Glargine (Lantus®) 15/6/2007. Dr. HK Pang. Endocrinologist, Endocrine team. Department of medicine. PYNEH

What is insulin Glargine (Lantus®) A type of modified insulin. Glargine (Lantus®) Detemir ( Levemir®) with property of the “Ideal” Long-Acting Insulin.

What is the “Ideal” Long-Acting Insulin? Should have the property of 1 injection daily  24 hours basal insulin coverage. No peaks (peakless)  provide an ideal, constant level of basal insulin – mimicks the physiological basal insulin level. This slide lists the characteristics of the ideal long-acting insulin The ideal long-acting insulin should safely provide a 24-hour peakless profile, thereby mimicking the normal physiological basal insulin profile The ideal long-acting insulin should help patients achieve target A1C levels with: Low incidence of hypoglycaemia Predictability Simple, once-daily injection High treatment satisfaction and acceptance

“Older” generation of insulin - with peak, and cannot last for 24 hrs……

To Provide 24-Hour Peakless Profile Hourly mean values 6 Insulin Glargine (n=20) NPH Insulin (n=20) 5 4 3 Glucose Utilisation Rate (mg/kg/min) 2 1 In contrast to NPH insulin, Lantus® (insulin glargine) had a peakless, long-lasting concentration/action profile closely mimicking a “square wave” shape1,2 The peakless profile over 24 hours seen with Lantus helps to reduce the risk of nocturnal hypoglycaemia3-5 Lantus mimicks the normal physiological basal insulin profile6 10 20 30 Time After SC Injection (hours) = End of observation period SC, subcutaneous. Adapted from Lantus (insulin glargine) EMEA Summary of Product Characteristics. 2002. 1. Lepore M, Kurzthals R, Pampanelli S, Fanelli CG, Bolli GB. Pharmacokinetics and dynamics of s.c. injection of the long-acting insulin glargine (HOE1) in T1DM. Diabetes. 1999;48(suppl):A97. Abstract 416. 2. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. Bridgewater, NJ: Aventis Pharmaceuticals; 2002. 3. Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA, and the US Study Group of Insulin Glargine in Type 1 Diabetes. Less hypoglycaemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care. 2000;23:639-643. 4. McKeage K, Goa KL. Insulin glargine: a review of its therapeutic use as a long-lasting agent for the management of type 1 and type 2 diabetes mellitus. Drugs. 2001;61:1599-1624. 5. Riddle MC, Rosenstock J, and the HOE901/4002 Study Group. Treatment to target study: insulin glargine vs NPH insulin added to oral therapy of type 2 diabetes. Successful control with less nocturnal hypoglycemia. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P. 6. Bolli GB, Owens DR. Insulin glargine. Lancet. 2000;356:443-445.

1. Insulin Glargine (Lantus®)

Glargine (Lantus®) Has the property of an “ideal” basal insulin A recombinant human insulin analogue1 A basal (long-acting) insulin1 Relatively constant peakless profile over 24 hours1,2 Once-daily SC administration1 Lantus® (insulin glargine) is a recombinant human insulin analogue for once-daily subcutaneous administration1 Lantus is indicated for the treatment of adult and paediatric patients1,2 with type 1 diabetes or adult patients with type 2 diabetes who require basal (long-acting) insulin for the control of hyperglycaemia1 It is slowly released after injection, resulting in a relatively constant peakless concentration/time profile over 24 hours1,2 This profile allows once-daily dosing as a patient’s basal insulin1 1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002. 2. Lantus® receives European approval for pediatric use. Aventis Pharma Web site. Available at: http://www.aventis.no/nyheter/nyheter/nyheter_lantus_eu_approval_pediatric.shtml. Accessed March 19, 2003. 1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. Bridgewater, NJ: Aventis Pharmaceuticals; 2002. 2. Lantus® receives European approval for pediatric use. Aventis Pharma Web site. Available at: http://www.aventis.no/nyheter/nyheter/nyheter_lantus_eu_approval_pediatric.shtml. Accessed March 19, 2003.

