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David Polidori - One of the best experts on this subject based on the ideXlab platform.
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effect of Canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes
Diabetes Obesity and Metabolism, 2019Co-Authors: David Polidori, Sue Sha, Atalanta Ghosh, Kristin Farrell, Kenneth Cusi, Fernando Bril, Diana Barb, Nishanth E Sunny, Srilaxmi KalavalapalliAbstract:AIM To evaluate the impact of the sodium glucose co-transporter 2 inhibitor Canagliflozin on intrahepatic triglyceride (IHTG) accumulation and its relationship to changes in body weight and glucose metabolism. MATERIALS AND METHODS In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c = 7.7% ± 0.7%) from two centres were randomly assigned (1:1) to Canagliflozin 300 mg or placebo. We measured IHTG by proton-magnetic resonance spectroscopy (primary outcome), hepatic/muscle/adipose tissue insulin sensitivity during a 2-step euglycaemic insulin clamp, and beta-cell function during a mixed meal tolerance test. Analyses were per protocol. RESULTS Between 8 September 2014-13 June 2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo-subtracted change: -0.71% [-1.08; -0.33]) and body weight (-3.4% [-5.4; -1.4]; both P ≤ 0.001). A numerically larger absolute decrease in IHTG occurred with Canagliflozin (-4.6% [-6.4; -2.7]) versus placebo (-2.4% [-4.2; -0.6]; P = 0.09). In patients with non-alcoholic fatty liver disease (n = 37), the decrease in IHTG was -6.9% (-9.5; -4.2) versus -3.8% (-6.3; -1.3; P = 0.05), and strongly correlated with the magnitude of weight loss (r = 0.69, P < 0.001). Body weight loss ≥5% with a ≥30% relative reduction in IHTG occurred more often with Canagliflozin (38% vs. 7%, P = 0.009). Hepatic insulin sensitivity improved with Canagliflozin (P < 0.01), but not muscle or adipose tissue insulin sensitivity. Beta-cell glucose sensitivity, insulin clearance, and disposition index improved more with Canagliflozin (P < 0.05). CONCLUSIONS Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with Canagliflozin.
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Pharmacokinetics and pharmacodynamics of Canagliflozin in pediatric patients with type 2 diabetes.
Pediatric diabetes, 2017Co-Authors: William V. Tamborlane, David Polidori, Domenick Argenti, Nicholas A. Di ProsperoAbstract:Objective Canagliflozin, a sodium glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes (T2D), increases urinary glucose excretion (UGE) and lowers plasma glucose (PG) levels by reducing the renal threshold for glucose (RTG ). This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of Canagliflozin in pediatric T2D patients. Methods Patients, aged 10 to 17 years with mean weight 107.2 kg and body mass index 38.2 kg/m2 , underwent PK and PD assessments after receiving a single daily dose of Canagliflozin 100 mg (n = 8) or 300 mg (n = 9) for 14 days. Data are presented as mean (SD). Results There were dose-dependent increases in the PK of Canagliflozin 100 and 300 mg, with maximum plasma concentrations and areas under plasma concentration curves that were similar to the corresponding values in adults. Mean 24-hour RTG fell to 84.6 (13.8) mg/dL with Canagliflozin 100 mg and to 69.1 (9.6) mg/dL with Canagliflozin 300 mg; also consistent with reductions in RTG in adults. Mean 24-hour UGE increased from 5.3 (10.5) g at baseline to 74.1 (37.4) g with Canagliflozin 100 mg and from 0.1 (0.04) g to 68.6 (26.5) g with Canagliflozin 300 mg. Both doses were well tolerated and the tablets had acceptable taste, smell, and swallowability. Conclusions In pediatric T2D patients, Canagliflozin 100 and 300 mg had PK and PD characteristics similar to those in adults with T2D, which is likely due to the relative maturity and increased body weight of youth affected with this disorder.
