Canagliflozin: Improving diabetes by making urine sweet

CANAGLIFLOZIN: PHARMACOKINETICS AND THERAPEUTIC EFFICACY

Canagliflozin reaches its peak plasma concentration within 1 to 2 hours of oral administration.¹¹ Its half-life is 10.6 hours with a 100-mg dose and 13.1 hours with a 300-mg dose. A steady state is typically achieved in 4 to 5 days.¹¹

Canagliflozin lowers fasting plasma glucose and hemoglobin A_1c levels in a dose-dependent manner.^10,11 These effects are independent of age, sex, body mass index, and race.¹² Postprandial glucose levels are also lowered.

Other potential benefits of canagliflozin include lowering of the systolic blood pressure and, especially important in obese people with type 2 diabetes, weight loss.¹² Aside from metformin, which occasionally results in modest weight loss, other oral drugs used in treating type 2 diabetes are weight-neutral or can cause weight gain.

Trials of canagliflozin

Nine phase III trials of canagliflozin have enrolled 10,285 patients, in one of the largest clinical trial programs in type 2 diabetes to date.¹⁰ Several of these trials evaluated canagliflozin as monotherapy, whereas others assessed its effect as an add-on therapy in combination with another antihyperglycemic agent such as a sulfonylurea, metformin, pioglitazone, or insulin. There has not yet been a trial directly comparing canagliflozin with metformin.

Four of the placebo-controlled trials evaluated canagliflozin as monotherapy, canagliflozin added to metformin alone, canagliflozin added to metformin plus glimepiride, and canagliflozin added to metformin plus pioglitazone.

When canagliflozin was used as monotherapy, hemoglobin A_1c levels at 26 weeks were an absolute 0.91% lower in the canagliflozin 100 mg/day group than in the placebo group, and an absolute 1.16% lower in the canagliflozin 300 mg/day group than in the placebo group (P < .001 for both).¹² Patients lost 2.8% of their body weight with canagliflozin 100 mg and 3.3% with canagliflozin 300 mg, compared with 0.6% with placebo. Systolic blood pressure fell by a mean of 3.7 mm Hg with the 100-mg dose and by a mean of 5.4 mm Hg with the 300-mg dose compared with placebo (P < .001 for both dose groups).¹²

When canagliflozin was added to metformin, with glimepiride as the comparator drug, there was a 5.2% weight reduction with the 100-mg dose, a 5.7% reduction with 300 mg, and a 1% gain with glimepiride. Hemoglobin A_1c fell about equally in the three groups.¹¹

When canagliflozin was added to metformin and a sulfonylurea, with sitagliptin as the comparator third drug, the 300-mg canagliflozin dosage group had a 2.8% weight reduction.¹¹

WHAT ARE THE ADVERSE EFFECTS?

Overall, canagliflozin seems to be well tolerated. The most common adverse effects reported in the clinical trials were genital yeast infections, urinary tract infections, and increased urination.

Genital yeast infections were more common in women than in men, occurring in 10.4% of women who received canagliflozin 100 mg and in 11.4% of women who received 300 mg, compared with only 3.2% in the placebo group.¹¹

Urinary tract infections occurred in 5.9% of the 100-mg group and in 4.3% of the 300-mg group, compared with 4.0% of the placebo group.¹¹

Postural hypotension. Lowering of blood pressure and symptoms of postural hypotension were also reported, and these may be attributed to the drug’s mild osmotic diuretic effect. The risk of adverse effects of volume depletion was dose-dependent; in patients over age 75, they occurred in 4.9% of those taking 100 mg and in 8.7% of those taking 300 mg, compared with 2.6% of those in the placebo or active-comparator groups.¹¹ Therefore, one should exercise particular caution when starting this drug in the elderly or in patients taking diuretics or multiple antihypertensive drugs.

Hypoglycemia. When canagliflozin was used as monotherapy, the incidence of hypoglycemia over 26 weeks was similar to that with placebo, occurring in 3.6% of the 100-mg group, 3.0% of the 300-mg group, and 2.6% of the placebo group.¹² Canagliflozin was associated with fewer episodes of hypoglycemia than were sulfonylureas, and the number of episodes was similar to that in patients taking gliptins. There was a higher overall incidence of hypoglycemia when canagliflozin was used in combination with a sulfonylurea or with insulin than when it was used as monotherapy.¹¹

Hyperkalemia. Patients with moderate renal impairment or who are on potassiumsparing drugs or drugs that interfere with the renin-angiotensin-aldosterone system may be at higher risk of hyperkalemia, so close monitoring of potassium is recommended. There was also a dose-dependent increase in serum phosphate and magnesium levels, more notably in patients with moderate renal impairment within the first 3 weeks of starting the drug.¹¹

Patients on canagliflozin who are also taking digoxin, ritonavir, phenytoin, phenobarbital, or rifampin should be closely monitored because of the risk of drug-drug interactions.¹¹ Specifically, there was an increase in mean peak digoxin concentrations when used with canagliflozin 300 mg, and the use of phenytoin, phenobarbital, and ritonavir decreased the efficacy of canagliflozin.

WHAT ARE THE CARDIOVASCULAR RISKS OR LONG-TERM CONCERNS?

Dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) may be seen with canagliflozin. Mean changes from baseline compared with placebo were 4.4 mg/dL (4.5%) with canagliflozin 100 mg and 8.3 mg/dL (8%) with canagliflozin 300 mg.¹¹

There was also an increase in non-high-density lipoprotein cholesterol (non-HDL-C).¹² Compared with placebo, mean non-HDL-C levels rose by 2.1 mg/dL (1.5%) with canagliflozin 100 mg and 5.1 mg/dL (3.6%) with 300 mg.¹¹

In the 26-week canagliflozin monotherapy trial, archived blood samples in a small subgroup of patients (n = 349) were measured for apolipoprotein-B, which was found to increase by 1.2% with canagliflozin 100 mg and 3.5% with canagliflozin 300 mg, compared with 0.9% in the placebo group.¹²

Although small, the increase in LDL-C seen with this drug could be a concern, as diabetic patients are already at higher risk of cardiovascular events. The mechanism of this increase is not yet known, though it may be related to metabolic changes from urinary glucose excretion.¹²

The Canagliflozin Cardiovascular Assessment Study (CANVAS) is a randomized placebo-controlled trial in more than 4,000 patients with type 2 diabetes who have a history of or are at high risk of cardiovascular events. Currently under way, it is evaluating the occurrence of major adverse cardiovascular events (the primary end point) in patients randomized to receive canagliflozin 100 mg, canagliflozin 300 mg, or placebo once daily for up to 4 years. Secondary end points will be the drug’s effects on fasting plasma insulin and glucose, progression of albuminuria, body weight, blood pressure, HDL-C, LDL-C, bone mineral density, markers of bone turnover, and body composition.¹⁰ This trial will run for 9 years, to be completed in 2018.¹³

The CANVAS investigators have already reported that within the first month of treatment, 13 patients taking canagliflozin suffered a major cardiovascular event, including stroke (one of which was fatal) compared with just one patient taking placebo. These events were not seen after the first month. The hazard ratio for major adverse cardiovascular events within the first 30 days was 6.49, but this dropped to 0.89 after the first 30 days.¹⁰

Additional issues that should be addressed in long-term postmarketing studies include possible relationships with cancers and pancreatitis and the safety of the drug in pregnancy and in children with diabetes.¹⁰