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Adding Insulin “Before” Sulfonylurea Inadequacy

Within 6 years patients with Type 2 diabetes will require another medication after starting on sulfonylurea.  Then why don’t we add small doses of insulin prior to need?  Should we be chasing elevated blood sugars or should be treating to prevent them? New Page 1 Adding Insulin “Before” Sulfonylurea Inadequacy
Within 6 years patients with Type 2 diabetes will require another medication after starting on sulfonylurea. Then why don’t we add small doses of insulin prior to need? Should we be chasing elevated blood sugars or should be treating to prevent them?
OBJECTIVE—To evaluate the efficacy of the addition of insulin when maximal sulfonylurea therapy is inadequate in individuals with type 2 diabetes.

RESEARCH DESIGN AND METHODS—Glycemic control, hypoglycemia, and body weight were monitored over 6 years in 826 patients with newly diagnosed type 2 diabetes in 8 of 23 U.K. Prospective Diabetes Study (UKPDS) 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.

RESULTS—Over 6 years, 53% of patients allocated to treatment with sulfonylurea required additional insulin therapy. Median HbA1c in the sulfonylurea ± insulin group was significantly lower (6.6%, interquartile range [IQR] 6.0–7.6) than in the group taking insulin alone (7.1%, IQR 6.2–8.0; P = 0.0066), and significantly more patients in the sulfonylurea ± insulin group had an HbA1c <7% (47 vs. 35%, respectively; P = 0.011). Weight gain was similar in the intensive therapy groups, but major hypoglycemia occurred less frequently over all in the sulfonylurea (± insulin) group compared with the insulin alone group (1.6 vs. 3.2% per annum, respectively; P = 0.017).

CONCLUSIONS—Early addition of insulin when maximal sulfonylurea therapy is inadequate can significantly improve glycemic control without promoting increased hypoglycemia or weight gain.

Comments: The addition of a basal insulin supplement when sulfonylurea monotherapy fails is now well established (11), but the introduction of insulin at the much earlier stage of sulfonylurea inadequacy (5) has not been evaluated in a long-term study. This report of the Glucose Study 2 component of the UKPDS shows that glycemic control can be significantly improved in patients with FPG levels >6.0 mmol/l (108mg/dl) despite maximal sulfonylurea therapy without promoting increased hypoglycemia or weight gain.

The further reduction in HbA1c by 0.5%, as seen with SI compared with insulin alone, is beneficial, considering that the UKPDS (1) confirmed that improved glycemic control significantly reduced the risk of diabetes-related complications. The epidemiological analysis of UKPDS data (12) suggests that an 0.5% decrement in HbA1c might equate to a 11.5% reduction in risk for diabetes-related complications.

The progressive nature of the hyperglycemia seen in type 2 diabetes (3) is exemplified by the evidence herein that 53% of patients with newly diagnosed diabetes treated with sulfonylurea therapy require additional treatment within 6 years to maintain FPG levels <6.0 mmol/l. A basal insulin regimen was used in this study because it is highly effective in suppressing basal hepatic glucose production (13,14). The overall improvement seen in glycemic control may reflect increased glucose-mediated release potentiated by the sulfonylureas in the setting of adequate basal insulin implementation. Insulin would seem to be the natural replacement therapy to offset the progressive loss of ß-cell function seen in type 2 diabetes (3).

Although there is always a concern that patients taking additional insulin will gain weight, this study indicates that the early combination of sulfonylurea and insulin does not promote weight gain over and above that seen in patients allocated to therapy with insulin alone. The slightly greater weight gain seen with CI compared with GI may be due to fluid retention associated with increased blood pressure (1). Although there may be concern about the incidence of hypoglycemic episodes in patients taking insulin, this study shows that the risk of major hypoglycemic episodes was not increased with the early addition of insulin to sulfonylurea therapy.

The decision to add insulin immediately when sulfonylurea monotherapy is inadequate, rather than alternative oral agents such as -glucosidase inhibitors, biguanides, thiazolidinediones, or meglitinides, cannot be answered by this study because these different combinations were not compared directly. This study suggests, however, that adding insulin to sulfonylurea therapy should be considered a viable alternative to adding other oral agents when maximal doses do not maintain FPG <108 mg/dl (6.0 mmol/l).