Adding Insulin Early to Sulfonylurea Therapy is Beneficial

Abstracts & Commentary

Synopsis: Early addition of insulin to maximal sulfonylurea therapy improved glycemic control without promoting hypoglycemia or weight gain.

Sources: Wright A, et al. Diabetes Care. 2002;25:330-336; Riddle MC. Diabetes Care. 2002;25:395-396.

The United Kingdom Prospective Diabetes Study (UKPDS 57) has added much to our knowledge regarding the progression of type 2 diabetes and the importance of tight glucose control. UKPDS 57 was activated when it was realized that progressive hyperglycemia was occurring in all of the patients being studied. It was thought that the addition of insulin to sulfonylurea therapy at the stage of inadequacy rather than sulfonylurea failure might prove to be beneficial.

Glycemic control, hypoglycemia, and body weight were monitored over 6 years in 826 patients with newly diagnosed type 2 diabetes in 8 of the 23 centers that used a modified protocol. Patients were randomly allocated to a conventional glucose control policy, primarily with diet (n = 242) or an intensive policy with insulin alone (n = 245), as in the main study. However, for patients randomized to an intensive policy with sulfonylurea (n = 339), insulin was added automatically if the fasting plasma glucose remained > 108 mg/dL (6.0 mmol/L) despite maximal sulfonylurea doses.

Over 6 years, 53% of patients allocated to treatment with sulfonylurea required additional insulin therapy. Median HbA1c in the sulfonylurea + or - insulin group was significantly lower (6.6%) than in the group taking insulin alone (7.1%), and significantly more patients in the sulfonylurea + or - insulin group had a HbA1c < 7. Weight gain was similar in the intensive therapy groups, but major hypoglycemia occurred less frequently over all in the sulfonylurea + or - insulin group, compared with the insulin alone group (1.6 vs 3.2% Per annum, respectively; P = 0.017).

The study concluded that the early addition of insulin when maximum sulfonylurea therapy is inadequate can significantly improve glycemic control without promoting increased hypoglycemia or weight gain.

Comment by Ralph R. Hall, MD, FACP

The UKPDS trials continue to shape our care of type 2 diabetes. As Riddle notes in his accompanying editorial "one of the main conclusions the UKPDS investigators themselves have drawn from their findings is that combinations of treatments will routinely be needed for type 2 diabetes."

In this report, sulfonylureas plus insulin resulted in an additional reduction in the HbA1c of 0.5%. Using the data from the UKPDS, this degree of reduction translates to an 11.5% decrease in the risk of diabetic complications.1

Riddle also points out that there has been a reluctance in the past to use insulin and sulfonylureas together because of a lack of long-term studies and the "lack of clear physiologic rational" for the use of these 2 agents together.

The weight gain resulting from the combination of the sulfonylurea plus insulin was not statistically greater than the weight gain from the insulin alone. One should note, however, that the weight gain was greater than in the less intensively treated group and the mean gain over the 6-year period was 8.8 lbs. This causes one to wonder what the effects of adding metformin to insulin might be. A previous short-term study found little weight gain over an 8-month period with insulin and metformin and a much lower incidence of hypoglycemia.2

Now that we have 2 long-acting sulfonylureas (glipizide and glimepiride) and a truly long-acting basal insulin (glargine) plus metformin and the thiazolidinediones, the potential for even better control of the blood glucose with less weight gain and hypoglycemia is excellent.


1. UKPDS Group. BMJ. 2000;321:405-412.

2. Aviles-Santa L, et al. Ann Intern Med. 1999;131: 182-189.

Dr. Hall, Emeritus Professor of Medicine, University of Missouri-Kansas City School of Medicine, is Associate Editor of Internal Medicine Alert.