Short acting insulin analogues versus structurally unchanged insulin in patients with diabetes mellitus
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate advantages or disadvantages of treating diabetic patients with short acting insulin analogues in comparison to structurally unchanged insulin. The main outcomes of interest are: Glycaemic control, hypoglycaemia, quality of life, number and severity of adverse events such as ketoacidosis, diabetic complications and total mortality.
Background
Diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion, insulin action, or both. This in turn leads to chronic hyperglycaemia (i.e. elevated levels of plasma glucose) with disturbances of carbohydrate, fat and protein metabolism. Long‐term complications of diabetes mellitus include retinopathy, nephropathy, neuropathy and increased risk of cardiovascular disease. For a detailed overview of diabetes mellitus, please see 'Additional information' in the information on the Metabolic and Endocrine Disorders Group on the Cochrane Library (see 'About the Cochrane Collaboration', 'Collaborative Review Groups'). For an explanation of methodological terms, see the main Glossary on the Cochrane Library.
Despite improved purity and stability of the available insulin preparations, it has become apparent that the pharmacokinetics following subcutaneous injection of the currently available structurally unchanged insulin preparations make it difficult to achieve day‐long normoglycaemia (Zinman 1989). In the last decade, considerable attention has been devoted to the development of insulin analogues with pharmacokinetic profiles that differ from those of existing insulin preparations. Compared to human insulin, lysine at position 28 and proline at position 29 of the B‐region were interchanged in the short acting insulin analogue Lispro (HumalogR). In the short acting insulin analogue Aspart (NovoRapidR), proline at position 29 of the B‐region was replaced by aspartic acid. Plasma insulin concentrations peak 2‐4 hours after injection of structurally unchanged insulin, unlike the much earlier plasma insulin peak in non‐diabetic individuals after meal ingestion. This low rise to peak insulin concentration is likely to account for much of the observed hyperglycaemia following meals in people with diabetes. The delay in the absorption of subcutaneously administered structurally unchanged insulin is due to the fact that in this preparation, insulin tends to associate in 'clusters' of six molecules (hexamers), and time is needed after injection for these clusters to dissociate to single molecules which can be used by the body (Mosekilde 1989). Short acting insulin analogues with less tendency toward self‐association are therefore absorbed more quickly, achieving peak plasma concentrations about twice as high and within approximately half the time compared to structurally unchanged insulin (Howey 1994; Torlone 1994).
This pharmacokinetic profile leads to lower glucose levels after meals (Howey 1994; Heinemann 1996) and should improve overall glycaemic control. It has been proposed that lower postprandial glucose may be associated with a lower risk of cardiovascular complications in diabetes (Haffner 1998). One suggested advantage of short acting insulin analogues is the possibility to inject insulin immediately before meals, even if in daily life most diabetic patients seem to use short or even no injection‐meal interval (Heinemann 1995). Further proposed advantages in terms of quality of life are changes in injection modes with the possibility of injecting short acting insulin analogues after meals (Schernthaner 1998).
Treatment with the two short acting insulin analogues (Lispro ‐ HumalogR, Aspart ‐ Novo RapidR) available on the market is currently promoted with purported advantages with respect to metabolic control and reduced incidence of hypoglycaemic episodes for patients with diabetes mellitus (type 1, type 2, diabetic children and diabetic pregnant women) (Martin 1994; Garg 1996; Pfützner 1996; Anderson 1997; Anderson JH Jr 1997; Holleman 1997; Jacobs 1997; Vignati 1997; Ahmed 1998). On the other hand, several studies failed to show a positive effect on overall blood glucose levels when short acting insulin analogues were compared with structurally unchanged insulin (Garg 1996; Pfützner 1996; Anderson 1997; Holleman 1997; Gale 2000). Insulin treatment strategies where short acting insulin analogues can be used include intensified insulin therapy (short acting insulin before meals, basal insulin at bedtime or twice daily, including adjustment of insulin dose based on carbohydrate intake) or conventional insulin therapy (basal or premixed insulin up to three times daily with or without oral hypoglycaemic agents). Only patients treated with continuous subcutaneous insulin infusion (CSII) performing intensified insulin therapy showed a significant decrease in HbA1c when short acting insulin analogues were used (Zinman 1997; Melki 1998). In the case of hypoglycaemic episodes, two recently published meta analyses also reported contradictory results with respect to hypoglycaemic episodes (Davey 1997; Brunelle 1998). Insulin analogues are more expensive than structurally unchanged insulin and in the year 2000 insulin Lispro and insulin Aspart had a 30% share of the market for short acting insulins in most developed countries.
