Insulin Glargine: a Long Acting Insulin Analog

Drug Review www.jpgmonline.com Insulin glargine: A long acting insulin analog

Chakkarwar PN, Manjrekar NA

Department of Pharma- ABSTRACT cology and Therapeutics. The main goal of treatment of diabetes mellitus (DM) is to maintain long term near normoglycemia. Insulin Seth GS Medical College and KEM Hospital, therapy plays a pivotal role in the management of DM. Most insulin preparations and insulin delivery systems, Mumbai, India do not mimic the physiological insulin secretion in the body, leading to impaired metabolic control and increased hypoglycemic attacks. Insulin glargine is newer, long acting insulin analog with duration of action of 24 hr. It Correspondence: practically does not show any peak over its duration of action. In various clinical trials, it has shown comparable/ P. N. Chakkarwar, better efficacy than the currently used insulin replacement therapies with no increased side effects. In the E-mail: [email protected] current scenario, though it is difficult to achieve an ideal insulin replacement therapy, insulin glargine is definitely a positive step in that direction. Received : 05-07-04 Review completed : 11-11-04 Accepted : 12-03-05 PubMed ID : 15793346 J Postgrad Med 2005;51:68-71 KEY WORDS: Diabetes mellitus, newer insulin, peak less insulin

nce regarded as a single disease entity, diabetes mellitus Presently practised regimens in the intensive management are O (DM) is now seen, as a heterogeneous group of diseases • Split Mixed regimen- twice daily injections of mixture of characterized by chronic hyperglycemia, from whatever cause regular and intermediate acting insulin. leading to complications involving cardiovascular, renal, neu- • Multiple Component insulin regimen- two shots of rological and ophthalmic systems. ultralente, one at breakfast and one at supper along with three shots of lispro, one each before the major meals. Over the years, prevalence of diabetes continuously increased; • CSII (Continues subcutaneous insulin infusion) with in- and according to recent estimates, around 143 million people fusion pump device adjusting a basal supply and then pro- worldwide are affected with DM. The number is expected to viding the bolus at breakfast, lunch and supper. This regi- reach 300 million mark by the year 2025. In India, the preva- men is taken as the gold standard. lence ranges from 2.4% to 11.6% with a higher prevalence in urban areas.[1] Though these regimens are commonly used, there are few draw- backs like The goal of treatment of DM is maintenance of long term • Intermediate and long acting insulin preparations do not near normoglycemia to prevent the onset and/or progression give a smooth and steady concentration of insulin of long-term complications. Pharmacotherapy plays a crucial • They all show a peak at some point in their duration of role in this regard. For type 1 DM, this goal can be achieved action, which carries a potential chance of precipitating with the use of different available models of insulin replace- hypoglycemia and also increase the need for mid morning, ment therapy that mimic physiologic insulin secretion, and in afternoon or evening snack resulting in weight gain. case of type 2 DM, oral hypoglycemic agents alone, or in com- • Multiple injections reducing patient adherence bination with insulin are used.[2] • Though CSII may offer better control, it requires lot of

Presently, insulin plays a pivotal role in the management of Table 1: Different insulin preparations with there time action DM. Different types of insulins are available for therapeutic profile use and are shown in Table 1. Type Insulin Onset Peak Effective preparation (h) (h) duration (h) The current approach in the treatment of DM consists of in- Rapid acting Lispro, Aspart, <0.25 0.5-1.5 3-4 tensive management with the help of insulin replacement Glulisine therapy and has two components Short acting Regular 0.5-1 2-3 4-6 1. Basal supply of insulin to mimic physiologic insulin secre- Intermediate acting NPH 2-4 6-10 10-16 tion, which is provided with longer-acting insulin prepara- Lente 3-4 6-12 12-18 tions. Long acting Ultralente 6-10 10-12 18-20 Insulin glargine* 4 —- 24 2. Rapid acting insulin to normalize the postprandial hyperglycemia *Glargine has no peak activity.

