Efficacy and Safety of Canagliflozin in Older Patients
Efficacy and Safety of Canagliflozin in Older Patients
This pooled analysis evaluated canagliflozin 100 and 300 mg and placebo using data from subsets of patients with T2DM <65 and ≥65 years of age from 4 randomised, double-blind, placebo-controlled, Phase 3 studies. These studies each included a 26-week, double-blind, core treatment period and a 26-week extension period, and assessed canagliflozin as monotherapy or added on to metformin, metformin plus sulphonylurea, and metformin plus pioglitazone ( Table 1 ). Data from the 26-week core treatment periods of each study were included in this pooled analysis; the high glycaemic subset (HbA1c >10.0% and ≤12.0%) of the monotherapy study, which was not placebo controlled, and the sitagliptin arm of the add-on to metformin study were excluded. For the pooled dataset, the mean duration of exposure to study drug was approximately 24 weeks in each treatment group.
Key inclusion criteria for the individual studies are summarised in Table 1 . In general, eligible patients were those with T2DM ≥18 and ≤80 years of age, with HbA1c ≥7.0% and ≤10.5% and estimated glomerular filtration rate (eGFR) ≥55 mL/min/1.73 m at screening. Key exclusion criteria that were common across studies included repeated FPG ≥15.0 mmol/L during the pretreatment phase; history of type 1 diabetes; history of cardiovascular (CV) disease (including myocardial infarction, unstable angina, revascularisation procedure, or cerebrovascular accident) within 3 months prior to screening; and alanine aminotransferase (ALT) level >2.0 times the upper limit of normal (ULN) or total bilirubin >1.5 the ULN at screening.
In each study, eligible patients who were on protocol-specified background diabetes treatment directly entered a 2-week, placebo run-in period; those not on protocol-specified background diabetes therapy entered an 8- to 12-week AHA adjustment/dose stabilisation period prior to the run-in period. Patients were to remain on their stable diabetes treatment regimen through the end of the double-blind treatment period. Randomisation to treatment group (canagliflozin 100 or 300 mg or placebo) was stratified to ensure adequate distribution of specific patient characteristics (eg, whether a patient entered the AHA adjustment/dose stabilisation period) across treatment groups. After randomisation, HbA1c and FPG were masked to study centres unless pre-defined criteria for initiation of glycaemic rescue therapy based on HbA1c or FPG values were met. Study databases were locked at the primary assessment time point (Week 26) and studies were unblinded by the sponsor for regulatory filing. Blinding was maintained for patients and study centre and local sponsor personnel throughout the double-blind treatment period.
Glycaemic rescue therapy was initiated during the double-blind treatment period for patients who met pre-specified criteria (in general, FPG >15.0 mmol/L after Day 1 to Week 6, >13.3 mmol/L after Week 6 to Week 12, and >11.1 mmol/L after Week 12 to Week 26). The agent for rescue therapy in each study was selected to be complementary to the protocol-specified background AHA therapy.
The studies were conducted in accordance with the ethical principles that comply with the Declaration of Helsinki, and are consistent with Good Clinical Practices and applicable regulatory requirements. Approval was obtained from institutional review boards and independent ethics committees for participating centres ( Additional file 1 ), and patients gave written informed consent prior to participation.
Efficacy endpoints evaluated at Week 26 included change from baseline in HbA1c, FPG, and systolic and diastolic BP, and percent change from baseline in body weight (reported for prior to rescue medication).
Assessments of overall safety and tolerability were based on AEs, safety laboratory tests, 12-lead electrocardiograms, vital sign measurements, physical examinations, and self-monitored blood glucose. The incidence of selected AEs, including UTIs, genital mycotic infections, AEs related to osmotic diuresis and volume depletion, and renal-related AEs, were also evaluated. Documented hypoglycaemia episodes included biochemically confirmed episodes (concurrent fingerstick or plasma glucose ≤3.9 mmol/L, with or without symptoms) and severe episodes (ie, those requiring the assistance of another individual or resulting in seizure or loss of consciousness).
Percent changes from baseline in fasting plasma lipids, including triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio, and non–HDL-C, were assessed as safety parameters.
Efficacy endpoints were analysed in the modified intent-to-treat (mITT) population consisting of randomised patients who received ≥1 dose of study drug. The last observation carried forward (LOCF) approach was used to impute missing efficacy data. For patients who received rescue therapy, the last post-baseline value prior to initiation of rescue therapy was used for efficacy analyses. Changes from baseline in efficacy parameters at Week 26 were assessed using an analysis of covariance (ANCOVA) model including treatment and study as fixed effects and baseline values as covariates. Least squares (LS) means and 2-sided 95% confidence intervals (CIs) were estimated for the comparisons of each canagliflozin dose versus placebo. Fasting plasma lipid parameters were assessed in the safety analysis set (identical to the mITT population) using a similar ANCOVA model as for efficacy endpoints. Statistical testing of comparisons of canagliflozin versus placebo within each age group, and of comparisons between age groups, was not conducted (not pre-specified). Therefore, no P values are reported; however, 95% CIs are provided.
