Insulin Lispro

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Abstract
Insulin lispro, a recombinant insulin analogue, is identical to human insulin except for the transposition of proline and lysine at positions 28 and 29 in the C- terminus of the B chain. The resultant reduced capacity for self-association in solution translates into more rapid absorption of insulin lispro than human regular insulin from subcutaneous sites. Maximum insulin concentrations are higher and are reached earlier with insulin lispro than with human regular insulin, and insulin concentrations return to baseline values more quickly with insulin lispro; consequently, insulin lispro has a more rapid onset and a shorter duration of glucose-lowering activity. These pharmacological properties provided the rationale for comparative clinical trials of subcutaneous insulin lispro (administered within 15 minutes before meals, preferably immediately before meals) and subcutaneous human regular insulin (administered 20 to 45 minutes before meals) in patients with type 1 diabetes (insulin-dependent diabetes mellitus) or type 2 diabetes (non-insulin-dependent diabetes mellitus) requiring premeal insulin therapy plus basal insulin therapy. Available clinical trials are well designed and results suggest that 1- and 2- hour postprandial blood glucose levels with insulin lispro are similar to or lower than those with human regular insulin; 1- and 2- hour postprandial glucose excursions are similar to or less pronounced than those with human regular insulin. Glycated haemoglobin A values were generally similar with both agents. Continuous subcutaneous insulin infusion was associated with greater improvements in postprandial blood glucose levels and glycated haemoglobin A1 values with insulin lispro than with human regular insulin. Confirmatory data are required. The incidence of hypoglycaemia with insulin lispro was similar to or lower than that with human regular insulin. In particular, insulin lispro appears to be associated with a lower incidence of night-time and severe hypoglycaemic episodes. Evidence also suggests that patients perceive their quality of life to be improved with insulin lispro compared with human regular insulin, and that satisfaction with treatment is greater with the insulin analogue. Thus, in patients with type 1 or 2 diabetes requiring premeal insulin therapy, insulin lispro appears to provide greater postprandial glycaemic control than human regular insulin without increasing the risk of hypoglycaemia. Furthermore, the reduced injection-meal interval with this agent offers greater convenience for the patient than regular human insulin. If longer term clinical experience supports these promising results it is likely that insulin lispro will offer important advantages over human regular insulin. Insulin lispro, a recombinant insulin analogue, is identical to human insulin except for the transposition of proline and lysine at positions 28 and 29 in the C-terminus of the B chain. Insulin lispro has a lower capacity for self-association than human insulin. The onset of glycaemic activity is more rapid and its duration shorter with insulin lispro than with human regular insulin. In euglycaemic clamp studies in healthy volunteers, maximum glucose infusion rates were greater and occurred earlier with insulin lispro than with human regular insulin, and the required duration of glucose infusion to maintain blood glucose levels was shorter with insulin lispro. In patients with type 1 diabetes (insulin-dependent diabetes mellitus; IDDM), blood glucose levels decreased more quickly, the required duration of glucose infusion was shorter and the required amount of glucose to maintain blood glucose levels ≥3 mmol/L was greater with insulin lispro than with human regular insulin. Insulin lispro increases the number and affinity of insulin binding sites on circulating monocytes compared with human regular insulin. This observation may be a reflection of the differences in absorption characteristics (see Pharmacokinetic Properties summary) and duration of glycaemic activity of these agents. Glycaemic thresholds for glucose counter-regulatory hormone responses and the development of autonomic and neuroglycopenic symptoms were similar with insulin lispro and human regular insulin. However, peak hormone responses, peak symptom scores and deterioration in cognitive function occurred earlier with insulin lispro than with human regular insulin. The overall immunological profiles of insulin lispro and human regular insulin appear to be similar. These agents also have similar effects on lipid levels. Maximum plasma insulin concentrations (Cmax) with subcutaneous insulin lispro 10U or 0.15 U/kg were significantly greater (0.8 to 4.1 vs 0.6 to 2.5 μg/L) and the time to Cmax significantly shorter (30 to 90 vs 50 to 120 minutes) than with the same dosage of subcutaneous human regular insulin in healthy volunteers and patients with type 1 diabetes or type 2 diabetes (non-insulin-dependent diabetes mellitus; NIDDM). However, the absolute bioavailability of these agents is similar (55 to 