SGLT2 Inhibitors Boost Metformin, Can Be Used Even in Late-Stage Diabetes
By Daniel J. DeNoon
WebMD Health News
Reviewed By Louise Chang, MD
June 25, 2010 – A new class of diabetes drug lowers blood sugar -- and weight -- by increasing the amount of sugar released in the urine.
Now the first of these so-called SGLT2 inhibitors has been tested in a phase III clinical trial. It's dapagliflozin, being jointly developed by Bristol-Myers Squibb and AstraZeneca.
Study leader Clifford J. Bailey, PhD, is professor of clinical science at Aston University in Birmingham, England. "It works through an entirely different mechanism than any other diabetes drugs currently available," Bailey tells WebMD. "And you can add it on to other treatments and get an additional benefit. Plus as far as we can see, it can be used at any stage in the disease process."
And that's not all. Because dapagliflozin makes the body excrete excess sugar, it makes diabetes patients lose weight. Metformin helps patients lose weight, too, but those adding dapagliflozin to metformin lost about 4 and 1/2 more pounds than those taking metformin alone in the 24-week study.
The lost weight was not just water. Patients taking dapagliflozin had smaller waistlines, so the lost weight appears to have been fat.
Might this new diabetes drug work as a weight loss pill? No, says Bailey.
"The weight loss effect of the drug becomes less and less as the blood-sugar level comes to near normal," he notes. "Therefore the weight loss potential of this drug is very small at normal blood-sugar levels."
Weight loss isn't dapagliflozin's only extra benefit. It lowers blood pressure, too. Another plus is that the oral medication is taken only once a day. And the drug does not lower blood sugar to dangerously low levels -- yet another plus.
On the down side, patients taking dapagliflozin had an increased risk of genital infections. People with diabetes already are at higher risk of genital and urinary infections. Dapagliflozin may increase this risk.
And because the drug changes the way the body excretes fluid, there may be as-yet-unseen long-term consequences, suggests Luigi F. Meneghini, MD, MBA, director of the University of Miami's diabetes treatment center. Meneghini was not involved in the Bailey study.
"If you have more sugar in your urinary tract, you have more risk of infection. This probably has to do with people with diabetes and high blood sugar having more fungal infections," Meneghini tells WebMD. "That said, if your doctor is careful in monitoring for you infections and treating them when they occur, this is still a drug with a relatively low side-effect profile. But we need to see data on lots more people exposed to the drug for a longer time."
The Bailey study enrolled patients whose blood sugar was not adequately controlled by metformin alone. Their blood sugar was too high but not wildly out of control.
Bailey and Meneghini suggest that patients with very high blood sugar would get a much larger effect from dapagliflozin. Indeed, study patients with the highest blood-sugar levels did get the largest effect, Bailey says.
Dapagliflozin works by inhibiting a molecule called SGLT2,- the sodium-glucose co-transporter. This molecule, found mainly in tubules of the kidney, makes the body reabsorb sugar that would otherwise be excreted in urine.
Dapagliflozin isn't the only experimental SGLT2 inhibitor in late-stage clinical trials. Johnson & Johnson is developing canagliflozin. If all goes according to plan -- a big "if" in the world of drug development -- canagliflozin will be submitted for FDA approval in 2012, says Johnson & Johnson spokesman Ernie Knewitz.
The Bailey study appears in the June 26 issue of The Lancet.
Bailey, C.J. The Lancet, June 26, 2010; vol 375: p: 2223-2233.
Hanefeld, M. and Forst, T. The Lancet, June 26, 2010; vol 375: pp 2196-2198.
Ernie Knewitz, head of communications, cardiovascular division, Johnson & Johnson.
Luigi F. Meneghini, MD, MBA, director, diabetes treatment center, University of Miami Miller School of Medicine.
Clifford J. Bailey, PhD, professor of clinical science, Aston University, Birmingham, England.
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