The Cochrane database of systematic reviews · 2026
(Ultra-)short-acting insulin analogues for adults with type 1 diabetes mellitus on multiple daily injections: a network meta-analysis.
СтатьяNetwork Meta-AnalysisСистематический обзорНазвание и аннотация: Перевод в очереди
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Guo Yang, Mei Yuqian, Bongaerts Brenda, Metzendorf Maria-Inti, Fullerton Birgit, Siebenhofer Andrea, Jeitler Klaus, Horvath Karl, Semlitsch Thomas, Berghold Andrea, Plank Johannes, Siegfried Nandi L, Franco Juan Va
Аннотация
RATIONALE: Ultra-short-acting insulin analogues have the potential to achieve clinical benefits for people with type 1 diabetes, but their relative effects in relation to regular human insulin remain unclear.
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 METHODS: 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.
ELIGIBILITY CRITERIA: We included all randomised controlled trials (RCTs) with an intervention duration of at least 24 weeks that compared (ultra-)short-acting insulin analogues with regular human insulins in non-pregnant adults with type 1 diabetes on multiple daily injections.
OUTCOMES: Critical outcomes included glycaemic control, hypoglycaemia, diabetic ketoacidosis, quality of life and adherence to treatment.
RISK OF BIAS: We evaluated studies with the Cochrane risk of bias tool (RoB 2).
SYNTHESIS METHODS: We performed statistical analyses using a frequentist network meta-analysis to compare estimates for the critical outcomes, with regular human insulin as the reference treatment, and a random-effects model for other outcomes and pairwise comparisons. We rated the certainty of the evidence using the CINeMA framework.
INCLUDED STUDIES: We included 15 RCTs with 6335 participants evaluating insulin aspart, lispro, glulisine, ultra-rapid lispro (URLi) and fast-acting insulin aspart (FIAsp). The duration of interventions ranged from 24 to 52 weeks. Participants had a mean age of 36.4 years and a mean HbA1c of 8.1%. Participants had different basal insulin regimens. Thirteen studies were funded by the pharmaceutical industry.
SYNTHESIS OF RESULTS: Network meta-analysis: (Ultra-)short-acting insulin analogues versus regular human insulin (RHI) Glycaemic control: haemoglobin A1c (HbA1c) Based on low-certainty evidence from 14 studies with 6039 participants, all five (ultra-)short-acting insulin analogues may result in little to no difference in HbA1c compared to RHI (mean difference (MD): URLi -0.25%, 95% confidence interval (CI) -0.51% to 0.00%; lispro -0.22%, 95% CI -0.46% to 0.02%; glulisine -0.21%, 95% CI -0.48% to 0.06%; FIAsp -0.17%, 95% CI -0.28% to -0.05%; aspart -0.14%, 95% CI -0.21% to -0.06%). Glycaemic control: fasting blood glucose (FBG) Based on extremely low-certainty evidence from four studies with 2737 participants, we are uncertain about the effects of aspart and FIAsp compared to RHI (MD: FIAsp 0.69 mmol/L, 95% CI -0.31 mmol/L to 1.69 mmol/L; aspart 0.80 mmol/L, 95% CI -0.01 mmol/L to 1.61 mmol/L). Lispro, glulisine and URLi could not be assessed in relation to RHI. Mild/moderate (non-severe) hypoglycaemia Based on very low-certainty evidence from six studies with 3967 participants, we are uncertain about the effects of aspart and FIAsp compared to RHI (risk ratio (RR): aspart 1.05, 95% CI 0.97 to 1.13; FIAsp 1.04, 95% CI 0.96 to 1.12). Lispro, glulisine and URLi could not be assessed in relation to RHI. Severe/serious hypoglycaemia Based on low- to very low-certainty evidence from 11 studies with 5390 participants, URLi may result in a reduction in severe/serious hypoglycaemia compared to RHI (RR: URLi 0.80, 95% CI 0.36 to 1.77), but the evidence is very uncertain for aspart and FIAsp (RR: aspart 0.89, 95% CI 0.73 to 1.09; FIAsp 0.79, 95% CI 0.55 to 1.15). Glulisine may result in an increase in severe/serious hypoglycaemia compared to RHI (RR glulisine 1.54, 95% CI 0.46 to 5.19). In contrast, lispro may result in little to no difference compared to RHI (RR: lispro 1.01, 95% CI 0.51 to 1.98). Mild/moderate nocturnal hypoglycaemia This outcome could not be evaluated with network meta-analysis. Severe/serious nocturnal hypoglycaemia Based on very low-certainty evidence from four studies with 3229 participants, we are uncertain about the effects of aspart and FIAsp compared to RHI (RR: aspart 0.63, 95% CI 0.46 to 0.88; FIAsp 0.52, 95% CI 0.26 to 1.04). Lispro, glulisine and URLi could not be assessed in relation to RHI. Diabetic ketoacidosis (DKA) Based on low- to very low-certainty evidence from nine studies with 4599 participants, lispro and URLi may result in a reduction in DKA compared to RHI (odds ratio (OR): lispro 0.74, 95% CI 0.10 to 5.39; URLi 0.74, 95% CI 0.03 to 16.64), whereas FIAsp may result in an increase compared to RHI (OR: FIAsp 1.18, 95% CI 0.12 to 11.24), but the evidence is very uncertain for aspart (OR: aspart 0.80, 95% CI 0.20 to 3.11). Glulisine could not be assessed in relation to RHI. Quality of life This outcome could not be evaluated with network meta-analysis. Adherence to treatment Based on very low-certainty evidence from five studies with 3579 participants, we are uncertain about the effects of aspart and FIAsp compared to RHI (RR: aspart 1.01, 95% CI 0.95 to 1.07; FIAsp 1.01, 95% CI 0.94 to 1.08). Lispro, glulisine and URLi could not be assessed in relation to RHI.
