1 and 2, canaglifozin 100 and 300 mg were associated with small increases in the incidence of UTIs compared with control, with no dose–dependence. Urinary tract infections with canaglifozin were similar to those with control in severity, and upper UTIs were infrequent across groups. No increase in serious events or those leading to discontinuation were seen with canagliflozin versus control. Time to the first occurrence of symptomatic UTIs tended to be earlier with canagliflozin than placebo in Population 1, and similar with canagliflozin and control in Population 2; median duration of events was similar across groups in both populations. The proportion of patients with recurrent events was low across groups. Conclusion: Canagliflozin was associated with a small increase in incidence of UTIs in patients with type 2 diabetes mellitus, with no increase in serious or upper UTIs.

Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes

To assess the efficacy and safety of canagliflozin, a sodium glucose co‐transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase‐4 (DPP‐4) inhibitor or glucagon‐like peptide‐1 (GLP‐1) receptor agonist].

Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes

OBJECTIVE This study assessed the efficacy/safety of canagliflozin (CANA), a sodium–glucose cotransporter 2 (SGLT2) inhibitor, plus metformin extended-release (MET) initial therapy in drug-naïve type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, phase 3 study randomized 1,186 patients to CANA 100 mg (CANA100)/MET, CANA 300 mg (CANA300)/MET, CANA100, CANA300, or MET. Primary end point was change in HbA1c at week 26 for combinations versus monotherapies. Secondary end points included noninferiority in HbA1c lowering with CANA monotherapy versus MET; changes in fasting plasma glucose, body weight, and blood pressure; and proportion of patients achieving HbA1c <7.0% (<53 mmol/mol). RESULTS From mean baseline HbA1c of 8.8% (73 mmol/mol), CANA100/MET and CANA300/MET significantly lowered HbA1c versus MET (median dose, 2,000 mg/day) by –1.77%, –1.78%, and –1.30% (–19.3, –19.5, and –14.2 mmol/mol; differences of −0.46% and –0.48% [–5.0 and –5.2 mmol/mol]; P = 0.001) and versus CANA100 and CANA300 by –1.37% and –1.42% (–15.0 and –15.5 mmol/mol; differences of –0.40% and –0.36% [–4.4 and –3.9 mmol/mol]; P = 0.001). CANA100 and CANA300 monotherapy met noninferiority for HbA1c lowering and had significantly more weight loss versus MET (–2.8, –3.7, and –1.9 kg [–3.0%, –3.9%, and –2.1%]; P = 0.016 and P = 0.002). Greater attainment of HbA1c <7.0% (50%, 57%, and 43%) and significantly more weight loss (–3.2, –3.9, and –1.9 kg [–3.5%, –4.2%, and –2.1%]; P = 0.001) occurred with CANA100/MET and CANA300/MET versus MET. The incidence of adverse events (AEs) related to SGLT2 inhibition (genital mycotic infections, osmotic diuresis– and volume depletion–related AEs) was higher in the CANA arms (0.4–4.4%) versus MET (0–0.8%). AE-related discontinuation rates were 1.3–3.0% across groups. The incidence of hypoglycemia was 3.0–5.5% in the CANA arms and 4.6% with MET. CONCLUSIONS Initial therapy with CANA plus MET was more effective and generally well tolerated versus each monotherapy in drug-naïve type 2 diabetes. CANA monotherapy demonstrated noninferior HbA1c lowering versus MET.

Efficacy and safety of twice-daily treatment with canagliflozin, a sodium glucose co-transporter 2 inhibitor, added on to metformin monotherapy in patients with type 2 diabetes mellitus

Aim To evaluate the efficacy/safety of canagliflozin twice daily (BID) compared with placebo in patients with type 2 diabetes mellitus (T2DM) on metformin. Methods In this 18-week, randomized, double-blind, placebo-controlled study, patients (N = 279) at 60 centers in 7 countries received canagliflozin 50 or 150 mg or placebo BID. The pre-specified primary endpoint was change from baseline in HbA1c at Week 18. Pre-specified secondary endpoints included proportion of patients reaching HbA1c <7.0%, change in fasting plasma glucose (FPG), and percent change in body weight; changes in systolic blood pressure (BP) and fasting plasma lipids were also evaluated. Adverse events (AEs) were recorded throughout the study. Results From a mean baseline HbA1c of 7.6% (60 mmol/mol), canagliflozin 50 and 150 mg BID significantly reduced HbA1c compared with placebo at Week 18 (−0.45%, −0.61%, −0.01% [−5, −7, −0.1 mmol/mol], respectively; P < 0.001). More patients achieved HbA1c <7.0% with canagliflozin than placebo (P < 0.05). Relative to placebo, both canagliflozin doses significantly lowered FPG and body weight (P < 0.001), and reduced systolic BP. Overall AE incidence was 35.5%, 40.9%, and 36.6% with canagliflozin 50 and 150 mg BID and placebo, respectively. Canagliflozin was associated with increased incidences of urinary tract infections, female genital mycotic infections, and osmotic diuresis-related AEs; these led to few discontinuations. The incidence of documented hypoglycemia was low across groups. Conclusions Canagliflozin 50 and 150 mg BID provided significant glycemic efficacy and body weight reduction, and were generally well tolerated in patients with T2DM on background metformin. ClinicalTrials.gov Identifier: NCT01340664

Apparent subadditivity of the efficacy of initial combination treatments for type 2 diabetes is largely explained by the impact of baseline HbA1c on efficacy.

To explain the subadditive efficacy typically observed with initial combination treatments for type 2 diabetes.