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

Sha, Sue; Devineni, Damayanthi; Ghosh, A.K.; Polidori, David; Hompesch, Marcus; Arnolds, Sabine; Morrow, Linda; Spitzer, Heike; Demarest, Keith T.; Rothenberg, Paul

doi:10.1371/journal.pone.0105638

Cited by 57 publications

(68 citation statements)

References 30 publications

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“…In patients with T2DM, canagliflozin increased UGE dose dependently [11,35,36] with similar UGE levels observed following sustained dosing compared with the first dose (Fig. 3a).…”

Section: Uge and Rt G In Patients With T2dmmentioning

confidence: 55%

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Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Devineni

Polidori

2015

Clin Pharmacokinet

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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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“…In patients with T2DM, canagliflozin increased UGE dose dependently [11,35,36] with similar UGE levels observed following sustained dosing compared with the first dose (Fig. 3a).…”

Section: Uge and Rt G In Patients With T2dmmentioning

confidence: 55%

“…3a). Approximately 80-120 g/day of UGE was observed in patients with T2DM treated with canagliflozin 100 mg and higher [11,[35][36][37]. In patients with T2DM, mean baseline (pre-treatment) RT G values were *240 mg/ dL [11,36] which are higher than values commonly quoted for normoglycemic participants (180-200 mg/dL).…”

Section: Uge and Rt G In Patients With T2dmmentioning

confidence: 75%

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Devineni

Polidori

2015

Clin Pharmacokinet

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“…Canagliflozin treatment was not associated with meaningful changes in serum or urine calcium, urine phosphate, urine magnesium, PTH, 1,25-dihydroxyvitamin D, or 25-hydroxyvitamin D (Supplemental Table 1) 6, [23][24][25][26][27][28][29] . In a pooled dataset of four placebo-controlled, Phase 3 studies (N ¼ 2215), mean percent changes from baseline in serum calcium were 0.2%, 0.8%, and 1.2% with canagliflozin 100 and 300 mg and placebo, respectively, at Week 26 29 .…”

Section: Mineral Homeostasismentioning

confidence: 99%

The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus

Alba

Xie

Fung

et al. 2016

Current Medical Research and Opinion

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(2016) The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus, Current Medical Research and Opinion, 32:8, 1375-1385, DOI: 10.1080/03007995.2016 Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower blood glucose levels in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. This review provides a comprehensive summary of preclinical and clinical data on the effects of the SGLT2 inhibitor canagliflozin on mineral balance and bone. Methods: Published articles and internal study reports through November 2015 were included.Results: In clinical studies, canagliflozin was not associated with meaningful changes in serum or urine calcium, parathyroid hormone, or vitamin D. Canagliflozin was associated with increases in serum magnesium and phosphate without changes in their urinary excretion. Increases in serum collagen type-1 beta-carboxy-telopeptide (beta-CTX), a bone resorption marker, and osteocalcin, a bone formation marker, were observed with canagliflozin. Decreases in total hip bone mineral density (BMD) of up to 1.2% were seen with canagliflozin after 2 years; no changes in BMD were seen at other skeletal sites. Changes in total hip BMD and serum beta-CTX with canagliflozin correlated with decreases in body weight. In a clinical program-wide analysis, canagliflozin was associated with increased fracture risk that was driven by a higher incidence in the cardiovascular safety study (CANVAS), with no fracture imbalance seen in pooled data from other Phase 3 studies. The fracture imbalance occurred within 12 weeks after initiating treatment, most frequently in the distal portion of the upper and lower extremities. Conclusions: Across clinical studies, canagliflozin did not meaningfully affect calcium homeostasis or hormones regulating calcium homeostasis. Increases in bone turnover markers and decreases in BMD at the total hip, but not at other sites, that correlated with weight loss were seen with canagliflozin. Canagliflozin was associated with a higher fracture incidence within 12 weeks, primarily in distal extremities. Data from ongoing canagliflozin studies will provide additional information on fracture risk.

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“…Canagliflozin lowers plasma glucose by promoting urinary glucose excretion, which results in a mild osmotic diuresis that may be associated with a reduction in intravascular volume 6, 7, 8, 9. While the insulin‐independent mechanism of canagliflozin leads to a low inherent risk of hypoglycaemia, the mild osmotic diuresis it causes may be associated with an increased risk of volume–depletion events, including dehydration.…”

Section: Introductionmentioning

confidence: 99%

Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS)

Hassanein

Echtay

Hassoun³

et al. 2017

Int J Clin Pract

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SummaryAimsThere is a large population of people with type 2 diabetes mellitus (T2DM) who are Muslim and fast during Ramadan. Changes in the pattern and amount of meal and fluid intake during Ramadan, in addition to the long fasting hours, may increase the risk of hypoglycaemia, hyperglycaemia, and dehydration. The Canagliflozin in Ramadan Tolerance Observational Study (CRATOS) evaluated the tolerability of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, compared with sulphonylureas among patients with T2DM who fast during Ramadan.MethodsThis non‐randomised, parallel‐cohort, prospective, comparative, observational study was conducted in the Middle East during Ramadan and enrolled patients who were taking canagliflozin (n=162) or any sulphonylurea (n=159) added to metformin±dipeptidyl peptidase‐4 inhibitor. The proportion of patients who experienced hypoglycaemia events was assessed as the primary end‐point. Between‐cohort comparisons were adjusted using propensity score analysis.ResultsDuring Ramadan, fewer patients experienced symptomatic hypoglycaemia with canagliflozin vs sulphonylurea (adjusted odds ratio: 0.273 [95% CI: 0.104, 0.719]). Of hypoglycaemia events for which blood glucose was measured, two of six with canagliflozin and 27 of 37 with sulphonylurea were confirmed by blood glucose <3.9 mmol/L. More patients treated with canagliflozin experienced volume depletion events compared with sulphonylurea (adjusted odds ratio: 3.5 [95% CI: 1.3, 9.2]). Missed fasting days were few and medication adherence was high in both groups. No patients treated with canagliflozin and 9.4% treated with sulphonylurea adjusted their medication dose near the beginning of Ramadan. Both treatments were generally well tolerated, with low rates of adverse events and no serious adverse events in either group.ConclusionsOverall, these findings support the use of canagliflozin for the treatment of adults with T2DM who fast during Ramadan.ClinicalTrials.gov Identifier: NCT02737657

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

Cited by 57 publications

References 30 publications

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus

Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS)

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