Pharmacology Update

Insulin Glargine Injection (Lantus—Aventis Pharmaceuticals Inc.)

By William T. Elliott, MD, FACP and James Chan, PharmD, PhD

Insulin glargine is a new long-acting insulin produced by recombinant DNA technology. The drug is an analog of human insulin with asparagine replaced by glycine in position A21 and two arginines are added to the C-terminus of the B-chain.1 These changes result in a relatively constant concentration/time profile over 24 hours allowing just one shot a day. The drug is produced using a nonpathogenic strain of Escherichia coli and is manufactured by Hoechst Marion Roussel in Germany. It will be marketed in this country by Aventis under the trade name Lantus.

Indications

Insulin glargine is indicated for once-daily administration at bedtime for the treatment of adults and pediatric patients with type 1 diabetes mellitus or adults with type 2 diabetes mellitus who require basal insulin for the control of hyperglycemia.2

Dosage

Insulin glargine is administered subcutaneously once daily at bedtime. The average starting dose is 10 IU once daily and is adjusted according to need. The range is 2-100 IU.2 Patients switching from once-daily NPH or ultralente insulin may be started at the same dose. Those switching from twice-daily NPH should be initiated at 80% of the total daily dose of NPH insulin to reduce the risk of hypoglycemia.2 There appears to be no significant difference in absorption characteristics from subcutaneous sites using the arm, leg, or abdomen.4

Insulin glargine is supplied at 100 IU per mL in 5 mL, 10 mL, and 3 mL cartridges (for OptiPen).

Potential Advantages

Insulin glargine is slowly released from the subcutaneous injection site resulting in relatively constant, peakless, plasma levels for over 24 hours. This pharmacokinetic profile permits once-daily dosing.1,2,4,5 Nocturnal hypoglycemia (blood glucose < 2 mmol/L) may be lower with insulin glargine compared to NPH insulin as basal-bolus treatment.3,6 In a published, multicenter, randomized, parallel trial in a well controlled type 1 subject, insulin glargine achieved a lower frequency of nocturnal hypoglycemia (18.2% vs 27.1%; P = 0.01).

Potential Disadvantages

Insulin glargine differs from other insulins in isoelectric point; therefore, it cannot be mixed or diluted with other insulins or solutions. Mixing may delay the onset of action.1 Due to its prolonged duration of action, should hypoglycemia occur, recovery will be prolonged.

Comments

The modification of human insulin to insulin glargine shifts the isoelectric point closer to neutral, making it more soluble, relative to human insulin in an acidic environment.3 This is accomplished by replacing glycine with asparagine in position A21 and two arginines are added to the C-terminus of the B-chain. These changes result in an insulin molecule, which precipitates in physiologic pH and favors hexamer formation and a relatively constant level over 24 hours with no pronounced peak. In a comparative trial, insulin glargine was compared to NPH insulin administered once or twice daily in type 1 or type 2 diabetic patients. Results indicate that insulin glargine was at least as effective as NPH insulin in terms of glycemic control (i.e., glycated hemoglobin) and overall rate of hypoglycemia.2 The incidence of nocturnal hypoglycemia may be lower with insulin glargine.

Clinical Implications

Insulin glargine is another "designer insulin," produced by modifying human insulin via recombinant technology to produce varied duration of action. Insulin lispro and the newly introduced insulin aspart are ultrashort-acting insulins, while insulin glargine is long acting. Insulin glargine offers the advantage of providing a basal insulin level for 24 hours, an important advantage for type 1 patients. The drug cannot be mixed with other insulins, but this may be only a minor disadvantage as diabetics move to combining long-acting bedtime insulin with short-acting insulin at mealtime. Insulin glargine is expected to be available in the fall of 2000.

References

1. Roskamp RH, et al. Diabetes Care 1999;22 (Suppl 2):B109-B113.

2. Lantus Product Information. Aventis Pharmaceuticals Inc. April 2000.

3. Gillies PS, et al. Drugs 2000;89(2):253-260.

4. Owens DR, et al. Diabetes Care 2000;23(6):813-819.

5. Heinemann L, et al. Diabetes Care 2000;23(5):644-649.

6. Ratner RE, et al. Diabetes Care 2000;23(6):639-643.