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Meta-Analysis
. 2018 Dec 17;12(12):CD013228.
doi: 10.1002/14651858.CD013228.

Short-acting insulin analogues versus regular human insulin for adult, non-pregnant persons with type 2 diabetes mellitus

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

Short-acting insulin analogues versus regular human insulin for adult, non-pregnant persons with type 2 diabetes mellitus

Birgit Fullerton et al. Cochrane Database Syst Rev. .

Abstract

Background: The use of short-acting insulin analogues (insulin lispro, insulin aspart, insulin glulisine) for adult, non-pregnant people with type 2 diabetes is still controversial, as reflected in many scientific debates.

Objectives: To assess the effects of short-acting insulin analogues compared to regular human insulin in adult, non-pregnant people with type 2 diabetes mellitus.

Search methods: For this update we searched CENTRAL, MEDLINE, Embase, the WHO ICTRP Search Portal, and ClinicalTrials.gov to 31 October 2018. We placed no restrictions on the language of publication.

Selection criteria: We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues to regular human insulin in the treatment of people with type 2 diabetes, who were not pregnant.

Data collection and analysis: Two review authors independently extracted data and assessed the risk of bias. We assessed dichotomous outcomes by risk ratios (RR), and Peto odds ratios (POR), with 95% confidence intervals (CI). We assessed continuous outcomes by mean differences (MD) with 95% CI. We assessed trials for certainty of the evidence using the GRADE approach.

Main results: We identified 10 trials that fulfilled the inclusion criteria, randomising 2751 participants; 1388 participants were randomised to receive insulin analogues and 1363 participants to receive regular human insulin. The duration of the intervention ranged from 24 to 104 weeks, with a mean of about 41 weeks. The trial populations showed diversity in disease duration, and inclusion and exclusion criteria. None of the trials were blinded, so the risk of performance bias and detection bias, especially for subjective outcomes, such as hypoglycaemia, was high in nine of 10 trials from which we extracted data. Several trials showed inconsistencies in the reporting of methods and results.None of the included trials defined all-cause mortality as a primary outcome. Six trials provided Information on the number of participants who died during the trial, with five deaths out of 1272 participants (0.4%) in the insulin analogue groups and three deaths out of 1247 participants (0.2%) in the regular human insulin groups (Peto OR 1.66, 95% CI 0.41 to 6.64; P = 0.48; moderate-certainty evidence). Six trials, with 2509 participants, assessed severe hypoglycaemia differently, therefore, we could not summarise the results with a meta-analysis. Overall, the incidence of severe hypoglycaemic events was low, and none of the trials showed a clear difference between the two intervention arms (low-certainty evidence).The MD in glycosylated haemoglobin A1c (HbA1c) change was -0.03% (95% CI -0.16 to 0.09; P = 0.60; 9 trials, 2608 participants; low-certainty evidence). The 95% prediction ranged between -0.31% and 0.25%. The MD in the overall number of non-severe hypoglycaemic episodes per participant per month was 0.08 events (95% CI 0.00 to 0.16; P = 0.05; 7 trials, 2667 participants; very low-certainty evidence). The 95% prediction interval ranged between -0.03 and 0.19 events per participant per month. The results provided for nocturnal hypoglycaemic episodes were of questionable validity. Overall, there was no clear difference between the two short-acting insulin analogues and regular human insulin. Two trials assessed health-related quality of life and treatment satisfaction, but we considered the results for both outcomes to be unreliable (very low-certainty evidence).No trial was designed to investigate possible long term effects (all-cause mortality, microvascular or macrovascular complications of diabetes), especially in participants with diabetes-related complications. No trial reported on socioeconomic effects.

Authors' conclusions: Our analysis found no clear benefits of short-acting insulin analogues over regular human insulin in people with type 2 diabetes. Overall, the certainty of the evidence was poor and results on patient-relevant outcomes, like all-cause mortality, microvascular or macrovascular complications and severe hypoglycaemic episodes were sparse. Long-term efficacy and safety data are needed to draw conclusions about the effects of short-acting insulin analogues on patient-relevant outcomes.

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Conflict of interest statement

BF: none known.

AS: was involved in the preparation of a report on the effects of long‐acting insulin analogues versus other basal insulins in the therapy of patients with type 1 and type 2 diabetes mellitus for IQWiG, the German Institute for Quality and Efficiency in Health Care.

KJ: was involved in the preparation of the reports on short‐acting insulin analogues for the treatment of diabetes mellitus for the Institute for Quality and Efficiency in Health Care.

