Key messages
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Compared to regular human insulin, five faster-acting insulin analogues may offer similar benefits in controlling blood glucose levels.
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Compared to regular human insulin, some of them (ultra-rapid lispro, fast-acting aspart and aspart) may reduce the risk of severe complications such as episodes of low blood glucose.
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The evidence about mild diabetes complications, quality of life and adherence to treatment was unclear.
What is type 1 diabetes?
Type 1 diabetes is a condition in which a person's blood sugar (glucose) level becomes too high because the pancreas cannot produce any insulin to control the levels of glucose.
How is the condition treated?
People with type 1 diabetes have to inject insulin to control their glucose levels and stay well. Faster-acting insulin analogues are modified versions of human insulin that are designed to act more quickly after injection than regular human insulin. Examples include insulin lispro, insulin aspart, insulin glulisine, fast-acting insulin aspart (FIAsp) and ultra-rapid lispro insulin (URLi). They can be injected immediately before meals and lead to lower blood sugar levels after food intake.
What did we want to find out?
We wanted to compare the effects of long-term treatment with fast (and very fast)-acting insulin analogues to regular human insulin or another fast-acting insulin in people with type 1 diabetes on multiple daily injections. We wanted to find out about the effects on blood sugar control, episodes of low blood sugar, low blood sugar at nighttime, a serious complication (diabetic ketoacidosis), quality of life and adherence to treatment.
What did we find?
We found 15 studies where people were randomly put into one of two or more treatment groups. The studies compared the faster-acting insulin analogues to regular human insulin and involved 6335 participants. The people in the included studies were monitored (called follow-up) for between 24 and 52 weeks.
Main results
According to our analyses, five faster-acting insulin analogues may be similar to regular human insulin in terms of short-term (defined as less than one year) glycaemic control, as measured by HbA1c (which reflects average blood sugar levels over the past two to three months). We are uncertain about the effects on control of fasting blood glucose levels, mild or moderate episodes of low blood sugar (called hypoglycaemia), severe or serious episodes of low blood sugar at nighttime (called nocturnal hypoglycaemia), or adherence to the insulin treatment. However, they may be better, especially regarding severe hypoglycaemia or a very dangerous complication with high blood sugar and urine ketones (acids) called diabetic ketoacidosis.
We found no clear evidence for mild or moderate hypoglycaemia at nighttime or health-related quality of life (which is physical, mental, emotional and social health). We also did not find any data for long-term follow-up (defined as longer than one year).
What are the limitations of the evidence?
We have limited confidence in the evidence, mainly because most of the studies were carried out in an unblinded way (where healthcare professionals and participants know which treatment they received). There was also a moderate number of dropouts (more than 5% but less than 20% of the participants did not continue the treatment until the end of the study) and there was not enough study detail provided, so that we can't be confident in all the studies. Furthermore, several studies showed inconsistencies in the reporting of their methods and results.
How up to date is this evidence?
This evidence is current as of May 2025.
Read the full abstract
Short-acting insulin analogue use for people with diabetes is still controversial, as reflected in many scientific debates.
Objectives
Primary objective: To compare the effects of long-term treatment with (ultra-)short-acting insulin analogues to regular human insulin or another (ultra-)short-acting insulin analogue in people with type 1 diabetes on multiple daily injections through a network meta-analysis.
Secondary objective: To obtain an estimate of the relative ranking of these (ultra-)short-acting insulin analogues compared to regular human insulin.
Search strategy
We searched CENTRAL, MEDLINE, Web of Science, the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov from inception to 14 May 2025, without language restrictions.
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
(Ultra-)short-acting insulin analogues may result in little to no difference in glycaemic control, non-severe hypoglycaemia and treatment adherence at short-term follow-up, but some agents may reduce severe/serious hypoglycaemia and DKA. We are uncertain about the effects of these insulins on mild to moderate nocturnal hypoglycaemia and quality of life. There were no long-term follow-up data.
Funding
World Health Organization (WHO).
Registration
Protocol for this update: PROSPERO CRD42024599817 (https://www.crd.york.ac.uk/PROSPERO/view/CRD42024599817); DOI of the previous review: 10.1002/14651858.CD012161.
