Insulin Glargine

Abstract

Insulin glargine is a recombinant human insulin analogue produced by DNA technology using a nonpathogenic strain of Escherichia coli. Two modifications of human insulin result in a stable molecule which is soluble in slightly acidic conditions (pH 4.0) and precipitates in the neutral pH of subcutaneous tissue. Because of these properties, absorption of insulin glargine is delayed and the analogue provides a fairly constant, basal insulin supply without peaks in plasma insulin levels for approximately 24 hours, similar to that achieved by a continuous subcutaneous insulin infusion. Insulin glargine is indicated as a once daily subcutaneous injection to provide basal glycaemic control in adults and children aged >6 years with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Fasting plasma glucose and fasting blood glucose levels generally improved to a greater extent in patients with type 1 diabetes mellitus receiving insulin glargine than patients who administered Neutral Protamine Hagedorn (NPH) insulin. In patients with type 1 or 2 disease, glycosylated haemoglobin levels were slightly reduced and to a similar extent with insulin glargine and NPH insulin. Most clinical trials in patients with type 1 or 2 diabetes mellitus demonstrated a lower incidence of hypoglycaemia, especially nocturnal hypoglycaemia, compared with NPH insulin. One of the most common adverse events with insulin glargine treatment was injection site pain which, in some studies, occurred more frequently than in patients receiving NPH insulin. In all cases the symptoms were mild and treatment discontinuation was not required. Otherwise, the drug is well tolerated and does not appear to be immunogenic. Conclusions: Insulin glargine once a day provides basal control of glycaemia for approximately 24 hours without inducing peaks in plasma insulin levels in patients with type 1 or 2 diabetes mellitus. In long term, well designed trials insulin glargine once daily improved glycaemic control at least as effectively as NPH insulin given once or twice daily. The drug was well tolerated and in most studies the incidence of nocturnal hypoglycaemia was significantly less in patients treated with insulin glargine compared with patients receiving NPH insulin. Therefore, insulin glargine is likely to be a useful addition to the armamentarium of insulin therapy by establishing basal glycaemic control with once daily administration and a reduced risk of nocturnal hypoglycaemia. Insulin glargine is manufactured by recombinant DNA technology. Modifications to the structure of natural human insulin produce an analogue with a stable hexameric form and an altered isoelectric point from a pH of 5.4 to 6.7. These changes enable insulin glargine to remain soluble in the slightly acidic pH of the vial (pH 4.0) and precipitate in the neutral pH of subcutaneous tissue after injection where it has a delayed absorption and a prolonged duration of action relative to other exogenous basal insulins. The addition of a small amount of zinc (30 mg/L) to the insulin glargine formulation is necessary for crystallisation in the subcutaneous tissue and further delays the absorption time. A single daily, subcutaneous injection of insulin glargine provides basal insulin requirements in patients with type 1 diabetes mellitus. Blood glucose levels recorded over a 24-hour period following a subcutaneous injection of insulin glargine were similar to those observed when the patient was given 4 doses of Neutral Protamine Hagedorn (NPH) insulin over 1 day. The metabolic effect of insulin glargine increased to a plateau within 4 hours and then remained more constant than that of NPH insulin, as evidenced by a lower area under the curve analysis for glucose consumption, at all time-points throughout a 24-hour period following a single insulin dose. Insulin glargine does not cause a peak effect but has a constant concentration/effect versus time profile which lasts 24 hours and was similar to that achieved by a continuous subcutaneous infusion of insulin lispro. In healthy volunteers and/or patients, equal doses of insulin glargine and regular human insulin, given as short intravenous infusions, produced similar effects on plasma glucose lowering, symptomatic responses to hypoglycaemia, suppression of hepatic glucose output and lipolysis. Insulin glargine appears to have no effect on immune response. In vitro, insulin glargine has a slightly increased insulin-like growth factor 1 (IGF-1) receptor affinity and mitogenic potency compared with regular human insulin, but a many-fold less binding affinity for IGF-1 receptors than endogenous IGF-1. In vivo, insulin glargine appears to exert mitogenic and growth-promoting activity similar to regular human insulin. Toxicity studies of insulin glargine in rats and mice for periods up to 24 months showed no histological evidence of mammary gland tumour development. The rate of absorption of insulin glargine provides a basal plasma insulin level which remains constant for at least 24 hours. The mean time to disappearance of 25% radioactivity from the subcutaneous injection site was twice as long for insulin glargine as for NPH insulin. The mean percentage of residual radioactivity remaining at the injection site of insulin glargine at 24 hours was almost twice that for NPH insulin. Similar rates of absorption of insulin glargine containing zinc 30 mg/L (standard formulation) were measured from the abdomen, thigh and deltoid subcutaneous injection sites. There was no evidence of accumulation after repeated injections of insulin glargine. The drug is partly metabolised in subcutaneous tissue to form 2 active metabolites with in vivo and in vitro activity similar to that of human insulin. Large, well designed trials of 4 to 52 weeks’ duration in over 5000 adults and children with type 1 diabetes mellitus and adults with type 2 diabetes mellitus have shown that a single daily injection of insulin glargine provides glycaemic control for approximately 24 hours with a lower incidence of nocturnal hypoglycaemia than NPH insulin. In patients with type 1 diabetes mellitus, insulin glargine caused a greater reduction of fasting plasma glucose (FPG) and fasting blood glucose (FBG) levels and a similar reduction of glycosylated haemoglobin (HbA_1c) levels compared with patients receiving NPH insulin (FPG levels not reported in children). FPG levels were significantly decreased from