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Glycaemic efficacy of Canagliflozin is largely independent of baseline β-cell function or insulin sensitivity.
Diabetic Medicine, 2016Co-Authors: David R. Matthews, Gary Meininger, B. Zinman, Cindy Tong, David PolidoriAbstract:Canagliflozin is a sodium-glucose co-transporter 2 inhibitor approved for the treatment of adults with Type 2 diabetes. In phase III studies, Canagliflozin reduced HbA1c, body weight and blood pressure, and was generally well tolerated [1–6]. Canagliflozin lowers plasma glucose by lowering the renal threshold for glucose and increasing urinary glucose excretion [7,8]. This article is protected by copyright. All rights reserved.
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Effect of Canagliflozin on liver function tests in patients with type 2 diabetes
Diabetes & metabolism, 2015Co-Authors: L.a. Leiter, David Polidori, Dainius Balis, T. Forst, John Xie, Sue ShaAbstract:Abstract Aims To report changes in liver function tests observed with Canagliflozin, a sodium glucose co-transporter 2 inhibitor, across phase 3 studies in patients with type 2 diabetes, and to examine the relationship between changes in liver function tests and the weight loss and glycaemic improvements observed with Canagliflozin. Methods Data were pooled from four 26-week, placebo-controlled studies of Canagliflozin 100 and 300mg ( n =2313) and two 52-week, active-controlled studies of Canagliflozin 300mg versus sitagliptin 100mg ( n =1488). Analysis of covariance was performed to determine the contribution of changes in body weight and HbA 1c to the changes in liver function tests. Results Reductions in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transferase, and increases in bilirubin were seen with Canagliflozin 100 and 300mg versus placebo (nominal P P P =0.015 for bilirubin [Canagliflozin 300mg only]) at week 26 and with Canagliflozin 300mg versus sitagliptin 100mg (nominal P P 1c and body weight reductions. Conclusions Canagliflozin provided improvements in liver function tests versus either placebo or sitagliptin treatments that were fully explained by the combined effects of HbA 1c and body weight reductions with Canagliflozin.
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Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor
Clinical Pharmacokinetics, 2015Co-Authors: Damayanthi Devineni, David PolidoriAbstract:The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RT_G) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered Canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1–2 h. Dose-proportional systemic exposure to Canagliflozin has been observed over a wide dose range (50–1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered Canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in Canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of Canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to Canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced Canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RT_G in a dose-dependent manner, thereby lowering the plasma glucose levels and reducing the glycosylated hemoglobin levels through an insulin-independent mechanism of action. The 300-mg dose provides near-maximal effects on RT_G throughout the full 24-h dosing interval, whereas the effect of the 100-mg dose on RT_G is near-maximal for approximately 12 h and is modestly attenuated during the overnight period. The observed pharmacokinetic/pharmacodynamic profile of Canagliflozin in patients with type 2 diabetes mellitus supports a once-daily dosing regimen.
Gary Meininger - One of the best experts on this subject based on the ideXlab platform.
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Longer-term safety and tolerability of Canagliflozin in patients with type 2 diabetes: a pooled analysis
Current medical research and opinion, 2017Co-Authors: Rong Qiu, Dainius Balis, Mehul Desai, John Xie, Michael J. Davies, Gary MeiningerAbstract:AbstractObjective: To evaluate the longer-term safety of Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM).Methods: The safety/tolerability of Canagliflozin 100 and 300 mg were assessed using data pooled from seven placebo- and active-controlled studies of 52–104 weeks in duration that enrolled a broad range of patients with T2DM (N = 5598). Canagliflozin 100 and 300 mg as monotherapy or in combination with various background antihyperglycemic agents (AHAs) were compared with pooled non-Canagliflozin treatments (i.e. placebo, sitagliptin, glimepiride). Safety was assessed based on adverse event (AE) reports, including the incidence of AEs related to the mechanism of SGLT2 inhibition.Results: Overall AE incidence was similar with Canagliflozin 100 and 300 mg and non-Canagliflozin (73.7%, 74.5%, and 73.7%). The incidence of AE-related discontinuations and serious AEs was low and balanced across groups. The incidence of male and female genita...