Methods
Study Design and Patient Population
This pooled analysis evaluated canagliflozin 100 and 300 mg and placebo using data from subsets of patients with T2DM <65 and ≥65 years of age from 4 randomised, double-blind, placebo-controlled, Phase 3 studies. These studies each included a 26-week, double-blind, core treatment period and a 26-week extension period, and assessed canagliflozin as monotherapy or added on to metformin, metformin plus sulphonylurea, and metformin plus pioglitazone ( Table 1 ). Data from the 26-week core treatment periods of each study were included in this pooled analysis; the high glycaemic subset (HbA1c >10.0% and ≤12.0%) of the monotherapy study, which was not placebo controlled, and the sitagliptin arm of the add-on to metformin study were excluded. For the pooled dataset, the mean duration of exposure to study drug was approximately 24 weeks in each treatment group.
Key inclusion criteria for the individual studies are summarised in Table 1 . In general, eligible patients were those with T2DM ≥18 and ≤80 years of age, with HbA1c ≥7.0% and ≤10.5% and estimated glomerular filtration rate (eGFR) ≥55 mL/min/1.73 m at screening. Key exclusion criteria that were common across studies included repeated FPG ≥15.0 mmol/L during the pretreatment phase; history of type 1 diabetes; history of cardiovascular (CV) disease (including myocardial infarction, unstable angina, revascularisation procedure, or cerebrovascular accident) within 3 months prior to screening; and alanine aminotransferase (ALT) level >2.0 times the upper limit of normal (ULN) or total bilirubin >1.5 the ULN at screening.
In each study, eligible patients who were on protocol-specified background diabetes treatment directly entered a 2-week, placebo run-in period; those not on protocol-specified background diabetes therapy entered an 8- to 12-week AHA adjustment/dose stabilisation period prior to the run-in period. Patients were to remain on their stable diabetes treatment regimen through the end of the double-blind treatment period. Randomisation to treatment group (canagliflozin 100 or 300 mg or placebo) was stratified to ensure adequate distribution of specific patient characteristics (eg, whether a patient entered the AHA adjustment/dose stabilisation period) across treatment groups. After randomisation, HbA1c and FPG were masked to study centres unless pre-defined criteria for initiation of glycaemic rescue therapy based on HbA1c or FPG values were met. Study databases were locked at the primary assessment time point (Week 26) and studies were unblinded by the sponsor for regulatory filing. Blinding was maintained for patients and study centre and local sponsor personnel throughout the double-blind treatment period.
Glycaemic rescue therapy was initiated during the double-blind treatment period for patients who met pre-specified criteria (in general, FPG >15.0 mmol/L after Day 1 to Week 6, >13.3 mmol/L after Week 6 to Week 12, and >11.1 mmol/L after Week 12 to Week 26). The agent for rescue therapy in each study was selected to be complementary to the protocol-specified background AHA therapy.
The studies were conducted in accordance with the ethical principles that comply with the Declaration of Helsinki, and are consistent with Good Clinical Practices and applicable regulatory requirements. Approval was obtained from institutional review boards and independent ethics committees for participating centres ( Additional file 1 ), and patients gave written informed consent prior to participation.
Endpoints and Assessments
Efficacy endpoints evaluated at Week 26 included change from baseline in HbA1c, FPG, and systolic and diastolic BP, and percent change from baseline in body weight (reported for prior to rescue medication).
Assessments of overall safety and tolerability were based on AEs, safety laboratory tests, 12-lead electrocardiograms, vital sign measurements, physical examinations, and self-monitored blood glucose. The incidence of selected AEs, including UTIs, genital mycotic infections, AEs related to osmotic diuresis and volume depletion, and renal-related AEs, were also evaluated. Documented hypoglycaemia episodes included biochemically confirmed episodes (concurrent fingerstick or plasma glucose ≤3.9 mmol/L, with or without symptoms) and severe episodes (ie, those requiring the assistance of another individual or resulting in seizure or loss of consciousness).
Percent changes from baseline in fasting plasma lipids, including triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio, and non–HDL-C, were assessed as safety parameters.
Statistical Analyses
Efficacy endpoints were analysed in the modified intent-to-treat (mITT) population consisting of randomised patients who received ≥1 dose of study drug. The last observation carried forward (LOCF) approach was used to impute missing efficacy data. For patients who received rescue therapy, the last post-baseline value prior to initiation of rescue therapy was used for efficacy analyses. Changes from baseline in efficacy parameters at Week 26 were assessed using an analysis of covariance (ANCOVA) model including treatment and study as fixed effects and baseline values as covariates. Least squares (LS) means and 2-sided 95% confidence intervals (CIs) were estimated for the comparisons of each canagliflozin dose versus placebo. Fasting plasma lipid parameters were assessed in the safety analysis set (identical to the mITT population) using a similar ANCOVA model as for efficacy endpoints. Statistical testing of comparisons of canagliflozin versus placebo within each age group, and of comparisons between age groups, was not conducted (not pre-specified). Therefore, no P values are reported; however, 95% CIs are provided.