Recent Advances in Insulin Therapy

Caroline Day, Helen Archer, Clifford J Bailey

Disclosures

Br J Cardiol. 2003;10(5) 

In This Article

Basal Insulin Analogues

Neutral protamine Hagedorn (also known as NPH; isophane) and ultralente insulins are prone to produce a 'dome-shaped' basal plasma profile. This leaves the patient vulnerable to hypoglycaemia at the peak insulin concentration and hyperglycaemia at the trough. Variability in the rates of absorption of these insulins can also pose difficulties when striving for tighter glycaemic control. Mixing isophane and short-acting insulins, particularly the convenience of premixed ('biphasic') formulations, have much improved the situation but still struggle to achieve good control without 'hypos'.[4,5]

The long-acting analogue glargine (figure 2), introduced in August 2002, creates a flatter plasma insulin profile, which more closely matches the basal component of normal insulin release.[6] Glargine (Lantus®) has an isoelectric point close to neutrality, conferring solubility and stability in acid solution within the vial. When injected into the slightly alkaline environment of interstitial fluid, the glargine quickly precipitates and then dissociates gradually providing a constant and ostensibly peak-less 'basal' supply of insulin into the circulation (figure 3). In principle, glargine can be given by once-daily subcutaneous injections at any time of the day, although bedtime is usually preferred. Several studies have reported similar or slightly improved glycaemic control with glargine compared with once- or twice-daily NPH. However, glargine therapy resulted in fewer episodes of nocturnal hypoglycaemia and less weight gain.[7,8,9]

Amino acid sequences of native human insulin, the long-acting analogues glargine and detemir, and the rapid-acting monomeric analogues lispro and aspart. Sequences shown as single letter amino acid code

Glucose infusion rate required to maintain euglycaemia after subcutaneous injection of either glargine, NPH-insulin or placebo at time zero. The glucose infusion rate provides an indication of the circulating concentration of insulin, showing an early peak and subsequent trough with NPH-insulin compared with a flatter 'peakless' profile with glargine. Based on data presented by Linkeschowa et al. at the European Association for the Study of Diabetes 1999. Published in Diabetologia 1999;42:(suppl 1); Abstract 880

Another long-acting 'basal' insulin analogue is detemir (Levemir®), expected to become available early in 2004 (figure 2). Detemir is insulin linked to a fatty acid (myristic acid). The fatty acid side chain promotes aggregation of detemir in interstitial fluid and delays dissociation and release into the circulation. On entering the blood, the fatty acyl group binds to albumin and a dynamic equilibrium occurs between the free and the albumin-bound forms. Gradual subsequent dissociation from the albumin gives a constant slow rate of release of active monomeric detemir. Studies to-date indicate a predictable effect of detemir on glycaemic control with fewer hypos and less weight gain than NPH.[10,11]

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