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New SGLT-2 Class of Diabetes Drug May Have Paradoxical Effect

Feb 6, 2014
But SGLT-2 inhibitors still yield net reduction in plasma glucose, A1C, and weight….
A new class of drugs for type 2 diabetic patients known as sodium-glucose cotransporter 2 (SGLT-2) inhibitors are the latest thing used to reduce plasma glucose levels in the body. The SLGT-2 protein is responsible for about 90% of glucose reabsorption in the kidney. Therefore, inhibiting this protein causes the glucose to be eliminated in the urine. Two such drugs are available in the United States named Invokana (canagliflozin) and Farxiga (dapagliflozin).

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Despite this remarkable drug class, two studies have been conducted recently that have reported that although there is an overall decrease in fasting plasma glucose, there is an actual increase in endogenous glucose production following the SGLT-2 inhibition. One such study looked at 18 diabetic subjects and placed 12 in the dapagliflozin group and 8 in a placebo group. Each group took the medication or placebo for 2 weeks. Their glucose was measured using a euglycemic insulin clamp. The results showed that those in the dapagliflozin group had an increased renal glucose excretion while also having a lower fasting plasma glucose – something that is supposed to happen when taking a SGLT-2 drug. But they also found out that they had an increase in glucagon levels as well as an increased endogenous glucose production. Those in the placebo group did not have this phenomenon occur. The second study yielded similar results with a different SGLT-2 drug current in trial: empagliflozin. Although glucose was being excreted through the urine, subjects saw an increase in glucagon levels and endogenous glucose.
In conclusion, although it would be expected that SGLT-2 inhibition would decrease endogenous glucose production, it seems to do the opposite. Also, although overall fasting blood glucose levels decrease, it could decrease by almost double if the endogenous glucose production were not to occur. Even though there was a small increase in glucagon production, it still showed a considerable reduction in A1c and weight loss.
Practice Pearls:
  • SGLT-2 inhibitors actually increase glucagon levels and therefore increase endogenous glucose production.
  • This was a small study group of 38 patients
  • There is an overall decrease in fasting plasma glucose despite the increased endogenous glucose production.