Drug Criteria & Outcomes
Lantus (insulin glargine [rDNA origin] injection): A therapeutic class review
By Kacie Griffin, PharmD
Scott and White Memorial Hospital
Temple, TX
Introduction 1
The beneficial effects of achieving blood glucose concentrations close to normal in type 1 and type 2 diabetes have been firmly established. However, the best means of attaining a near- normal physiological pattern of insulin secretion is still uncertain. In healthy individuals without diabetes, insulin secretion is characterized by continuous basal secretion, with peaks immediately after meals and steady release throughout the night, hence avoiding nocturnal hypoglycemia or hyperglycemia at dawn. To achieve the basal insulin requirement in diabetic patients, one or more doses of intermediate or long-acting insulin are necessary. Due to the short duration of NPH insulin, the considerable variation in absorption of long-acting insulins, and the peak-action profile of both, these current strategies may not provide an appropriate basal supply. Therefore, development of an improved, long-acting insulin is a critical step toward improving glycemic control and preventing long-term complications of diabetes.
General 2
Lantus (insulin glargine, Aventis Pharmaceuticals) is a long-acting basal insulin approved by the Food and Drug Administration on April 20, 2000, and launched on May 14, 2001. The product is a synthetic human insulin that has been modified using DNA technology to slightly change the structure of the insulin molecule. Insulin glargine mimics normal basal secretion of endogenous insulin with a duration of action of up to 24 hours. The manufacturer suggests that this near-constant supply of low-level basal insulin appears to be essential to improving overall glycemic control. The extended action of the most commonly used basal insulin formulations, NPH and lente, is produced by combining insulin with a retarding agent, protamine and zinc ions, respectively. In contrast to NPH and lente insulins, the extended action of insulin glargine is produced by the substitution and addition of amino acids in the insulin molecule itself. In addition, a small amount of zinc has been added to the formulation to further extend its absorption time.
Clinical pharmacology 2
The primary activity of insulin, including insulin glargine, is a regulation of glucose metabolism. Each milliliter of Lantus contains 100 IU insulin glargine, 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, and water for injection. Insulin glargine is a human insulin analog that has been designed to have low aqueous solubility at neutral pH. At a pH of 4, as in the Lantus injection solution, insulin glargine is completely soluble. Following injection into the subcutaneous tissue, the acidic solution is neutralized, leading to formation of microprecipitates, from which small amounts of insulin glargine are released slowly. This results in a relatively constant concentration/time profile over 24 hours with no pronounced peak. The slower rate of absorption prolongs duration of action and enables once-a-day dosing. Insulin glargine is metabolized partly at the carboxyl terminus of the B-chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of insulin. Unchanged drug and metabolites also are present in the circulation.
Indications and usage 2
Insulin glargine is indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal, long-acting insulin for the control of hyperglycemia.
Contraindications 2
Insulin glargine is contraindicated in patients hypersensitive to insulin glargine or the excipients.
Precautions 2
Insulin glargine is not intended for intravenous administration. The prolonged duration of activity of insulin glargine is dependent on injection into subcutaneous tissue. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia. Insulin glargine must not be diluted or mixed with any other insulin or solution. If insulin glargine is diluted or mixed, the solution may become cloudy and the pharmacokinetic/pharmacodynamic profile of insulin glargine and/or mixed insulin may be altered in an unpredictable manner. Interpatient and intrapatient variability may occur.
As with all insulin preparations, hypoglycemic reactions may be associated with the administration of insulin glargine. The time occurrence of hypoglycemia depends on the action profile of the insulins used and, therefore, may change when the treatment regimen is altered. The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycemia.
Although studies have not been performed in patients with diabetes and either renal or hepatic impairment, insulin glargine requirements may be diminished similar to observations found with other insulins. Lipodystrophy may occur at the injection site and delay insulin absorption as with other insulins. Reports of injection-site pain were more frequent with insulin glargine than NPH insulin (2.7% vs. 0.7%). The reports of pain at the injection site were usually mild and did not result in discontinuation of therapy.
Insulin glargine is pregnancy category C. It is unknown whether insulin glargine is excreted in significant amounts in human milk. Caution should be exercised when insulin glargine is administered to nursing women.
Safety and effectiveness of insulin glargine have been established in the age group 6 to 15 years with type 1 diabetes. In elderly patients, the initial dose increments and maintenance dosage should be conservative to avoid hypoglycemic reactions.
