Pharmacotherapeutic Group: Drugs used in diabetes. Insulins and analogues for injection, long acting. ATC Code: A10AE04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Insulin glargine is a human insulin analogue designed to have low solubility at neutral pH. It is completely soluble at the acidic pH of the injection solution (pH 4). After injection into subcutaneous tissue, the acidic solution is neutralised leading to formation of micro precipitates from which small amounts of insulin glargine are continuously released, providing a smooth, peakless, predictable concentration/time profile with a prolonged duration of action. Insulin receptor binding: insulin glargine is very similar to human insulin with respect to insulin receptor binding kinetics and can therefore, be considered to mediate a similar effect via the insulin receptor.
The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.
Clinical Studies-Efficacy Results: The clinical efficacy of BASALOG was accessed in a open label, randomised, multi-centric, comparative, phase 3 study in Type 1 Diabetes Mellitus patients with Lantus.
The results established non-inferiority of BASALOG compared to the reference product (Lantus), with respect to change in HbA1c. The changes in FPG, PPG and 7-point glucose were comparable between the 2 study arms. The proportion of patients who achieved target HbA1c <7% was comparable between groups. Mean insulin dose was also comparable between the 2 arms. Compliance was good during the study, with average compliance >98% for both basal and pre-meal soluble insulin which was comparable for both study arms. Overall the 2 study treatments were comparable with respect to efficacy.
This study established the non inferiority of BASALOG compared to Lantus with respect to primary efficacy parameter HbA1c and also supports the safety and efficacy of BASALOG in the treatment of patients of diabetes mellitus.
The following data for clinical efficacy in the patients administered with Insulin glargine is summarised from the publicly available information of Lantus.
In clinical pharmacology studies, intravenous insulin glargine and human insulin have shown to be equipotent when given at the same doses. As with all insulins, the time course of action of insulin glargine may be affected by physical activity and other variables.
In euglycemic clamp studies in healthy subjects or in patients with type1 diabetes, the onset of action of subcutaneous insulin glargine was slower than neutral protamine Hagedorn (NPH) human insulin. The efficacy profile of insulin glargine was relatively constant with no pronounced peak and the duration of its effect was prolonged compared to NPH human insulin.
The longer duration of action (up to 24 hours) of insulin glargine is directly related to its slower rate of absorption and supports once daily subcutaneous administration. The time course of action of insulins, including insulin glargine, may vary between individuals and/or within the same individual.
In a clinical study, symptoms of hypoglycaemia or counter-regulatory hormone responses were similar on administration of after intravenous insulin glargine and human insulin both in healthy volunteers and in patients with type 1 diabetes.
In an another 5 year NPH-controlled study (NPH given bid) in 1024 type 2 diabetic patients, in which progression of retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale was investigated by fundus photography. No significant difference was seen in the progression of diabetic retinopathy when insulin glargine was compared to NPH insulin.
Paediatric Population: In a randomised, controlled clinical study, paediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal bolus insulin regimen where regular human insulin was used before each meal. Insulin glargine was administered once daily at bedtime and NPH human insulin was administered once or twice daily. Similar effects on glycohaemoglobin and the incidence of symptomatic hypoglycaemia were observed in both treatment groups, however fasting plasma glucose decreased more from baseline in the insulin glargine group than in the NPH group. There was less severe hypoglycaemia in the insulin glargine group as well. One hundred and forty three patients treated with insulin glargine in this study continued treatment with insulin glargine in an uncontrolled extension study with mean duration of follow up of 2 years. No new safety signals were seen during this extended treatment with insulin glargine.
A crossover study comparing insulin glargine plus lispro insulin to NPH plus regular human insulin (each treatment administered for 16 weeks in random order) in 26 adolescent type 1 diabetic patients aged 12 to 18 years was also performed. As in the paediatric study described previously, fasting plasma glucose reduction from baseline was greater in the insulin glargine group than in the NPH group. HbA1c changes from baseline were similar between treatment groups; however blood glucose values recorded overnight were significantly higher in the insulin glargine/ lispro group than the NPH/regular group, with a mean nadir of 5.4 mM vs 4.1 mM. Correspondingly, the incidences of nocturnal hypoglycaemia were 32% in the insulin glargine / lispro group vs 52% in the NPH / regular group.
A 24-week parallel group study was conducted in 125 children with type 1 diabetes mellitus aged 2 to 6 years, comparing insulin glargine given once daily in the morning to NPH insulin given once or twice daily as basal insulin. Both groups received bolus insulin before meals. The primary aim of demonstrating non-inferiority of insulin glargine to NPH in all hypoglycaemia was not met and there was a trend to an increase of hypoglycemic events with insulin glargine [insulin glargine: NPH rate ratio (95% CI) = 1.18 (0.97-1.44)]. Glycohaemoglobin and glucose variabilities were comparable in both treatment groups. No new safety signals were observed in this study.
Pharmacokinetics: A randomised, double blind, single dose, 3-way crossover Euglycaemic clamp study in subjects with Type 1 diabetes mellitus is conducted to compare the relative Pharmacokinetics and Pharmacodynamics properties of BASALOG with Lantus. This comparative study showed that BASALOG is bioequivalent to Lantus.
The following data for the pharmacokinetics in various subjects administered with Insulin glargine is summarised from publicly available information of Lantus.
In healthy subjects and in diabetic patients, insulin glargine serum concentrations indicated a slower and much more prolonged absorption and showed a lack of a peak after subcutaneous injection of insulin glargine in comparison to human NPH insulin. Concentrations were thus consistent with the time profile of the Pharmacodynamics activity of insulin glargine. Insulin glargine injected once daily will reach steady state levels in 2 to 4 days after the first dose. When given intravenously the elimination half-life of insulin glargine and human insulin were comparable.
In patient with diabetes, insulin glargine is partly degraded in the subcutaneous tissue at the A carboxyl terminus of the chain with formation of the active metabolites 21A-Gly-insulin and 21A -Gly-des-308-Thr-insulin. Unchanged insulin glargine and degradation products are also present in plasma. In clinical studies, subgroup analyses based on age and gender did not indicate any difference in safety and efficacy in insulin glargine-treated patients compared to the entire study population.
Paediatric Population: Pharmacokinetics in children aged 2 to less than 6 years with type 1 diabetes mellitus was assessed in one clinical study. Plasma "trough" levels of insulin glargine and its main M1 and M2 metabolites were measured in children treated with insulin glargine, revealing plasma concentration patterns similar to adults, and providing no evidence for accumulation of insulin glargine or its metabolites with chronic dosing.
Toxicology: Preclinical Safety Data: Nonclinical data of insulin glargine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.