Combination Therapy-Oral Antidiabetic Agents & Injectable Medication

COMBINATION THERAPY—ORAL ANTIDIABETIC AGENTS & INJECTABLE MEDICATION

Combination Therapy in Type 2 Diabetes Mellitus

Failure to maintain a good response to therapy over the long term owing to a progressive decrease in beta-cell mass, reduction in physical activity, decline in lean body mass, or increase in ectopic fat deposition remains a disconcerting problem in the management of type 2 diabetes. Multiple medications may be required to achieve glycemic control. Unless there is a contraindication, medical therapy should be initiated with a biguanide. If clinical failure occurs with metformin monotherapy, a second agent or insulin is added. The second-line drug can be an insulin secret-agogue, Tzd, incretin-based therapy, amylin analog, or a glucosi-dase inhibitor; preference is given to sulfonylureas or insulin because of cost, adverse effects, and safety concerns. Third-line therapy can include metformin, multiple other oral medications, or a noninsulin injectable and metformin and intensified insulin therapy. Recommended fourth-line therapy is intensified insulin management with or without metformin or Tzd.

A. Combination Therapy with GLP-1 Receptor Agonists

Exenatide and liraglutide are approved for use in individuals who fail to achieve desired glycemic control on metformin, sulfonyl-ureas, metformin plus sulfonylureas, or (for liraglutide) metformin plus sulfonylureas and Tzds. Hypoglycemia is a risk when the GLP-1 receptor agonists are used with an insulin secretagogue or with insulin. The doses of the latter drugs should be reduced at the initiation of therapy and subsequently titrated.

B. Combination Therapy with DPP-4 Inhibitors

Sitagliptin, saxagliptin, and linagliptin are approved for use in individuals who fail to achieve desired glycemic control on metformin, sulfonylureas, or Tzds. Hypoglycemia is a risk when the DPP-4 inhibitors are used with an insulin secretagogue or with insulin, and a dosage adjustment of the latter drugs may be required to prevent hypoglycemia.

C. Combination Therapy with Pramlintide

Pramlintide is approved for concurrent mealtime administration in individuals with type 2 diabetes treated with insulin, met-formin, or a sulfonylurea who are unable to achieve their post-prandial glucose targets. Combination therapy results in a significant reduction in early postprandial glucose excursions; mealtime insulin or sulfonylurea doses usually have to be reduced to prevent hypoglycemia.

D. Combination Therapy with Insulin

Bedtime insulin has been suggested as an adjunct to oral anti-diabetic therapy in patients with type 2 diabetes who have not responded to maximal oral therapy. Although not formally FDA approved, clinical practice has evolved to include sulfonylureas, meglitinides, D-phenylalanine derivatives, biguanides, thiazoli-dinediones, α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and bile acid sequestrants given in conjunc-tion with insulin. National and international committee prac-tice guidelines, however, recommend avoiding polypharmacy, especially with more expensive agents, and urge early introduc-tion of insulin when an individual is unable to achieve glycemic targets.Persons unable to achieve glycemic control with bedtime insulin as described generally require full insulin replacement and multiple daily injections of insulin. Insulin secretagogues are redundant when a person is receiving multiple daily insulin injections, but persons with severe insulin resistance may benefit from the addi-tion of metformin. When metformin is added to the regimen of a person already taking insulin, the blood glucose should be closely monitored and the insulin dosage decreased as needed to avoid hypoglycemia.

Combination Therapy in Type 1 Diabetes Mellitus

Insulin secretagogues (sulfonylureas, meglitinides, or D-phenylalanine derivatives), Tzds, metformin, α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or bile acid sequestrants are not approved for use in type 1 diabetes.

Combination Therapy with Pramlintide

Pramlintide is approved for concurrent mealtime administration in individuals with type 1 diabetes who have poor glucose control after eating despite optimal insulin therapy. The addition of pram-lintide leads to a significant reduction in early postprandial glu-cose excursions; mealtime insulin doses usually should be reduced to prevent hypoglycemia.