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patient education and motivation. · CSII is not a very cost effective option for a vast majority of the population.[2,3]

Hence, there is a need for better insulin preparation that can overcome these shortcomings, and mimic physiological insulin secretion.

Insulin glargine is a human insulin analog, with a duration of action of 24 hrs with no peak and gives good glycemic control. Though it doesn’t address all the above problems, it is definitely a remarkable step towards the goal.

Salient features[4-6]

Insulin glargine is a long acting human insulin analog produced by DNA recombinant technology. • Aspargine is replaced by glycine at 21 position in A.A. chain, and two arginine residues are added to the C- terminus of Figure 1a: Plasma (free) insulin concentrations after SC injection of glargine, NPH, and ultralente and after CSII of lispro the B chain of normal insulin to produce insulin glargine. • This is a clear solution at lower pH(pH=4) but forms amor- phous micro-precipitates at normal body pH, when given subcutaneously. • From these micro precipitates, insulin is slowly and stead- ily released in the circulation for about 24 hr. • It has no pronounced peak effect. • Has lesser incidence of nocturnal hypoglycemia.

Pharmacokinetic

Absorption The rate of absorption of insulin glargine is very slow with a significant residual activity at 24 hrs compared to NPH. There is also little or no difference in the rate of absorption of insulin glargine among the main subcutaneous injection sites.[7]

In the study conducted by Lepore et al to compare the pharmacokinetics/dynamics of insulin glargine with NPH, Figure 1b: Rates of glucose infusion needed to maintain plasma glucose at the target value of 130 mg/dl after SC injection of glargine, NPH, and Ultralente and CSII of insulin Lispro, 20 patients of type 1 ultralente and after CSII of lispro diabetes were studied on four occasions, by using an (Copyright © 2000 American Diabetes Association. From Diabetes, Vol. 49, isoglycemic 24hr clamp technique. 2000; 2142-2148 Reprinted with permission from the American Diabetes Association”.) Patients received SC injection of either 0.3 U/kg glargine or NPH insulin. On two subsequent occasions, they received Biotransformation either a SC injection of Ultralente or CSII (0.3U/kg/24hr). After SC insulin injection or CSII, intravenous insulin was Insulin glargine is metabolized by sequential cleavage at the tapered, and glucose was infused to clamp plasma glucose at carboxy terminus of the B chain, to yield products M1 and 130 mg/dl for 24 hr. More than 50% reduction in IV insulin M2, both of which are structurally similar to human insulin. was taken as onset of action and an increase in plasma glu- Studies also suggest that metabolism of insulin glargine is ini- cose above 150 mg/dl was considered the end of action of tiated at the injection site and continues within the circula- insulin preparation. tory system.[9]

Figure 1a and 1b illustrate that - NPH and Ultralente both Not many trials are done regarding its pharmacokinetics in case show a peak activity. Duration of action of Ultralente is greater, of pregnant women, lactating mothers and paediatric age group but inter-subject variability is more than that of NPH. Glargine below 6 years of age. In case of hepatic and renal disease, dose is peak-less insulin, its duration of actin is almost 24 hr, it has reduction is recommended.[10] lower inter-subject variability than NPH and Ultralente, and it closely mimics CSII, the gold standard of basal insulin re- Pharmacodynamics[6,11-15] placement therapy.[8] • Activation and deactivation kinetics of EGO (endogenous

