FROM THE CONCEPT OF RAPID ACTING ANALOGS TO THE PROPERTIES OF THE INSULIN LISPRO

The difficulties of achieving good glycaemic control in insulin-depend ent diabetes are due in large part to the inadequacies of subcutaneous ly administered insulin. In particular, resorption with the long actin g form is variable from one subject to another and from one day to ano ther and irregular overtime, whereas the action of the rapid acting fo rm is too late and prolonged. The slowness of absorption of the rapid acting form is attributable to the need for hexamer dissociation, The Lilly Laboratories, by inverting the amino acids lysine and proline in positions 28 and 29 in the B chain, have created an insulin (Lispro) which more rapidly dissociates into monomers after injection. The stab ility of Lispro is good, probably because of its phosphate buffer. In our experience, in conditions simulating use in portable insulin pumps , Lispro proved to be more stable than insulins specially intended for this use. The affinity in vitro was identical to that of insulin for its receptor. The affinity for insulin-like growth factor-I (IGF-I) re ceptor has been found to be 1.5 times as high as that of fast insulin in some models and comparable in others, and nearly 1,000 times less t han that of IGF-I. Studies on in vivo potency and ex vivo cell growth, as well as of tolerance in the animal (mutagenicity, toxicity and car cinogenicity), have not shown a different effect from regular insulin (contrary to results for analogue Asp B10). The pharmacokinetics has s hown an earlier and higher insulinaemic peak and a more rapid return t o baseline values than regular insulin. On the basis of pharmacokineti c studies in normal subjects and diabetic patients, the characteristic s retained by the licensing authorities are onset of action at 15 min, insulinemic peak between 30 and 70 min, and duration of action 2 to 5 h. Some clinical studies have shown a shortened action period of 1 to 3 h as compared to regular insulin and less influence of dose and inj ection site, notably with a return to normal insulin levels. The time required for normalisation is increased by 1 h if the injection is mad e in the thigh rather than the abdomen, as compared to 2 to 3 h for co nventional insulin. This suggests that Lispro should be administered j ust before the meal (0 to 15 min). In some patients, an insulin with p rolonged action can be added ii the interval between injections is pro longed, i.e. always at the evening meal but possibly also at the noon meal. Lispro can be mixed with Umuline NPH or Umuline zinc without any alteration in its pharmacokinetics and potency if the injection is pe rformed immediately. The few studies that have considered glycaemic st ability and reproductibility have shown a tendency toward improvement in glycaemic excursions during the day, as measured by MAGE, and in in sulinaemia variability expressed in area under the curve, which was re duced by half in the same individual or from one individual to another , with less marked impact on the variability from one day to another o f glycaemic excursions. On the whole, Lispro provides faster kinetics, greater stability and possibly better reproducibility than fast insul in. These advantages, if confirmed by clinical experience, should allo w an improvement in the comfort and glycaemic stability of dia betic p atients.