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Type 2 diabetes is a progressive and prevalent chronic disease characterized by hyperglycemia and associated with metabolic abnormalities that result in chronic complications such as retinopathy, nephropathy, neuropathy and cardiovascular disorders.1 According to the CDC, diabetes (Type 1 and 2) affects 25.8 million people, or 8.3% of the U.S. population and the estimated total direct and indirect costs of diabetes for the U.S. healthcare system is 174 billion dollars.2 Due to the immense prevalence and financial burden of Type 2 diabetes, as well as the progressive nature of the disease, there are several classes of medications available to help control this disease state. A new class to treat diabetes was recently approved and available in the U.S. Canagliflozin (Invokana) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor. It works by helping to control blood glucose levels by inhibiting the SGLT2 in the proximal renal tubules of the kidneys leading to an inhibition of glucose reabsorption and increased glucosuria.3

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Stenlöf and colleagues conducted a 26-week, randomized, double blind, placebo-controlled phase 3 trial to examine the effects of canagliflozin in subjects with Type 2 diabetes not controlled with diet and exercise. Subjects included in the study were 18–80 years of age who were either not on an antihyperglycemic agent (AHA) with a hemoglobin A1c (A1c) 7-10% or on AHA monotherapy (except PPARγ agonists) or metformin plus sulfonylurea therapy (at ≤ 50% of maximum or near maximum effective doses) with an A1c 6.5-9.5%. Those on AHA therapy underwent an 8 week washout period and were eligible if after 6 weeks their A1c was 7-10% and fasting plasma glucose (FPG) < 270mg/dL. Individuals with an A1c between 10.1-12% were included in a high glycemic sub-study. Exclusion of subjects occurred if they had repeated FPG >270 mg/dL during the pre-treatment phase (or >349 mg/dL for the high glycemic sub-study); Type 1 diabetes; cardiovascular (CV) disease; eGFR < 50ml/min/1.73 m2; treatment with a PPARγ agonist, insulin, another SGLT2 inhibitor or any other AHA except as specified in the inclusion criteria. Patients were randomly assigned to canagliflozin 100mg, canagliflozin 300mg or placebo daily (1:1:1). Subjects in the sub-study received either canagliflozin 100 or 300mg daily (1:1). The primary efficacy endpoint for both study groups was the change in A1c from baseline to week 26. Secondary endpoints for both study groups included: proportion of subjects reaching A1c < 7%; changes from baseline in systolic blood pressure (BP); and percent changes from baseline in body weight, high-density lipoprotein cholesterol (HDL-C) and triglycerides.4

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A total of 587 subjects were randomized to the main study and 91 subjects were randomized to the sub-study. Over the 26 weeks, both canagliflozin 100 and 300 mg resulted in significant reductions in A1c (p < 0.001) and FPG (p < 0.001) compared to placebo. For canagliflozin 100mg, 44.5% met the A1c goal of <7% and 62.4% on 300mg met the A1c goal (p<0.001 compared to placebo). Individuals receiving canagliflozin also saw reductions in weight (p < 0.001) and systolic BP (p < 0.001), and increases in HDL-C (p < 0.001 for canagliflozin 100mg and p < 0.01 for 300mg). Significant decreases in A1c and FPG were seen in the high glycemic sub-study subjects for both canagliflozin groups. The overall adverse effects (AEs) experienced were slightly higher in both canagliflozin groups with urinary tract infections and genital mycotic infections being the leading AEs.4

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The results of the study demonstrate that canagliflozin is another effective option for the management of Type 2 diabetes. Given the heterogeneous nature of the disease, treatment should be patient specific and individualized.5 While this study demonstrates that canagliflozin may be a viable first-line treatment option, it should not replace other first line agents, particularly metformin that has been shown to reduce mortality in Type 2 diabetics.6,7 It would be helpful for further studies to examine the role of the SGLT2 inhibitors in reduced renal function, as add-on therapy later in the course of diabetes and on long-term microvascular and cardiovascular outcomes. Until more trials or post-market analyses are performed, this agent should be used as an add-on therapy to achieve glycemic control or as a first-line agent when all other options have been exhausted.

1. Triplitt CL, Reasner CA. Diabetes mellitus. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM eds. ...

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