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Canagliflozin slows progression of renal function decline independently of glycemic effects
Journal of The American Society of Nephrology, 2017Co-Authors: Hiddo J L Heerspink, Dainius Balis, Gary Meininger, Mehul Desai, Meg Jardine, Vlado PerkovicAbstract:Sodium-glucose cotransporter 2 inhibition with Canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that Canagliflozin confers renoprotection. We determined whether Canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily Canagliflozin 100 mg, Canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, Canagliflozin 100 mg, and Canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m2 per year (95% confidence interval [95% CI], 2.8 to 3.8), 0.5 ml/min per 1.73 m2 per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m2 per year (95% CI, 0.4 to 1.4), respectively (P<0.01 for each Canagliflozin group versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, urinary albumin-to-creatinine ratio decreased more with Canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or Canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P<0.001) than with glimepiride. Patients receiving glimepiride, Canagliflozin 100 mg, or Canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, Canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and Canagliflozin may confer renoprotective effects independently of its glycemic effects.
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Canagliflozin slows progression of renal function decline independently of glycemic effects
Journal of The American Society of Nephrology, 2017Co-Authors: Hiddo J L Heerspink, Dainius Balis, Gary Meininger, Mehul Desai, Meg Jardine, Vlado PerkovicAbstract:Sodium-glucose cotransporter 2 inhibition with Canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that Canagliflozin confers renoprotection. We determined whether Canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily Canagliflozin 100 mg, Canagliflozin 300 mg, or glimepiride uptitrated to 6–8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, Canagliflozin 100 mg, and Canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m 2 per year (95% confidence interval [95% CI], 2.8 to 3.8), 0.5 ml/min per 1.73 m 2 per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m 2 per year (95% CI, 0.4 to 1.4), respectively ( P P =0.01) or Canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P
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Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes
Diabetes Therapy, 2016Co-Authors: Dainius Balis, George Capuano, Gary MeiningerAbstract:Metformin is typically the first pharmacologic treatment recommended for type 2 diabetes mellitus (T2DM), but many patients do not achieve glycemic control with metformin alone and eventually require combination therapy with other agents. Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was assessed in a comprehensive Phase 3 clinical development program consisting of ~10,000 participants, of which ~80% were on background therapy that consisted of metformin alone or in combination with other antihyperglycemic agents (AHAs; e.g., pioglitazone, sulfonylurea, and insulin). In addition, the efficacy and safety of Canagliflozin and metformin as the initial combination therapy and Canagliflozin monotherapy were assessed versus metformin in treatment-naïve patients with T2DM. Across studies in patients with T2DM who were on metformin alone or in combination with other AHAs, Canagliflozin 100 and 300 mg provided improvements in glycated hemoglobin for up to 104 weeks. Canagliflozin was also associated with reductions in body weight and systolic blood pressure when added to background therapy consisting of metformin alone or with other AHAs. Canagliflozin was generally well tolerated, with increased incidence of adverse events (AEs) related to the mechanism of SGLT2 inhibition (i.e., genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs). Consistent with its insulin-independent mechanism of action, Canagliflozin was associated with low rates of hypoglycemia when background therapy did not include sulfonylurea or insulin. Due to its favorable efficacy and safety profile, these results suggest that adding Canagliflozin to a background regimen consisting of metformin or implementing treatment with a fixed-dose regimen of Canagliflozin and metformin would provide an effective and safe treatment regimen for T2DM management. Funding : Janssen Global Services, LLC.
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Glycaemic efficacy of Canagliflozin is largely independent of baseline β-cell function or insulin sensitivity.
