Although they increase the amount of blood sugar dumped into the urine, the newest class of diabetes drugs appears to increase endogenous glucose production, two studies found.
Sodium glucose cotransporter 2 (SGLT2) inhibitors increased endogenous glucose and raised levels of the hormone glucagon, which prompts the body to produce glucose, according to the studies in theJournal of Clinical Investigation.
This is "clearly a surprising finding that would be considered a paradoxical response," William Cefalu, MD, of Pennington Biomedical Research Center in Louisiana, said in an accompanying editorial.
Two SGLT2 inhibitors are now available on the U.S. market -- canagliflozin (Invokana)and dapagliflozin (Farxiga).
In one study, Ralph DeFronzo, MD, of the University of Texas Health Sciences Center in San Antonio, and colleagues performed a euglycemic hyperinsulinemic clamp on 18 men with diabetes who were given either dapagliflozin or placebo for 2 weeks.
They found that the drug did what it's supposed to do -- increase renal glucose excretion in the urine and lower fasting plasma glucose.
But it also substantially increased endogenous glucose production, which was accompanied by an increase in glucagon levels, although these levels didn't change in patients on placebo.
The increase in endogenous glucose production offset about half the amount of blood sugar dumped into the urine by inhibiting SGLT2, they reported.
"If the increase in endogenous glucose production would have been prevented," they wrote, "the decrease in fasting plasma glucose caused by dapagliflozin would have been approximately double."
Ele Ferrannini, MD, of the University of Pisa in Italy, and colleagues made similar observations in their study of 66 patients with type 2 diabetes who were given empagliflozin(25 mg) for 4 weeks.
They had mixed-meal testing with a double tracer technique at baseline, after a single first dose of the drug, and then after 28 days of daily therapy.
By the end of the study, the researchers found that the drug was also effective at excreting blood glucose through the urine, but, as with dapagliflozin, both endogenous glucose production and glucagon levels were increased.
They wrote that the rise in endogenous glucose production exactly balanced the glucose lost through the urine, suggesting the glycosuria "results in a compensatory increase in endogenous glucose release ... as a consequence of lower glucose and insulin levels and higher glucagon levels."
In the editorial, Cefalu said it "would be expected that SGLT2 inhibition would decrease endogenous glucose production."
"The observation that neither dapagliflozin nor empagliflozin reduced endogenous glucose production despite the lowering of blood glucose is clearly a surprising finding that would be considered a paradoxical response," he wrote.
He noted that if the findings are replicated, clinicians may want to use SGLT2 inhibitors together with incretin therapies, which have effects on glucagon and could attenuate the increase in endogenous glucose production, although further metabolic studies are needed.
Graham
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