Insulin lispro

Observational studies

During Ramadan, insulin lispro reduced the number of attacks of hypoglycemia and reduced postprandial blood glucose [ ]. It also reduced post-snack raised blood glucose concentrations when sugar-rich snacks were used [ ].

Combinations with long-acting insulins

The combinations insulin lispro + insulin glargine and regular + NPH have been compared in a randomized, crossover study for 32 weeks in 25 patients [ ]. HbA _1c was not different, but the total insulin dose was lower with insulin lispro + insulin glargine and there were fewer episodes of nocturnal hypoglycemia.

The newer short-acting insulins can be bound to protamine, allowing the preparation of mixed formulations. In a randomized, open, crossover study for 24 weeks, a 50% mixture of insulin lispro and protamine lispro injected immediately before each meal plus NPH in the evening gave a comparable profile to regular insulin injected 30 minutes before each meal plus NPH in the evening [ ]. There were no differences in HbA _1c or episodes of hypoglycemia. When Mix25TM (25% insulin lispro plus 75% protamine lispro) was compared with 30/70 human insulin in an open, randomized, crossover study during Ramadan, the daily average blood glucose concentration was better with the insulin lispro combination; the number of hypoglycemic episodes was the same with the two formulations [ ].

In an open, randomized, single-dose, three-way, crossover trial, biphasic insulin aspart 30 (30% aspart plus 70% protaminated aspart, BIAsp 30), biphasic insulin lispro 25 (25% lispro plus 75% protaminated lispro, Mix 25), and biphasic human insulin 30 (30% regular plus 70% NPH insulin, BHI 30) were compared in 45 patients [ ]. Biphasic insulin aspart improved postprandial control better. There were 23 episodes of hypoglycemia with BIAsp 30, 19 with Mix 25, and 11 with BHI 30; two episodes with BIAsp 30, five with Mix 25, and two with BHI 30 required third-party intervention.

Comparative studies

In an open, randomized, crossover study, 113 patients with at least 6 months of continuous subcutaneous insulin infusion before the study were treated with regular insulin or insulin lispro [ ]. Postprandial blood glucose was lower and HbA _1c fell more with insulin lispro. There were no differences in catheter obstruction, hypoglycemic episodes, or other adverse effects. Satisfaction with treatment was better with insulin lispro.

There were no differences between human protamine zinc insulin and human ultralente insulin when either was added once or twice daily to insulin lispro [ ].

When either insulin lispro or regular insulin was given during the evening meal in a randomized, double-blind study in insulin-using adolescents, insulin lispro reduced the number of hypoglycemic episodes at night but redistribution of evening carbohydrate might be necessary to reduce postprandial hypoglycemia [ ].

Premeal hyperglycemia is common. The short action of insulin lispro can then be extended by the addition of protamine zinc insulin. In a 3-month study in addition to a once-daily injection of protamine zinc insulin, at each meal insulin lispro or insulin lispro + protamine zinc insulin was injected; the postprandial blood glucose concentration was lower, but the post-absorptive glucose concentration was higher in the insulin lispro-only group; there was no difference in HbA _1c . The addition of protamine zinc insulin (30% at breakfast, 40% at lunch, and 10% at dinner) improved post-absorptive glucose and HbA _1c [ ].

Insulin Mix 25 (25% insulin lispro and 75% neutral protamine zinc insulin) reduced the glucose response to a standardized breakfast meal better than premixed 30% regular + 70% protamine zinc insulin when 22 patients with type 2 diabetes were studied three times in a double-blind fashion [ ]. Protamine zinc insulin mixed with insulin lispro has the same action profile of insulin lispro, with the continuing action of the long-acting component [ ]. The same mixture given three or four times daily provides acceptable control [ ], but gives no possibility of adjusting the short-acting insulin regularly. Protamine zinc insulin must be mixed with insulin lispro in the syringe immediately before the meal [ ]. The mixture is not stable for longer as there is partial exchange of the rapid-acting analogue and the protamine-bound human insulin. Instant mixing is no solution when pens are used.

The use of insulin lispro instead of regular insulin reduced the frequency of nocturnal attacks of hypoglycemia but did not change HbA _1c [ ]. This was confirmed by the UK Prospective Diabetes Study [ ], which also found a fall in postprandial glucose with an increase in fasting and preprandial glucose.

In an open, crossover, randomized study in 33 patients with type 1 diabetes who used regular or insulin lispro, the latter was associated with a lower incidence of severe hypoglycemia, mostly due to reduced nocturnal hypoglycemia; HbA _1c was not different [ ].

A crossover comparison of regular insulin + protamine zinc insulin at bedtime with insulin lispro + multiple protamine zinc insulin showed no effect on overall hypoglycemia but there was less frequent severe hypoglycemia with the second treatment [ ]. The reduction in HbA _1c was small and not significant. Insulin doses were the same. Patients preferred the second treatment.

In an open, randomized, multicenter study, 33 women with type 1 diabetes for at least 2 years were randomized to preprandial lispro or regular insulin in week 15 of their pregnancy; both groups used NPH insulin as well [ ]. HbA _1c concentrations fell at the same rate. One patient in the regular group had one episode of severe hypoglycemia and one had three episodes. Biochemical hypoglycemia (under 3.0 mmol/l) was significantly more frequent in the lispro group (5.5% versus 3.9%). Retinopathy progressed during pregnancy in three of the 16 who used lispro and six of the 17 who used regular insulin; retinal aneurysms were seen at the beginning of the study in 10/16 and 5/17 patients respectively. There were no differences in the neonates.

When insulin lispro and insulin aspart were compared in a single-blind, randomized crossover study in 14 patients with type 1 diabetes, insulin lispro had a faster onset of action but a shorter duration [ ]. However, in another study, the pharmacokinetic and pharmacodynamic profiles of insulin aspart compared with human insulin in 24 healthy Japanese were the same as those in non-Japanese subjects [ ].

Insulin aspart, insulin lispro, and buffered regular insulin in continuous subcutaneous insulin infusion have been compared in an open, randomized, parallel-group study in 146 patients [ ]. HbA _1c , hypoglycemic episodes, and blockages of pumps or infusion sets did not differ.

Insulin lispro and insulin aspart were equally effective in 24 patients with type 1 diabetes [ ].

Insulin lispro and repaglinide were given to seven patients with diabetes related to cystic fibrosis [ ]. They had normal fasting blood glucose and insulin concentrations, but postprandial glucose concentrations were substantially raised. Insulin lispro had a larger and more sustained effect in lowering postprandial glucose than repaglinide. However, the doses of insulin lispro (0.1 U/kg) and repaglinide (1 mg) may not have been comparable.