Insulin lispro was the first short-acting insulin analogue to be marketed in 1996. Like the other short-acting insulin analogues, it has a quicker s.c. absorption, with a higher peak action and a shorter duration of action compared to regular insulin. In clinical trials, the main advantage over regular insulin seems to be a slight reduction in the occcurence of (severe) hypoglycemia (more clearly in type 1 diabetes than in type 2 diabetes). Moreover, patients appreciate the fact that lispro can be injected right before the meal, but these benefits have to be weighed against the higher cost of the analogue.
It was a structural homology with IGF-I that led to the development of insulin lispro. Researchers noted that IGF-I, which strongly resembles insulin in structure, has little tendency to self-associate. It was hypothesized and subsequently shown that differences in the C-terminal end of the B-chain influenced the tendency of insulin to self-associate. In insulin lispro (LysB28,ProB29 human insulin analogue) the natural sequence of proline at position B28 and lysine at position B29 has been inverted. This leads to a conformational shift in the C-terminal end of the B-chain that sterically hinders the anti-parallel association of the insulin monomers to dimers. Thus, the dimer association constant is reduced 300-fold compared to regular insulin. The monomeric nature of insulin lispro at physiologic concentrations was demonstrated through various methods.
The affinity of insulin lispro for the insulin receptor is comparable to the affinity of regular insulin. The affinity of insulin lispro for the IGF-I receptor is about 1½ times the affinity of regular insulin, but still only 0,1% of the affinity of IGF-I itself. Thus, in a range of pre-clinical and clinical studies, no adverse effects of insulin lispro (e.g. carcinogenicity) were found. Likewise, insulin lispro only rarely leads to the development of antibodies, and usually their presence has little clinical relevance.
During a euglycemic clamp study, serum insulin levels peaked significantly higher (550 vs. 308 pmol/l) and earlier (53 vs. 101 min.) following subcutaneous administration of insulin lispro than following regular insulin. Glucose infusion peaked at 90 minutes (versus 3 hrs for regular insulin) and the total hypoglycemic potency of the insulins was equivalent, as was the systemic clearance rate. The duration of action is shorter for insulin lispro (about 3 hours) than for regular insulin (about 5 hours). As with other insulins, absorption of lispro is faster from the abdominal region than from the deltoid or femoral regions and absorption is increased by heat. However, these effects are less pronounced for insulin lispro than for regular insulin. Recent studies suggest that in the obese, and when using high insulin doses, the absorption of both insulin lispro and regular insulin is more protracted, leading to longer durations of actions for both while retaining the difference between the two.
Figure 1. Clinical benefits of the short-acting insulin analogues compared to regular insulin in type 1 diabetes are limited to a small decrease in HbA1c and no difference in hypoglycaemia.rigorous Cochrane meta-analysis looking at the efficacy of short-acting insulin analogues compared to regular insulin, the effects of the short-acting insulin analogues are limited to a small reduction in HbA1c of about 1 mmol/mol (0.12%) in type 1 diabetes, with no effects on hypoglycaemia in type 1, and no effects at all in type 2 diabetes (see figure 1). This was confirmed in a more recent Canadian meta-analysis although in this meta-analysis some reduction in nocturnal hypoglycaemia in type 1 was noted. In less rigorous meta-analyses, often sponsored by the producers, somewhat larger benefits are found. Thus, a meta-analysis by Brunelle found a 30% reduction in the risk of severe hypoglycaemia with insulin lispro (Figure 2).
fig. 2. A meta-analysis of 8 studies demonstrated a reduced risk for severe hypoglycaemia in type 1 diabetes with insulin lispro compared to regular insulin