Human Insulin Analog to Treat Diabetes

The FDA approved Humalog^® (insulin lispro) in June 1996 to improve glycemic control in adults and children with diabetes. The drug, a rapid acting human insulin analog, is marketed by Eli Lilly and Company.

Insulin lispro comes in various forms, including 3-mL and 10-mL vials, 3-mL prefilled pens, and 3-mL cartridges. Other versions of the product include a mixture of 75% insulin lispro protamine suspension and 25% insulin lispro injection as well as a mixture of 50% insulin lispro protamine suspension and 50% insulin lispro injection.

In October 2012, the product’s labeling was updated to indicate a change in the intravenous administration. Patients using the drug intravenously should use insulin lispro at concentrations from 0.1 unit/mL to 1 unit/mL in infusion systems containing 0.9% sodium chloride. When patients administer the drug intravenously, they should be under medical supervision and have their blood glucose and potassium levels closely monitored to avoid hypoglycemia and hypokalemia.

In addition, patients using insulin lispro as a subcutaneous injection should use it with intermediate- or long-acting insulin. They are advised to administer the drug 15 minutes before a meal or immediately after a meal.

If patients receive insulin lispro in a continuous subcutaneous infusion pump, they should change the insulin lispro every 7 days and change the infusion set and infusion set insertion site at least every 3 weeks. If insulin lispro is used in an external insulin infusion pump, it cannot be mixed or diluted.

This First Report Managed Care Product Spotlight provides a summary of a meta-analysis of 8 large, randomized trials that evaluated the prevalence of hypoglycemia in patients with type 1 diabetes who received insulin lispro.

PHASE 3 TRIAL

Below is a summary of a meta-analysis that evaluated the frequency of hypoglycemia in in patients with type 1 diabetes taking insulin lispro.

Reference

Brunelle RL, Llewelyn J, Anderson JH, et al. Meta-analysis of the effect of insulin lispro on severe hypoglycemia in patients with type 1 diabetes. Diabetes Care [1998;21(10):1726-1731]

Study Objective

The trial was designed to determine if taking insulin lispro with a meal could reduce the incidence of severe hypoglycemia in type 1 diabetes patients.

Method

The authors used an Eli Lilly database that included data from 8 large, multicenter, randomized studies that compared insulin lispro with regular human insulin. Insulin lispro is absorbed more rapidly than regular human insulin from subcutaneous injection sites, according to the authors, and is associated with a faster onset of action, a shorter time to peak activity, and a shorter duration of action.

Of the trials, 3 had a parallel design and 5 had a crossover design. There were a total of 2576 patients with type 1 diabetes in the studies, and 2327 received insulin lispro. The investigators in the trials were from numerous countries, including the United States, Canada, South Africa, Australia, New Zealand, and several European countries.

Patients were excluded if they had a history of recurrent hypoglycemia. In each of the studies, there was a formal protocol and similar standardized case report forms. All patients received isophane insulin or ultralente as their basal insulin and insulin lispro or regular human insulin before each meal.

The authors defined severe hypoglycemia as patients having a coma or requiring glucagon or intravenous glucose. They noted that hypoglycemia is the most common adverse effect associated with intensive insulin therapy.

Results

The authors concluded that the frequency of hypoglycemia was lower in patients with type 1 diabetes who took insulin lispro compared with those who received regular human insulin therapy. Of the patients in the insulin lispro group, 3.1% had a total of 102 severe hypoglycemic episodes compared with 4.4% of patients in the human insulin therapy group for a total of 131 episodes (P=.024).

Within the individual studies, there were no statistically significant differences between the groups in terms of the incidence of severe hypoglycemic events. In the meta-analysis, there was also no significant difference in the diurnal distribution of severe hypoglycemia.

In the insulin lispro group, the rate of severe hypoglycemia per 100 patient-years was 14.2 compared with 18.2 for patients taking regular human insulin therapy. Between midnight and 6:00 a.m., the proportion of severe hypoglycemia was 31% in the insulin lispro group and 34% in the regular human insulin group.

The authors also mentioned that in the 5 crossover studies, 40 patients in the insulin lispro group had a severe hypoglycemic episode compared with 65 patients in the human insulin group (P=.019). In addition, they noted that the mean hemoglobin A1c (HbA1c) level during a severe hypoglycemic episode was 8.15 in the insulin lispro group and 8.14 in the human insulin group (P=.370). Thus, they said the reduction of hypoglycemia in the insulin lispro group was not due to a difference in the HbA1c levels.

The difference in hypoglycemia may be because insulin lispro has a more precise time action profile at mealtimes and a shorter duration of action compared with regular human insulin, according to the authors.

SAFETY NOTES

The product’s Prescribing Information notes that hypoglycemia is the most common adverse event associated with all insulins, and the risk increases with tighter glycemic control. Although symptoms associated with hypoglycemia differ, it can occur suddenly and can cause seizures and even death.

In addition, patients taking all insulin products can have severe, life-threatening allergy symptoms, including anaphylaxis. They can also suffer from hypokalemia, which, when left untreated, can cause respiratory paralysis, ventricular arrhythmia, and death. Patients are at risk of hypokalemia if they use potassium-lowering medications, medications sensitive to serum potassium concentrations, and intravenously administered insulins.

In March 2013, the Prescribing Information was updated to note that patients taking insulin with thiazolidinediones can suffer from dose-related fluid retention that can lead to, or exacerbate, heart failure.

Patients taking insulin lispro should receive instructions on self-management techniques such as glucose monitoring, proper injection techniques, and management of hypoglycemia. They should also know how to deal with conditions such as illness, stress, or emotional disturbances, an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals.

To avoid mix-ups with other insulins, patients prescribed insulin lispro are advised to check the label before injecting the insulin.

Humalog Facts

·    Humalog was approved by the FDA on June 14, 1996, to improve glycemic control in adults and children with diabetes.

·    Humalog is marketed by Eli Lilly and Company.

Additional Resource

Prescribing Information for Humalog: https://pi.lilly.com/us/humalog-pen-pi.pdf