Diabetic Medicine, 2016Co-Authors: David R. Matthews, Gary Meininger, B. Zinman, Cindy Tong, David PolidoriAbstract:Canagliflozin is a sodium-glucose co-transporter 2 inhibitor approved for the treatment of adults with Type 2 diabetes. In phase III studies, Canagliflozin reduced HbA1c, body weight and blood pressure, and was generally well tolerated [1–6]. Canagliflozin lowers plasma glucose by lowering the renal threshold for glucose and increasing urinary glucose excretion [7,8]. This article is protected by copyright. All rights reserved.
Damayanthi Devineni - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor
Clinical Pharmacokinetics, 2015Co-Authors: Damayanthi Devineni, David PolidoriAbstract:The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RT_G) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered Canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1–2 h. Dose-proportional systemic exposure to Canagliflozin has been observed over a wide dose range (50–1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered Canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in Canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of Canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to Canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced Canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RT_G in a dose-dependent manner, thereby lowering the plasma glucose levels and reducing the glycosylated hemoglobin levels through an insulin-independent mechanism of action. The 300-mg dose provides near-maximal effects on RT_G throughout the full 24-h dosing interval, whereas the effect of the 100-mg dose on RT_G is near-maximal for approximately 12 h and is modestly attenuated during the overnight period. The observed pharmacokinetic/pharmacodynamic profile of Canagliflozin in patients with type 2 diabetes mellitus supports a once-daily dosing regimen.
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clinical pharmacokinetic pharmacodynamic and drug drug interaction profile of Canagliflozin a sodium glucose co transporter 2 inhibitor
Clinical Pharmacokinectics, 2015Co-Authors: Damayanthi Devineni, David PolidoriAbstract:The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered Canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1–2 h. Dose-proportional systemic exposure to Canagliflozin has been observed over a wide dose range (50–1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered Canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in Canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of Canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to Canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced Canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose levels and reducing the glycosylated hemoglobin levels through an insulin-independent mechanism of action. The 300-mg dose provides near-maximal effects on RTG throughout the full 24-h dosing interval, whereas the effect of the 100-mg dose on RTG is near-maximal for approximately 12 h and is modestly attenuated during the overnight period. The observed pharmacokinetic/pharmacodynamic profile of Canagliflozin in patients with type 2 diabetes mellitus supports a once-daily dosing regimen.
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Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects
Clinical therapeutics, 2015Co-Authors: Xia Chen, David Polidori, Hans Stieltjes, Nicole Vaccaro, Sue Sha, Christopher R Curtin, Sveta Weiner, Damayanthi DevineniAbstract:Purpose: Canagliflozin, an orally active sodium– glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of Canagliflozin is 100 or 300 mg once daily. This Phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety profile of Canagliflozin in healthy Chinese subjects. Methods: In this double-blind, single-dose, 3-way crossover study, 15 healthy subjects were randomized (1:1:1) to receive single oral doses of Canagliflozin 100 mg, Canagliflozin 300 mg, or placebo. Pharmacokinetic, pharmacodynamic, and safety assessments were made at prespecified time points. Findings: All participants are healthy Chinese adults. Mean AUC and Cmax of Canagliflozin increased in a dose-dependent manner after single-dose
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Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of Canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants
International journal of clinical pharmacology and therapeutics, 2015Co-Authors: Damayanthi Devineni, Shean-sheng Wang, Rao N V S Mamidi, Joseph Murphy, Hans Stieltjes, Nicole Vaccaro, Christopher R Curtin, Sveta Weiner, Jay Ariyawansa, Ewa WajsAbstract: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.
