Addition of Basal Insulin to Oral Antidiabetic Agents: A Goal-Directed Approach to Type 2 Diabetes Therapy

Louis Kuritzky, MD

Disclosures

November 15, 2006

Use of Oral Antidiabetic Agents in Combination With Insulin in Patients With Type 2 Diabetes: Clinical Data

Therapy with either oral agents or insulin alone can be suboptimal for many patients with type 2 diabetes, and there is an abundance of clinical evidence that supports combining insulin with oral agents to improve glycemic control. In the Veterans Affairs Cooperative Study--Diabetes Mellitus, results demonstrated that a single injection of evening NPH insulin in combination with glipizide, as part of an intensive insulin therapy regimen in patients poorly controlled on other pharmacologic therapies, maintained near-normal glycemic control.[55] A meta-analysis of 16 randomized, placebo-controlled studies revealed significant reductions in A1C as well as decreased insulin requirements with insulin plus sulfonylurea therapy vs insulin monotherapy.[56] Data from the United Kingdom Progressive Diabetes Study have provided the most definitive evidence demonstrating the inadequacy of oral agent therapy alone and the eventual requirement for insulin to maintain glycemic control in most patients.[24]

In a 24-week study examining the efficacy of metformin added to insulin therapy in patients with type 2 diabetes uncontrolled on insulin alone, A1C was significantly reduced compared with intensive insulin therapy alone (P < .04). Less weight gain and a decrease in insulin dose were also observed in the insulin-metformin group.[57] Another study, involving patients poorly controlled on sulfonylurea plus insulin therapy, showed that metformin plus once-daily insulin was significantly more effective than insulin plus glyburide, insulin plus glyburide and metformin, or additional insulin (a second injection).[31] The insulin-plus-metformin group also had less symptomatic and biochemical cases of hypoglycemia and did not experience weight gain.[31]

Acarbose was shown to be an effective adjunct therapy in combination with insulin. After 24 weeks of treatment, A1C was reduced by 0.40%, and insulin requirements were substantially lowered in patients in whom acarbose was added to their insulin regimen vs those remaining on insulin monotherapy.[58] A similar trial demonstrated a 0.69% A1C reduction as well as significant reductions in postprandial glucose and triglyceride levels with the addition of acarbose to existing insulin therapy.[59]

Pioglitazone added to insulin regimens, in which patients are not optimally controlled, has also been shown to provide a significant decrease in A1C and FPG vs placebo and has the added benefit of increasing high-density lipoprotein and decreasing triglyceride levels. However, hypoglycemia and edema were more common in patients in whom pioglitazone was added to their existing insulin regimen in this study.[33]

Addition of rosiglitazone to the regimens of patients who are inadequately controlled on insulin monotherapy (A1C approximately 9.0%) has also been demonstrated to be effective in reducing glycemic parameters when compared with placebo.[60] A dose response in lowering A1C over 26 weeks was seen between 4-mg and 8-mg daily doses of rosiglitazone (0.7%, and 1.3%, reductions, respectively; P < .0001 for both compared with placebo). This study and the pioglitazone study discussed above indicate that addition of a thiazolidinedione to insulin monotherapy regimens that are not adequately controlling hyperglycemia can contribute to overall A1C reduction by more than 1% in a dose-dependent manner.

The initiation of basal insulin has demonstrated efficacy for improving glycemic parameters in combination with oral agents. Basal insulin replacement improves not only FPG but also results in improved postprandial glucose. Since postprandial glucose excursions are, effectively, superimposed peaks on basal (interprandial) glucose levels, the efficacy of insulin glargine in lowering basal glucose levels favorably impacts postprandial levels throughout the day.[61] In trials comparing insulin glargine with NPH insulin added to existing oral therapy, both insulins were equally effective in achieving target A1C. However, insulin glargine produced less hypoglycemia and weight gain than NPH insulin.[29,62,63] In a recent study of 371 insulin-naive patients inadequately controlled on a sulfonylurea plus metformin, target A1C ≤ 7.0% was achieved by a significantly larger proportion of patients who received once-daily insulin glargine (plus glimepiride and metformin) relative to patients who received 70% NPH and 30% regular human insulin (with no oral agents) (P = .0003). Similarly, more patients achieved target FPG ≤ 100 mg/dL (5.5 mmol/L) in the insulin glargine treatment group and fewer patients in this group experienced confirmed hypoglycemic events (P = .0001 and P < .0001, respectively).[30]

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