Insulin Glargine

Abstract

Insulin glargine is a human insulin analogue prepared by recombinant DNA technology. Modification of the human insulin molecule at position A21 and at the C-terminus of the B-chain results in the formation of a stable compound that is soluble at pH 4.0, but forms amorphous microprecipitates in subcutaneous tissue from which small amounts of insulin glargine are gradually released. The plasma concentration versus time profile of insulin glargine is therefore relatively constant in relation to conventional human insulins, with no pronounced peak over 24 hours. This allows once-daily administration as basal therapy. Early randomised trials with insulin glargine generally showed greater reductions in fasting blood or plasma glucose levels and a reduced frequency of nocturnal hypoglycaemia relative to neutral protamine Hagedorn (NPH) insulin in patients with type 1 diabetes mellitus. In addition to this basal therapy, patients continued to use the regular mealtime insulin regimen to which they were accustomed. More recent data with insulin glargine have included evidence of improved glycaemic control, with improvements in satisfaction with treatment over NPH insulin. Furthermore, the time of day at which insulin glargine is injected has no clinically relevant effect on glycaemic control in these patients. There are also data from small, nonblind studies to suggest comparable glycaemic control with insulin glargine and continuous subcutaneous insulin infusion. Results from comparative studies and meta-analyses in individuals with type 2 diabetes show lower incidences of nocturnal hypoglycaemia with insulin glargine than with NPH insulin, with two studies showing a significantly greater improvement in glycosylated haemoglobin levels with insulin glargine than with NPH. Insulin glargine is well tolerated, and is not associated with greater immunogenicity or increases in bodyweight than NPH insulin. Long-term data show maintenance of glycaemic control with insulin glargine for up to 39 months in adults and children with type 1 and adults with type 2 diabetes. In conclusion, insulin glargine is an effective and well tolerated basal insulin therapy when given as a single daily subcutaneous injection to patients with diabetes, with benefits in terms of glycaemic control and reduced frequency of hypoglycaemia over regimens based on conventional basal insulins. Accumulating data and official recommendations show the suitability of insulin glargine for first-line use in selected patients with type 2 diabetes who require insulin treatment, as well as in patients with type 1 disease, and confirm its use in children and adolescents. Insulin glargine is a long-acting recombinant human insulin analogue made by modifying human insulin using recombinant DNA technology. These changes at position 21 of the A-chain and at the C-terminus of the B-chain enable insulin glargine to remain soluble in the acidic environment of the vial, but form amorphous microprecipitates in the neutral pH of subcutaneous tissue after injection. Insulin glargine is slowly released from these microprecipitates to provide basal insulin supplementation over its once-daily dosage interval. Isoglycaemic and euglycaemic clamp studies in patients with diabetes mellitus and healthy volunteers have been conducted to evaluate the glucose-lowering effects of insulin glargine. Results show a time profile of pharmacodynamic activity characterised by a slower onset but longer duration of activity than neutral protamine Hagedorn (NPH) insulin. Unlike NPH or ultralente insulin, insulin glargine has no peak effect and has almost constant glucose-lowering activity lasting 24 hours. In general, at clinically relevant concentrations, insulin receptor binding kinetics of insulin glargine are similar to those of regular human insulin, and blood glucose levels are lowered by stimulation of peripheral glucose uptake and inhibition of hepatic glucose production. Physiological and biochemical responses to hypoglycaemia induced by insulin glargine in patients with type 1 diabetes mellitus and healthy volunteers were similar to those induced by regular human insulin. Mitogenic effects of insulin are thought to be primarily mediated via the insulin-like growth factor-1 (IGF-1) receptor, and insulin glargine appears to have a generally higher affinity for the IGF-1 receptor than regular human insulin in vitro . However, the clinical relevance of this is probably limited since the affinity of insulin glargine for the IGF-1 receptor is in vitro, mitogenic activity was similar between insulin glargine and regular human insulin. The rate of absorption of insulin glargine appears to provide a basal insulin level that remains constant for at least 24 hours. Following subcutaneous injection, the absorption of insulin glargine (containing zinc 15 or 80 μg/mL) was significantly slower than that of NPH insulin in healthy volunteers, in terms of the time to disappearance of 25% radioactivity (8.8 and 11.0 vs 3.2h; p < 0.0001). Importantly, in healthy volunteers, absorption of the drug was similar irrespective of the site (arm, leg or abdomen) of administration of insulin glargine containing zinc 30 μg/ mL (standard formulation). No accumulation of insulin glargine occurred with daily subcutaneous injections in patients