Glargine (Lantus®) Modification of the insulin molecule makes it acquires the property of the “ ideal” .…

Structure of Glargine (Lantus®) A chain Gly Substitution 1 5 10 15 20 Asn B chain 1 5 10 10 15 15 19 25 30 Extension Asparagine at position A21 replaced by glycine Provides stability Addition of 2 arginines at the C- terminus of the B chain Soluble at slightly acidic pH Arg Arg Lantus® (insulin glargine) is manufactured using recombinant DNA technology1 Two arginine molecules added to the B chain shift the isoelectric point from pH 5.4 to pH 6.72 Substitution of one glycine unit in place of an asparagine results in a stable hexamer2 Lantus is soluble in a slightly acidic condition within the vial (pH 4), but is less soluble in the neutral pH of subcutaneous tissue1 The change of pH allows Lantus to form microprecipitates in subcutaneous tissue, resulting in delayed absorption and a prolonged duration of action1 Lantus, injected once daily, results in steady-state levels 2 to 4 days after the first dose, and there is no evidence of accumulation after 12 days of injections1 1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002. 2. McKeage K et al. Drugs. 2001;61:1599-1624. 1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. Bridgewater, NJ: Aventis Pharmaceuticals; 2002. 2. McKeage K, Goa KL. Insulin glargine: a review of its therapeutic use as a long-acting agent for the management of type 1 and type 2 diabetes mellitus. Drugs. 2001;61:1599-1624.

Mechanism of Action - Glargine (Lantus®) Injection of an acidic solution (pH 4.0)3  Microprecipitation of insulin glargine in subcutaneous tissue (pH 7.4)3 Slow dissolution of free insulin glargine hexamers from microprecipitates (stabilised aggregates)3 Protracted action3 The mechanics of sustained release1,2 Absorption. The solubility characteristics of LANTUS® differ from other insulins as a result of the molecular structure differences brought about by the amino acid substitutions. LANTUS® is completely soluble in an acidic pH (4.0) and much less soluble in neutral physiologic pH (7.4), allowing two important properties. First, LANTUS® is a solution, and therefore does not require resuspension before injection. This eliminates the concerns about inconsistent dosing that are associated with insulins in suspension (such as NPH and Ultralente). Second, LANTUS® forms microprecipitates once it is injected into the neutral pH of the body, creating a depot. [Bolli, 1999, 1161] The formation of microprecipitates allows for small amounts of LANTUS® to be dissolved and absorbed slowly into the bloodstream. [Owens, 2000, 813] This systemic release mechanism provides a relatively constant time/concentration profile over 24 hours—allowing for once-daily injections—with no pronounced peak. The prolonged action of Lantus® (insulin glargine) is based on a slow dissolution of a microprecipitate1,2 After injection into subcutaneous tissue, the acidic Lantus solution is neutralised, leading to formation of microprecipitates from which small amounts of Lantus are slowly released1,2 The presence of zinc in the Lantus preparation is required for formation of microprecipitates in the subcutaneous tissue and extends the activity by reducing the absorption rate from the injection site3 Balance state at day 2 with 1 injection/day and without accumulation 1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002. 2. McKeage K et al. Drugs. 2001;61:1599-1624. 3. Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61. 1. Kramer W. New approaches to the treatment of diabetes. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61. 2. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. Bridgewater, NJ: Aventis Pharmaceuticals; 2002. 3. McKeage K, Goa KL. Insulin glargine: a review of its therapeutic use as a long-acting agent for the management of type 1 and type 2 diabetes mellitus. Drugs. 2001;61:1599-1624.

2. Detemir (Levemir®) the amino acid threonine in position B30 is omitted a C14 fatty acid chain is attached to the amino acid B29, imparting its long-acting properties

2. Detemir (Levemir®) Form depot - slow systemic absorption from the injection site detemir is highly bound to albumin - slow distribution.

END Thanks