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Canagliflozin bests sitagliptin for type 2 diabetes.


CHICAGO -- Canagliflozin outperformed sitagliptin for the treatment of patients with type 2 diabetes in the first randomized head-to-head comparison of drugs representing the two different classes of oral antidiabetic medications.

Canagliflozin (Invokana) was approved by the Food and Drug Administration in March as the first in a new class of medications for type 2 diabetes known as sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 is responsible for most glucose reabsorption in the kidney, so inhibition boosts urinary glucose excretion.

In a phase III, double-blind, 52-week clinical trial, canagliflozin improved glycemic control, lowered body weight, and reduced blood pressure to a significantly greater extent than did sitagliptin (Januvia), a dipeptidyl peptidase-4 (DPP-4) inhibitor, Dr. Fernando Lavalle Gonzalez reported at the annual scientific sessions of the American Diabetes Association.

The multicenter four-armed study included 1,020 type 2 patients with diabetes who had inadequate glycemic control on metformin monotherapy. They were randomized to canagliflozin at 100 or 300 mg/day, sitagliptin at 100 mg/day, or 26 weeks of placebo followed by 26 weeks on sitagliptin at 100 mg/day. All participants continued on metformin.

Reductions in fasting plasma glucose at 52 weeks averaged 26.2 mg/dL in the lower-dose canagliflozin group and 35.2 mg/dL in the higher-dose group, both significantly greater than the 17.7-mg/dL decrease in patients on sitagliptin.

In addition to the better outcomes seen with canagliflozin in terms of the major efficacy endpoints involving glycemic control, weight loss, and blood pressure, the SGLT2 inhibitor resulted in a bigger boost in HDL cholesterol (see chart). On the downside, both canagliflozin and sitagliptin resulted in modest increases in low-density lipoprotein (LDL), noted Dr. Gonzalez, an endocrinologist at the Autonomous University of Nuevo Leon in Monterrey, Mexico.

Canagliflozin was associated with significantly higher rates of genital mycotic infections in both men and women, as well as more adverse events related to osmotic diuresis, according to Dr. Gonzalez.

He said mechanistic studies have identified two factors as being responsible for the clinically meaningful reductions in blood pressure seen with canagliflozin in this study, which amounted to a mean 3.5-mm Hg decrease in systolic blood pressure at 100 mg/day and a 4.7-mm Hg reduction at 300 mg/day. It appears that about half of the blood pressure reduction is due to the negative salt and water balance, on the order of 750-1,000 cc, occurring in the first 3-4 days of treatment, and the other half is related to the weight loss accompanying canagliflozin therapy.

Session chair Dr. Ralph A. DeFronzo, who is involved in SGLT2 inhibitor research, said a widespread misconception exists that the medications are associated with an increased risk of urinary tract infections.

"It's very commonly stated that this class of drugs is associated with an increase in UTIs [urinary tract infections]. In fact, if you look at the data rather than what's said, this really in my opinion doesn't hold up. You can see it in this study, where there's no significant difference between the groups," said Dr. DeFronzo, director of the diabetes division at the University of Texas Health Science Center, San Antonio.

Dr. DeFronzo reported serving on advisory panels for Janssen, which markets canagliflozin, as well as for Amylin Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk, and Takeda. Dr. Gonzalez is on speakers bureaus and advisory panels for Janssen and numerous other companies.
Key outcomes in year long, head-to-head trial

                  Canagliflozin  Canagliflozin  Sitagliptin
                         100 mg         300 mg       100 mg

Decrease in           -26 mg/dL      -35 mg/dL    -18 mg/dL
fasting plasma

Reduction in             -0.73%         -0.88%       -0.73%

Weight loss               -3.8%          -4.2%        -1.3%

Increase in HDL       4.5 mg/dL      5.5 mg/dL    2.4 mg/dL

Increase in LDL       4.3 mg/dL      4.4 mg/dL    3.1 mg/dL

Incidence of               7.9%           4.9%         6.3%

Genital mycotic           11.3%           9.9%         2.6%

Genital mycotic            5.2%           2.4%         1.2%
infections, men

Documented               6.8% *           6.8%       4.1% *

Osmotic                    8.2%           4.4%         1.9%
adverse events

* One severe episode in each arm

Notes: Study involved 1,020 patients with type 2 diabetes.
Placebo/sitagliptin efficacy results were folded into sitagliptin
100-mg arm for convenience because they were closely similar.

Source: Dr. Gonzalez

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Title Annotation:ENDOCRINOLOGY
Author:Jancin, Bruce
Publication:Internal Medicine News
Date:Jul 1, 2013
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