Structural homology of insulin analogues to insulin‐like‐growth‐factor‐I (IGF‐I) has caused concern regarding the progression of diabetic late complications and potential mitogenic (induction of cell division) effects, especially with long‐term use of insulin analogues. IGF‐I may affect the progression of retinopathy (King 1985; Grant 1993) and certain modified insulin analogues have shown a carcinogenic effect in the mammary glands in female rats (Jørgensen 1992) or mitogenic potency in osteosarcoma cells (Kurtzhals 2000). Despite these potentially adverse properties of insulin analogues, only very limited data on long term safety are currently available, mainly because patients with clinically relevant microvascular complications have been excluded from most clinical studies.
As only a few reviews (Bolli 1999; Holleman 1997; Shukla 1999; Davey 1997; Brunelle 1998) are currently available, we would like to present a systematic review on possible advantages of treatment with short acting insulin analogues to provide adequate information for medical personnel and patients.
Objectives
To evaluate advantages or disadvantages of treating diabetic patients with short acting insulin analogues in comparison to structurally unchanged insulin. The main outcomes of interest are: Glycaemic control, hypoglycaemia, quality of life, number and severity of adverse events such as ketoacidosis, diabetic complications and total mortality.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (blinded and open, parallel and cross‐over design) with a duration of four weeks or more, designed to compare diabetic patients who are treated with the short acting insulin analogues Lispro or Aspart versus structurally unchanged insulin will be included in the review, regardless of dose or schedule, if insulin was injected subcutaneously via syringe, pen or pump. Effects of different administration schedules will be investigated. Only a small number of blinded studies are expected, as in most cases different injection schedules are used for insulin analogues and structurally unchanged insulin. Effects of blinding will be investigated separately in a sensitivity analysis.
Types of participants
People of any age or sex with type 1 or type 2 diabetes on insulin, and diabetic pregnant women (including gestational diabetes), using the diagnostic criteria valid at the time of beginning of the trial (WHO 1985; ADA 1997). Changes in diagnostic criteria may have produced significant variability in the clinical characteristics of the patients included as well as in the results obtained. Therefore, if enough data are available, these differences will be considered and explored in a sensitivity analysis.
Types of interventions
We will consider all diabetic patients receiving a short acting insulin analogue treatment (intervention group) in comparison to patients receiving treatment with structurally unchanged insulin (control group), no matter if the short acting insulin treatment was used with or without other long‐ or intermediate acting insulin, as long as any additional treatment was given equally in both groups.
Types of outcome measures
We plan to extract information on the following outcome measures:
MAIN
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Glycaemic control (e.g. glycated haemoglobin, fasting plasma glucose, 24 hour glucose profile)
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Number of overall, severe (e. g. requiring third party help) and non‐severe hypoglycaemic episodes (subdivided by time of day of occurrence)
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Quality of life assessment, ideally using a validated instrument like the Diabetes Quality of Life Clinical Trial Questionnaire (Bradley 1990)
ADDITIONAL
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Number and severity of adverse events (e.g. local reactions, ketoacidosis, carcinogenicity)
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Diabetic complications (nephropathy, retinopathy, neuropathy, other diabetes related complications)
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Diabetes related mortality (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, hypoglycaemia, sudden death)
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Total mortality
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Costs
TIMING OF OUTCOME MEASUREMENT
Outcome measurement will be divided in short term (< 3 months) and long term (> 3 months) outcome measurement.
Search methods for identification of studies
A. ELECTRONIC SEARCHES:
Published studies will be identified through a literature search using the Cochrane Library (including the Cochrane Controlled Trials Register), Medline, Embase, and the CRD Databases (DARE, NHSEED, HTA). We will use the standard search strategies provided by the Cochrane Metabolic and Endocrine Disorders Group and search terms for short acting insulin analogues which are shown in the Medline search strategy below. The search strategies will be adapted for the other databases.
The general search strategy consists of
1. short acting insulin analogues (see below)
2. diabetes mellitus (see search strategy of the Cochrane Metabolic and Endocrine Disorders Group)
3. systematic reviews/meta‐analyses (see search strategy of the Cochrane Metabolic and Endocrine Disorders Group)
4. randomised/controlled trials (see search strategy of the Cochrane Metabolic and Endocrine Disorders Group)
5. economic studies (see search strategy of the Cochrane Metabolic and Endocrine Disorders Group).
and will be combined as follows:
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#1 and #2 and #3 for systematic reviews/meta‐analyses
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#1 and #2 and #4 for randomised controlled trials
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#1 and #2 and #5 for economic studies
in the field of insulin analogues.
