Insulin lispro for diabetes mellitus (last update: March 2007)

05 Jun 2007 Insulin lispro for diabetes mellitus (last update: March 2007)

Background information on the condition

Diabetes Mellitus is a chronic disease in which the body does not produce or properly use insulin. Type 1 diabetes is an autoimmune disease in which the patient has to take insulin daily to live because the pancreas make little or no insulin. In type 2 diabetic patients, the pancreas is not making enough insulin, or the body cannot use the insulin effectively (insulin resistant).

Drug

Category: Insulin lispro is a short-acting insulin analogue that differs from regular human insulin in the reversed amino-acids proline and lysine at position 28 and 29 on the insulin B-chain. This analogue is modified to increase speed absorption.

Mechanism of action:
The primary activity of insulins is the regulation of glucose metabolism. In muscle and other tissues (except the brain), insulin causes rapid transport of glucose and amino acids intracellularly, promotes anabolism, and inhibits protein catabolism. In the liver, insulin promotes the uptake and storage of glucose in the form of glycogen, inhibits gluconeogenesis and promotes the conversion of excess glucose into fat.

Indication: “For the treatment of patients with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis.” Humalog insulins are also indicated for the initial stabilization of diabetes mellitus. Humalog (insulin lispro injection) is a short-acting insulin analogue and is for use in conjunction with longer-acting human insulin, such as Humulin N, Humulin L or Humulin U except when used in a subcutaneous insulin infusion pump.

Dose: Insulin lispro should be given within 15 minutes before a meal, or when necessary shortly after a meal instead (within 20 minutes of the start of the meal).

Duration: patients with type I diabetes mellitus require life-long therapy.

Methodology of systematic review

Research question: In double blind randomized controlled trials, does insulin lispro provide a significant therapeutic advantage over regular human insulin (Humulin, Novolin) or other insulin analogues (aspart, glargine, detemir) or animal insulin (purified pork insulin) in patients with type I or type II diabetes mellitus?

Assessment principles: Double blind randomized controlled trials of at least 4 weeks duration comparing insulin lispro to other types of insulin in patients with type I or type II diabetes will be included and critically appraised.  Randomization and blinding are required for assessment of outcomes of diabetes treatments, as glucose control reflects not only drug therapy, but also patient dietary and exercise habits. As a result, even objective outcomes measures (for example biochemical markers of blood glucose) are subject to bias in open label and non-randomized trials.
The overall health impact will be assessed according to the following hierarchy and includes all cause mortality (including diabetes-related death from myocardial infarction, stroke, peripheral vascular disease, renal disease, and hyper- or hypoglycaemia or sudden death); Serious adverse events including diabetes-related morbidity: retinopathy, nephropathy, neuropathy, amputation, cardiovascular events (myocardial infarction, stroke, peripheral vascular disease), and hyper- or hypoglycaemic episodes; Diabetes-related symptoms (polyuria, polydypsia, polyphagia); and  Glycemic control including glycated haemoglobin (HbA1c and blood glucose levels).

Search strategy: Databases searched: (Medline, Embase and Cochrane Library from 1996 to February 2007), the manufacturer’s submission, and references of review articles.

Search findings: Two double blind randomized controlled cross over trials (Zinman et al 1997, Gale et al 2000) of 6 months and 24 weeks duration respectively, comparing insulin lispro to regular human insulin in 123 patients with type I diabetes met the inclusion criteria for critical appraisal.

Results: None of the trials examined the effect of insulin aspart on serious diabetes-related morbidity or mortality. Hypoglycemic rates were not significantly different between insulin lispro and human insulin groups at the end of both studies. In the trial by Zinman et al 1997, the end point HbA1c levels were significantly lower with insulin lispro (p=0.004) but no significance differences in HbA1c levels between insulin lispro and human insulin group was found in the other study. In Gale et al 2000 study, although the post-prandial blood glucose levels were lower during insulin lispro treatment, fasting and pre-prandial blood glucose levels were increased in the insulin lispro group.  Patients were asked to express their preference without knowing which insulin analog they have used. No clear preference was found.

Summary and rationale of conclusions

Trials should report on clinically relevant outcomes such as total mortality, diabetes related mortality and morbidity, serious adverse events, drug tolerability, or symptomatic improvement.  Decrease in surrogate biochemical markers such as HbA1c and glucose levels are considered meaningful if the amount and duration of decrease has been associated with a decrease in mortality or morbidity in patients with insulin dependent diabetes.  The relationship between short term differences in surrogate outcome measures and clinically relevant outcome measures has not been established.

Conclusions:

1. There is no evidence of a reduction in total morbidity and mortality, or in diabetes-related serious morbidity or mortality, with insulin lispro in comparison to other types of insulin.
2. There is insufficient evidence from published double-blind randomized controlled trials that insulin lispro provides a therapeutic advantage versus regular insulin in the treatment of type I diabetes mellitus. No DB RCTs compared insulin lispro versus regular insulin in patients with type II diabetes mellitus. No DB RCTs compared insulin lispro versus insulin aspart or animal insulins.
3. There is insufficient evidence that the new dosing regimen recommended for insulin lispro, immediately prior to meals, provides a therapeutic advantage over the recommended dosing regimen for alternate forms of human or animal insulin, 30 minutes prior to meals.

References:

1. Product monograph (e-CPS, 2007)
2. Zinman et al.Insulin lispro in CSII: Results of a double-blind crossover study.  Diabetes. 46(3):440-3, 1997
3. Gale et al. A randomized, controlled trial comparing insulin lispro with human soluble insulin in patients with Type 1 diabetes on intensified insulin therapy. Diabetic Medicine. 17(3):209-14, 2000