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

Louis Kuritzky, MD

Disclosures

November 15, 2006

Currently Available Insulins

Basal Insulins

Exogenous basal insulin replacement (ie, with NPH, insulin detemir, or insulin glargine) suppresses hepatic gluconeogenesis between meals and overnight. This effect may reduce the insulin resistance associated with type 2 diabetes.[35] Once-daily basal insulin administered at bedtime was initially shown to be effective for achieving glycemic control in small studies of patients with type 2 diabetes who were failing sulfonylurea therapy.[36,37] In a recent large, randomized, multicenter study by Riddle and colleagues,[29] a single bedtime injection of long-acting insulin (insulin glargine or NPH) was given to patients with inadequate glycemic control on 1 or 2 oral agents. Existing oral agents were continued, and the insulin dose was systematically titrated toward a fasting glucose target ≤ 100 mg/dL (5.6 mmol/L) ( Table 3 ). By using this forced-titration algorithm, a majority of patients were able to reach an A1C goal ≤ 7.0% on once-daily basal insulin combined with oral agents. Although the insulin titration regimen used in this clinical trial was successful, some clinicians or their patients were daunted by the suggested increment of as much as 8 U of basal insulin for a fasting glucose > 180 mg/dL (10 mmol/L). An alternate dosing strategy that has been successfully implemented in recent trials is to increase the basal insulin by 2 U every 3 days until FPG ≤ 100 mg/dL (5.5 mmol/L).[38,39]

NPH is the conventional intermediate-acting insulin. NPH has an onset of action of 2-4 hours, peak activity at 4-10 hours, and a duration of action of 10-16 hours.[40] The pattern of peak activity of NPH insulin can lead to a risk of nocturnal hypoglycemia, even if administered at bedtime. Conversely, waning insulin activity in the morning can cause some patients to develop hyperglycemia. The lente insulins are long-acting insulins that have been used effectively for basal insulin coverage for many years in patients with type 1 and type 2 diabetes. These insulin preparations, however, were recently discontinued by the manufacturer.[41]

The development of insulin analogs represents an important advancement in the treatment of diabetes. Insulin analogs are generated by substituting or rearranging the amino acid sequence of human insulin. These alterations lead to changes in the pharmacokinetic/pharmacodynamic properties of the insulin molecule. Insulin glargine is the only long-acting basal insulin analog currently in widespread use in both the United States and Europe, while insulin detemir has recently become available in the United States but was approved for use in Europe in June 2004. Insulin glargine has a steady absorption profile that allows consistent systemic delivery from the site of injection. As a result, insulin glargine provides a sustained metabolic effect over nearly 24 hours without a pronounced peak of activity.[42] In a study comparing the pharmacokinetic/pharmacodynamic profiles of insulin glargine, NPH, and continuous subcutaneous insulin infusion (CSII), insulin glargine demonstrated lower intersubject variability than NPH and appeared to more closely resemble the profile of CSII.[42] The sustained, consistent action of insulin glargine may, in part, be responsible for the lower incidence of nocturnal hypoglycemia and weight gain associated with its use in patients with type 2 diabetes compared with NPH insulin therapy.[4,29,43] Because both NPH and insulin glargine were equally effective in reaching target A1C in the largest trial to date, either is a rational choice. It should be noted, however, that episodes of hypoglycemia in this study were higher with NPH insulin. The lesser expense of NPH makes it preferable for some patients, while less weight gain and hypoglycemia associated with insulin glargine makes it preferable by other patients. A recent study assessed the cost consequence associated with NPH vs insulin glargine in a managed care setting. In this setting, it was found that the savings associated with reduced hypoglycemic events in patients taking insulin glargine more than offset the increased acquisition cost associated with glargine use relative to NPH.[44]

Insulin detemir is also a soluble insulin analog that recently has been approved in the United States.[45,46] As with insulin glargine, the pharmacodynamic profile of insulin detemir is associated with low interpatient variability compared with NPH insulin.[47] This new insulin analog also has a peak in its time-action profile.[48] However, published pharmacodynamic results for insulin detemir show that it is comparable to NPH insulin for blood glucose control and may be associated with a reduced risk of hypoglycemia.[49] Similar to NPH insulin, insulin detemir can be dosed once to twice daily with the majority of patients requiring twice-daily administration to achieve glycemic control.[50] Pharmacokinetic studies that directly compare insulin detemir with insulin glargine will be needed to accurately address any time-action profile similarities or differences between these 2 basal insulin analogs.

Similar to the Treat-To-Target study by Riddle and colleagues, a recent study also used a forced titration algorithm to examine the addition of basal insulin to existing oral agent regimens, but compared insulin detemir with NPH insulin over 26 weeks.[51] This study demonstrated that insulin detemir and NPH insulin similarly reduced A1C but that weight gain and hypoglycemia, including nocturnal hypoglycemia, was significantly reduced with insulin detemir compared with NPH insulin (P < .001).

The efficacy of insulin detemir has been evaluated in patients with type 1 diabetes as well. In a multicenter, randomized study involving 448 patients with type 1 diabetes who received basal insulin detemir and insulin aspart at meals, A1C concentrations were identical (7.6%) after 6 months of treatment with insulin detemir or NPH insulin. Overall, FPG levels were slightly but not significantly lower in patients treated with insulin detemir than in patients who received NPH insulin. Nightly plasma glucose profiles were significantly more stable and smoother in the insulin detemir group than in the NPH insulin group, and early-morning FPG levels were significantly lower in the patients who received insulin detemir than in the patients who received NPH insulin. A comparison of pharmacodynamic profiles suggests a slightly delayed onset of action with insulin detemir compared with NPH insulin. The risks of hypoglycemia and nocturnal hypoglycemia were significantly lower with insulin detemir than with NPH insulin (22% vs 34%), and weight gain was significantly higher in patients receiving NPH insulin.[52]

A similar study also used a forced titration algorithm in examining the addition of basal insulin to existing oral agent regimens, but compared insulin detemir with NPH insulin over 24 weeks. This study demonstrated that insulin detemir and NPH insulin similarly reduced A1C but that weight gain and hypoglycemia, including nocturnal hypoglycemia, were significantly reduced with insulin detemir compared with NPH insulin (P < .001).

Although both insulin glargine and insulin detemir may be useful for basal therapy, there are differences between the two. Insulin detemir is designed to bind to serum albumin. Serum protein binding can be a vital point of interaction between drugs with high intrinsic binding affinity. Displacement of bound drug by a competing substance may significantly increase the free concentration of the drug and potentiate its actions. However, in vitro data have not shown insulin detemir to have interactions with other drugs known to bind to albumin.[53] Clinical trials directly comparing insulin glargine with insulin detemir have not been completed but are currently under way and will provide insight to additional potential differences between these 2 basal insulins.[54]

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