Canagliflozin

Canagliflozin is a novel, potent, and highly selective sodium glucose co-transporter (SGLT) 2 inhibitor [1]. It has been proved that Canagliflozin can increase urine glucose excretion by reducing the renal glucose threshold and by decreasing the filtered glucose re-absorption [2].

Canagliflozin has been shown to inhibit the Na+-mediated 14C-AMG intakes in CHO-hSGLT2, CHO-rat SGLT2 and CHO-mouse SGLT2 with IC50 values of 4.4, 3.7 and 2.0 nM, respectively [1].

Canagliflozin has been reported to reduce the blood glucose (BG) levels dose-dependently in both db/db Mice and Zucker diabetic fatty (ZDF) Rats. Additionally, canagliflozin has proved to decrease the respiratory exchange ratio, and body weight in DIO mice and ZDF rats [1].

Canagliflozin can be taken orally [1].

References:
[1] Liang Y1, Arakawa K, Ueta K, Matsushita Y, Kuriyama C Martin T, Du F, Liu Y, Xu J, Conway B, Conway J, Polidori D, Ways K, Demarest K. Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models. PLoS One. 2012;7(2):e30555
[2] Sarnoski-Brocavich S, Hilas O. Canagliflozin (Invokana), a Novel Oral Agent For Type-2 Diabetes. P T. 2013 Nov;38(11):656-66

Efficacy and safety of canagliflozin in patients with type 2 diabetes based on history of cardiovascular disease or cardiovascular risk factors: a post hoc analysis of pooled data.[Pubmed:28327140]

Cardiovasc Diabetol. 2017 Mar 21;16(1):40.

BACKGROUND: Treatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and the use of concomitant medications. The sodium glucose co-transporter 2 inhibitor, Canagliflozin, has been shown to improve glycaemic control and reduce body weight and blood pressure (BP) with a favourable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of Canagliflozin in patients with T2DM based on CV disease history or CV risk factors. METHODS: Analyses were based on pooled data from four 26-week, placebo-controlled, Phase 3 studies that evaluated Canagliflozin 100 and 300 mg in patients with T2DM (N = 2313; mean HbA1c, 8.0%; body weight, 89 kg; systolic BP, 128 mmHg). Changes from baseline to week 26 in HbA1c, body weight, and systolic BP were assessed based on history of CV disease, history of hypertension, baseline statin use, and number of CV risk factors. Safety was assessed based on adverse event (AE) reports. RESULTS: At week 26, both Canagliflozin doses lowered HbA1c, body weight, and systolic BP compared with placebo in patients with and without CV disease history or risk factors. Placebo-subtracted HbA1c reductions with Canagliflozin 100 and 300 mg were similar in patients with a history of CV disease (-0.95 and -1.07%) versus no history of CV disease (-0.71 and -0.90%), history of hypertension (-0.72 and -0.89%) versus no history of hypertension (-0.73 and -0.95%), baseline statin use (-0.77 and -0.99%) versus no statin use (-0.69 and -0.85%), and 0-1 CV risk factor (-0.72 and -0.87%) versus >/=2 CV risk factors (-0.74 and -1.02%). Similar body weight and systolic BP reductions were seen with Canagliflozin versus placebo across subgroups. The incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups. CONCLUSIONS: The efficacy and safety of Canagliflozin were generally consistent across subgroups of patients with T2DM and varying degrees of CV disease history or risk factors. Trial registration numbers and dates ClinicalTrials.gov: NCT01081834, 4 March 2010; NCT01106625, 1 April 2010; NCT01106677, 1 April 2010; NCT01106690, 1 April 2010.

Canagliflozin in the treatment of type 2 diabetes: an evidence-based review of its place in therapy.[Pubmed:28352212]

Core Evid. 2017 Mar 15;12:1-10.

INTRODUCTION: Deciding on an optimal medication choice for type 2 diabetes is often challenging, due to the increasing number of treatment options. Canagliflozin is a novel glucose-lowering agent belonging to sodium-glucose co-transporter 2 (SGLT2) inhibitors. AIM: The aim of this study was to examine and summarize the evidence based on the efficacy, safety, and cost-effectiveness of Canagliflozin for type 2 diabetes. EVIDENCE REVIEW: Compared to placebo, Canagliflozin 100 and 300 mg lower glycated hemoglobin (HbA1c) by ~0.6%-0.8%, respectively. Canagliflozin appears to be slightly more effective than dipeptidyl peptidase-4 (DPP-4) inhibitors in reducing HbA1c. It also has a favorable effect on body weight and blood pressure, both versus placebo and most active comparators. However, treatment with Canagliflozin is associated with increased incidence of genital tract infections and osmotic diuresis-related adverse events. Based on short-term data, Canagliflozin is not associated with increased risk for all-cause mortality and cardiovascular outcomes. Economic evaluation studies from various countries indicate that Canagliflozin is a cost-effective option in dual- or triple-agent regimens. PLACE IN THERAPY: As monotherapy, Canagliflozin could be used in patients for whom metformin is contraindicated or not tolerated. For patients on background treatment with metformin, Canagliflozin appears to be superior to sulfonylureas with respect to body weight, blood pressure and risk for hypoglycemia, and to DPP-4 inhibitors in terms of lowering HbA1c, body weight, and blood pressure. Canagliflozin also seems to be cost-effective compared with sulfonylureas and DPP-4 inhibitors as add-on to metformin monotherapy, and compared with DPP-4 inhibitors as add-on to metformin and sulfonylurea. CONCLUSION: Current evidence on intermediate efficacy outcomes, short-term safety and cost-effectiveness support the use of Canagliflozin in patients on background treatment with metformin. Robust long-term data regarding the effect of Canagliflozin on cardiovascular endpoints will be available upon completion of the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial.

