Paul Rothenberg

Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion: Results of a randomized, placebo-controlled study

OBJECTIVE Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption. RESEARCH DESIGN AND METHODS This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, 3H-glucose, 14C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (RaO) in plasma, endogenous glucose production, and glucose disposal. RESULTS Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0–2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0–6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in RaO. Total glucose disposal over 0 to 6 h was similar across groups. CONCLUSIONS Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition.

Pharmacokinetics and Pharmacodynamics of Canagliflozin, a Sodium Glucose Co‐Transporter 2 Inhibitor, in Subjects With Type 2 Diabetes Mellitus

This study characterized single‐ and multiple‐dose pharmacokinetics of canagliflozin and its O‐glucuronide metabolites (M5 and M7) and pharmacodynamics (renal threshold for glucose [RTG], urinary glucose excretion [UGE0–24h], and 24‐hour mean plasma glucose [MPG0–24h]) of canagliflozin in subjects with type 2 diabetes. Thirty‐six randomized subjects received canagliflozin 50, 100, or 300 mg/day or placebo for 7 days. On Days 1 and 7, area under the plasma concentration‐time curve and maximum observed plasma concentration (Cmax) for canagliflozin and its metabolites increased dose‐dependently. Half‐life and time at which Cmax was observed were dose‐independent. Systemic molar M5 exposure was half that of canagliflozin; M7 exposure was similar to canagliflozin. Steady‐state plasma canagliflozin concentrations were reached by Day 4 in all active treatment groups. Pharmacodynamic effects were dose‐ and exposure‐dependent. All canagliflozin doses decreased RTG, increased UGE0–24h, and reduced MPG0–24h versus placebo on Days 1 and 7. On Day 7, placebo‐subtracted least‐squares mean decreases in MPG0–24h ranged from 42–57 mg/dL with canagliflozin treatment. Adverse events (AEs) were balanced between treatments; no treatment‐related serious AEs, AE‐related discontinuations, or clinically meaningful adverse changes in routine safety evaluations occurred. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in subjects with type 2 diabetes supports a once‐daily dosing regimen.

Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus

To evaluate the effects of canagliflozin on plasma volume, urinary glucose excretion (UGE), fasting plasma glucose (FPG), glycated haemoglobin (HbA1c) and additional measures of fluid/electrolyte balance in patients with type 2 diabetes on background therapy with metformin and angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers.

Validation of a Novel Method for Determining the Renal Threshold for Glucose Excretion in Untreated and Canagliflozin-treated Subjects With Type 2 Diabetes Mellitus

Context: The stepwise hyperglycemic clamp procedure (SHCP) is the gold standard for measuring the renal threshold for glucose excretion (RTG), but its use is limited to small studies in specialized laboratories. Objective: The objective of the study was to validate a new method for determining RTG using data obtained during a mixed-meal tolerance test (MMTT) in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus (T2DM). Design: This was an open-label study with 2 sequential parts. Setting: The study was performed at a single center in Germany. Patients: Twenty-eight subjects with T2DM were studied. Interventions: No treatment intervention was given in part 1. In part 2, subjects were treated with canagliflozin 100 mg/d for 8 days. In each part, subjects underwent an MMTT and a 5-step SHCP on consecutive days. Main Outcome Measures: For both methods, RTG was estimated using measured blood glucose (BG) and urinary glucose excretion (UGE); estimated glomerular filtration rates were also used to determine RTG during the MMTT. The methods were compared using the concordance correlation coefficient and geometric mean ratios. Results: In untreated and canagliflozin-treated subjects, the relationship between UGE rate and BG was well described by a threshold relationship. Good agreement was obtained between the MMTT-based and SHCP-derived RTG values. The concordance correlation coefficient (for all subjects) was 0.94; geometric mean ratios (90% confidence intervals) for RTG values (MMTT/SHCP) were 0.93 (0.89–0.96) in untreated subjects and 1.03 (0.78–1.37) in canagliflozin-treated subjects. Study procedures and treatments were generally well tolerated in untreated and canagliflozin-treated subjects. Conclusions: In both untreated and canagliflozin-treated subjects with T2DM, RTG can be accurately estimated from measured BG, UGE, and estimated glomerular filtration rates using an MMTT-based method.