KH: has received payment for lectures, travel/accommodations/meeting expenses and consultancy from various sources (Novo Nordisk, Novartis, Medtronic, Eli Lilly, Sanofi Aventis, Merck Sharp & Dohme, AstraZeneca).

TS: none known.

AB: none known.

FMG: none known.

Figures

Figure 1
Figure 1
Study flow diagram
Figure 2
Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials (note that not all trials measured all outcomes)
Figure 3
Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study (note that not all trials measured all outcomes)
Figure 4
Figure 4
Forest plot of comparison: Short‐acting insulin analogues versus regular human insulin (RHI); outcome 1.4. HbA1c changes for different types of insulin (%)
Figure 5
Figure 5
Forest plot of comparison: Short‐acting insulin analogues versus regular human insulin (RHI); outcome 1.6. All non‐severe hypoglycaemic episodes (mean episode/participant/month) for different types of insulin
Analysis 1.1
Analysis 1.1
Comparison 1 Short‐acting insulin analogues versus regular human insulin (RHI), Outcome 1 All‐cause mortality.
Analysis 1.2
Analysis 1.2
Comparison 1 Short‐acting insulin analogues versus regular human insulin (RHI), Outcome 2 All‐cause mortality for different types of insulin.
Analysis 1.3
Analysis 1.3
Comparison 1 Short‐acting insulin analogues versus regular human insulin (RHI), Outcome 3 HbA1c changes.
Analysis 1.4
Analysis 1.4
Comparison 1 Short‐acting insulin analogues versus regular human insulin (RHI), Outcome 4 HbA1c changes for different types of insulin.
Analysis 1.5
Analysis 1.5
Comparison 1 Short‐acting insulin analogues versus regular human insulin (RHI), Outcome 5 All non‐severe hypoglycaemic episodes (mean episode/participant/month).
Analysis 1.6
Analysis 1.6
Comparison 1 Short‐acting insulin analogues versus regular human insulin (RHI), Outcome 6 All non‐severe hypoglycaemic episodes (mean episode/participant/month) for different types of insulin.
See this image and copyright information in PMC

Comment in

References

References to studies included in this review

    1. Altuntas Y, Ozen B, Ozturk B, Sengul A, Ucak S, Ersoy O, et al. Comparison of additional metformin or NPH insulin to mealtime insulin lispro therapy with mealtime human insulin therapy in secondary OAD failure. Diabetes, Obesity and Metabolism 2003;5(6):371‐8. [PUBMED: 14617222] - PubMed
    2. IQWiG (Institute for Quality and Efficiency in Health Care). Short‐acting insulin analogues in the treatment of diabetes mellitus type 2. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG); 2005 December. Abschlusbericht A05‐04.
    1. Bastyr EJ III, Huang Y, Brunelle RL, Vignati L, Cox DJ, Kotsanos JG. Factors associated with nocturnal hypoglycaemia among patients with type 2 diabetes new to insulin therapy: experience with insulin Lispro. Diabetes Obesity and Metabolism 2000;2(1):39‐46. [PUBMED: 11220353] - PubMed
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References to studies excluded from this review

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References to studies awaiting assessment

    1. Farshchi A, Aghili R, Oskuee M, Rashed M, Noshad S, Kebriaeezadeh A, et al. Biphasic insulin Aspart 30 vs. NPH plus regular human insulin in type 2 diabetes patients; a cost‐effectiveness study. BMC Endocrine Disorders 2016;16(1):35. [PUBMED: 27278922] - PMC - PubMed
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    1. NCT01500850. Establishing cardiovascular biomarkers to define preferred Lantus® use. clinicaltrials.gov/ct2/show/NCT01500850 (first posted 29 December 2011).

Additional references

    1. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. New England Journal of Medicine 2008;358:2545‐59. - PMC - PubMed
    1. American Diabetes Association (ADA). Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183‐97. - PubMed
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    1. American Diabetes Association (ADA). Standards of medical care in diabetes ‐ 2017. Diabetes Care 2017;40(Supplement 1):S 11‐33.
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References to other published versions of this review

    1. Siebenhofer A, Plank J, Berghold A, Jeitler K, Horvath K, Narath M, et al. Short acting insulin analogues versus regular human insulin inpatients with diabetes mellitus. Cochrane Database of Systematic Reviews 2006, Issue 2. [DOI: 10.1002/14651858.CD003287.pub4] - DOI - PubMed

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