Impact of SGLT2 Inhibitors on Type 2 Diabetics Examined

Two small studies have examined the effects of sodium glucose cotransporter 2 (SGLT2) inhibitors in individuals with type 2 diabetes, with both studies reporting an increase in endogenous glucose production (EGP) and an overall decrease in fasting plasma glucose.

SGLT2 is a protein found in the human body that is responsible for glucose reabsorption. SGLT2 inhibitors are a newer class of type 2 diabetes medications that include canagliflozin and dapagliflozin. They work by enhancing urinary glucose excretion, thereby lowering blood glucose levels.
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“Inhibiting SGLT2 offloads the body of glucose, sodium, calories, and water,” said Ele Ferrannini, MD, University of Pisa School of Medicine, Pisa, Italy. “In the typical patient with type 2 diabetes, who is overweight/obese and hypertensive, there are beneficial effects extending beyond improved glycaemia to better control of blood pressure and body weight.”

Ferrannini led the first study, which included 66 patients with type 2 diabetes. Researchers evaluated the patients at baseline, after a single dose of empagliflozin (25 mg), and after 4 weeks of treatment with empagliflozin (25 mg/day). Empagliflozin is an SGLT2 inhibitor that is currently in Phase III clinical trials.

A mixed meal was offered to the participants at each of the three time points. Dual-tracer glucose administration and indirect calorimetry were also performed at these times.

Ferrannini and colleagues found that both the single dose of empagliflozin and chronic treatment caused glycosuria during fasting and after meals. EGP increased after 3 hours of fasting, while glycemia decreased. Glucose and insulin AUC decreased after meals, while glucagon response increased. In addition, researchers reported that tissue glucose disposal decreased with an accompanying rise in lipid oxidation after chronic empagliflozin administration. Finally, participants experienced an increase in beta-cell glucose sensitivity and improvements in insulin sensitivity.

Essentially, drug-induced glycosuria improved beta-cell function and insulin sensitivity in the participants, “despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia,” the authors wrote.

“Massive glycosuria elicits a physiological adaptation whereby the liver prevents the emptying out of the body glucose pool by augmenting its release of glucose into the bloodstream,” explained Ferrannini. “Changes in plasma glucose concentrations and in the insulin-to-glucagon ratio are among the immediate mechanisms responsible for such adaptation. Longer-term consequences include a shift in substrate utilization from carbohydrate to fat, which is the basis for the ensuing loss of body weight.”

“The results of our study imply that the body has wired-in mechanisms to sense the energy deficit that glycosuria causes (200-300 kcal per day) and is therefore capable of mounting a reaction aimed at maintaining glycaemia and preserving energy stores,” said Ferrannini. “Some of these mechanisms, involving a cross-talk between the kidney, the liver and the brain, are yet to be discovered.”

According to Ferrannini, an unexpected finding was that most of the changes observed after 6 weeks of treatment with empagliflozin were already evident following the administration of the first pill. The improvement in beta-cell function was particularly noteworthy, which suggests that “even a modest relief of hyperglycaemia immediately translates into some recovery of ß-cell competence,” she said.

The second SGLT2 inhibitor study examined whether a reduction of plasma glucose with an SGLT2 inhibitor could improve insulin-mediated tissue glucose disposal in 18 men with type 2 diabetes, who were randomized to receive either dapagliflozin or placebo. Researchers used the euglycemic hyperinsulinemic clamp technique to calculate insulin-mediated whole body glucose uptake and EGP at baseline and at 2 weeks after treatment.

The authors found that the drug induced glucosuria and lowered fasting plasma glucose in the treatment group. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of drug treatment compared with no change in the placebo group. In addition, EGP increased significantly after dapagliflozin treatment while the patients were also experiencing an increase in fasting plasma glucagon concentration, a finding that senior researcher Ralph A. DeFronzo, MD, University of Texas Health Sciences Center, San Antonio, Texas, said was unexpected.

DeFronzo explained that improved glucose tolerance with dapagliflozin resulted in enhanced tissue sensitivity to insulin, increased beta-cell function, and a paradoxical rise in EGP that, in part, offsets the loss of glucose in the urine.

“This study demonstrates the efficacy of the SLGT2 inhibitors and is the first proof in man of the glucotoxicity hypothesis,” he said. “It also demonstrates the existence of a novel renal-hepatic interaction whereby the onset of glucosuria leads to an increase in hepatic glucose production.”

When asked about how he hopes the study findings may eventually impact the care of patients with type 2 diabetes, he stated, “The results indicate that, if the paradoxical rise in endogenous glucose production in response to dapagliflozin can be blocked (ie, with a GLP1 receptor agonist), the efficacy of dapagliflozin can be markedly increased.”

Both studies were published in the Journal of Clinical Investigation. The study by Ferrannini and colleagues was funded by Boehringer Ingelheim. The study by DeFronzo and associates was supported by NIH grant 5R01DK240923, and Bristol-Myers Squibb supplied the drug and placebo. Full disclosure information is available in the articles.

-Meredith Edwards White