baseline to end-point in patients with type 1 diabetes mellitus receiving insulin glargine, whereas levels remained stable or decreased slightly in patients who administered NPH insulin. A greater reduction in FPG and FBG levels was evident in patients receiving insulin glargine who had administered NPH insulin twice daily prior to the trial than those previously receiving NPH insulin once daily. This was despite these patients having lower baseline glucose levels than patients on once daily NPH insulin. The same patients, randomised to insulin glargine, also showed a greater reduction from baseline in basal insulin requirements throughout the study than patients on a once daily NPH regimen prior to the trial. In contrast, patients randomised to NPH insulin had a gradual increase in insulin dose from baseline to end-point. The improvement in FPG and FBG levels was evident as early as the first week and was sustained throughout the trial period, whereas the beneficial effect of NPH took longer to develop. Variability in self-monitored FBG levels declined more in patients with type 1 disease receiving insulin glargine than NPH insulin. Overall, the incidence of nocturnal hypoglycaemia was significantly less in patients with type 1 diabetes mellitus receiving insulin glargine than NPH insulin, particularly patients who administered NPH insulin once daily. Episodes of symptomatic hypoglycaemia occurred frequently in insulin glargine and NPH insulin treatment groups in patients with type 1 disease and overall the incidence was similar. Overnight plasma glucose profiles were generally stable in patients with type 1 diabetes mellitus receiving insulin glargine, whereas patients who administered NPH insulin had an increase in blood glucose levels after 5am. In clinical trials of patients with type 2 diabetes mellitus, FPG, FBG and Hb_A1 clevels were reduced from baseline to a similar extent with both insulin glargine and NPH insulin. In most studies the incidence of nocturnal hypoglycaemia was significantly less in patients with type 2 diabetes mellitus who received insulin glargine compared with NPH insulin. Symptomatic hypoglycaemia was also lower in the insulin glargine groups than the NPH insulin groups but, overall, the difference was not as large as for nocturnal hypoglycaemia. The between-group difference in symptomatic hypoglycaemia was significant when compared with insulin-naive patients randomised to NPH insulin. Insulin glargine produced greater treatment satisfaction than NPH insulin in patients with type 1 and 2 diabetes mellitus. In a 6-month study of patients with type 1 disease, treatment satisfaction improved in the insulin glargine group but deteriorated slightly in the NPH insulin group. Patients with type 2 diabetes mellitus showed improved treatment satisfaction over a 1 year study in both the insulin glargine and NPH insulin groups. At week 36 and endpoint the improvement was greater in the insulin glargine group compared with NPH insulin. The incidence of adverse events in patients treated with insulin glargine is similar to that in patients treated with NPH insulin. In some studies, reactions at the injection site occurred more often in patients receiving insulin glargine than those receiving NPH insulin, whereas other studies reported a similar incidence in insulin glargine and NPH insulin groups. In all cases, the injection site reaction was mild and discontinuation of the drug was not required. Patient withdrawals from clinical trials relating to treatment were few and there were no significant differences between treatment groups in this parameter. There was no evidence of an increased immunogenic response to insulin glargine compared with NPH insulin. An increase in antibody levels from pretreatment levels was reported in some long term trials for both insulin glargine and NPH insulin, but was found to be higher in the NPH insulin group. The clinical relevance of insulin antibodies remains unclear. No clinically relevant changes in Escherichia coli antibody formation were observed. Compared with NPH insulin, insulin glargine was associated with a similar or lower increase in bodyweight gain. Similarly, insulin glargine did not carry an increased risk for the development or progression of diabetic retinopathy compared with NPH insulin. Insulin glargine is self-administered subcutaneously once daily to provide basal insulin levels. It is indicated for use in adults with type 1 or 2 diabetes mellitus and, in the US only, is also indicated for use in children aged >6 years with type 1 disease. Administration is via a conventional insulin syringe or an injection pen. Insulin glargine must not be diluted or mixed with other insulin formulations. Rolling or shaking of the vial prior to administration is not required as insulin glargine is available as a clear solution. The dosage of insulin glargine is determined individually for each patient based on previous insulin therapy, if any, and blood glucose levels. In a study of patients with type 2 diabetes mellitus with no previous treatment with insulin, insulin glargine was started at an average dose of 10U once daily. Dosage was then adjusted according to patient blood glucose levels and average daily doses ranged from 2 to 100U. Patients transferred to insulin glargine from a once daily injection of NPH insulin generally require the same initial dose. To reduce the risk of hypoglycaemia the manufacturer recommends that the initial dose of insulin glargine be reduced by approximately 20% for the first week of treatment in patients previously receiving NPH insulin or long-acting insulin twice daily. Ongoing dosage should then be adjusted based on blood glucose levels. Medical supervision is recommended during transfer and the early weeks of treatment. Paediatric patients should be managed in the same way. The timing and dosage of additional short-acting insulin or oral antidiabetic agents may need to be adjusted. As for other insulin injections, rotation of the site should be managed so that one site within an area is not injected more than once every 1 to 2 weeks. Similar rates of absorption of insulin glargine occur from abdominal, thigh and deltoid regions. It is recommended that the dosage of insulin glargine be reduced in patients with renal or hepatic impairment, followed by careful monitoring of blood glucose levels. Initial dosage and titration should be conservative in the elderly.