Abstract
Rapid-acting insulin analogues such as insulin lispro and insulin aspart produce a more physiological profile of insulin activity than does conventional regular human insulin because of their unique pharmacokinetics. These insulin analogues are absorbed rapidly from the subcutaneous injection site, resulting in a better matching of the appearance of insulin in the circulation with nutrient absorption from the intestine. In addition, they are shorter-acting than regular human insulin, thus decreasing the risk of late postprandial hypoglycaemia due to inappropriate hyperinsulinaemia. Because self-prepared mixtures of these rapid-acting insulin analogues with longer-acting insulins such as neutral protamine Hagedorn (NPH) insulin have been shown to be clinically useful, and because manufactured fixed-ratio mixtures of regular human insulin and NPH already represent a large proportion of insulin use, manufactured fixed-ratio mixtures of insulin lispro and a sustained-release insulin known as NPL have been developed (insulin lispro mixtures).
NPL is a protamine-based insulin lispro formulation with pharmacokinetics and glucodynamics comparable to those of human NPH insulin. NPL was developed for use within insulin lispro mixtures because an exchange between soluble insulin lispro and protamine-bound human insulin within human NPH precludes prolonged storage of mixtures of these insulins. An insulin lispro mixture consisting of 25% insulin lispro and 75% NPL is now commercially available. This preparation is intended primarily as an alternative to human insulin 30/70, which is commonly used within a twice-daily injection regimen. A mixture containing 50% insulin lispro and 50% NPL is also available.
The rapid activity of insulin lispro is maintained within insulin lispro mixtures, allowing injection just prior to a meal, a convenience that is not available with commercial mixtures of regular human insulin and human NPH insulin, which should be injected 30 to 45 minutes prior to meals. As with insulin lispro itself, the rapid action of insulin lispro within the insulin lispro mixtures also results in a smaller increase in blood glucose levels after meals than with comparable human insulin mixtures. In addition, data from two studies have shown that when Mix25 is injected prior to the evening meal the incidence of nocturnal hypoglycaemia is decreased in comparison with the same dose of human insulin 30/70. The combined rapid and prolonged insulin activity provided by insulin lispro mixtures has been defined both in healthy subjects without diabetes and in patients with diabetes.
Similar content being viewed by others
Notes
Use of tradenames is for product identification only and does not imply endorsement.
References
Brange J, Owens DR, Kang S, et al. Monomeric insulins and their experimental and clinical implications. Diabetes Care 1993; 13: 23–954
Pfeifer MA, Halter JB, Porte D Jr. Insulin secretion in diabetes mellitus. Am J Med 1981; 70(3): 579–88
Torlone E, Pampanelli S, Lalli C, et al. Effects of the short-acting insulin analog [Lys(B28), Pro(B29)] on postprandial blood glucose control in IDDM. Diabetes Care 1996; 19(9): 945–52
Dimitriadis GD, Gerich JE. Importance of timing of preprandial subcutaneous insulin administration in the management of diabetes mellitus. Diabetes Care 1983; 6: 374–7
Brems DN, Alter LA, Beckage MJ, et al. Altering the association properties of insulin by amino acid replacement. Protein Eng 1992; 5(6): 527–33
Koivisto VA. The human insulin analogue insulin lispro. Ann Med 1998; 30(3): 260–6
Anderson JH Jr, Koivisto VA. Clinical studies on insulin lispro. Drugs Today 1998; 34 Suppl. C: 37–50
Bantle JP, Lonzette N, Frankamp LM. Effects of anatomical region used for insulin injections on glycemia in type I diabetes subjects. Diabetes Care 1993; 16: 1592–7
ter Braak EW, Woodworth JR, Bianchi R, et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care 1996; 19: 1437–40
Kelley DB, editor-in-chief. Medical management of type 1 diabetes. 3rd ed. Alexandria (VA): American Diabetes Association; 1998: 55–116
Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: application, benefits, and risks. Diabetes Rev 1995; 3(2): 308–34
Corcoran JS, Yudkin JS. A comparison of premixed with patient-mixed insulins. Diabet Med 1986; 3(3): 246–9
