The benefits of intensive glycemic control in patients with type 2 diabetes have focused greater attention on the use of various combinations of insulin and oral antidiabetic drugs (Table 3). Such combinations not only utilize complementary mechanisms of action but also lower doses of both insulin and oral agents, thereby minimizing the risk of adverse effects and enhancing compliance. Combination therapy is indicated for patients who cannot maintain glycemic goals with monotherapy.
| Table 3 Combinations of Oral Agents and Insulin for the Management of Type 2 Diabetes | ||
| Expected Decrease | ||
| Combination | FPG (mg/dL) | HbA1c (%) |
| Sulfonylureas + insulinMetformin + insulin | 60 to 8060 to 80
0 to 16 110 |
0.5 to 1.81.7 to 2.5
0.4 to 0.5 2.2 |
| *Approved for use by the U.S. Food and Drug Administration | ||
The combination of a sulfonylurea and insulin has been studied extensively in type 2 diabetes patients. A recent meta-analysis of 15 studies that evaluated combinations of glyburide or glibenclamide with exogenous insulin demonstrated unequivocally that combination therapy significantly lowered both fasting serum glucose (FSG) (p<0.01) and HbA1c (p<0.025), and that metabolic control was achieved with significantly smaller daily doses of insulin (p<0.01) and little change in body weight. Combination therapy also enhanced endogenous insulin secretion, as evidenced by significant increases in fasting serum C-peptide concentrations (p<0.05).
Numerous studies have also demonstrated the benefits of combinations of other oral agents with insulin. For example, a 6-month placebo-controlled study in 50 obese patients with type 2 diabetes poorly controlled by insulin treatment found that the addition of metformin (850 mg/day) improved glycemic control substantially. The reduction in HbA1c levels in the insulin/metformin group was significant, decreasing from 11.6% to 9.8% (p<0.05), and the daily insulin requirement was reduced by about 25%, from 90 U to 68 U (p<0.05).
The combination of acarbose and insulin appears to be less effective than a sulfonylurea/insulin combination at restoring glycemic control. In a 1-year study, 354 patients with type 2 diabetes currently on diet therapy alone (n=77), metformin (n=83), a sulfonylurea (n=103), or insulin (n=91) were assigned to treatment with either acarbose or placebo, in addition to their current regimen. The addition of acarbose to the insulin regimen produced a small and insignificant decrease in HbA1c of 0.4% (p=0.077), and no significant change in FPG was observed.
Thiazolidinediones have been found to improve glycemic control when added to an existing insulin regimen. Addition of pioglitazone 15 mg/dL once daily to an existing insulin regimen for 16 weeks was associated with significant reductions in HbA1c of 0.7% and 1.0%, respectively, and FBG of 35 mg/dL and 49 mg/dL, respectively, when compared with an insulin/placebo regimen (p0.05). Similarly, 26 weeks of treatment with a combination of rosiglitazone 2 mg or 4 mg twice daily and insulin resulted in significant reductions from baseline values for HbA1c of 0.6% and 1.2%, respectively (p<0.006). Rosiglitazone/insulin combinations also were associated with a reduction in daily insulin dose of 5 U with the 2-mg dose and 9 U with 4-mg dose. Pioglitazone is FDA approved for combination treatment with insulin.