Safety and Effectiveness of Modern Insulin Therapy: The Value of Insulin Analogs

Great improvements have been made to insulin preparations over the years, including the development of insulin analogs, which were designed to overcome the disadvantages of traditional human insulins in the treatment of type 1 and type 2 diabetes. Insulin analogs more closely mimic the physiological insulin profile and are therefore associated with an improved balance between glycemic control and tolerability. They are also associated with a lower risk of hypoglycemia, less weight gain, and greater treatment flexibility than human insulins. These benefits, in combination with new insulin delivery devices, such as pens, have greatly improved patients’ treatment satisfaction and medication adherence, leading to improvements in clinical outcome. This article reviews the advantages of insulin analogs over human insulin for the treatment of type 1 and type 2 diabetes. Insulin was first used to treat diabetes in the 1920s. Early advances in therapy consisted of improvements in the purification and modification of pharmaceutical formulations in order to extend their duration of action. The addition of protamine reduced the solubility of insulin at physiological pH, slowing down its absorption after subcutaneous injection and thereby prolonging its action.1 In 1935, Scott and Fisher2 further demonstrated that the addition of zinc to insulin prolonged its action profile. Neutral protamine hagedorn (NPH), developed in the 1940s, was the first intermediate-acting insulin containing equal amounts of insulin, zinc, and protamine.3 In the early 1980s, recombinant DNA technology enabled the synthesis of human insulin.4 However, the suboptimal pharmacokinetic and pharmacodynamic characteristics of human insulin, particularly its natural tendency to form absorption-delaying hexamers, prompted further improvements in the insulin molecule. Recent advances in molecular biology have enabled us to modify the insulin molecule, resulting in analogs with pharmacokinetic and pharmacodynamic properties that more closely resemble those of endogenous insulin in healthy persons. Rapid-acting analogs, such as insulin aspart, insulin lispro, and insulin glulisine, are typically used as mealtime insulin replacement because they mimic the physiological insulin response to food intake (Figure).3,5 These analogs, which provide a faster onset and a shorter duration of action than human insulin,3,5 are administered immediately before meals and reduce the risk of hypoglycemia in the intervals between meals that is often seen with human insulin.3,4 Traditional basal (long-acting) insulins such as NPH have suboptimal pharmacodynamic profiles, making them an inadequate replacement for endogenous insulin. After injection, basal insulins exhibit a peak concentration and action followed by waning6; they have been associated with significant within-subject absorption variability.7 The drawbacks of traditional basal insulins prompted the development of long-acting insulin analogs STEPHEN BRUNTON, MD Cabarrus Family Medicine Residency Program, Charlotte, NC Safety and Effectiveness of Modern Insulin Therapy: The Value of Insulin Analogs Dr Brunton is director of faculty development at the Cabarrus Family Medicine Residency Program in Charlotte, North Carolina JULY 2009 (SUPPLEMENT) CONSULTANT S13 www.ConsultantLive.com CONS_07012009_00013.ps 6/29/09 9:50 AM Page 13