Adding Glargine Insulin or a TZD Enhances Glycemic Control

But Important Metabolic/Cardiovascular Differences Found

When a patient with type 2 diabetes cannot achieve glycemic control despite maximally effective doses of metformin (Glucophage) and a sulfonylurea, the 2 most common next steps are adding a third oral agent, in the form of a thiazolidinedione (TZD), or adding long-acting insulin at bedtime.

Diabetes Care.

Although both strategies have been shown to be effective, the reasons for their success have remained obscure. A new study has now illuminated the respective mechanisms involved, which may also explain some of the other differences seen with these 2 agents ( 2006; 29: 2371-2377).

The benefits of bedtime glargine insulin and the TZD rosiglitazone (Avandia) were investigated in 20 adult patients (8 men, 12 women; mean age, 47 years; mean body mass index, 31 kg/m2) with type 2 diabetes. All patients were taking maximally effective doses of a sulfonylurea—glyburide (DiaBeta, Micronase) ≥20 mg/day or glipizide (Glucotrol) ≥20 mg/day—and metformin (≥2000 mg/day) but still had poorly controlled diabetes, which was defined as hemoglobin (Hb) A_1c levels ≥9%.

In this 4-month study, the patients were randomized to either rosiglitazone 4 mg/day, or to glargine insulin at an average bedtime dose of 17 units/day by the end of the study.

Comparing baseline measurements with those taken after 4 months of triple therapy showed similar reductions in HbA_1c levels and fasting plasma glucose (FPG) concentrations in both groups (Table).

Despite the similarity in glucose control, several clinically important differences were found between the 2 add-on therapies. Use of rosiglitazone resulted in added benefits of reduced diastolic blood pressure (BP) and elevated high-density lipoprotein cholesterol (HDL-C) levels, but also with negative effects of elevated total and low-density lipoprotein cholesterol (LDL-C) levels. And although glargine insulin did not affect BP, HDL-C, or triglyceride levels, it did significantly reduce total and LDL-C levels.

These additional benefits and adverse events may reflect the different mechanism of action by which each of these agents operates.

The similar reductions in HbA_1c and FPG levels with rosiglitazone and glargine insulin were primarily the result of decreased endogenous glucose production, which is achieved differently by each agent.

“Rosiglitazone produced these changes by enhancing hepatic and peripheral tissue (muscle) sensitivity to insulin, while the glucose-lowering action of glargine insulin was related to suppression of hepatic glucose production by nocturnal hyperinsulinemia,” the authors write.

These different mechanisms may also explain the difference in the other metabolic and cardiovascular effects associated with these 2 agents. But although the choice of add-on therapy may come down to which other beneficial metabolic and cardiovascular effects are needed, the authors caution that “at present, it is not possible to assign a weighting value to the beneficial effects of glargine versus rosiglitazone on plasma lipid levels and blood pressure.”

They conclude that either intervention would be a reasonable option in patients with poorly controlled disease despite dual oral therapy.