77%). Insulin concentrations return to baseline values more rapidly with insulin lispro than with human regular insulin; however, the areas under the plasma concentration-time curve for these agents are similar. The elimination half-life and mean residence time of insulin lispro are significantly shorter than those of human regular insulin (46 to 60 vs 82.5 to 90 minutes and 101 vs 235 minutes, respectively). The volume of distribution of insulin lispro is similar to that of human regular insulin (0.26 to 0.36 L/kg). The rate of absorption of insulin lispro is faster than that of human regular insulin, irrespective of the site of injection, and is maintained when the drug is administered as part of a multiple injection regimen. The addition of zinc (to increase the long term stability in solution) has a minimal effect on the pharmacokinetics of insulin lispro. Limited data suggest that, as with regular insulin, circulating insulin lispro concentrations may be increased in patients with renal or hepatic impairment. Results from well-designed clinical trials involving a total of >3000 patients with type 1 or 2 diabetes (some data presented in abstract form) suggest that intensive insulin therapy with subcutaneous insulin lispro administered immediately before meals (up to 15 minutes before meals in some trials) is associated with improved postprandial glycaemic control over that seen with human regular insulin (usually administered 20 to 45 minutes before meals). Basal insulin therapy with intermediate- or long-acting insulins was administered in addition to these fast-acting insulins. One- and 2-hour postprandial blood glucose levels in patients receiving insulin lispro were similar to or lower than those with human regular insulin, and 1- and 2-hour postprandial glucose excursions were similar or less pronounced with insulin lispro. Fasting blood glucose levels with insulin lispro were either similar to or higher than those with human regular insulin, and glycated haemoglobin A1 (HbA1c) values were similar in all but 2 trials. The greater postprandial glycaemic control achieved with insulin lispro compared with human regular insulin occurred with similar total daily insulin dosages. Improvements in postprandial blood glucose levels and HBA1c values were greater with insulin lispro than with human regular insulin, when administered via a continuous subcutaneous insulin infusion, in 5 crossover trials involving a total of 255 patients with diabetes. Further studies are required to confirm these findings, which have been presented in abstract form only. The effects of improved glycaemic control with insulin lispro on long term complications of diabetes mellitus have not been assessed. Evidence suggests that patients perceive their quality of life to be improved with insulin lispro compared with human regular insulin, and that satisfaction with treatment is greater with insulin lispro. In clinical trials of patients with type 1 or 2 diabetes, the overall rate of hypoglycaemia with insulin lispro was lower than or similar to that with human regular insulin (1.5 to 13.3 vs 1.6 to 17.7 episodes/month). In 3 trials, insulin lispro resulted in significantly fewer hypoglycaemic episodes at night than human regular insulin. Pooled data from four 1-year trials showed that intensive premeal therapy with insulin lispro was associated with a similar incidence of hypoglycaemic episodes to that with human regular insulin in patients with type 1 or 2 diabetes (3 vs 3.2 events/month). A meta-analysis of data from patients with type 1 diabetes showed insulin lispro (n=2337) to be associated with a lower incidence of severe hypoglycaemia than human regular insulin (n=2339) [3.1 vs 4.4% of patients had at least 1 severe episode]. Evidence suggests that insulin lispro and human regular insulin are associated with a similar incidence of local or systemic insulin allergy, lipodystrophy and changes in laboratory parameters. Agents with hyper- or hypoglycaemic activity may, respectively, increase or decrease insulin lispro dosage requirements. In patients with type 1 or 2 diabetes requiring insulin therapy, insulin lispro should be administered subcutaneously within 15 minutes before meals (preferably immediately before meals) in addition to basal insulin therapy with an intermediate-or long-acting human insulin. The dosage of insulin lispro, available as a solution containing 40 or 100 U/ml, should be individualised according to body weight, level of physical activity and meal plans. Dosage adjustments may be required during illness and emotional disturbances/stress, and may be necessary in patients with renal or hepatic impairment. Blood glucose levels should be monitored regularly and HbAic values periodically measured. Insulin lispro is contraindicated in patients who are sensitive to this analogue. Because hypokalaemia is a potential adverse effect of all insulins, caution is advised in patients who are fasting, in those who have autonomic neuropathy and in those receiving potassium-lowering agents. The effects of insulin lispro in pregnant or nursing women have not been assessed.