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Canagliflozin as a Monotherapy in Type 2 Diabetes

Is the SGLT-2 inhibitor best used along with metformin, or is canagliflozin as a monotherapy a good choice?

Type 2 diabetes mellitus is a chronic disease that develops as a result of defective insulin secretion and is frequently associated with obesity-related insulin resistance. Type 2 diabetes is progressively decreased beta cell function over time. Glucose lowering agents are regularly implemented to manage hyperglycemia when lifestyle modifications are not enough. In individuals with hyperglycemia, plasma glucose levels can be lowered by inhibiting sodium glucose co-transporter 2 (SGLT-2). The kidney plays an important role in glucose homeostasis, in large part through reabsorption of filtered glucose at the proximal tubule. Majority of renal glucose reabsorption is mediated by SGLT-2. Canagliflozin is an SGLT-2 inhibitor which lowers the renal threshold for glucose, thereby promoting urinary glucose excretion (UGE). Increased UGE with SGLT-2 inhibition is associated with a mild osmotic diuresis and a loss of calories leading to body weight reduction. Canagliflozin improved glycemic control, reduced body weight and systolic blood pressure.  It was generally well tolerated in a broad range of patients with type 2 diabetes inadequately controlled by their current regimens. It also activates AMP- activated protein kinase (AMPK), which signals a pathway similar to metformin mechanism.

The aim of this study is to evaluate the pharmacodynamics effects and safety /tolerability of single and multiple ascending oral doses of canagliflozin in patients with type 2 diabetes mellitus. A randomized double blind placebo controlled, single and multiple ascending dose was conducted in the United States, Germany and South Korea. Eligible patients were men, postmenopausal or surgically sterile women from 25 to 65 years with BMI between 20 to 40 kg/m2. Patients meeting criteria were assigned to cohorts according to randomization (4:1) within each cohort.  They received canagliflozin or placebo and patients were admitted from day 3 to day 20. Patients received placebo after an overnight fast and canagliflozin increment doses of 30,100, 200 or 400 mg QD or 300 mg twice daily BID. Various doses were given at specific times and they were discharged on day 20 for subsequent safety assessment on day 21 and 22. ANCOVA model is the statistical analyses used.

116 patients were randomized to canagliflozin (n=93) and placebo (n=23). Canagliflozin treatment produced dose dependent increases in UGE on both day 1 and day 16 as compared to placebo. The effect of canagliflozin on 24-hour UGE observed on Day 1 was sustained after the last dose of canagliflozin. Doses of ≥200 mg near maximal suppression of renal threshold for reduction (RTG) was sustained throughout the 24 hour dosing period. 100 mg dose of canagliflozin provided also provided near maximal reduction in RTG for the first 13 hours after dosing with a modest waning of the effect in the overnight period, for the 100 mg dose on day 16. 30 mg however provided submaximal reductions in RTG. Canagliflozin was generally well tolerated with no clinically notable imbalances among treatment; no hypoglycemia was reported.

Another post hoc was done to analyze the effects of canagliflozin on HbA1c by baseline HbA1c and known duration of type 2 diabetes mellitus. Data was pooled from patients with type 2 diabetes enrolled in four 26 week placebo controlled phase 3 studies of canagliflozin (N=2313). Change in HbA1c from baseline to week 26 was assessed in the overall population and in subgroups by baseline HbA1c and known duration of type 2 diabetes. Statistical analysis used is the ANCOVA model. Canagliflozin 100 and 300 mg provided greater HbA1c reduction as compared to the placebo. Both canagliflozin doses were generally well tolerated across subgroups with a safety and tolerability profile consistent with that seen in phase 3 studies. The limitation of this study was that that there was no pre-specified statistical testing across subgroups based on baseline HbA1c and known duration of type 2 diabetes. Yet another study led by Professor Grahame Hardie showed that canagliflozin also activates AMPK, and therefore it is not necessary to use it as add on therapy to metformin since both act through AMPK mechanism.

In conclusion, it was shown that treatment with canagliflozin at doses ≥ 100mg QD for 2 weeks was associated with increased UGE and a decreased RTG. Also it is not necessary to combine canagliflozin to metformin since they both act through the same mechanism of action.

Practice Pearls:                                                                           

  • Canagliflozin is an SGLT-2 inhibitor developed for the treatment of adults with type 2 diabetes which lowers the renal threshold for glucose, thereby promoting urinary glucose excretion.
  • Canagliflozin is well tolerated and treatment showed an improvement in glycemic control and reductions in body weight.
  • It is not really necessary to combine canagliflozin with metformin since they both act through the same AMPK mechanism

 

References:

The PLOS ONE Staff. “Correction: Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes.” PLoS ONE 9.9 (2014): e110069. PMC. Web. 12 July 2016.

Wilding John P.H et al. “Efficacy and safety of canagliflozin by baseline HbA1c and known duration of type 2 diabetes mellitus.” Diabetes and its complications 29 (2015). Web. 12 July 2016.

Hardie Grahame et al. “Effectiveness in treating type 2 diabetes”. Medical press. July 6 2016. Web 12 July.