Insulin Therapy for Type 2 Diabetes: Insulin Analogs

Insulin Analogs: Additional Options

The pharmacokinetic profile of regular human insulin is such that most patients on insulin therapy require multiple daily injections to maintain glycemic control. Regular insulin has an onset of action of 0.5–1 hour after subcutaneous injection, reaches a peak effect in 2–3 hours, and has an effective duration of action of 3–6 hours (Table 4). The semisynthetic insulin analogs currently available have been developed to simulate endogenous insulin secretion more closely, and other agents are in development to provide a peakless pharmacokinetic profile.

The rapid-acting insulin analog lispro was introduced in 1996. After subcutaneous administration, insulin lispro is absorbed more quickly than regular human insulin, having an almost immediate onset of action and reaching peak levels within 1 hour. With its improved absorption profile, insulin lispro can be administered 15 minutes or less prior to a meal, compared to 30–45 minutes with regular insulin. The duration of action of insulin lispro is comparable to that of regular insulin. A meta-analysis of randomized clinical trials comparing human regular insulin and insulin lispro found that insulin lispro was significantly more effective in controlling postprandial glycemia control, without increasing the incidence of hypoglycemic episodes; there were no differences between the two insulin preparations in maintaining basal glycemic control or HbA1c levels. For individuals with type 2 diabetes and sufficient insulin reserve to cover meal-stimulated glucose production, postprandial insulin is relatively less important than basal insulin in maintaining glycemic control. Nonetheless, insulin lispro and other rapid-acting analogs can improve convenience when mealtime therapy is necessary. A new insulin formulation containing lispro and Neutral Protamine Lispro (NPL) in a ratio of 25%/75% was recently compared with human insulin 70/30. Twice daily administration of the new lispro formulation, 75% NPL and 25% lispro, called Humalog Mix 75/25, resulted in improved postprandial glycemic control, comparable overall glycemic control, and the convenience of administration immediately before meals.

Another rapid-acting insulin analog in development is insulin aspart. Clinical studies comparing insulin aspart with regular human insulin have demonstrated that the time-action profile of insulin aspart more closely resembles physiologic postprandial insulin release and improved postprandial glucose control.

The intermediate-acting insulins, neutral protamine Hagedorn (NPH) and lente insulins, have a longer pharmacokinetic profile than regular insulin, with onset of action of 2–4 hours, peak effect after 4–12 hours, and duration of action up to 20 hours. These agents offer one approach to basal insulin therapy for patients with moderate type 2 diabetes; some patients may need additional doses of a short-acting insulin for meal coverage.

Ultralente insulin is the only currently available long-acting insulin. Its onset of action is 6–10 hours, and the timing of a peak effect is dose dependent; the maximal duration of action is 24–30 hours. Long-acting insulin is both useful and convenient for basal insulin therapy. Many patients with type 2 diabetes can maintain glycemic control with only one or two daily injections of ultralente insulin and can manage postprandial excursions with endogenous insulin secretion or doses of short-acting insulin. However, ultralente insulin does not mimic endogenous basal secretion, i.e., continuous insulin release without significant peaks and troughs in serum levels. Long-acting insulin analogs are being developed to better achieve the peakless profile of endogenous insulin secretion.

Insulin glargine (Lantus), approved by the FDA, is a long-acting human insulin analog that can provide an effective basal supply. It is produced by recombinant DNA technology using nonpathogenic E. coli as the production organism. Insulin glargine differs from human insulin in that the amino-acid asparagine at position A-21 has been replaced by glycine, and additionally two arginines are added to the C-terminus of the B chain.

This insulin provides a relatively constant concentration/time profile over 24 hours with no pronounced peak. Insulin glargine is administered as a single injection at bedtime. In clinical trials with both type 1 and type 2 patients, Insulin glargine as a single subcutaneous injection was shown to have similar efficacy and similar rates of hypoglycemia when compared to one and two injections of NPH insulin. Insulin glargine’s potency is approximately the same as human insulin. However, it should be remembered that its duration of action is 24 plus hours. In contrast to other insulins, insulin glargine was shown to have no relevant difference in absorption from the abdominal, deltoid, or thigh after subcutaneous administration.

Insulin glargine can be used in patients with intensive insulin regimens who have type 1 disease, and may be an appropriate first insulin for patients with type 2 disease. Insulin glargine may also be appropriate therapy along with oral agents in patients with type 2 disease.

In summary, compared to human insulin, Basal Insulin Glargine (Lantus) shows clinical benefits that include once-daily dosing because of its prolonged duration of action and smooth, peakless time-action profile; comparable or better glycemic control; lower risk of clinically important hypoglycemic events, and a similar safety profile.

Other long-acting insulin analogs are in earlier stages of development, including a C16 fatty-acid-acylated analog. Researchers are also exploring another approach to basal glycemic control that targets hepatic glucose production, which may be responsible for fasting hyperglycemia in patients with type 2 diabetes. Hepatospecific insulin analogs are being developed that could reduce hepatic glucose production but exert minimal effect on peripheral glucose disposal.