Until just over six years ago, patients with type 2 diabetes were started on treatment with a sulfonylurea. When this treatment failed, insulin was added to or substituted for the sulfonylurea. With only these agents available, achieving the target glycosylated hemoglobin 7 percent was A_1c (HbA_1c) concentration of difficult in many patients. Now it is possible to obtain this target level by using combination oral therapy or combined oral and insulin therapy. The order in which hypoglycemic agents are added has also changed.¹

Before therapy is initiated, I obtain a serum C-peptide level.² If the level is low normal or low, as it is in 10 to 20 percent of patients with type 2 diabetes, I start treatment with a sulfonylurea to increase the release of insulin from pancreatic beta cells.³ In most patients, however, the C-peptide level is high normal or high, indicating hyperinsulinemia, and I start with an insulin sensitizer such as metformin (Glucophage). If not contraindicated, metformin is the preferred insulin sensitizer in obese patients because of its ability to promote weight loss.⁴ However, with evidence accumulating in animal studies that thiazolidinediones rejuvenate the ability of pancreatic beta cells to produce insulin, these drugs may become alternative agents for monotherapy.^5,6

When monotherapy fails, the combination of metformin and a thiazolidinedione, although inferior to the combination of a sulfonylurea and an insulin sensitizer in lowering the HbA_1c concentration, can have beneficial effects on cardiovascular risk factors. Metformin reduces the number of low-density lipoprotein (LDL) cholesterol particles, whereas thiazolidinediones reduce the size of LDL particles, lower triglyceride levels, and increase high-density lipoprotein (HDL) cholesterol levels (particularly the cardioprotective HDL particle). Furthermore, thiazolidinediones reduce C-reactive protein by 30 percent (twice as much as statins), improve endothelial dysfunction, and suppress vascular smooth muscle proliferation and migration.

If a combination of insulin sensitizers fails, a sulfonylurea, the benzoic acid derivative repaglinide (Prandin), or the D-phenylalanine derivative nateglinide (Starlix) can be added. Although the literature contains only two articles on triple oral therapy, my colleague and I have found that this approach is effective in both the short and long term.⁷ Recently, we demonstrated that at 37 months, 76.3 percent of patients remained well controlled on triple therapy (average 6.8 percent) as a HbA1c: result of an elevation of the C-peptide level in this group, which did not occur in patients who failed triple therapy.⁸

When insulin is needed, I usually withdraw the insulin secretagogues and retain one or both insulin sensitizers. However, other physicians favor using insulin secretagogues with insulin. A combination of an oral agent and insulin is especially needed in obese patients with type 2 diabetes because insulin therapy alone usually does not achieve glycemic control in these patients.

Insulin therapy can be started with an injection of intermediate-acting insulin (NPH) or long-acting insulin (insulin glargine [Lantus]) given at bedtime, or with an injection of a 70/30 percent insulin mixture (e.g., Humulin) or a 75/25 percent insulin mixture given at the evening meal. I prefer administration at the evening meal because this meal is usually the largest of the day and occurs at a time when physical activity is negligible in most patients. However, with either evening-meal or bedtime insulin administration, the goal is to reduce the pre-breakfast glucose level (the highest of the day in most patients with type 2 diabetes because of the release of glucose from the liver) to 110 mg per dL (6.1 mmol per L) or lower. It is hoped that oral agents can control the glucose level for the rest of the day.

If a morning injection is needed, premixed insulin is recommended, with retention of one or more insulin sensitizers. On occasion, small doses (4 to 8 units) of a fast-acting insulin (e.g., lispro [Humalog] or insulin aspart [Novolog]) can be used when patients wish to eat a bigger meal or the glucose level is elevated because of stress, infection, or another factor.

Combination oral therapy or combined insulin and oral therapy has become the norm, rather than the exception. Just as different agents are added for a cumulative lowering of blood pressure in patients with essential hypertension, effective treatment of diabetes often requires combination therapy. In patients with type 2 diabetes, each of the agents used in a combination lowers the HbA_1c concentration by 1 to 2 percent (the exception being the alpha-glucosidase inhibitors). If further lowering is needed, another agent acting at a different site is added.⁹ As with hypertension, first-line therapy for type 2 diabetes will continue to change as more efficacious therapies become available.¹