Bell DS, Cutter GR, Lauritano AA. Efficacy of a premixed semisynthetic human insulin regimen. Clin Ther 1989; 11(6): 795–801
Cucinotta D, Mannino D, Lasco A, et al. Premixed insulin at ratio 3/7 and regular + isophane insulins at mixing ratios from 2/8 to 4/6 achieve the same metabolic control. Diabete Metab 1991; 17: 49–54
Aronoff S, Goldberg R, Kumar D. Use of a premixed insulin regimen (Novolin® 70/30) to replace self-mixed insulin regimens. Clin Ther 1994; 16(1): 41–9
Vignati L, Anderson JH Jr, Iverson PW, et al. Efficacy of insulin lispro in combination with NPH human insulin twice per day in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. Clin Ther 1997; 19(6): 1408–21
Looney KS, De Felippis MR, Hofer JD, et al. The chemical stability of insulin lispro protamine suspension and insulin lispro mixtures [abstract 942]. Diabetologia 1998; 41 (1 Suppl. 1): A243
De Fronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214–23
Radziuk JR, Bradley B, Welsh L, et al. Neutral protamine lispro: activity profile of s.c. administration with and without admixture of soluble lispro [abstract 849]. Diabetologia 1996; 39 (1 Suppl. 1): A224
Heise T, Weyer C, Serwas A, et al. Time-action profiles of novel premixed preparations of insulin lispro and NPL insulin. Diabetes Care 1998; 21(5): 800–3
Rave K, Heinemann L, Puhl L, et al. Premixed formulations of insulin lispro: activity profiles in type 1 diabetic patients [letter]. Diabetes Care 1999; 22(5): 865–6
Koivisto VA, Tuominen JA, Ebeling P. Lispro Mix25 insulin as premeal therapy in type 2 diabetic patients. Diabetes Care 1999; 22(3): 459–62
Malone JK, Arora V, Woodworth JR, et al. Improved postprandial glycemic control with Humalog® Mix75/25™ after a standard test meal in patients with type 2 diabetes mellitus. Clin Ther 2000; 22: 222–30
Malone J, Yang H, Woodworth JR, et al. Humalog® Mix25™ offers better and more consistent mealtime control in patients with type 1 and type 2 diabetes than human insulin 30/70. Diabetes Metab 2000; 26: 481–7
Roach P, Trautmann M, Arora V, et al. Improved postprandial blood glucose control and reduced nocturnal hypoglycemia during treatment with two novel insulin lispro-protamine formulations, insulin lispro Mix25 and insulin lispro Mix50. Clin Ther 1999; 21(3): 523–34
Roach P, Yue L, Arora V. Improved postprandial glycemic control during treatment with Humalog Mix25, a novel protamine-based insulin lispro formulation. Diabetes Care 1999; 22: 1258–61
Brash PD, Shaw K, UK Humalog Mix25 Study Group. Reduced nocturnal hypoglycaemia with twice daily insulin lispro low mixture compared to human insulin 30/70 in patients with type 2 diabetes [abstract]. Diabet Med 2001; 18 (2 Suppl.): 15
Anderson JH Jr, Brunelle RL, Keohane P, et al. Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Arch Intern Med 1997; 157(11): 1249–55
Anderson JH Jr, Brunelle RL, Koivisto VA, et al. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients in insulin-analog treatment. Diabetes 1997; 46(2): 265–70
Heller SR, Amiel SA, Mansell P, et al. Effect of the fast-acting insulin analog lispro on the risk of nocturnal hypoglycemia during intensified insulin therapy. Diabetes Care 1999; 22(11): 1607–11
American Diabetes Association. Insulin administration. Diabetes Care 2001; 24 Suppl. 1: S94–S7
Pein M, Deibler J, Roach P, et al. Improved glucose control following administration of a 75% insulin lispro/25% NPL mixture in patients with type 1 diabetes [abstract P942]. Diabetes Res Clin Pract 2000; 50 (1 Suppl.): S220
Weyer C, Heise T, Heinemann L. Insulin aspart in a 30/70 premixed formulation: pharmacodynamic properties of a rapid-acting insulin analog in stable mixture. Diabetes Care 1997; 20(10): 1612–4
Christiansen JS, Ejskjaer N, Rasmussen M, et al. Testing the concept of administering thrice daily premixed insulin aspart in type 2 diabetes [abstract P318]. Diabetes Res Clin Pract 2000; 50 (1 Suppl.): S67
Acknowledgements
This work was sponsored by Eli Lilly and Company.
Appreciation is expressed to Pam Erickson for editorial assistance with the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Roach, P., Woodworth, J.R. Clinical Pharmacokinetics and Pharmacodynamics of Insulin Lispro Mixtures. Clin Pharmacokinet 41, 1043–1057 (2002). https://doi.org/10.2165/00003088-200241130-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200241130-00003