NOTES: unless stated otherwise, search terms are free text terms; a Dollar sign ($) stands for 'any character(s)'; 'adj' is equivalent to 'near'.
1 (insulin$ adj (analog$ or derivat$ or short acting)) [in abstract or title]
2 (fast acting or rapid acting) adj insulin$ [in abstract or title]
3 ((novel or new) adj insulin$) [in abstract or title]
4 1 or 2 or 3
5 (Lyspro$ or Lispro$) [in abstract or title]
6 (Lys adj B28) [in abstract or title]
7 (B28 or LysB28 or ProB29) [in abstract or title]
8 Humalog$ [in abstract or title]
9 5 or 6 or 7 or 8
10 Novorapid [in abstract or title]
11 (Asp$ adj B10) [in abstract or title]
12 (B28‐Asp$ or B28Asp$) [in abstract or title]
13 (Insulin$ adj aspart$) [in abstract or title]
14 10 or 11 or 12 or 13
15 4 or 9 or 14
Electronic searches will be carried out at the editorial base and by the reviewers.
B. ADDITIONAL SEARCH
Additional searching will be done by using cross‐references from original articles and reviews, and by screening of abstracts of major diabetology meetings (European Association for the Study of Diabetes, American Diabetes Association) ongoing from 1992.
With the help of the International Register of Clinical Trials Registers at (http://www.trialscentral.org) and the register at Current Science (http://www.controlled‐trials.com) we will look for ongoing trials.
The three main pharmaceutical companies producing short‐acting insulin analogues (Aventis, Eli Lilly, Novo Nordisk) will also be asked whether any uncompleted or unpublished studies may have been overlooked. We plan to contact experts and approval agencies (e.g. EMEA ‐ The European Agency for the Evaluation of Medicinal Products, FDA ‐The Food and Drug Administration, MCA ‐ Medicines Control Agency, TGA ‐ Therapeutic Goods Administration).
Concerning economic analyses, we will additionally contact the Pharmaceutical Evaluation Section of the Pharmaceutical Benefits Branch of the Commonwealth Department of Health and Aged Care of Australia.
Finally the bibliography of standard textbooks (Diabetes Annual, 12. Elsevier Science B.V. 1999; Praxis der Insulintherapie; Berger M. und Jörgens V.; 6. Auflage, Springer‐Verlag, Heidelberg Berlin 2001, Evidence‐based Diabetes Care; Gerstein H.C. and Haynes R.B.; BC Decker Inc 2001) and of economic studies found will be reviewed.
Data collection and analysis
STUDY SELECTION
Two reviewers will independently screen the title, abstract and key words of each reference identified by the search and apply the inclusion criteria. Interrater agreement will be calculated using the kappa‐statistic (Cohen 1960). Articles that appear to fulfil the inclusion criteria will be retrieved in full. In case of disagreement between the two reviewers, the full article will be obtained and inspected independently by the two reviewers. Where differences in opinion exist, the differences will be resolved by a third party. If resolving disagreement is not possible, the article will be added to those 'awaiting assessment' and the authors of the study will be contacted for clarification.
QUALITY ASSESSMENT OF TRIALS
Trials fulfilling the review inclusion criteria will be assessed independently for methodological quality by two reviewers. Interrater agreement will be calculated using the kappa‐statistics. In cases of disagreement, the rest of the group will be consulted and a judgement will be made based on consensus. Assessment for methodological quality will be done using a modification of the criteria given in the Cochrane Handbook and the criteria of Schulz and Jadad (Schulz 1995; Jadad 1996).
1. Minimisation of selection bias
a) was the randomisation procedure adequate?
b) was the allocation concealment adequate?
2. Minimisation of performance bias
a) were the patients and people administering the treatment blind to the intervention?
3. Minimisation of attrition bias
a) were withdrawals and dropouts completely described?
b) was analysis done by intention‐to‐treat?
4. Minimisation of detection bias
a) were outcome assessors blind to the intervention?
Based on these criteria, studies will be broadly subdivided into the following three categories (see Cochrane Handbook):
A ‐ all quality criteria met: low risk of bias.