The association of weight loss with patient experience and outcomes in a population of patients with type 2 diabetes mellitus prescribed canagliflozin.[Pubmed:28360528]

Diabetes Metab Syndr Obes. 2017 Mar 20;10:89-99.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a chronic condition complicated by being overweight or obese. This study used a patient survey to assess health, satisfaction, and diabetes self-management in relation to weight management. METHODS: A survey including the Current Health Satisfaction Questionnaire, Diabetes Distress Scale, and Diabetes Treatment Satisfaction Questionnaire was administered using an online platform to a sample of 205 patients with T2DM prescribed Canagliflozin. Patients were placed into 5 groups based on their self-reported weight change since initiation of Canagliflozin: Lost >10 lbs, Lost 5-10 lbs, Lost <5 lbs, No Change, and Gained Weight. One-way ANOVAs, Kruskall-Wallis tests, and multivariable regression were used to explore differences between weight loss groups. RESULTS: The majority of patients (66.8%) reported losing weight. Compared to other groups, patients who lost >10 lbs were more likely to be engaged in a weight loss program for at least 6 months. Patients in the Lost >10 lbs and Lost 5-10 lbs groups reported the greatest satisfaction with Canagliflozin (p<0.05 for both). Multivariable analyses controlling for patient demographic and treatment characteristics revealed that losing >10 lbs was associated with reduced diabetes distress, improved A1c and blood glucose levels, and decreased perceived frequency of hyperglycemia (p<0.05). CONCLUSION: Increased positive patient outcomes, engagement in diabetes self-management, and medication satisfaction were observed among patients who reported weight loss. These findings suggest that a T2DM regimen that includes Canagliflozin as part of a weight loss regimen can help improve patient outcomes and experiences with T2DM.

Evaluating the costs of glycemic response with canagliflozin versus dapagliflozin and empagliflozin as add-on to metformin in patients with type 2 diabetes mellitus in the United Arab Emirates.[Pubmed:28323512]

Curr Med Res Opin. 2017 Jun;33(6):1155-1163.

OBJECTIVE: This study evaluates the cost of achieving glycemic control with three sodium glucose co-transporter 2 (SGLT2) inhibitors, Canagliflozin, dapagliflozin, and empagliflozin, in patients with type 2 diabetes mellitus (T2DM) from the payer perspective in the United Arab Emirates (UAE). METHODS: A systematic literature review identified randomized controlled trials of antihyperglycemic agents as add-on to metformin in patients with T2DM of 26 +/- 4 weeks in duration, published by 10 September 2014. A Bayesian network-meta analysis (NMA) compared HbA1c changes with Canagliflozin 100 and 300 mg versus dapagliflozin 10 mg and empagliflozin 10 and 25 mg. The cost associated with a 1% placebo-adjusted HbA1c reduction with each SGLT2 inhibitor as add-on to metformin was calculated based on NMA results and UAE drug costs. RESULTS: In the NMA, Canagliflozin 100 and 300 mg were associated with HbA1c reductions (-0.67% and -0.79%) compared with dapagliflozin 10 mg (-0.41%) and empagliflozin 10 and 25 mg (-0.57% and -0.64%). Probabilities of Canagliflozin 100 mg performing better were 79%, 60%, and 53% versus dapagliflozin 10 mg and empagliflozin 10 and 25 mg, respectively; probabilities for Canagliflozin 300 mg performing better were 88%, 72%, and 65%, respectively. The cost per 1%-point reduction in HbA1c was projected to be lower with Canagliflozin 100 and 300 mg ($448 and $422) compared with dapagliflozin 10 mg ($785) and empagliflozin 10 and 25 mg ($527 and $563). CONCLUSIONS: Canagliflozin may provide a greater glycemic response at a lower effective cost than dapagliflozin or empagliflozin for patients with T2DM inadequately controlled with metformin from the payer perspective in the UAE.

Canagliflozin (JNJ 28431754) is a selective SGLT2 inhibitor with IC50s of 2 nM, 3.7 nM, and 4.4 nM for mSGLT2, rSGLT2, and hSGLT2 in CHOK cells, respectively.

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