Critical appraisal of the safety and efficacy of insulin detemir in glycemic control and cardiovascular risk management in diabetics

Abstract

Insulin detemir is an analog of human insulin designed to provide a long duration of basal insulin action. This is achieved by protracted absorption from the injection depot, which results in part from increased self-association of insulin detemir molecules and in part from reversible albumin binding. Subsequent albumin binding in the circulation is thought to buffer changes in the effects at target tissues that could otherwise arise from variability in absorption rate. In consequence, insulin detemir has shown a less variable pharmacodynamic profile than alternative basal insulins; this manifests as more consistent temporal glucose reduction profiles in repeat-clamp studies. In clinical trials, insulin detemir has been characterized by consistent risk reductions in hypoglycemia, as well as reduced weight gain in comparison with other basal insulins. Given some recent associations that have been made in prospective and epidemiologic studies between glucose variability and/or hypoglycemia and increased cardiovascular risk, and the long-known association between excess weight and cardiovascular risk, it is possible that the clinical profile of insulin detemir may carry prognostic value with regard to cardiovascular safety, although this is yet to be substantiated. There have also been some concerns raised recently over the use of insulin analogs and cancer risk, but available clinical data and the receptor interaction profile of insulin detemir suggest no excess in risk in comparison with human insulin therapy. Optimal approaches for the clinical use of insulin detemir have been emerging through an increasing clinical study base, and the analog is becoming established as a potentially valuable therapy option.

Keywords: glucose variability; hypoglycemia; insulin detemir; type 2 diabetes; weight gain.

Figure 1

Molecular structure of insulin detemir.

Figure 2

Mean 24-hour action profiles of three doses of insulin detemir and insulin glargine (A: 0.4 U/kg; B: 0.8 U/kg; C: 1.4 U/kg) in a glycemic clamp study in patients with insulin-requiring type 2 diabetes (fasting C-peptide concentration ≤ 1 nmol/L). Reprinted from Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T. Albumin-bound basal insulin analogues (insulin detemir and NN344): Comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab. 2007;9:290–299. Copyright © 2007, with permission from John Wiley and Sons.

Figure 3

Weight change stratified by baseline body mass index in previously insulin-naïve patients adding basal insulin to oral antidiabetic therapy. A) In a comparative treat-to-target trial. B) In the observational PREDICTIVE study. Figure 3a reprinted from Philis-Tsimikas A. Tolerability, safety and adherence to treatment with insulin detemir injection in the treatment of type 2 diabetes. Patient Prefer Adherence. 2008;2:323–332. Copyright 2008, with permission from Dove Medical Press Ltd. Figure 3b reprinted from Dornhorst A, Lüddeke HJ, Sreenan S, et al; PREDICTIVE Study Group. Insulin detemir improves glycaemic control without weight gain in insulin-naïve patients with type 2 diabetes: Subgroup analysis from the PREDICTIVE study. Int J Clin Pract. 2008;62:659–665. Copyright © 2008, with permission from John Wiley & Sons, Inc.