Combination Therapy for Patients with Type 2 Diabetes: Repaglinide in Combination with Metformin

Robert G Moses


Expert Rev Endocrinol Metab. 2010;5(3):331-342. 

In This Article

Rationale for Combination Therapy

After diet and lifestyle modification, monotherapy may assist patients in achieving a target of HbA1c less than 7%. However, with disease progression, in most instances, monotherapy loses efficacy over time as evidenced by a continued increase in HbA1c. For example, in patients with high mean baseline HbA1c of 8.2–8.4%, glycemic control was reached by only 25% of patients treated with metformin monotherapy.[8,12] Additionally, 3 years in to the UKPDS study, half of the patients required combination therapy, and by 9 years, 75% of the patients needed combination therapy.[13] Combination therapy with established medications is frequently used when adequate glycemic control has not been achieved with monotherapy.[10,14,15]

In addition to insulin resistance, β-cell dysfunction plays a key role in the progression of T2DM. As demonstrated by the UKPDS, patients with T2DM had only 60% of their predicted β-cell function as measured by the homeostatic model assessment (HOMA); furthermore, the β-cell function deteriorated to 25% after 6 years.[16] Therefore, the primary objective of combining oral antidiabetic treatments for T2DM is to address the dual problems of insulin deficiency and insulin resistance.

Combination therapy with two therapeutic agents that target both insulin resistance and defects in insulin secretion has been shown to be helpful in establishing glycemic control and lowering HbA1c levels by an additional 0.5–1.0%.[17] In addition, the chosen regimen, should ideally exert a physiologically rapid prandial insulin response to maintain tight glycemic control with minimal side effects such as hypoglycemia and weight gain. It is also important for the combination therapy to be at least additive and possibly synergistic in their mechanisms of action. Some of the therapies that are currently being used include an insulin sensitizer (metformin) combined with an insulin secretagog (a sulfonylurea or meglitinide) or two insulin sensitizer agents with different mechanisms such as metformin and a thiazolidinedione ( Table 1 ).[18,19]


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