with type 1 diabetes. On days 1, 4 and 11, the maximum free serum insulin concentration (C_max) ranged from 192–250 pmol/L, trough free serum insulin concentrations ranged from 77–86 pmol/L and the time to C_max ranged from 2.8–4.1 hours. Steady-state insulin glargine concentrations are achieved 2–4 days after the first dose. Insulin glargine is partially degraded in the subcutaneous tissues to two active metabolites. Both unchanged drug and metabolites are present in the plasma. There is a lack of data concerning the pharmacokinetics of insulin glargine in special patient populations, including paediatric patients and those with renal or hepatic impairment. Numerous drugs may affect glucose metabolism resulting in the need for adjustment of the insulin glargine dosage. Type 1 diabetes: Six previously reviewed randomised trials, each involving more than 250 adults (aged 18–70 years) with type 1 diabetes, compared insulin glargine given once daily at bedtime with NPH insulin once or twice daily over 4–28 weeks. In all these studies patients continued to use the regular mealtime insulin regimen to which they were accustomed, and dosages of basal insulin (glargine or NPH) were based on fasting blood glucose (FBG) targets ranging from around 4–7 mmol/L. In these studies, patients receiving insulin glargine showed greater reductions in mean FBG levels at study endpoint than NPH insulin recipients, with significant (p < 0.05) reductions from baseline in insulin glargine groups (but not the NPH insulin group) in one of the trials. Mean glycosylated haemoglobin (HbA_1c) levels were reduced to a similar extent with both insulin types in all 16- and 28-week trials. The incidence of symptomatic hypoglycaemia was greater (p < 0.05) with NPH than with insulin glargine in two 28-week studies. Percentages of patients reporting at least one episode of nocturnal hypoglycaemia were higher with NPH than with insulin glargine in most trials, and significantly (p < 0.05) higher in two. Since the last review in Drugs, data have become available from several further randomised comparisons of insulin glargine with NPH insulin in patients with type 1 diabetes. Study durations ranged from 28 weeks to 1 year, and all findings are currently available as abstracts. One trial recruited 585 patients whereas the others randomised approximately 50–120 patients each. Findings were broadly similar to those of the earlier comparisons, although smaller studies showed statistically significantly greater improvements in glycaemic control as shown by FBG and/or HbA_1c levels with insulin glargine than with NPH insulin. Frequencies of moderate or severe episodes of nocturnal hypoglycaemia were reduced with insulin glargine relative to NPH insulin in one trial and the other reported statistically significant reductions with insulin glargine in incidences of overall and nocturnal hypoglycaemia. Additional German data from 378 patients have shown no effect on glycaemic control of the timing of the daily injection of insulin glargine (breakfast, dinner or bedtime). Long-term findings demonstrate maintenance of glycaemic control, with minimal effects on bodyweight, with insulin glargine for up to 3 years in patients with type 1 diabetes. A 28-week analysis in 517 patients has shown improved levels of satisfaction with treatment according to the Diabetes Treatment Satisfaction Questionnaire and Well-Being Questionnaire with insulin glargine relative to NPH insulin treatment. Preliminary 1-year results from a further study in 121 Italian patients support these findings. Basal therapy with insulin glargine has also been compared with continuous subcutaneous insulin infusion (CSII) in three small studies. Results are currently inconclusive, although one parallel-group comparison in 32 patients has shown insulin glargine therapy and CSII to offer equivalent glycaemic control together with reductions in frequency of hypoglycaemia relative to previously used conventional multiple-dose insulin regimens. Randomised comparisons in children and adolescents (one large 28-week parallel-group study and one small crossover trial with 16-week treatment periods) have shown greater antihyperglycaemic efficacy of insulin glargine than NPH insulin in terms of FBG but not HbA_1c levels, with less nocturnal hypoglycaemia with insulin glargine. Maintenance of glycaemic control for up to 3 years has been reported in a long-term extension study in 129 children and adolescents. Recent nonrandomised trials and noncomparative investigations in which series of patients were switched to treatment with insulin glargine show results broadly concordant with the randomised studies. Type 2 diabetes: Previously reviewed studies, each in over 100 patients with type 2 diabetes, were of up to 1 year’s duration and showed similar improvements in glycaemic control with either insulin glargine or NPH insulin. Lower incidences of nocturnal hypoglycaemia were found in most trials with insulin glargine relative to NPH insulin (ranges of 10–31.3% vs 24–40.2%). Two further large, randomised trials that compared insulin glargine with NPH insulin (with concurrent oral antihyperglycaemic therapy) have shown statistically significant (p < 0.05 all comparisons) reductions in risk of nocturnal hypoglycaemia with insulin glargine therapy. One study has