What is the role of combination therapy (insulin plus oral medication) in type 2 diabetes?

Another open-label RCT evaluated 281 patients with at least 3 months of inadequate glycemic control (HbA_1c=7.4%–14.7%) on a sulfonylurea.⁷ Patients were randomized to a) switching to a combination of biphasic insulin aspart 30/70 plus pioglitazone, b) adding pioglitazone to the sulfonylurea, or c) switching to insulin alone (biphasic insulin aspart 30/70). After 18 weeks, insulin plus pioglitazone reduced HbA_1c significantly more than either glyburide plus pioglitazone (P=.005) or insulin alone (P=.005). However, the insulin plus pioglitazone group had the most weight gain (mean 4 kg, similar to other pioglitazone trials). There were no major hypoglycemic events.

Another open-label RCT evaluated 217 patients inadequately controlled (HbA_1c=7.5%–11%) on a 2-drug oral regimen (metformin and a sulfonylurea, each drug dosed at ≥50% of the recommended maximum), randomized to add either insulin glargine or rosiglitazone (Avandia).⁸ Both groups reduced HbA_1c equivalently after 24 weeks (–1.7% for glargine vs –1.5% for rosiglitazone). However, in patients with a baseline HbA_1c >9.5%, adding insulin glargine reduced HbA_1c significantly more than rosiglitazone.

Recommendations from others

A comparative analysis of guidelines on diabetes from 13 different countries (including the US) found general agreement in the recommendation to add a second oral agent to maximum doses of an initial agent in patients with poor glycemic control.⁹ However, no consensus was reached on the value or indications of combination therapy with oral agents and insulin.

The European Diabetes Policy Group recommends adding a second oral agent when the maximum dose of a single agent is reached, and using triple therapy when targets are not reached on maximum tolerated doses of 2 agents. Continued therapy with oral agents is advised when initiating insulin.¹⁰