Canagliflozin: Improving diabetes by making urine sweet
ABSTRACTCanagliflozin is the first sodium-glucose cotransport 2 (SGLT2) inhibitor approved in the United States for treating type 2 diabetes mellitus. This drug blocks reabsorption of glucose in the proximal tubule, lowering the renal threshold for glucose and thereby increasing glucose excretion. Its novel mechanism of action is insulin-independent. Trials have demonstrated reductions in fasting glucose and hemoglobin A1c levels, with the added benefit of weight loss. The adverse effects most often reported include genital yeast infections and urinary tract infections. Ongoing trials will further elucidate possible long-term risks of this drug.
KEY POINTS
- Type 2 diabetes is ubiquitous and, despite an abundance of agents, often remains uncontrolled.
- Canagliflozin and other drugs of its class cause glucose to be spilled in the urine by reducing the amount reabsorbed by the kidney.
- In clinical trials, canagliflozin lowered hemoglobin A1c levels by approximately 1 absolute percentage point.
- Beyond the adverse effects to be expected from the mechanism of action of the drug (ie, genital yeast infections, urinary tract infections, and hypotension caused by osmotic diuresis), canagliflozin seems to increase plasma levels of low-density lipoprotein cholesterol. This may be worrisome, as diabetic patients are already at increased risk of cardiovascular disease.
WHO IS A CANDIDATE FOR THIS DRUG?
Canagliflozin is approved for use as monotherapy in addition to lifestyle modifications. It is also approved for use with other antihyperglycemic drugs, including metformin.
Obese patients with type 2 diabetes and normal kidney function may have the greatest benefit. Because of canagliflozin’s insulinin-dependent mechanism of action, patients with both early and late type 2 diabetes may benefit from its ability to lower hemoglobin A1c and blood glucose.14
Although it can be used in patients with moderate (but not severe) kidney disease, canagliflozin does not appear to be as effective in these patients, who had higher rates of adverse effects.11 It is not indicated for patients with type 1 diabetes, type 2 diabetes with ketonuria, or end-stage renal disease (estimated glomerular filtration rate < 45 mL/min or receiving dialysis).11 It also is not yet recommended for use in pregnant women or patients under age 18.
The recommended starting dose of canagliflozin is 100 mg once daily, taken with breakfast. This can be increased to 300 mg once daily if tolerated. However, patients with an estimated glomerular filtration rate of 45 to 60 mL/min should not exceed the 100- mg dose. No dose adjustment is required in patients with mild to moderate hepatic impairment. It is not recommended, however, in patients with severe hepatic impairment.11
Comment. Although canagliflozin is approved as monotherapy, metformin remains my choice for first-line oral therapy. Because canagliflozin is more expensive and its long-term affects are still relatively unknown, I prefer to use it as an adjunct, and believe it will be a useful addition, especially in obese patients who are seeking to lose weight.
WHAT IS THE COST OF THIS DRUG?
The suggested price is $10.53 per tablet (AmerisourceBergen), which is comparable to that of other newer drugs for type 2 diabetes.
THE BOTTOM LINE
The availability of canagliflozin as an additional oral antihyperglycemic option may prove helpful in managing patients with type 2 diabetes who experience adverse effects with other antihyperglycemic drugs.
As with any new drug, questions remain about the long-term risks of canagliflozin. However, it seems to be well tolerated, especially in patients with normal kidney function, and poses a low risk of hypoglycemia. The slight increase in LDL-C may prompt more aggressive lipid management. Whether blood pressure-lowering and weight loss will offset this increase in LDL-C is yet to be determined. Ongoing studies will help to further elucidate whether there is an increased risk of cardiovascular events.
Finally, canagliflozin distinguishes itself from other oral diabetes drugs by its added benefit of weight loss, an appealing side effect, especially in the growing population of obese individuals with type 2 diabetes mellitus.