Adverse reactions 2
The adverse effects commonly associated with insulin glargine include allergic reactions, injection-site reactions, lipodystrophy, pruritis, rash, and hypoglycemia. Retinopathy was evaluated in clinical studies, and the numbers of retinal adverse events reported for insulin glargine and NPH treatment groups were similar for patients with type 1 and type 2 diabetes. In one clinical study involving type 2 diabetics, a difference in the number of patients with > 3-step progression in ETDRS (Early Treatment Diabetic Retinopathy Study grading protocol) scale over a six-month period was noted by fundus photography (7.5% insulin glargine vs. 2.7% NPH insulin-treated group). The overall relevance of this isolated finding cannot be determined due to the small number of patients involved, the short follow-up period, and the fact that this finding was not observed in other clinical studies.
Dosing and administration 2,3
The potency of insulin glargine is approximately the same as human insulin. The product exhibits a relatively constant glucose-lowering profile over 24 hours that permits once-daily dosing and should be administered subcutaneously once a day at bedtime. Insulin glargine is not intended for intravenous administration. The prolonged duration of activity of insulin glargine is dependent on injection into subcutaneous space. In clinical studies, no relevant difference in insulin glargine absorption was observed after abdominal, deltoid, or thigh subcutaneous administration. Insulin glargine is not the treatment of choice for the treatment of diabetic ketoacidosis.
In a clinical study of insulin-naïve patients with type 2 diabetes already treated with oral antidiabetic drugs, insulin glargine was initiated at an average of 10 IU once daily, and subsequently adjusted according to patient need for a total daily dose ranging from 2 to 100 IU. No information is available regarding the starting dose in type 1 patients. Patients being switched from twice-daily NPH insulin to once-daily insulin glargine should have their insulin glargine dose reduced by 20% from the previous total daily NPH dose to reduce the risk of hypoglycemia. Switching from once-daily NPH or ultralente to once-daily insulin glargine may not require initial dose change. Insulin glargine can be administered safely to pediatric patients 6 years of age or older. Administration in pediatric patients less than 6 years of age has not been studied. The dose changeover to insulin glargine is the same as described for adults.
Clinical trials
The following are summaries of a variety of studies evaluating the use of insulin glargine vs. other insulins. (R = randomized, MC = multicenter, PG = parallel-group, FBG = fasting blood glucose, FPG = fasting plasma glucose, HgbA1C = hemoglobin A1C, OL = open-label)
Insulin glargine in intensive insulin therapy for type 1 diabetes 4
Design: R, MC, PG 28-week study of 534 well-controlled type 1 diabetic patients treated with pre-meal regular insulin and either insulin glargine (at bedtime) or NPH insulin (at bedtime for patients on once-daily therapy and at bedtime and in the morning for patients on twice-daily therapy).
Treatment: Dose titration of both basal insulins was based on capillary FBG. The goal was a pre-meal blood glucose concentration of 80-120 mg/dL. Any episode of hypoglycemia that met the criteria for a serious adverse event (e.g., death, a life-threatening episode, hospitalization, or medical intervention to prevent permanent impairment) was considered to be a treatment-related adverse event.
Results: Reductions in HgbA1C were similar in the insulin glargine and NPH insulin treatment groups. No difference in reductions in FBG was observed between groups at the end of the study; however, reductions in FBG occurred earlier with the insulin glargine group than with the NPH group. At end point, insulin glargine patients had a significant reduction in FPG compared to NPH insulin patients (P = 0.0145). The incidence of all symptomatic hypoglycemic episodes was similar between the two groups over the entire study period. After the one-month titration phase, significantly fewer subjects receiving insulin glargine experienced symptomatic hypoglycemia (39.9% vs. 49.2%, P = 0.0219), nocturnal hypoglycemia (18.2% vs. 27.1%, P = 0.0116), or severe hypoglycemia (1.9% vs. 5.6%, P = 0.0117) with blood glucose levels of < 36 mg/dL.
Safety: Insulin glargine and NPH were equally well tolerated and the frequency and types of adverse events were similar in both groups. No evidence existed of an immunogenic response to insulin glargine compared to NPH insulin. The number of patients with treatment emergent injection site reactions was higher in the insulin glargine group than in the NPH group (15.2% vs. 10.4%), but all were rated mild in severity, and none required drug discontinuation.