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glucose output) peripheral glucose utilization and abso- were compared with NPH. All these studies have shown that lute disposal rate are similar to human insulin. insulin glargine is as safe as NPH insulin when given with the • Symptomatic and counter regulatory hormone responses oral hypoglycemic treatment. Insulin glargine has shown bet- during hypoglycemia are similar to human insulin. ter glycemic control and fewer incidences of hypoglycemias, • It has a favorable effect on lipid profile by reducing plasma especially nocturnal hypoglycemias, as compared to NPH in- levels of fatty acids through inhibition of lipolysis. sulin. Similar effects were found in a study where 518 patients • In type 2 DM patients it has shown to improve endothelial with type 2 DM, who were previously treated with insulin dependent and endothelial independent vasodilatation. alone.[25-28] • It has 6-8 times more affinity for insulin receptors as compared to human insulin and has more mitogenic poten- Adverse reactions[6,29] tial. • It can cause hypoglycemia if the dose is not properly deter- mined. Comparative clinical trials • Weight gain is a common problem of insulin replacement therapy; in case of insulin glargine, there is mixed type of Type 1 diabetes mellitus information with insulin found in different studies. But An open labeled parallel group trial with 32 type 1 DM pa- when compared with NPH insulin, no difference in weight tients comparing CSII of insulin lispro and Insulin glargine gain was observed. with pre-meal lispro has shown that both CSII and MDI of • Insulin glargine has shown more injection site reactions Lispro+glargine equally improves metabolic control (improve- like redness, hives, and itching,as compared to NPH ment in HBA1c levels, fasting plasma glucose, and triglycerides) insulin. and reduce episodes of sever hypoglycemia in type 1 DM pa- • Immunological reaction to insulin glargine may occur due tients that are unsatisfactorily controlled on MDIs using NPH to its slight structural difference with that of regular hu- as basal insulin.[16] A study recently published has also shown man insulin. that the MDI with a glargine based regimen was less expen- • Rarely, convulsions or unconsciousness may develop as a sive by $5000 annually with similar efficacy to CSII.[17] consequence of hypoglycemia. • Initially, it was thought that its high binding affinity with In another study, the effects of insulin glargine bedtime or IGF-1 receptors may have an adverse effect on progression dinnertime and NPH insulin (17 patients in each group) were of retinopathy in diabetic patients. But further studies done studied for 3 months. Insulin glargine had not shown any sig- in this regard don’t show much significant relation of insu- nificant improvement in plasma glucose levels but was more lin glargine therapy and progression of retinopathy. effective in reducing HBA1c levels and hypoglycemic attacks. • Overall, insulin glargine is well tolerated. There was no significant difference in bedtime or dinnertime insulin glargine.[18] It is also been documented that glargine Drug interactions can be given anytime of the day with similar glycemic control.[17,19] No specific interaction has been reported regarding the pharmacokinetic profile. Large open labeled controlled randomized trials for 16 weeks (619 subjects) and 4 weeks (comparing two preparations of in- Only the drugs like beta-blockers, ACE inhibitors, clonidine, sulin glargine) where NPH was compared with insulin glargine, alcohol and glucose lowering antimicrobials, which can alter showed that basal insulin therapy with insulin glargine is at least blood glucose metabolism, should be cautiously used when as safe as NPH, and as effective as NPH insulin twice a day in given concomitantly.[29] maintaining glycemic control in type 1 DM patients.[20,21] Dosage and administration In five different studies where insulin glargine was compared with NPH in children and adolescent age group (controlled Dose of insulin glargine should be individualized after due randomized clinical trials. sample size 114,37,25, 361 and 349), consideration to patient’s previous insulin therapy and con- three studies suggest that insulin glargine gives better or at comitant oral antidiabetic therapy. least comparable glycemic control (in one study glycemic control was not a study objective). Four studies also show that While switching from single dose NPH to glargine, dose of incidence of sever hypoglycemic attack is reduced in case of insulin can be kept same, but when there is multiple daily dose glargine, when compared with NPH. Three of those studies schedule of NPH that is to be switched to glargine, initial dose have also shown that insulin glargine significantly reduces in- should be 80% of the previous dose and then depending upon cidence of nocturnal hypoglycemia without jeopardizing the blood sugar levels, dose should be titrated. glycemic control.[22-24] During administration, Insulin glargine should not be mixed Type 2 diabetes mellitus with any other insulin preparation. In three studies done with patients of type 2 diabetes mellitus who are on oral hypoglycemic agents, effects of insulin glargine It can be given at any time of day without any problem of

