Pharmacology Update
Insulin Aspart Injection (NovoLog—Novo Nordisk)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Insulin aspart is a new rapid-onset, short-acting insulin produced with recombinant technology. This new insulin’s activity is the result of replacing proline at position B28 of human insulin with aspartic acid. Insulin aspart joins insulin lispro as rapid onset, short-acting insulin analogs. Insulin aspart will be marketed by Novo Nordisk as NovoLog.
Indications
Insulin aspart is indicated for the treatment of adult patients with diabetes mellitus for the control of hyperglycemia. This insulin should normally be used with an intermediate or long-acting insulin.
Dosage
Insulin aspart is generally given immediately before a meal. In a meal-related treatment regimen, 50-70% of the total daily requirement may be provided by insulin aspart. The remaining is provided with intermediate or long-acting insulin. The meal should be started within 5-10 minutes after injection of insulin aspart.1
Insulin aspart will be supplied as 100 units of insulin per mL (10 mL, 3 mL PenFill cartridges).
Potential Advantages
Postprandial glycemic control may be better with insulin aspart compared to human insulin.3,4 Particularly the positive excursion outside a predefined normal range (4.0-7.0 nmol/L) was significantly better with insulin aspart.3 Rapid-acting insulin permits patients to time their dose with their meals and more closely mimic normal release of insulin in response to food intake. The excursion was 78% that of human insulin with majority of the gain in positive excursion.3 There may be fewer major hypoglycemic episodes with insulin aspart compared to human insulin (20 events in 16 subjects vs 44 events in 24 subjects; P < 0.002).3
Potential Disadvantages
Nighttime glucose levels were higher with insulin aspart than human insulin. Nighttime hyperglycemia tends to persist until morning.
For patients not at risk for hypoglycemia, an adjustment of the evening NPH insulin dose may be needed to restore nighttime glycemic control.3
Antibodies that cross react with human insulin and insulin aspart were higher in patients treated with insulin aspart compared to human insulin. The clinical significance is, however, uncertain.1 The mean total daily doses of insulin in type 1 patients were 1-3 U/d greater with insulin aspart than human insulin and 2 U/d greater for type 2 patients.1
Comments
The substitution of aspartic acid for proline at B28 reduces the insulin molecule’s tendency to form hexamers. The predominate mixture of monomers and dimers rapidly dissociates after injection resulting in increases in the rate of absorption compared to human insulin.1,2,5 Serum insulin concentrations are about twice as high in about one-half the time compared to an equal dose of human insulin. Insulin aspart has a similar pharmacokinetic profile to insulin lispro. The latter is produced by reversing the proline-lysine sequence at positions B28 and B29. These changes result in faster pharmacodynamic action than human insulin but with the same potency on a per unit basis. This permits the patient to inject immediately before meals as well as adjust to the carbohydrate load of the meal. While these insulin analogs appear to improve postprandial hyperglycemia, their overall glycemic control as measured by HbA1c or fructosamine has generally been equivocal.1,3,5,6 However, it appears that if improved glycemic control is to be achieved basal insulin needs to be optimized.5,7
Clinical Implications
Insulin aspart will provide another rapid, short-acting insulin analog. These insulins may be best suited for patients on intensive therapy using multiple injections or patients using insulin pumps.8 It is important that patients adjust their basal insulin dosage and/or the timing of the injections to maximize glycemic control.5,7 As of early September, Novo Nordisk has not announced a launch date for Novolog.
References
1. NovoLog Product Information. Novo Nordisk. June 2000.
2. Simpson KL, Spencer CM. Drugs 1999;57:759-765.
3. Home PD, et al. Diabetes Care 1998;21:1904-1909.
4. Raskin P, et al. Diabetes Care 2000;23:583-588.
5. Bolli GB, et al. Diabetologia 1999;42:1151-1167.
6. Chehade JM, et al. Drugs 2000;60:95-113.
7. Del Sindaco, et al. Diabet Med 1998;15:592-600.
8. Melki V, et al. Diabetes Care 1998;21:977-982.
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