Basal insulin therapy in type 2 diabetes 5
Design: R, MC, OL 28-week study of 518 patients with type 2 diabetes who were receiving NPH insulin with or without regular insulin, randomized to receive insulin glargine once daily or NPH insulin once- or twice-daily. Patients were excluded if they had received an oral antidiabetic agent within three months prior to study entry.
Treatment: Doses were titrated individually for both insulins based on a target FPG of 80-140 mg/dL. Evening doses were increased if FPG was > 180 mg/dL on three consecutive measurements unless nocturnal hypoglycemia had occurred. Targets for use of regular insulin were pre-meal blood glucose of 80-140 mg/dL and bedtime blood glucose of 120-180 mg/dL. Hypoglycemia was defined symptomatically and by a blood glucose level of < 50 mg/dL. Severe hypoglycemia was defined as an event consistent with hypoglycemia in which the patient required the assistance of another person and was accompanied by a blood glucose of < 36 mg/dL, or had prompt recovery after administration of glucose or carbohydrates. Nocturnal hypoglycemia was defined as that occurring while the patient was asleep between bedtime after the evening injection and before getting up in the morning.
Results: The treatment groups showed similar significant improvements in HgbA1C and fasting blood glucose levels from baseline to endpoint on an intent-to-treat analysis. Overall, mild symptomatic hypoglycemia was similar in insulin glargine patients (61.4%) and NPH insulin patients (66.8%). However, nocturnal hypoglycemia was 25% less in the insulin glargine group compared to the NPH group after the dose-titration phase (26.5% vs. 35.5%, P = 0.0136). Patients in the insulin glargine group experienced less weight gain than did those in the NPH group (0.4 kg vs. 1.4 kg, P < 0.0007).
Safety: Nine insulin glargine patients discontinued treatment because of adverse events. Only cellulitis at the injection site was considered related to study medications and was attributed to poor injection technique. Seven NPH insulin patients discontinued treatment because of adverse events, of which none were attributed to study medication. Treatment-related adverse events occurred in 10.4% of insulin glargine patients compared with 7.7% of NPH insulin patients. Mild pain at the injection site occurred more frequently with insulin glargine than with NPH insulin but did not result in discontinuation of treatment.
Nocturnal hypoglycemia and post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes 3
Design: 52-week study of 426 type 2 diabetic patients with poor glycemic control on oral antidiabetic agents for at least one year, randomized to treatment with bedtime insulin glargine or bedtime NPH insulin.
Treatment: Insulin dose was to be adjusted to an FBG of < 120 mg/dL. The dose of insulin glargine or NPH insulin injected on the first treatment day, as well as subsequent adjustments, was left to the discretion of the investigator. Doses of oral agents were maintained unchanged.
Results: Insulin glargine and NPH insulin had similar significant effects on HgbA1C between baseline and end of study. Blood glucose concentrations were significantly lower in the insulin glargine group than the NPH insulin group both before and after dinner (P = 0.035 and P = 0.0094, respectively). The percentage of patients experiencing at least one symptomatic hypoglycemic episode was significantly lower in the insulin glargine group than the NPH insulin group (P = 0.04). The frequency of nocturnal hypoglycemia also was significantly lower in the insulin glargine group compared to the NPH insulin group (9.9% vs. 24%, P < 0.001). Antibodies against both insulin glargine and human insulin were less prevalent in patients treated with insulin glargine compared with NPH insulin (P < 0.0001).
Safety: During the treatment phase, no difference in treatment of emergent adverse events possibly related to study medication, except for frequency of hypoglycemia, was observed.
Conclusion
Insulin glargine is a human insulin modified using DNA technology that provides once-daily dosing at bedtime. The formulation allows for a relatively constant concentration/time profile with no pronounced peak. Insulin glargine has comparable or better glycemic control than NPH insulin and exhibits a lower risk of hypoglycemia, specifically nocturnal hypoglycemia. The safety profile of insulin glargine is similar to that of human insulin; however, an increased risk of injection site reactions does appear to be present. Lantus is more expensive than standard NPH formulations.
References
1. Nakhmanovich Y, Belenkaya R, Rozenfeld V. Insulin glargine in the management of diabetes mellitus. P&T 2001; 26:176-181.
2. Lantus product information. Parsippany, NJ: Aventis Pharmaceuticals; 1999.
3. Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 2000; 23:1130-1136.
4. Ratner RE, Hirsch I, Neifing JL. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care 2000; 23:639-643.
5. Rosenstock J, Schwartz SL, Clark CM, Jr, et al. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 2001; 24:631-636.
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