Rationale and options for combination therapy in the treatment of Type 2 diabetes

Abstract

Pharmacological therapy for Type 2 (non-insulin-dependent) diabetes mellitus aims at controlling hyperglycaemia to delay or prevent complications associated with the disease. Most patients with Type 2 diabetes present with both stimulated insulin deficiency and insulin resistance. In general, the former can manifest as postprandial hyperglycaemia and the latter as fasting hyperglycaemia, though a definitive association has not been established. Emerging data show a high failure rate of long-term monotherapy and establishes the significance of mealtime glycaemia and the role of postprandial glucose excursions in the development and progression of vascular complications. To overcome such failures of monotherapy and to address the different underlying defects of the pathology of Type 2 diabetes, a combined therapy of oral antidiabetic agents with complementary modes of action should be considered. Currently used oral antidiabetic agents such as sulphonylureas, biguanides (metformin) and the thiazolidinediones (rosiglitazone, pioglitazone) commonly target fasting hyperglycaemia and have limited additive effects on postprandial glycaemia. In contrast, α-glucosidase inhibitors can reduce postprandial hyperglycaemia but gastrointestinal side effects restrict their use. The development of new agents to control postprandial glucose excursions could be considered as an additional objective for the management of Type 2 diabetes. To this end new short-acting enhancers of insulin secretion such as repaglinide (benzoic acid derivative) and nateglinide (amino acid derivative) have been developed. The combination of such agents with other complementary modes of action, e.g. an insulin sensitizer, could target better major underlying defects of Type 2 diabetes and thereby provide a better approach for controlling the entire glycaemic risk. [Diabetologia (2003)

Efficacy of Some Combination Regimens of Oral Hypoglycaemic Agents in Type 2 Diabetes Mellitus Patients

“…Metformin plus gliclazide (63.46 %) was the most commonly prescribed regimen for type 2 DM, consistent with the findings of other studies [6,7]. Indeed, metformin is recommended by International Diabetes Federation as the firstline monotherapy for type 2 DM.…”

Comparison of metformin, gliclazide MR and rosiglitazone in monotherapy and in combination for type 2 diabetes

“…Nevertheless, the most recent consensus statement for the management of type 2 diabetes from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends metformin, due to its greater safety, as the best drug to be used together with lifestyle changes at the beginning of treatment (7). Most patients with type 2 diabetes will eventually require the combination of two or more drugs with different mechanisms of action to achieve an appropriate glycemic control (25)(26)(27). Different regimens have been proposed, but the most commonly used is metformin combined with a sulphonylurea (26,32,33).…”

“…Most patients with type 2 diabetes will eventually require the combination of two or more drugs with different mechanisms of action to achieve an appropriate glycemic control (25)(26)(27). Different regimens have been proposed, but the most commonly used is metformin combined with a sulphonylurea (26,32,33). The rationale for the combination therapy with metformin and rosiglitazone or pioglitazone would be the fact that these drugs, despite being insulin sensitizers, target insulin resistance through different and complementary mechanisms (34,35).…”

“…Indeed, whereas metformin has a stronger effect to suppress hepatic glucose output, TZDs have a stronger effect to increase peripheral glucose disposal (27,34,35). However, this therapy does not directly increase insulin secretion that is impaired in type 2 diabetes (3,26). Conversely, the co-administration of a sulphonylurea with an insulin sensitizer enables both reduction of insulin resistance and stimulation of Mean reduction in total cholesterol (%) 9.6 ± 1. insulin secretion from pancreatic β-cells (5,8).…”

“…For patients who do not take insulin, accumulating evidence suggests that the combination therapy using oral antidiabetic agents with different mechanisms of action may be highly effective in achieving and maintaining target plasma glucose and HbA1c levels (25,26). However, there has been some debate on which combination therapy would be more effective (26,27).…”