11-Oct-2011

Antidiabetic agent – canagliflozin

Abstract

The need for effective drug treatments for Type II diabetes has never been more important, particularly in the light of the problems experienced by some of the drugs that have reached the market, such as the glitazones.

Canagliflozin

The need for effective drug treatments for Type II diabetes has never been more important, particularly in the light of the problems experienced by some of the drugs that have reached the market, such as the glitazones.

Another mechanism that is being investigated by several companies is to inhibit sodium/glucose co-transporter 2, or SGLT-2. This is involved in the reabsorption of glucose in the kidneys, and thus if it is blocked the result should be more glucose being excreted, resulting in lower blood glucose levels.

One such inhibitor, canagliflozin, is being developed by Johnson & Johnson under licence from Mitsubishi Tanabe Pharma.1 In an ascending single oral dose Phase I trial, 63 healthy subjects were given ascending doses of 10 to 800mg of the drug once a day, 400mg twice a day, or placebo.2 It gave a dose-dependent decrease in the renal threshold for glucose, as well as increasing the amount of glucose excreted in the urine. It also reduced postprandial plasma glucose and serum insulin excursion when given in doses of at least 200mg before breakfast.

Trials in diabetic patients have also taken place. In a double-blind, multiple dose study, for example, 97 patients with Type II diabetes, who had stopped taking antihyper-glycaemic medicines for two weeks previously, were given 30, 100, 200 or 400mg of the drug once a day, 300mg twice a day, or placebo for two weeks, while maintaining an isocaloric diet.3 Urinary glucose excretion increased and the renal threshold for glucose excretion decreased in a dose-dependent manner. Adverse events were mild to moderate and transient. Other trials showed that it improves glycaemic control and lowers body weight in patients taking metformin,4 and improves beta cell function in subjects with Type II diabetes.5

references

1. S. Nomura et al. J. Med. Chem. 2010, 53, 6355

2. S. Sha et al. Diabetes Obes. Metab. 2011, 13, 1463

3. S. Sha et al. Diabetes 2010, 59 (Suppl. 1), Abst. 568-P

4. J. Rosenstock et al. Diabetes 2010, 59 (Suppl. 1), Abst. 77-OR

5. D. Polidori et al. Diabetes 2010, 59 (Suppl. 1), Abst. 646-P

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