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Absolute oral bioavailability and pharmacokinetics of Canagliflozin: A microdose study in healthy participants
Clinical pharmacology in drug development, 2014Co-Authors: Damayanthi Devineni, Shean-sheng Wang, Joseph Murphy, Hans Stieltjes, Paul Rothenberg, Ellen Scheers, Rao N V S MamidiAbstract:Absolute oral bioavailability of Canagliflozin was assessed by simultaneous oral administration with intravenous [(14) C]-Canagliflozin microdose infusion in nine healthy men. Pharmacokinetics of Canagliflozin, [(14) C]-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 [(14) C]-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 [(14) C]-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 [(14) C]-Canagliflozin and metabolites accounted for about 57% and 43% of the plasma total [(14) C] radioactivity AUC∞ , respectively. For total [(14) C] 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 [(14) C] radioactivity. The absolute oral bioavailability of Canagliflozin was 65% (90% confidence interval: 55.41; 76.07). Overall, oral Canagliflozin 300 mg coadministered with intravenous [(14) C]-Canagliflozin (10 µg) was generally well-tolerated in healthy men, with no treatment-emergent adverse events.
Mehul Desai - One of the best experts on this subject based on the ideXlab platform.
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effects of Canagliflozin on amputation risk in type 2 diabetes the canvas program
Diabetologia, 2019Co-Authors: David R. Matthews, Vlado Perkovic, Kenneth W Mahaffey, Dick De Zeeuw, Greg Fulcher, Mehul Desai, William R Hiatt, Mark R Nehler, Elisa FabbriniAbstract:The primary analysis of the Canagliflozin cardioVascular Assessment Study (CANVAS) Program showed Canagliflozin to have a beneficial effect on cardiovascular and renal outcomes in people with type 2 diabetes at high cardiovascular risk, but also an unexpected increased risk of major or minor lower extremity amputation. These secondary analyses explore this finding in more detail. The effect of Canagliflozin on amputation risk in the CANVAS Program was calculated for amputations of different types and proximate aetiologies and different Canagliflozin doses. Univariate and multivariate associations of baseline characteristics with amputation risk were determined and proportional and absolute effects of Canagliflozin were compared across subgroups. There were 187 (1.8%) participants with atraumatic lower extremity amputations (minor 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with Canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was similar for ischaemic and infective aetiologies and for 100 mg and 300 mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of Canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted. The CANVAS Program demonstrated that Canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for Canagliflozin was identified.
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risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium glucose co transporter 2 inhibitors in the usa a retrospective cohort study
Diabetes Obesity and Metabolism, 2018Co-Authors: Zhong Yuan, Mehul Desai, Frank J Defalco, Patrick B Ryan, Martijn J Schuemie, Paul E Stang, Jesse A Berlin, Norm RosenthalAbstract:Aims To examine the incidence of amputation in patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose co-transporter 2 inhibitors (SGLT2i) overall, and Canagliflozin specifically, compared with non-SGLT2i antihyperglycemic agents (AHAs). Materials and Methods Patients with T2DM newly exposed to SGLT2i or non-SGLT2i AHAs were identified using the Truven MarketScan database. The incidence of below-knee lower extremity (BKLE) amputation was calculated for patients treated with SGLT2i, Canagliflozin, or non-SGLT2i AHAs. Patients newly exposed to Canagliflozin and non-SGLT2i AHAs were matched 1:1 on propensity scores, and a Cox proportional hazards model was used for comparative analysis. Negative controls (outcomes not believed to be associated with any AHA) were used to calibrate P values. Results Between April 1, 2013-October 31, 2016, 118,018 new users of SGLT2i, including 73,024 of Canagliflozin, and 226,623 new users of non-SGLT2i AHAs were identified. The crude incidence rate of BKLE amputation was 1.22, 1.26, and 1.87 events per 1,000 person-years with SGLT2i, Canagliflozin, and non-SGLT2i AHAs, respectively. For the comparative analysis, 63,845 new users of Canagliflozin were matched with 63,845 new users of non-SGLT2i AHAs, resulting in well-balanced baseline covariates. The incidence rate of BKLE amputation was 1.18 and 1.12 events per 1,000 person-years with Canagliflozin and non-SGLT2i AHAs, respectively; the hazard ratio (95% confidence interval) was 0.98 (0.68-1.41; P=0.92, calibrated P=0.95). Conclusions This real-world study observed no evidence of increased risk of BKLE amputation for new users of Canagliflozin compared with non-SGLT2i AHAs in a broad population of patients with T2DM.
