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      Emerging treatments in type 2 diabetes: focus on canagliflozin

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          Abstract

          Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder, which affects more than 300 million people globally. The common effect of uncontrolled diabetes is the state of hyperglycemia, which results from beta-cell dysfunction as well as insulin resistance, which is accompanied with microvascular and macrovascular complications. As hyperglycemia defines diabetes, glycemic control is fundamental to the management of diabetes. Sodium glucose co-transporter 2 inhibitors (SGLT2) are a new group of oral antidiabetic medications that act by blocking the reabsorption of glucose, causing it to be excreted in the urine. Canagliflozin was the first SGLT2 inhibitor to be approved in the US by the Food and Drug Administration for the treatment and control of T2DM and on September 19, 2013, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Invokana ®. Canagliflozin is a SGLT2 inhibitor, which acts upon the proximal tubules of the kidneys and reduces the renal threshold for glucose. It is highly selective, binding 250 times more potently to SGLT2 than sodium glucose co-transporter 1 inhibitor. This action allows a higher amount of glucose to be excreted within the urine, causing the patient’s plasma glucose level to be decreased and indirectly causing weight loss. Among the most common adverse events are hypoglycemia, headache, nausea, female genital and urinary tract infections, nasopharyngitis, and transient postural dizziness. Given its high efficacy in reducing hyperglycemia and good safety profile as either monotherapy or an add-on treatment to metformin, sulfonylureas, or insulin, canagliflozin seems to be a promising antihyperglycemic drug. Nevertheless, further large-scale and long-term studies should be conducted to evaluate the impact of canagliflozin on cardiovascular risk in T2DM patients.

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          Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease

           J-F Yale,  G Bakris,  B Cariou (2013)
          Aims Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in subjects with T2DM and stage 3 chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m2]. Methods In this randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 269) received canagliflozin 100 or 300 mg or placebo daily. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Prespecified secondary endpoints were change in fasting plasma glucose (FPG) and proportion of subjects reaching HbA1c <7.0%. Safety was assessed based on adverse event (AE) reports; renal safety parameters (e.g. eGFR, blood urea nitrogen and albumin/creatinine ratio) were also evaluated. Results Both canagliflozin 100 and 300 mg reduced HbA1c from baseline compared with placebo at week 26 (–0.33, –0.44 and –0.03%; p < 0.05). Numerical reductions in FPG and higher proportions of subjects reaching HbA1c < 7.0% were observed with canagliflozin 100 and 300 mg versus placebo (27.3, 32.6 and 17.2%). Overall AE rates were similar for canagliflozin 100 and 300 mg and placebo (78.9, 74.2 and 74.4%). Slightly higher rates of urinary tract infections and AEs related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with other groups. Transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin. Conclusion Canagliflozin improved glycaemic control and was generally well tolerated in subjects with T2DM and Stage 3 CKD.
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            Dose-Ranging Effects of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-On to Metformin in Subjects With Type 2 Diabetes

            OBJECTIVE To evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy. RESEARCH DESIGN AND METHODS This was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed. RESULTS Canagliflozin was associated with significant reductions in A1C from baseline (7.6–8.0%) to week 12: −0.79, −0.76, −0.70, −0.92, and −0.95% for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus −0.22% for placebo (all P < 0.001) and −0.74% for sitagliptin. FPG was reduced by −16 to −27 mg/dL, and body weight was reduced by −2.3 to −3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non–dose-dependent increase in symptomatic genital infections with canagliflozin (3–8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3–9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low. CONCLUSIONS Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females.
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              Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin.

              Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that is being investigated for the treatment of type 2 diabetes mellitus (T2DM). This was a randomized, double-blind, placebo-controlled, parallel-group, 28-day study conducted at two sites, in 29 subjects with T2DM not optimally controlled on insulin and up to one oral antihyperglycaemic agent. Subjects were treated with canagliflozin 100 mg QD or 300 mg twice daily (BID) or placebo. Safety, tolerability, pharmacokinetic characteristics and pharmacodynamic effects of canagliflozin were examined. Glucose malabsorption following a 75-g oral glucose challenge was also examined. Canagliflozin pharmacokinetics were dose-dependent, and the elimination half-life ranged from 12 to 15 h. After 28 days, the renal threshold for glucose excretion was reduced; urinary glucose excretion was increased; and A1C, fasting plasma glucose and body weight decreased in subjects administered canagliflozin (A1C reductions: 0.19% with placebo, 0.73% with 100 mg QD, 0.92% with 300 mg BID; body weight changes: 0.03 kg increase with placebo, 0.73 kg reduction with 100 mg QD, 1.19 kg reduction with 300 mg BID). Glucose malabsorption was not observed with canagliflozin treatment. There were no deaths, serious adverse events or severe hypoglycaemic episodes. The incidence of adverse events was similar across groups. There were no clinically meaningful changes in routine laboratory safety tests, vital signs or electrocardiograms. In subjects receiving insulin and oral antihyperglycaemic therapy, canagliflozin was well tolerated without evidence for glucose malabsorption, had pharmacokinetic characteristics consistent with once-daily dosing, and improved glycaemic control. © 2012 Blackwell Publishing Ltd.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2014
                21 August 2014
                : 10
                : 683-689
                Affiliations
                [1 ]Department of Cardiology and Hypertension, Central Clinical Hospital, the Ministry of the Interior, Warsaw, Poland
                [2 ]Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Poland
                [3 ]Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
                Author notes
                Correspondence: Dariusz A Kosior, Department of Cardiology and Hypertension, Central Clinical Hospital, the Ministry of the Interior, 137 Woloska Street, Warsaw, Poland, Tel +48 508 16 70, Email: s.iadariusz@ 123456upcpoczta.pl
                Article
                tcrm-10-683
                10.2147/TCRM.S39145
                4149387
                25187722
                © 2014 Rosiak et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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