Abstract and Introduction
In patients with Type 2 diabetes mellitus (T2DM), adequate glycemic control is a critical factor in reducing long-term micro- and macro-vascular complications. Traditionally, the approach is to initiate monotherapy first, followed by combination therapy that targets two main defects in T2DM. Repaglinide, a rapidly acting insulin secretagog, stimulates insulin secretion via closure of ATP-dependent potassium channels on the cell membrane of β-cells. Repaglinide is ideally used at mealtime to reduce postprandial glucose levels, thus lowering the 24-h blood glucose profile and improving HbA1c levels. Metformin is an insulin sensitizer that effectively acts against insulin resistance, one of the predominant metabolic defects in T2DM. A combination of repaglinide and metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. When monotherapy with oral antidiabetic agents fails, combination therapy with repaglinide plus metformin has been demonstrated to be safe and effective in the treatment of T2DM.
Type 2 diabetes mellitus (T2DM) is a complex progressive disorder characterized by impaired insulin sensitivity, reduced insulin secretion and progressive failure of β-cells. Early in the disease, the physiological rise in plasma insulin levels immediately following a meal is attenuated and the time to peak is delayed. This initial surge in insulin is important for effective postprandial suppression of hepatic glucose production. Failure to suppress endogenous glucose production exacerbates postprandial hyperglycemia, which, when not controlled, can worsen insulin resistance and further impair insulin secretory capacity.
Postprandial hyperglycemia is associated with increased production of free radicals, leading to oxidative stress and endothelial dysfunction. Epidemiological reports have shown that the effect of postprandial hyperglycemia on cardiovascular risk is greater than the effect of fasting hyperglycemia. Thus, effective treatment of postprandial hyperglycemia remains a therapeutic goal to potentially reduce long-term macrovascular complications.
Recent guidelines recommend tight glycemic control and intensifying or changing therapy when proposed targets are not met.[4–6] The American Diabetes Association (ADA) advocates treatment goals for glycemic control as HbA1c less than 7%, fasting plasma glucose (FPG) 70–130 mg/dl (3.9–7.2 mmol/l), and postprandial glucose (PPG) under 180 mg/dl (<10 mmol/l). The most recent guidelines published by the American Association of Clinical Endocrinologists (AACE) recommend a lower PPG treatment goal of less than 140 mg/dl (<7.8 mmol/l). Less than half of all Americans with diabetes have achieved the ADA's recommended HbA1c levels, and only a third have achieved the HbA1c goal of 6.5% or less jointly recommended by AACE and the American College of Endocrinology (ACE). Interestingly, it has been demonstrated that a progressive shift in the respective contributions of fasting and postprandial hyperglycemia to overall glycemic control occurs at different levels of hyperglycemia. The contribution of postprandial glucose hyperglycemia is predominant in patients who suffers from moderate diabetes, whereas the contribution of fasting hyperglycemia increases with diabetes worsening.
A proactive approach is required in the management of T2DM beginning at the time of diagnosis. The UK Prospective Diabetes Study (UKPDS) successfully demonstrated the benefits of intensified glycemic control on microvascular complications. These results demonstrated that a 1% reduction in HbA1c was associated with a 21% reduction in diabetes-related deaths, a 14% reduction in myocardial infarction and a 21% reduction in diabetes-related end points. In order to reduce vascular complications, a multifactorial approach including diet, exercise and drug therapy is recommended, as validated by the Steno-2 study.
Expert Rev Endocrinol Metab. 2010;5(3):331-342. © 2010 Expert Reviews Ltd.
Cite this: Combination Therapy for Patients with Type 2 Diabetes: Repaglinide in Combination with Metformin - Medscape - May 01, 2010.