When to Advance From Oral Agents to Insulin

AADE Program Session
Thursday, August 12, 2004
2:00 PM – 3:30 PM

The decision to treat diabetes with insulin must reflect the entire scope of the disease. Diabetes involves abnormalities of insulin secretion and use, glucose production, and β-cell function. Many traditional therapies do not treat the whole disease process, but it is important to do so. The pathogenesis of type 2 diabetes begins clinically with an increase in insulin resistance. The body overproduces insulin to compensate for this resistance, and insulin-producing pancreatic β cells become overworked. The pancreas may be viewed as an “innocent bystander” of the pathology. Adiposity plays an important role in the development of diabetes. Adipocytes reach the point where they cannot continue to store fat, and they release free fatty acids (FFAs). Insulin prevents some of this release of FFAs, but as insulin production declines, more FFAs are allowed to circulate. FFAs deposit in the liver, in muscle, and in β-cell islets. When too much fat accumulates, β cells die from lipotoxicity, and muscles use fat instead of glucose, further contributing to the metabolic imbalance. This complicated inter-relationship affects drug therapy choices. Thiazolidinediones (TZDs) help adipocytes retain FFAs and decrease the amount of fat in muscle and the liver. Metformin treats the liver, and secretagogues help with β-cell function. The answer for achieving A1C control would seem to be combination therapy.

Therapeutic goals for A1C levels set by the ADA, ACE, and EASD are <7%, <6.5%, and <6.5%, respectively. However, the ADA offers the option of trying to reach a normal A1C, which is <6%, and the formal recommendation in Canada is <6%. The traditional treatment algorithm calls for a secretagogue, then an initiation of bedtime insulin. A new proposed algorithm proposes a more disease-oriented approach: start with ½ to ¼  of the maximum dosage of 2 or 3 agents. Next, increase the secretagogue and/or biguanide to ½ the maximum effective dose. Increase all medications to at least ½ the maximum dose before adding insulin.

With type 2 diabetes, adding insulin is not an option; it will happen eventually when the patient with diabetes can no longer produce enough insulin to support the body’s exaggerated insulin requirements.. Oral medications must continue when insulin is initiated, because oral medications address different aspects of the disease. Monitor patients at 3- to 6-month intervals. The basal/bolus insulin regimen mimics natural physiology. The defect in type 2 is that the postprandial insulin peak is not as high and is delayed compared to normal patients. It makes sense, therefore, to begin with basal analogs but carefully monitor postprandial glucose to be alert to any rise. The focus of therapy should be on normalizing A1C levels, and not merely reacting to blood glucose levels, which is the end result of the disease. This focus would require an earlier initiation of insulin therapy than is traditionally implemented.