Canagliflozin: a sodium glucose co‐transporter 2 inhibitor for the treatment of type 2 diabetes mellitus

The sodium glucose co‐transporter 2 (SGLT2) inhibitor canagliflozin is a novel treatment option for adults with type 2 diabetes mellitus (T2DM). In patients with hyperglycemia, SGLT2 inhibition lowers plasma glucose levels by reducing the renal threshold for glucose (RTG) and increasing urinary glucose excretion (UGE). Increased UGE is also associated with a mild osmotic diuresis and net caloric loss, which can lead to reductions in body weight and blood pressure (BP). After promising results from preclinical and phase I/II studies, the efficacy and safety of canagliflozin was evaluated in a comprehensive phase III development program in over 10,000 patients with T2DM on various background therapies. Canagliflozin improved glycemic control and provided reductions in body weight and BP versus placebo and active comparators in studies of up to 2 years’ duration. Canagliflozin was generally well tolerated, with higher incidences of adverse events (AEs) related to the mechanism of action, including genital mycotic infections and AEs related to osmotic diuresis. Results from the preclinical and clinical studies led canagliflozin to be the first‐in‐class SGLT2 inhibitor approved in the United States, and support canagliflozin as a safe and effective therapeutic option across a broad range of patients with T2DM.

Pharmacodynamic differences between canagliflozin and dapagliflozin: results of a randomized, double-blind, crossover study.

To compare the pharmacodynamic effects of the highest approved doses of the sodium glucose co‐transporter 2 (SGLT2) inhibitors canagliflozin and dapagliflozin on urinary glucose excretion (UGE), renal threshold for glucose excretion (RTG) and postprandial plasma glucose (PPG) excursion in healthy participants in a randomized, double‐blind, two‐period crossover study.

Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes

Introduction This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes. Methods Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days –1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations. Results Canagliflozin increased UGE dose-dependently (∼80–120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ∼4–5 mM (72–90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values. Conclusions Canagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes. Trial Registration ClinicalTrials.gov NCT00963768

Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.

Objective: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetes mellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. Methods: Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4 – 12); study 2: canagliflozin 300 mg (days 1 – 17), probenecid 500 mg twice daily (days 15 – 17); and study 3: canagliflozin 300 mg (days 1 – 8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at pre-specified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2 – 8 (study 3). Results: Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. Conclusion: Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control.

CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study.

Macrophage recruitment through C‐C motif chemokine receptor‐2 (CCR2) into adipose tissue is believed to play a role in the development of insulin resistance and type 2 diabetes mellitus (T2DM). The objective of this Phase 2 proof‐of‐concept study was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ‐41443532, an orally bioavailable CCR2 antagonist, in patients with T2DM.

Absolute oral bioavailability and pharmacokinetics of canagliflozin: A microdose study in healthy participants

Absolute oral bioavailability of canagliflozin was assessed by simultaneous oral administration with intravenous [14C]‐canagliflozin microdose infusion in nine healthy men. Pharmacokinetics of canagliflozin, [14C]‐canagliflozin, and total radioactivity, and safety and tolerability were assessed at prespecified timepoints. On day 1, single‐dose oral canagliflozin (300 mg) followed 105 minutes later by intravenous [14C]‐canagliflozin (10 µg, 200 nCi) was administered. After oral administration, the mean (SD) Cmax of canagliflozin was 2504 (482) ng/mL at 1.5 hours, AUC∞ 17,375 (3555) ng.h/mL, and t1/2 11.6 (0.70) hours. After intravenous administration, the mean (SD) Cmax of unchanged [14C]‐canagliflozin was 17,605 (6901) ng/mL, AUC∞ 27,100 (10,778) ng.h/mL, Vdss 83.5 (29.2) L, Vdz 119 (41.6) L, and CL 12.2 (3.79) L/h. Unchanged [14C]‐canagliflozin and metabolites accounted for about 57% and 43% of the plasma total [14C] radioactivity AUC∞, respectively. For total [14C] radioactivity, the mean (SD) Cmax was 15,981 (2721) ng‐eq/mL, and AUC∞ 53,755 (15,587) ng‐eq.h/mL. Renal (34.5% in urine) and biliary (34.1% in feces) excretions were the major elimination pathways for total [14C] radioactivity. The absolute oral bioavailability of canagliflozin was 65% (90% confidence interval: 55.41; 76.07). Overall, oral canagliflozin 300 mg coadministered with intravenous [14C]‐canagliflozin (10 µg) was generally well‐tolerated in healthy men, with no treatment‐emergent adverse events.