Dual SGLT Inhibitor Causes Rapid Drop in Glucose Values

Neil Osterweil

June 29, 2010

June 29, 2010 (Orlando, Florida) — An investigational oral antidiabetic agent — a dual sodium-glucose transporter (SGLT)-2/SGLT-1 inhibitor — showed significant improvement in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and oral glucose tolerance testing (OGTT) levels over 4 weeks in patients with type 2 diabetes, investigators reported here at the American Diabetes Association 70th Scientific Sessions.

In a phase 2a trial of LX4211 (Lexicon Pharmaceuticals) in 36 patients, mean HbA1c levels declined from baseline by 1.5% (P = .036) among patients treated with a 150 mg dose of the drug, and by 1.25% (P = .017) among patients treated with a 300 mg dose, compared with a 0.49% drop for patients treated with placebo, reported Joel Freiman, MD, MPH, medical director of drug safety at Lexicon Pharmaceuticals in Princeton, New Jersey.

The euphoniously named LX4211 is a novel small-molecule inhibitor of SGLT-1 and SGLT-2. It has been reported that the oral drug improves glycemic parameters by reducing glucose transport. LX4211 inhibits glucose reabsorption in the kidneys, leading to glucose loss through urine, and in the small intestine, and possibly stimulating the normal incretin pathway, the investigators write in their late-breaking poster presentation.

Data on a similar agent, dapagliflozin, were also reported at this year's meeting. But LX4211 differs from dapagliflozin in that the latter is a selective inhibitor of SGLT-2, whereas the former is a dual inhibitor, said Dr. Freiman in an interview with Medscape Diabetes.

"We believe that we're hitting both targets — in the kidney perhaps, but we also think we're hitting SGLT-1 in the intestinal tract," he said. "As we expected from the mechanism of action, we got a very robust increase in urinary glucose excretion."

A total of 36 patients were enrolled and randomly assigned, 12 in each group, to receive LX4211 150 mg, LX4211 300 mg, or placebo once daily. All patients had a 14-day washout of metformin, were sequestered for 5 days before dosing started, and remained sequestered for the 4-week treatment period. During the trial, patients were placed on a low glycemic index diet according to body mass index (BMI); patients who had a BMI of 35 kg/m2 or less consumed 2500 calories per day, and those with a BMI above 35 kg/m2 consumed 2800 calories per day.

The patients were evaluated for urinary glucose excretion over 24 hours, HbA1c, FPG, response to OGTT, plasma fructosamine levels, and postprandial glucose elevation.

In addition to the HbA1c changes mentioned earlier, LX4211 at both doses was associated with sustained improvement in FPG values during the study period, with 50% of patients on the drug achieving FPGs below 120 mg/dL, and 33% achieving FPGs below 105 mg/dL. Patients in the placebo group did not achieve either threshold. The active drug groups also had significant decreases in mean glucose area under the curve, compared with the placebo group (< .001 for both doses).

The drug appeared to be well tolerated at both doses, with treatment-emergent adverse events similar in all 3 groups, including headache, constipation, dizziness, nausea, and abdominal pain.

Despite the increased urinary glucose secretion in patients in the LX4211 groups, there were no treatment-related urinary tract or genital infections, the authors reported.

The concept of SGLT-1 and SGLT-2 inhibitors is an intriguing one, but drugs in this category are still "wet behind the ears," and it will take several more years of testing before their true role in diabetes therapy, if any, can be determined, said John Buse, MD, PhD, director of the Diabetes Care Center at the University of North Carolina at Chapel Hill, in an interview with Medscape Diabetes.

"I've always thought that having a very selective agent has advantages and disadvantages, and the only way to find out what they really are would be to have a spectrum of these agents and try to figure out what the optimal combination is," Dr. Buse said.

He noted that the supposed action of LX4211 on SGLT-1 in the gastrointestinal tract could be cause for concern, because unless it is completely and perfectly absorbed proximally, it would have the potential to cause significant gastrointestinal distress.

The study was funded by Lexicon Pharmaceuticals. Dr. Freiman is an employee of the company. Dr. Buse is a consultant to multiple companies, including Bristol-Myers Squibb, the maker of dapagliflozin.

American Diabetes Association (ADA) 70th Scientific Sessions: Abstract 0017-LB. Presented June 28, 2010.

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