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.
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 METHODS: 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.
ELIGIBILITY CRITERIA: We included all randomised controlled trials (RCTs) with an intervention duration of at least 24 weeks that compared (ultra-)short-acting insulin analogues with regular human insulins in non-pregnant adults with type 1 diabetes on multiple daily injections.
OUTCOMES: Critical outcomes included glycaemic control, hypoglycaemia, diabetic ketoacidosis, quality of life and adherence to treatment.
RISK OF BIAS: We evaluated studies with the Cochrane risk of bias tool (RoB 2).
SYNTHESIS METHODS: We performed statistical analyses using a frequentist network meta-analysis to compare estimates for the critical outcomes, with regular human insulin as the reference treatment, and a random-effects model for other outcomes and pairwise comparisons. We rated the certainty of the evidence using the CINeMA framework.
INCLUDED STUDIES: We included 15 RCTs with 6335 participants evaluating insulin aspart, lispro, glulisine, ultra-rapid lispro (URLi) and fast-acting insulin aspart (FIAsp). The duration of interventions ranged from 24 to 52 weeks. Participants had a mean age of 36.4 years and a mean HbA1c of 8.1%. Participants had different basal insulin regimens. Thirteen studies were funded by the pharmaceutical industry.
SYNTHESIS OF RESULTS: Network meta-analysis: (Ultra-)short-acting insulin analogues versus regular human insulin (RHI) Glycaemic control: haemoglobin A1c (HbA1c) Based on low-certainty evidence from 14 studies with 6039 participants, all five (ultra-)short-acting insulin analogues may result in little to no difference in HbA1c compared to RHI (mean difference (MD): URLi -0.25%, 95% confidence interval (CI) -0.51% to 0.00%; lispro -0.22%, 95% CI -0.46% to 0.02%; glulisine -0.21%, 95% CI -0.48% to 0.06%; FIAsp -0.17%, 95% CI -0.28% to -0.05%; aspart -0.14%, 95% CI -0.21% to -0.06%). Glycaemic control: fasting blood glucose (FBG) Based on extremely low-certainty evidence from four studies with 2737 participants, we are uncertain about the effects of aspart and FIAsp compared to RHI (MD: FIAsp 0.69 mmol/L, 95% CI -0.31 mmol/L to 1.69 mmol/L; aspart 0.80 mmol/L, 95% CI -0.01 mmol/L to 1.61 mmol/L). Lispro, glulisine and URLi could not be assessed in relation to RHI. Mild/moderate (non-severe) hypoglycaemia Based on very low-certainty evidence from six studies with 3967 participants, we are uncertain about the effects of aspart and FIAsp compared to RHI (risk ratio (RR): aspart 1.05, 95% CI 0.97 to 1.13; FIAsp 1.04, 95% CI 0.96 to 1.12). Lispro, glulisine and URLi could not be assessed in relation to RHI. Severe/serious hypoglycaemia Based on low- to very low-certainty evidence from 11 studies with 5390 participants, URLi may result in a reduction in severe/serious hypoglycaemia compared to RHI (RR: URLi 0.80, 95% CI 0.36 to 1.77), but the evidence is very uncertain for aspart and FIAsp (RR: aspart 0.89, 95% CI 0.73 to 1.09; FIAsp 0.79, 95% CI 0.55 to 1.15). Glulisine may result in an increase in severe/serious hypoglycaemia compared to RHI (RR glulisine 1.54, 95% CI 0.46 to 5.19). In contrast, lispro may result in little to no difference compared to RHI (RR: lispro 1.01, 95% CI 0.51 to 1.98). Mild/moderate nocturnal hypoglycaemia This outcome could not be evaluated with network meta-analysis. Severe/serious nocturnal hypoglycaemia Based on very low-certainty evidence from four studies with 3229 participants, we are uncertain about the effects of aspart and FIAsp compared to RHI (RR: aspart 0.63, 95% CI 0.46 to 0.88; FIAsp 0.52, 95% CI 0.26 to 1.04). Lispro, glulisine and URLi could not be assessed in relation to RHI. Diabetic ketoacidosis (DKA) Based on low- to very low-certainty evidence from nine studies with 4599 participants, lispro and URLi may result in a reduction in DKA compared to RHI (odds ratio (OR): lispro 0.74, 95% CI 0.10 to 5.39; URLi 0.74, 95% CI 0.03 to 16.64), whereas FIAsp may result in an increase compared to RHI (OR: FIAsp 1.18, 95% CI 0.12 to 11.24), but the evidence is very uncertain for aspart (OR: aspart 0.80, 95% CI 0.20 to 3.11). Glulisine could not be assessed in relation to RHI. Quality of life This outcome could not be evaluated with network meta-analysis. Adherence to treatment Based on very low-certainty evidence from five studies with 3579 participants, we are uncertain about the effects of aspart and FIAsp compared to RHI (RR: aspart 1.01, 95% CI 0.95 to 1.07; FIAsp 1.01, 95% CI 0.94 to 1.08). Lispro, glulisine and URLi could not be assessed in relation to RHI.
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.