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renal safety of Canagliflozin a sodium glucose co transporter 2 inhibitor in patients with type 2 diabetes mellitus
Diabetes Obesity and Metabolism, 2017Co-Authors: Mehul Desai, Dainius Balis, William Canovatchel, John Xie, Yshai Yavin, Don Sun, Norm RosenthalAbstract:The incidence of renal-related adverse events (AEs) with Canagliflozin in patients with type 2 diabetes mellitus from a pooled population of patients in 7 active- and placebo-controlled trials (N = 5598) and in a 104-week study vs glimepiride (N = 1450) was low and similar in Canagliflozin and non-Canagliflozin groups. In the study vs glimepiride, Canagliflozin was associated with an initial acute decrease in estimated glomerular filtration rate (eGFR) that attenuated over time, while eGFR declined progressively over 104 weeks with glimepiride. The incidence of renal-related AEs with Canagliflozin was generally stable over time, while the incidence with glimepiride increased over 104 weeks. In the present analysis, based on postmarketing reports from the US Food and Drug Administration Adverse Event Reporting System, a potential signal was identified for acute kidney injury with all approved sodium glucose co-transporter 2 (SGLT2) inhibitors (ie, Canagliflozin, dapagliflozin and empagliflozin). The early onset of acute kidney injury events with SGLT2 inhibitors in postmarketing reports probably reflects the acute changes in eGFR attibutable to the known renal haemodynamic effects of SGLT2 inhibition.
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Longer-term safety and tolerability of Canagliflozin in patients with type 2 diabetes: a pooled analysis
Current medical research and opinion, 2017Co-Authors: Rong Qiu, Dainius Balis, Mehul Desai, John Xie, Michael J. Davies, Gary MeiningerAbstract:AbstractObjective: To evaluate the longer-term safety of Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM).Methods: The safety/tolerability of Canagliflozin 100 and 300 mg were assessed using data pooled from seven placebo- and active-controlled studies of 52–104 weeks in duration that enrolled a broad range of patients with T2DM (N = 5598). Canagliflozin 100 and 300 mg as monotherapy or in combination with various background antihyperglycemic agents (AHAs) were compared with pooled non-Canagliflozin treatments (i.e. placebo, sitagliptin, glimepiride). Safety was assessed based on adverse event (AE) reports, including the incidence of AEs related to the mechanism of SGLT2 inhibition.Results: Overall AE incidence was similar with Canagliflozin 100 and 300 mg and non-Canagliflozin (73.7%, 74.5%, and 73.7%). The incidence of AE-related discontinuations and serious AEs was low and balanced across groups. The incidence of male and female genita...
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Canagliflozin slows progression of renal function decline independently of glycemic effects
Journal of The American Society of Nephrology, 2017Co-Authors: Hiddo J L Heerspink, Dainius Balis, Gary Meininger, Mehul Desai, Meg Jardine, Vlado PerkovicAbstract:Sodium-glucose cotransporter 2 inhibition with Canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that Canagliflozin confers renoprotection. We determined whether Canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily Canagliflozin 100 mg, Canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, Canagliflozin 100 mg, and Canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m2 per year (95% confidence interval [95% CI], 2.8 to 3.8), 0.5 ml/min per 1.73 m2 per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m2 per year (95% CI, 0.4 to 1.4), respectively (P<0.01 for each Canagliflozin group versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, urinary albumin-to-creatinine ratio decreased more with Canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or Canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P<0.001) than with glimepiride. Patients receiving glimepiride, Canagliflozin 100 mg, or Canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, Canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and Canagliflozin may confer renoprotective effects independently of its glycemic effects.