also demonstrated a statistically significantly (p < 0.01) greater decrease from baseline in mean HbA_1c level with insulin glargine given at breakfast time (reduction of 1.24%) than with NPH insulin (0.84%). In another similarly designed trial, there were no differences in the mean reduction in HbA1c levels or in the incidence of nocturnal, all symptomatic or severe hypoglycaemia with morning versus evening administration of insulin glargine. Notably, two large (n = 2304 and 1786) meta-analyses of phase III and IV clinical trials indicated that there was a significantly (p ≤ 0.01 all comparisons) lower risk of all confirmed symptomatic or nocturnal hypoglycaemia with insulin glargine when compared with NPH insulin treatment. Poisson regression analysis showed that when the incidence of confirmed symptomatic hypoglycaemia or confirmed nocturnal hypoglycaemia was made equivalent in the two treatment groups, there was a clinically relevant and statistically significant reduction in HbA_1c with insulin glargine versus NPH insulin. Patients with type 2 diabetes showed improved treatment satisfaction during a 1-year randomised, multicentre trial in both the insulin glargine and NPH insulin groups. At weeks 36, the improvement was greater in the insulin glargine group than in the NPH insulin group. Long-term data from a multicentre, nonblind, extension study in 239 patients with type 2 diabetes who received insulin glargine in combination with oral antidiabetic agents showed that he mean HbA_1c level was reduced from 9.44% at baseline to 8.42% over a period of up to 39 months. Only two severely symptomatic episodes of hypoglycaemia were reported during this period. Significant (p < 0.05 all comparisons) reductions from baseline in mean HbA_1c levels after starting insulin glargine treatment have also been reported in patients with type 2 diabetes in several nonrandomised studies and in a small (n = 20; 16 with type 2 diabetes) retrospective analysis of patients with end-stage renal disease. Effect on bodyweight: Bodyweight gains were no greater with insulin glargine than with NPH insulin in comparative studies in patients with type 2 diabetes, with one previously reviewed trial showing less weight gain with insulin glargine and another showing similar increases with either type of insulin. Although more recently reported trials have not yet reported details of effects on bodyweight of randomised treatment, several prospective case series have shown no clinically relevant increases in mean bodyweight in patients with type 2 disease receiving insulin glargine for up to 9 months, despite significant improvements in glycaemic control relative to baseline. Data collected over up to 36 months in patients with type 1 diabetes receiving insulin glargine during long-term follow-up have shown a minimal increase in mean bodyweight with insulin glargine treatment. The incidence of adverse events with insulin glargine has been generally similar to that with NPH insulin in randomised clinical studies. Injection site reactions, most of which are minor, are the most common adverse events with insulin glargine, and are seen in around 3–4% of patients. Observations in 239 patients with type 2 diabetes who participated in a recent long-term extension study revealed no injection site reactions with insulin glargine for up to 39 months. Evidence to date shows that insulin glargine is no more immunogenic than NPH insulin, and there have been no clinically relevant increases in levels of antibodies to Escherichia coli reported in clinical trials. There have also been no indications of any increases in risk of progression of diabetic retinopathy related to the generally higher affinity of insulin glargine than regular human insulin for IGF-1 receptors. Recent data from patients with end-stage renal disease who received insulin glargine have shown no specific tolerability concerns, and animal studies have indicated no effect of insulin glargine on fetal or postnatal development, and no evidence of carcinogenicity linked to interaction with IGF-1 receptors. Once-daily, self-administered, subcutaneous injections of insulin glargine provide basal insulin levels for the treatment of adults or children (aged >6 years) with type 1 diabetes and adults with type 2 diabetes. Insulin glargine should not be diluted or mixed with any other insulin or solution as this could alter its time-action profile because of the acidic nature of its formulation. The dosage of insulin glargine is determined individually for each patient and adjustments to dosage are made according to blood glucose levels. In clinical trials, insulin-naive patients were started with a dose of 10 IU once daily and were maintained at dosages ranging from 2–100 IU once daily. In patients receiving once-daily NPH or ultralente insulin, the initial dose of insulin glargine was usually matched in terms of the number of international units administered, whereas the initial dose was reduced by approximately 20% for the first week and then adjusted according to blood glucose levels in patients previously treated with twice-daily NPH insulin. Paediatric patients should be managed in the same way. The dosage and timing of additional short-acting insulin or oral antidiabetic agents may need to be adjusted with the initiation of insulin glargine.