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4. Rang HP, Dale MM, Ritter JM, Moore PK. The endocrine pancreas and the control safety and efficacy. of blood glucose. In: Pharmacology. 5th Edn. London, UK: Churchill Livingston; 2003, p. 380-93. 5. McKeage K, Goa KL. Insulin glargine: A review of its therapeutic use as a long- It can be given safely at any of the commonly used subcutane- acting agent for management of type 1 and type 2 diabetes mellitus. Drugs ous site like arm, thigh or abdomen. 2001;61:1599-624. 6. Christopher JD, Greg LP, Gillman MK, Kate M, Lesley JS. Insulin glargine: An up- dated review of its use in the management of diabetes mellitus. Drugs The site of injection should be regularly rotated. 2003;63:1743-78. 7. Owens DR, Coales PA, Luzio SD, Tinbergen JP, Kurzhals R. Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous inject ion sites. Diabetes Care Presently, Lantus is the only brand available in India as well as 2000;23:813-9. in the international market, costs approximately 2500 Rs/ 50$ 8. Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Vincenzo AD, et al. Phar- [6,10,29] macokinetics and pharmacodynamics of subcutaneous injection of long-acting for 1 vial of 10 ml (100 units/ml). human insulin analog glargine, NPH insulin, and Ultralente human insulin and continuous subcutaneous infusion of insulin Lispro. Diabetes 2000;49:2142-8. 9. Kuerzel GU, Shukla U, Scholtz HE, Pretorius SG, Wessels DH, Venter C, et al. Bi- Current status of insulin glargine in otransformation of insulin glargine after subcutaneous injection in healthy sub- management of diabetes jects. Curr Med Res Opin 2003;19:34-40. 10. Package insert of the product Lantus® (Aventis Pharma) 11. Mudaliar S, Mohideen P, Deutsch R, Ciaraldi TP, Armstrong D, Kim B, et al. Intrave- nous glargine and regular insulin have similar effects on endogenous glucose out- Good glycemic control is the key in management of diabetes. put and peripheral activation/ deactivation kinetic profile. Diabetes Care DCCT (Diabetes control and complication trial) and UKPDS 2002;25:1597-602. 12. Vekhvaara S, Yki JH. 3.5 years of insulin therapy with insulin glargine improves in (United Kingdom prospective diabetes study) have shown that vivo endothelial function in type 2 diabetes. Arterioscler Thromb Vasc Biol improved glycemic control reduces the risk or progression of 2004;24:325-30. 13. Westerbacka J, Bergholm R, Tiikkainen M, Yki JH. Glargine and regular human complications. insulin similarly acutely enhance endothelium-dependent vasodilation in normal subjects. Arterioscler Thromb Vasc Biol 2004;24:320-4. 14. Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, et al. Given subcutaneously, insulin glargine mimics the physiologic correlation of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49:999-1005. basal insulin secretion, which is a very important aspect in the 15. Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, et al. management of DM. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49:999-1005. 16. Lepore G, Dodesini AR, Nosari I, Trevisan R. Both continuous insulin infusion and multiple daily insulin injection regimen with glargine as basal insulin are equally Various studies have shown that it gives better glycemic con- better than traditional multiple daily insulin injection treatment. Diabetes Care trol than NPH insulin. It also reduces the incidence of 2003;26:1321-2. 17. Garg SK, Gottlieb PA, Hisatomi ME, D’Souza A, Walker AJ, Izuora KE, et al. Im- hypoglycemias induced by intensive management with insu- proved glycemic control without an increase in severe hypoglycemic episodes in lin. intensively treated patients with type 1 diabetes receiving morning, evening, or split dose insulin glargine. Diabetes Research and Clinical Practice 2004;66:49-56. 