Highlights of the American Diabetes Association 52nd Annual Advanced Postgraduate Course

New York, New York, February 4-6, 2005

Zachary T. Bloomgarden, MD


June 14, 2005

In This Article

Oral Agent Combination Therapy

At the General Session of the 2005 American Diabetes Association Postgraduate Course addressing "New Approaches to Diabetes Treatment," Janet McGill, MD, Washington University School of Medicine, St. Louis, Missouri, discussed approaches to oral agent combination therapy.[1] She pointed out that "expenditures for medications are a very small part of total diabetes care," with oral agents not only far less costly than inpatient care but also less costly than insulin with associated supplies. She noted the American Diabetes Association and American Association of Clinical Endocrinologists respective A1C goals of 7.0 and 6.5, pointing out that A1C 6.3 vs 7.3 may be predicted to decrease the time to onset of retinopathy by 15 years and to reduce nephropathy risk by 40%, so we should "go as low as we can with acceptable risk."

In epidemiologic studies, at fasting blood glucose ~110 "we begin to see retinopathy," she stated. The United Kingdom Prospective Diabetes Study (UKPDS) epidemiologic analysis showed no evidence of a "lower limit," while there is "a [ cardiovascular disease risk] plateau after we reach an A1C of 8 to 9."[2] These considerations suggest that therapeutic approaches that will allow maintenance of near euglycemia are optimal. However, only a minority of patients have A1C at target. The problem with monotherapy in the UKPDS fashion is that there is progressive deterioration in control, largely because of worsening beta-cell function.

Current trends are to use combination approaches ("goal-oriented approach") rather than a variety of different individual agents followed by the addition of insulin and then the adoption of a complex insulin regimen over decades, as had been previously recommended. Monotherapy with either a sulfonylurea or metformin[3] may achieve initial glycemic goals but typically will lead to mean A1C well above target levels over time. Combination oral agent treatment, Dr. McGill stated, should be initiated before the loss of beta-cell insulin secretory capacity.

Given the 4 different classes of oral agents, based on differing mechanisms of action, there are no drug-drug interactions, and the mechanisms of action are complementary, leading to additive A1C lowering. The availability of combination tablets reduces "pill burden" and cost and, therefore, may be particularly appropriate. When metformin became available, the initial studies addressed combination metformin-glyburide therapy, suggesting "almost a pure additive effect."[4] Another early example of such an approach is seen with the additive effect of acarbose plus tolbutamide.[5] Other approaches that have been shown effective are combinations of sulfonylureas with thiazolidinediones, and the addition of insulin. Thus, even if "individual agents may not have the power to attain tight control," the use of combinations is effective and may actually lead to fewer side effects. Metformin also has the advantage of lessening the weight gain seen with other agents. These approaches to combination therapy have been reviewed by several investigators.[6,7]

"The biggest question," McGill stated, is whether to "use 2 different sensitizers, and, if so, when should we use them?" She described metformin-rosiglitazone combination studies comparing metformin at a dosage increasing from 1 to 2 g daily to the combination of metformin 1 g plus rosiglitazone 8 mg daily, suggesting that the latter approach led to greater reduction in A1C with fewer side effects. Such an approach also reduces postprandial glycemic excursion. Combination sensitizer treatment also has the advantage of reducing the likelihood of hypoglycemia, which is particularly useful for "skittish" patients who have had reactions. There appears to be less weight gain with such an approach (although not leading to the weight loss with metformin) and adherence improves. Furthermore, the availability of multiple fixed-dose combinations allows dosing flexibility.

In a proposed algorithm, one might start with a sensitizer, either a thiazolidinedione or biguanide, reassessing every 3 months and considering the use of both in combination, "and then move to other therapeutic options" such as insulin and sulfonylureas. Given the low hypoglycemia risk with sensitizers and alpha-glucosidase inhibitors, Dr. McGill recommended that this useful approach should be more commonly used, and she suggested the use either of generic immediate-release glipizide or the meglitinides -- nateglinide or repaglinide -- in variable dose based on meal size and exercise in a manner similar to that used with variable prandial insulin dosing. Although complexity may reduce patient compliance in general, in this setting she suggested that it may improve compliance by allowing greater patient flexibility, and noted that, in general, lower doses of individual agents may reduce side effects. Available combinations include metformin plus glipizide, metformin plus glyburide, rosiglitazone plus metformin, and rosiglitazone plus glimepiride. Addressing a question about patients who "run higher A1C," and have higher levels of glycation, Dr. McGill noted that such patients are actually at higher risk, although she suggested that, in general, management should be based on home blood glucose testing.


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