ADA 2010: Will DPP-4 inhibitors replace sulfonylureas? Debaters make their case

June 30, 2010

Although their ability to control glycemia is essentially the same, do other merits of dipeptidyl peptidase 4 (DPP-4) inhibitors favor their replacing sulfonylureas in the treatment armamentarium for type 2 diabetes? Michael Nauck, MD, and David Matthews, FRCP, were on opposing sides of this issue.

Although their ability to control glycemia is essentially the same, do other merits of dipeptidyl peptidase 4 (DPP-4) inhibitors favor their replacing sulfonylureas in the treatment armamentarium for type 2 diabetes? Michael Nauck, MD, and David Matthews, FRCP, were on opposing sides of this issue.

Nauck, head of the Diabetes Centre, Diabeteszentrum Bad Lauterberg, Germany, made the case that the mode of action of sulfonylureas-no glucose dependence of insulinotropic effects-is dangerous, then supported this argument with clinical data from 4 studies in which DPP-4 inhibitors were compared with sulfonylureas. In each study, there was no difference between the drug classes in reduction of glycated hemoglobin levels. However, body-weight changes consistently favored the DPP-4 inhibitors, and superior effects on lipid profiles were observed in patients treated with DPP-4 inhibitors relative to those treated with sulfonylureas.

Rates of hypoglycemia are also lower with DPP-4 inhibitors, Nauck said, and recovery of hypoglycemia is delayed with sulfonylureas. “I am not as concerned about hypoglycemia as I am about severe hypoglycemia,” he said, and on this endpoint, DPP-4 inhibitors are clearly superior. The rate of severe hypoglycemia is up to 1.5% over 2 years with sulfonylureas but is extremely rare with DPP-4 inhibitors, he said.

“I am most concerned about hospitalization . . . and deaths due to severe hypoglycemia,” said Nauck, and again sulfonylureas show a “lethality” of 5.7%, which is the combined rate of hospitalizations and deaths caused by severe hypoglycemia. He calculated that 80 excess deaths occur per year in the United States because of sulfonylurea treatment.

Going back to the 4 comparator trials between DPP-4 inhibitors and sulfonylureas, in the 2 trials in which cardiovascular events were reported, the rate was nearly half with the DPP-4 inhibitors, said Nauck.

Matthews, professor of diabetes medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism in England, did not argue that either treatment is better than the other but that, for practical reasons, DPP-4 inhibitors would not replace sulfonylureas but would rather complement them, as sulfonylureas are a proven and safe therapy.

“I am not saying that sulfonylureas are better than DPP-4 inhibitors. What I am saying is that there is no information about DPP-4 inhibitors as related to glycemic outcomes,” Matthews said.

In contrast, clinical trial evidence is abundant with sulfonylureas. In the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, intensive blood glucose control using gliclazide modified release resulted in a 14% relative risk reduction in major microvascular events compared with a conventional strategy. In the United Kingdom Prospective Diabetes Study (UKPDS), intensive blood glucose control with insulin and/or a sulfonylurea reduced the incidence of microvascular but not macrovascular complications compared with conventional treatment; however, insulin was the primary treatment in this study, and the use of multiple combination drug regimens in the intensive arm to maintain glycemic separation between the 2 arms preclude making definitive conclusions, Matthews said. Although there were more deaths in the tolbutamide recipients in the University Group Diabetes Program (UGDP), patients in this arm had a frequency of baseline electrocardiographic abnormalities that was 30% higher than the comparator arms.

Hypoglycemia is not a true side effect of sulfonylureas, said Matthews, but rather too “much of the effect,” and the lesson to be learned is to use caution in dosing, as with many drugs. Part of the weight gain that occurs with sulfonylureas may be the result of the body defending against hypoglycemia, added Matthews, Finally, he said, cost is always a consideration in treatment, and sulfonylureas offer an inexpensive and safe therapy for a disease that is a worldwide pandemic.