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effect of Canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes
Diabetes Obesity and Metabolism, 2019Co-Authors: David Polidori, Sue Sha, Atalanta Ghosh, Kristin Farrell, Kenneth Cusi, Fernando Bril, Diana Barb, Nishanth E Sunny, Srilaxmi KalavalapalliAbstract:AIM To evaluate the impact of the sodium glucose co-transporter 2 inhibitor Canagliflozin on intrahepatic triglyceride (IHTG) accumulation and its relationship to changes in body weight and glucose metabolism. MATERIALS AND METHODS In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c = 7.7% ± 0.7%) from two centres were randomly assigned (1:1) to Canagliflozin 300 mg or placebo. We measured IHTG by proton-magnetic resonance spectroscopy (primary outcome), hepatic/muscle/adipose tissue insulin sensitivity during a 2-step euglycaemic insulin clamp, and beta-cell function during a mixed meal tolerance test. Analyses were per protocol. RESULTS Between 8 September 2014-13 June 2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo-subtracted change: -0.71% [-1.08; -0.33]) and body weight (-3.4% [-5.4; -1.4]; both P ≤ 0.001). A numerically larger absolute decrease in IHTG occurred with Canagliflozin (-4.6% [-6.4; -2.7]) versus placebo (-2.4% [-4.2; -0.6]; P = 0.09). In patients with non-alcoholic fatty liver disease (n = 37), the decrease in IHTG was -6.9% (-9.5; -4.2) versus -3.8% (-6.3; -1.3; P = 0.05), and strongly correlated with the magnitude of weight loss (r = 0.69, P < 0.001). Body weight loss ≥5% with a ≥30% relative reduction in IHTG occurred more often with Canagliflozin (38% vs. 7%, P = 0.009). Hepatic insulin sensitivity improved with Canagliflozin (P < 0.01), but not muscle or adipose tissue insulin sensitivity. Beta-cell glucose sensitivity, insulin clearance, and disposition index improved more with Canagliflozin (P < 0.05). CONCLUSIONS Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with Canagliflozin.
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Effect of Canagliflozin on liver function tests in patients with type 2 diabetes
Diabetes & metabolism, 2015Co-Authors: L.a. Leiter, David Polidori, Dainius Balis, T. Forst, John Xie, Sue ShaAbstract:Abstract Aims To report changes in liver function tests observed with Canagliflozin, a sodium glucose co-transporter 2 inhibitor, across phase 3 studies in patients with type 2 diabetes, and to examine the relationship between changes in liver function tests and the weight loss and glycaemic improvements observed with Canagliflozin. Methods Data were pooled from four 26-week, placebo-controlled studies of Canagliflozin 100 and 300mg ( n =2313) and two 52-week, active-controlled studies of Canagliflozin 300mg versus sitagliptin 100mg ( n =1488). Analysis of covariance was performed to determine the contribution of changes in body weight and HbA 1c to the changes in liver function tests. Results Reductions in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transferase, and increases in bilirubin were seen with Canagliflozin 100 and 300mg versus placebo (nominal P P P =0.015 for bilirubin [Canagliflozin 300mg only]) at week 26 and with Canagliflozin 300mg versus sitagliptin 100mg (nominal P P 1c and body weight reductions. Conclusions Canagliflozin provided improvements in liver function tests versus either placebo or sitagliptin treatments that were fully explained by the combined effects of HbA 1c and body weight reductions with Canagliflozin.