18. Rossetti P, Pampanelli S, Fanelli C, Porcellati F, Costa E, Torlone E, et al. Intensive In one randomized controlled clinical trial; insulin glargine had replacement of basal insulin patients with type 1 diabetes given rapid-acting insulin analog at mealtime; a 3-month comparison between administration of NPH significantly improved patient treatment satisfaction, together insulin four times daily and glargine insulin at dinner or bedtime. Diabetes Care 2003;26:1490-6. with lower perceived frequency of hyperglycemia as well as 19. Fritsche A, Matthias A, Haring H. Improved glycemic control and reduced noctur- hypoglycemia, compared to NPH insulin. nal hypoglycemia in patients with type 2 diabetes with morning administration of insulin glargine compared with NPH insulin. Diabetes 2002;51:A54. 20. Raskin P, Klaff L, Bergenstal R, Halle JP, Donley D, Mecca T. A 16-week comparison In accordance with this, National Institute Of Clinical Excel- of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin Lispro in patients with type 1 diabetes. Diabetes Care 2000;23:1666- lence, UK has recommended that it could be prescribed to: 71. 21. Rosentock J, Park G, Zimmerman J. Basal insulin glargine versus NPH insulin in • Any patient with type 1 DM. patients with type 1 diabetes on multiple daily insulin regimens. Diabetes Care • Type 2 DM patients who 2000;23:1137-42. 22. Chase HP, Dixon B, Pearson J, Fiallo SR, Walravens P, Klingensmith G, et al. Re- - Require assistance from a caregiver or healthcare produced hypoglycemic episodes and improved glycemic control in children with type fessional for taking insulin. 1 diabetes using insulin glargine and Neutral Protamine Hagedorn insulin. J Pediatr 2003;143:737-40. - Whose lifestyle is significantly restricted because of re- 23. Murphy NP, Keane SM, Ong KK, Ford AM, Edge JA, Acerini CL, et al. Randomized current symptomatic hypoglycemia. cross-over trial of insulin glargine plus Lispro or NPH inulin plus regular human insulin in adolescents with type 1 diabetes on intensive insulin regimens. Diabe- - Who would otherwise need twice daily basal insulin tes Care 2003;26:799-804. 24. Mohn A, Strang S, Wernike PK, Lang AM, Edge JA, Dunger DB. Nocturnal glucose injections in combination with oral hypoglycemic drugs. control and free insulin levels in children with type 1 diabetes by use of the long acting insulin HOE 901 as part of a three-injection regimen. Diabetes Care 2000;23:557-9. For an ideal insulin replacement therapy, we still have to go a 25. Massi BM, Humberg E, Dressler A, Ziemen M. A one-year, randomized, multicen- long way, and insulin glargine definitely appears to be a re- tric trial comparing insulin glargine with NPH insulin IN combination with oral agents in patients with type 2 diabetes. Horm Metab Res 2003;35:189-96. markable step in that direction. 26. Yki JH, Dressler A, Ziemen M; HOE 901/300s Study Group. 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 References diabetes. HOE 901/3002 study Group. Diabetes Care 2000;23:1130-6. 27. Fritsche A, Schweitzer MA, Haring HU. Glimeparide combined with morning insulin glargine, bedtime Neutral Protamine Hagedorn insulin, or bedtime insulin glargine 1. Park K. Epidemiology of chronic non-communicable diseases and condition, dia- in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med betes mellitus. In: Park’s textbook of preventive and social medicine. 17th Edn. 2003;138:952-9. Jabalpur, India: M/s Banarasidas Bhanot; 2002, p. 294-8. 28. Julio R, Sherwyn LS, Charles MC, Glen DP, David WD, Mike BE. Basal insulin therapy 2. Alvin CP. Diabetes mellitus. In: Eugene B, Stephen LH, Anthony SF, Dan LL, Jameson in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH JL, Dennis LK, editors. Harrison’s principles of internal medicine. 15th Edn. New insulin. Diabetes Care 2001;24:631-6. York, USA: Mc Graw Hill; 2001, p. 2109-37. 29. Aventis pharmaceuticals Inc. Lantus® (insulin glargine [r DNA origin] injection) pre- 3. Richard G. Is there a need for better basal insulin? Clinical Diabetes 2001;19:66-70. scribing information [online].

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