B ‐ one or more of the quality criteria only partly met: moderate risk of bias.
C ‐ one or more criteria not met: high risk of bias.
For the purpose of the analysis in this review, trials will be included if they meet the criteria A, B or C according to the Handbook (Clarke 1998; Kunz 1998) (see also sensitivity analysis below).
DATA COLLECTION
Data from each included study will be extracted by two independent reviewers using our data extraction form. Differences in data extraction will be resolved by consensus, referring back to the original article. When necessary, information will be sought from the authors of the primary studies. Our data extraction form will be headed by the identification of the trial, the name of the first author, the year in which the trial was first published and the quality assessment criteria. The following data will be extracted, checked and recorded:
1. General Information:
The general information includes the publication status (published or unpublished), if it is a duplicate publication, the sponsor of trial (specified, known or unknown), the language of publication, the country of publication, the geographical area (urban or rural) and the setting, where the trial was carried out (hospital inpatient, hospital outpatient, physicians office).
2. Methods Section
The information about the methods summarises the characteristics of the trial, the characteristics of participants, the characteristics of interventions and the outcome measures used and reported in the publication.
2.1. Characteristics of the trial:
The items to report cover the design and the duration of the trial, the randomisation (and method), the allocation concealment (and method), the blinding (patients, people administering treatment, outcome assessors) and the check of blinding.
2.2. Characteristics of participants:
Information about the participants includes the number of participants in each group, how the participants were selected (random, convenience), the exclusion criteria used and the general characteristics (e.g. age, gender, nationality, ethnicity). Disease related information concerning duration of diabetes and late complications such as retinopathy, nephropathy, neuropathy and foot complications will be extracted. The similarity of groups at baseline will be checked and the reports about withdrawals and losses to follow‐up (reasons/description). If subgroup analysis was done, the reported reasons and the method will be noted.
2.3. Characteristics of interventions:
The relevant information to extract is the time of intervention, the length of follow‐up (in months), the types of insulin (analogues versus common), the dose and route of administration and the schedule of administration.
2.4. Characteristics of outcome measures
The measures mentioned in the outcome section and any other outcomes measured in the study will be reported.
DATA ANALYSIS
The results of the trial will be extracted for outcomes (including a measure of variation) and times of assessment, if necessary converted to measures of effect (specified below).
Exploratory data analysis will be performed of all relevant data and summary measures will be used where appropriate. There will be both continuous and categorical data. Continuous data will be expressed as weighted mean differences (WMD) and an overall WMD will be calculated. Dichotomous data will be expressed as odd ratios (OR). If possible, these will be converted to numbers‐needed‐to‐treat (NNT), to make data easier to understand for the reader. The meta‐analysis will be carried out using a fixed effects model. Heterogeneity will be tested for using the Z score and the Chi square statistic, with a level of significance of p < 0.1. If heterogeneity is present and a meta‐analysis seems appropriate, the assumptions of a fixed effects model no longer apply, and a random effects model will be used. Possible sources of heterogeneity will be assessed by subgroup and sensitivity analyses as described below. Publication bias and small study effects in general will be tested for using the funnel plot or other corrective analytical methods depending on the number of clinical trials included in the systematic review.
SUBGROUP ANALYSES
We will aim to perform subgroup analyses in order to explore effect size differences as follows:
1. Age (<15 years, 15 ‐ 65 years, older than 65 years)
2. Gender
3. Diabetes type (1 and 2), diabetes in pregnant women
4. Different comparison interventions such as conventional versus intensified treatment
5. Duration of intervention
6. Different types of insulin analogues (Lispro versus Aspart)
SENSITIVITY ANALYSES
We plan to perform sensitivity analyses in order to explore the influence of the following factors on effect size:
1. Repeating the analysis excluding unpublished studies (if there are any).
2. Repeating the analysis taking account of study quality, as specified above ((A + B) versus C; individual quality criteria, e.g. blinding).
3. Repeating the analysis taking account of different diagnostic criteria.
4. Repeating the analysis excluding any very long or large studies to establish how much they dominate the results.
5. Repeating the analysis excluding studies using the following filters: language of publication, source of funding (industry versus other), quality of life measurements.
The robustness of the results will also be tested by repeating the analysis using different measures of effect size (risk difference, odds ratio etc.) and different statistic models (fixed and random effects models).
The analyses will be carried out using MetaView 4.1 in Review Manager 4.1 (Cochrane software).
