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

06 Jun 2007 Insulin aspart for diabetes mellitus (last update: March 2007)

Background information of 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 aspart is homologous with regular human insulin with the exception of a substitution of amino acid aspartic acid for proline in position B28. The modification was designed to decrease the tendency for the molecule to self-associate into hexamers due to charge repulsion, causing insulin aspart to be absorbed more rapidly and have a faster onset of action.

Mechanism of action:
The primary activity of insulin aspart is the regulation of glucose metabolism. Insulins, including insulin aspart, bind to the insulin receptors on muscle and fat cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously inhibit the output of glucose from the liver.

Indication: “for the treatment of patients with type I and type II diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis”. Insulin aspart should normally be used in regimens together with intermediate or long-acting insulin.

Dose: Insulin aspart should generally be administered immediately before a meal. When necessary it may be given immediately after the meal. The individual insulin requirements vary between 0.5-1.0 Units/kg/day (100U/ml). In a meal-related treatment, 50 to 70% of this requirement may be provided by insulin aspart and the remainder provided by intermediate-acting or long-acting insulin.

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 aspart provide a significant therapeutic advantage over regular human insulin (Humulin, Novolin) or other insulin analogues (lispro, 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 aspart 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: Three double blind randomized controlled cross over trials (Home et al 1998, Heller et al 2004 and Gallagher et al 2005) of 4, 16 and 6 weeks duration respectively, comparing insulin aspart to regular human insulin in 259 patients with type I diabetes and 21 patients with Type II 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.  One of the three DB RCTs (Home et al, 1998) reported on number of patients with major hypoglycaemic events (16/104 vs. 24/104 p = not significant).  Data on total hypoglycaemic events between treatment groups cannot be interpreted without complete information on the number of patients with one or more hypoglycaemic episodes in both treatment groups.  There was no significant difference in HbA1c and serum fructosamine or glucose levels between treatment groups.  Diabetes related symptoms have not been reported.

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 fructosamine 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 aspart in comparison to other types of insulin.
2. There is insufficient evidence from published double-blind randomized controlled trials that insulin aspart provides a therapeutic advantage versus regular insulin in the treatment of type I or type II diabetes mellitus.  No DB RCTs compared insulin aspart versus insulin lispro or animal insulins.
3. There is insufficient evidence that the new dosing regimen recommended for insulin aspart, 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. Gallagher et al. The effect of improved post-prandial blood glucose control on post-prandial metabolism and markers of vascular risk in people with Type 2 diabetes. Diabetes Research & Clinical Practice.  67(3):196-203, 2005.
3. Heller et al. Hypoglycaemia with insulin aspart: a double-blind, randomised, crossover trial in subjects with Type 1 diabetes. Diabetic Medicine.  21(7):769-75, 2004.
4. Home PD, Lindholm A, Hylleberg B, Round P, UK Insulin Aspart Study Group. Improved Glycemic Control with Insulin Aspart. A multicenter randomized double-blind crossover trial in type I diabetic patients. Diabetes Care 1998; 21(11):1904-1909.