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EASD: Weight Loss with SGLT2 Inhibitors but More Infections

Sep 28, 2010

Three possible first in class drugs in the sodium glucose co-transporter (SGLT2 inhibitor) class showed improvements in glycemic control and weight loss, but infections proved troublesome, researchers reported….

Michael Nauck, MD, and colleagues of Diabeteszentrum Bad Lauterberg in Harz, Germany, looked at studies involving three investigational drugs in the sodium glucose co-transporter (SGLT2 inhibitor) class.

In one study, patients saw a similar drop in A1c — a mean 0.52% over a year — whether dapagliflozin or glipizide was added to their metformin regimen that confirmed the noninferiority of the investigational sodium glucose co-transporter (SGLT2 inhibitor). In a news release during the meeting they also announced the results of a study that lasted for a period of over a year conducted by Bristol-Myers and Astra Zeneca.

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Nauck stated that, Dapagliflozin patients also had significantly more weight loss, although they had significantly more genital infections, a common side effect seen in this class of medication.

The new class of SGLT2 inhibitors stalls renal glucose reabsorption, independent of insulin. Researchers also reported data on canagliflozin and a new compound BI 10773.

Nauck and colleagues conducted a randomized controlled trial of diabetic patients whose disease was inadequately controlled. A total of 406 patients received 2.5 mg a day of dapagliflozin and 408 took 5 mg of glipizide once daily. All patients were taking metformin, with the dose titrated over the first 18 weeks to optimize fasting plasma glucose, then continued through the end of 53 weeks.

Besides the similar drop in A1c in both groups, the researchers found that dapagliflozin patients lost a mean of 3.2 kg (7 lbs), compared with a gain of 1.4 kg (3 lbs) in the glipizide patients. The difference was significant at P<0.0001. And significantly more patients lost 5% or more of their body weight with dapagliflozin than with glipizide (33.3% versus 2.5%, P<0.0001).

Dapagliflozin patients also had significantly greater improvements in blood pressure and HDL cholesterol (P<0.0001), the researchers said. Hypoglycemia was more common with glipizide (40.8% versus 3.5%, P<0.0001), and there were slightly more serious adverse events with that drug (11.3% versus 8.6%).

But patients had more urinary tract infections with dapagliflozin (10.8% versus 6.4%) as well as more genital infections, a common side effect with the SGLT2 inhibitor class (12.3% versus 2.7%). The effect was more pronounced in women.

The same side effect was seen in another 24-week trial of dapagliflozin presented at a poster session here by Krzysztof Strojek, MD, of Silesian Medical University in Zabrze, Poland, and colleagues.

Patients who had dapagliflozin added to glimepiride had more genital infections — 3.9%, 6.2%, and 6.6% for those on 2.5 mg, 5 mg, and 10 mg, respectively, compared with 0.7% for those who had placebo added to their regimens.

The dapagliflozin patients were also more likely to develop hypoglycemia (7.1%, 6.9% and 7.9% versus 4.8% of those on placebo).

But the researchers did see dose-dependent reductions in A1c compared with placebo, and greater weight loss for those on the two higher doses of the drug (-1.56 kg and -2.26 kg versus -0.72 kg).

Patients on those doses also had significantly greater improvements in oral glucose tolerance and fasting plasma glucose than those on glimepiride.

Another SGLT2 inhibitor — canagliflozin — also had issues with genital infections compared with sitagliptin, notably one case of posthitis (inflammation of the foreskin) for a patient on the lowest dose of 50 mg.

Troy Sarich, MD, of Johnson & Johnson, and colleagues also investigated the potential of canagliflozin for weight loss in those without diabetes. They assessed 80 obese patients, some of whom had impaired fasting glucose or impaired glucose tolerance, who were randomized to placebo or 30 mg, 100 mg, 300 mg, or 600 mg of canagliflozin daily. Another group took 300 mg twice a day.

After two weeks, patients on all doses of canagliflozin had significant weight loss compared with placebo, except for those on the 300 mg dose. Still, self-reported measures of appetite and satiety didn’t change.

Nor were there any changes in fasting plasma glucose, mean 24-hour glucose, or insulin levels. But those with impaired fasting glucose or impaired glucose tolerance did have a significant reduction in mean 24-hour glucose (P<0.05).

Although genital infections weren’t reported in these patients, they did have more cases of rash (13%) and pruritus (5%) compared with none among placebo patients.

In fact, 42% of those on the highest dose of canagliflozin (600 mg) had a rash and 25% had pruritus.

According to Ele Ferrannini, MD, of the University of Pisa in Italy, and colleagues, for the investigational SGLT2 inhibitor BI 10773, patients had improvements in glycemic control comparable with metformin, but more weight loss after 12 weeks.

In that study, a total of 408 patients were randomized to placebo, metformin or 5 mg, 10 mg, or 25 mg of the investigational agent. The researchers found a significant dose-dependent reduction in fasting plasma glucose and HbA1c compared with placebo across all groups.

Those on the drug also had more weight loss than those on placebo or metformin. They lost a mean 2 kg compared with a gain of 0.75 kg for those on placebo and 1.32 kg for those on metformin.

The rate of genital infections was low — 0.8% of those on the drug had mycosis and 1.2% had pruritus compared with no infections for those on metformin or placebo — but daytime urinary frequency and thirst were higher (3.3% versus 0% for both).

Nauck M, et al “Dapagliflozin vs glipizide in patients with Type 2 diabetes mellitus inadequately controlled on metformin: 52-week results of a double-blind, randomised, controlled trial” EASD 2010; Abstract 241.

Strojek K, et al “Efficacy and safety of dapagliflozin in patients with Type 2 diabetes mellitus and inadequate glycaemic control on glimepiride monotherapy” EASD 2010; Abstract 870.

Sarich T, et al “Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, increases 24-hour urinary glucose excretion and reduces body weight in obese subjects over 2 weeks of treatment” EASD 2010; Abstract 874.

Ferrannini E, et al “The potent and highly selective sodium-glucose co-cransporter (SGLT-2) inhibitor BI 10773 is safe and efficacious as monotherapy in patients with Type 2 diabetes mellitus” EASD 2010; Abstract 877.