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Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects
Clinical therapeutics, 2015Co-Authors: Xia Chen, David Polidori, Hans Stieltjes, Nicole Vaccaro, Sue Sha, Christopher R Curtin, Sveta Weiner, Damayanthi DevineniAbstract:Purpose: Canagliflozin, an orally active sodium– glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of Canagliflozin is 100 or 300 mg once daily. This Phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety profile of Canagliflozin in healthy Chinese subjects. Methods: In this double-blind, single-dose, 3-way crossover study, 15 healthy subjects were randomized (1:1:1) to receive single oral doses of Canagliflozin 100 mg, Canagliflozin 300 mg, or placebo. Pharmacokinetic, pharmacodynamic, and safety assessments were made at prespecified time points. Findings: All participants are healthy Chinese adults. Mean AUC and Cmax of Canagliflozin increased in a dose-dependent manner after single-dose
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pharmacodynamic differences between Canagliflozin and dapagliflozin results of a randomized double blind crossover study
Diabetes Obesity and Metabolism, 2015Co-Authors: Sue Sha, David Polidori, Paul Rothenberg, Nicole Vaccaro, Jaya Natarajan, Atalanta Ghosh, Kristin Farrell, J Pinheiro, L PlummorschelAbstract:Aims 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. Methods In each treatment period, participants (n = 54) received Canagliflozin 300 mg or dapagliflozin 10 mg for 4 days (20 min before breakfast). A mixed-meal tolerance test (600 kcal; 75 g glucose) was performed at baseline and on day 4 of each treatment period to assess changes in incremental PPG (PPGΔAUC0–2 h). We measured 24-h UGE and plasma glucose on day 4 to determine 24-h mean RTG. Results Canagliflozin 300 mg and dapagliflozin 10 mg had similar effects on UGE and RTG for 4 h after dosing, but Canagliflozin was associated with higher UGE and greater RTG reductions for the remainder of the day. Mean 24-h UGE was ∼25% higher with Canagliflozin than with dapagliflozin (51.4 vs. 40.8 g), and 24-h mean RTG was ∼0.4 mmol/l (7 mg/dl) lower with Canagliflozin than with dapagliflozin (3.79 vs. 4.17 mmol/l; p < 0.0001). Dapagliflozin had no effect on PPG excursion; Canagliflozin delayed and reduced PPG excursion (between-treatment difference in PPGΔAUC0–2 h from baseline expressed as a percentage of baseline mean, −10.2%; p = 0.0122). Canagliflozin and dapagliflozin were generally well tolerated. Conclusions In healthy participants, Canagliflozin 300 mg provided greater 24-h UGE, a lower RTG and smaller PPG excursions than dapagliflozin 10 mg.
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effect of the sodium glucose co transporter 2 inhibitor Canagliflozin on plasma volume in patients with type 2 diabetes mellitus
Diabetes Obesity and Metabolism, 2014Co-Authors: Sue Sha, Shean-sheng Wang, David Polidori, Paul Rothenberg, Tim Heise, Jaya Natarajan, Kristin Farrell, D Sica, L PlummorschelAbstract:Aim 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. Methods Patients (N = 36) were randomized (1 : 1) to receive Canagliflozin 300 mg or placebo for 12 weeks. Pharmacodynamic parameters were assessed at baseline and at weeks 1 and 12. Results Increased 24-h UGE was seen in the Canagliflozin group compared with a reduction in the placebo group at both week 1 (91.8 vs. −2.4 g) and week 12 (82.6 vs. −0.4 g). Canagliflozin also reduced both FPG and HbA1c. Reductions in body weight and blood pressure were observed at weeks 1 and 12. Canagliflozin decreased plasma volume compared with an increase with placebo at week 1 (−5.4 vs. 4.3%; p = 0.02), but this was largely attenuated at week 12 (4.6 vs. 5.8%; p = 0.76). A modest numerical increase in urine volume was observed with Canagliflozin at week 1 that was attenuated at week 12; other measures of volume status (i.e. blood urea nitrogen, serum creatinine and haematocrit) remained modestly increased with Canagliflozin at week 12. Conclusion Canagliflozin provided sustained effects on UGE and FPG over 12 weeks and a transient reduction in plasma volume that was largely attenuated by week 12.