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Meta-Analysis
. 2016 Jun 30;2016(6):CD012161.
doi: 10.1002/14651858.CD012161.

Short-acting insulin analogues versus regular human insulin for adults with type 1 diabetes mellitus

Birgit Fullerton  1 , Andrea Siebenhofer, Klaus Jeitler, Karl Horvath, Thomas Semlitsch, Andrea Berghold, Johannes Plank, Thomas R Pieber, Ferdinand M Gerlach
Affiliations
Meta-Analysis

Short-acting insulin analogues versus regular human insulin for adults with type 1 diabetes mellitus

Birgit Fullerton et al. Cochrane Database Syst Rev. .

Abstract

Background: Short-acting insulin analogue use for people with diabetes is still controversial, as reflected in many scientific debates.

Objectives: To assess the effects of short-acting insulin analogues versus regular human insulin in adults with type 1 diabetes.

Search methods: We carried out the electronic searches through Ovid simultaneously searching the following databases: Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (1946 to 14 April 2015), EMBASE (1988 to 2015, week 15), the Cochrane Central Register of Controlled Trials (CENTRAL; March 2015), ClinicalTrials.gov and the European (EU) Clinical Trials register (both March 2015).

Selection criteria: We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues with regular human insulins in the treatment of adults with type 1 diabetes who were not pregnant.

Data collection and analysis: Two review authors independently extracted data and assessed trials for risk of bias, and resolved differences by consensus. We graded overall study quality using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) instrument. We used random-effects models for the main analyses and presented the results as odds ratios (OR) with 95% confidence intervals (CI) for dichotomous outcomes.

Main results: We identified nine trials that fulfilled the inclusion criteria including 2693 participants. The duration of interventions ranged from 24 to 52 weeks with a mean of about 37 weeks. The participants showed some diversity, mainly with regard to diabetes duration and inclusion/exclusion criteria. The majority of the trials were carried out in the 1990s and participants were recruited from Europe, North America, Africa and Asia. None of the trials was carried out in a blinded manner so that the risk of performance bias, especially for subjective outcomes such as hypoglycaemia, was present in all of the trials. Furthermore, several trials showed inconsistencies in the reporting of methods and results.The mean difference (MD) in glycosylated haemoglobin A1c (HbA1c) was -0.15% (95% CI -0.2% to -0.1%; P value < 0.00001; 2608 participants; 9 trials; low quality evidence) in favour of insulin analogues. The comparison of the risk of severe hypoglycaemia between the two treatment groups showed an OR of 0.89 (95% CI 0.71 to 1.12; P value = 0.31; 2459 participants; 7 trials; very low quality evidence). For overall hypoglycaemia, also taking into account mild forms of hypoglycaemia, the data were generally of low quality, but also did not indicate substantial group differences. Regarding nocturnal severe hypoglycaemic episodes, two trials reported statistically significant effects in favour of the insulin analogue, insulin aspart. However, due to inconsistent reporting in publications and trial reports, the validity of the result remains questionable.We also found no clear evidence for a substantial effect of insulin analogues on health-related quality of life. However, there were few results only based on subgroups of the trial populations. None of the trials reported substantial effects regarding weight gain or any other adverse events. No trial was designed to investigate possible long-term effects (such as all-cause mortality, diabetic complications), in particular in people with diabetes related complications.

Authors' conclusions: Our analysis suggests only a minor benefit of short-acting insulin analogues on blood glucose control in people with type 1 diabetes. To make conclusions about the effect of short acting insulin analogues on long-term patient-relevant outcomes, long-term efficacy and safety data are needed.

PubMed Disclaimer

Conflict of interest statement

BF: none known.

AS: was involved in the preparation of the report on short‐acting insulin analogues for the treatment of type 1 diabetes mellitus for the Institute for Quality and Efficiency in Health Care (www.iqwig.de).

KJ: was involved in the preparation of the report on short‐acting insulin analogues for the treatment of type 1 diabetes mellitus for the Institute for Quality and Efficiency in Health Care (www.iqwig.de).

KH: was involved in the preparation of the report on short‐acting insulin analogues for the treatment of type 1 diabetes mellitus for the Institute for Quality and Efficiency in Health Care (www.iqwig.de). KH has received payment for lectures, travel/accommodations/meeting expenses and consultancy from various sources (Novartis, Medtronic, Eli Lilly, Novo Nordisk, Sanofi Aventis, Merck Sharp & Dohme).

TS: none known.

AB: none known.

JP: none known.

TRP: the Medical University of Graz (employee of Thomas Pieber) has received unrestricted grants from AstraZenaca and Novo Nordisk.Thomas Pieber has received personal fees for advisory boards and steering committees for AstraZeneca, Eli Lilly and Novo Nordisk; and has received personal fees in speaker bureaus for AstraZeneca and Novo Nordisk.

FMG: none known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Insulin analogues versus regular human insulin, outcome: 1.1 Severe hypoglycaemic episodes including cross‐over trials, paired.
5
5
Forest plot of comparison: 1 Insulin analogues versus regular human insulin, outcome: 1.7 HbA1c, random‐effects model.
6
6
Forest plot of comparison: 1 Insulin analogues versus regular human insulin, outcome: 1.12 Weight gain, random‐effects model.
1.1
1.1. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 1 Severe hypoglycaemic episodes including cross‐over trials, paired.
1.2
1.2. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 2 Severe hypoglycaemic episodes without cross‐over trials.
1.3
1.3. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 3 Severe hypoglycaemic episodes including cross‐over trials, unpaired.
1.4
1.4. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 4 Severe hypoglycaemic episodes including cross‐over trials, paired.
1.5
1.5. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 5 Severe hypoglycaemic episodes including cross‐over trials, paired, fixed‐effect model.
1.6
1.6. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 6 Severe hypoglycaemic episodes including cross‐over trials, paired.
1.7
1.7. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 7 HbA1c, random‐effects model.
1.8
1.8. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 8 HbA1c by different short‐acting insulin analogues (%).
1.9
1.9. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 9 HbA1c by different types of study design.
1.10
1.10. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 10 HbA1c, random‐effects model, unpaired analysis.
1.11
1.11. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 11 HbA1c, fixed‐effect model.
1.12
1.12. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 12 Weight gain, random‐effects model (kg).
1.13
1.13. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 13 Weight gain, fixed‐effect model (kg).
1.14
1.14. Analysis
Comparison 1 Insulin analogues versus regular human insulin, Outcome 14 Weight gain, by different short‐acting insulin analogues (kg).
See this image and copyright information in PMC

References

References to studies included in this review

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Z015 2007 {published data only}
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Persson 2002 {published data only}
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