Introduction
Methods
Sources of Data and Search Criteria
Selection of Studies and Eligibility Criteria
Data Extraction
Data Synthesis and Statistical Analysis
Compliance with Ethics Statement
Results
Pregnancy
First author, year of study | Analog (n) vs. comparator (n) | HbA1c outcomes | BG levels | Hypoglycemia | Secondary outcomes | ||||
---|---|---|---|---|---|---|---|---|---|
Definition | Results | Definition | Results (mmol/L) | Definition | Results | Measures | Results | ||
Aspart (157) vs. RHI (165) | Tested in early pregnancy and end of each trimester (1) Mean difference (95% CI) between aspart and RHI at end of second trimester (%) (2) Mean difference at end of third trimester | (1) − 0.04% (− 0.18; 0.11) (p = NS) (2) − 0.08 (− 0.23; 0.06) (p = NS) | 8-point SMBG performed for 1 week in each trimester (1) Mean 24-h BG at first trimester (2) Mean 24-h BG at second trimester (3) Mean 24-h BG at third trimester (4) Mean difference in post-breakfast glucose in aspart vs. RHI in first trimester (5) Mean difference in post-breakfast BG in second trimester (6) Mean difference in post-breakfast BG in third trimester | (1) 6.82 vs. 6.82 (2) 6.96 vs. 7.10 (3) 6.23 vs. 6.48 (4) NR, p = 0.044 (5) NR, p = 0.153 (6) NR, p = 0.0007 | Self-reported diary (1) Relative risk (95% CI) of major nocturnal hypoglycemia (2) Relative risk (95% CI) of major hypoglycemia in aspart vs. RHI | (1) 0.48 (0.20, 1.14) (p = NS) (2) 0.72 (0.36; 1.46) (p = NS) | (1) Mean (± SD) overall treatment satisfaction score (2) Corrected BW (SEM) (3) Preterm birth (4) Neonatal hypo | (1) 87.6 ± 12.0 vs. 83.4 ± 15.3 (p = 0.03) (2) 3438 (71.5) vs. 3555 (72.9) (p = 0.09) (3) 20.3% vs. 30.6% (p = 0.05) (4) 33.6 vs. 39.7% | |
Persson, 2002 [15] | Lispro (16) vs. RHI (17) | Tested monthly (1) Median (range) HbA1c at baseline (6–8 weeks gestation) (%) (2) Median HbA1c at 24 weeks gestation (3) Median HbA1c before delivery | (1) 6.5 (4.8–8.6) vs. 6.6 (4.5–8.6) (2) 5.4 (4.3–5.9) vs. 5.3 (4.7–6.7), p = NS (3) 5.2 (4.6–5.9) vs. 5.0 (4.6–6.7), p = NS | Combined values in second and third trimester of 6-point SMBG (1) Mean (± SD) post-breakfast BG (mmol/L) (2) Mean post-breakfast glucose increase (3) Mean post-lunch glucose increase (4) Mean post-dinner glucose increase | (1) 6.50 ± 3.18 vs. 8.56 ± 3.55 (p < 0.01) (2) 0.40 ± 3.20 vs. 1.81 ± 3.42 (p < 0.01) (3) 0.70 ± 3.16 vs. 0.60 ± 3.34 (p = NS) (4) − 0.24 ± 3.10 vs. 0.28 ± 2.94 (p < 0.04) | Self-reported diary (1) Number of patients experiencing severe hypo (2) Rate of biochemical hypo (BG < 3.0) (%) | (1) 0 vs. 2 (2) 5.5 vs. 3.9 (p < 0.05) | (1) Progression of retinopathy, % in each group (2) Neonatal outcomes (i.e., anthropometry, complications, malformations, symptomatic hypo) | (1) 18.8 vs. 35.2 (2) No difference in perinatal outcome or neonatal complications |
Mecacci, 2003 [17] | Lispro (25) vs. RHI (24) | Tested at diagnosis of GDM and delivery (1) Mean difference (± SD) from pre-intervention to delivery (%) | (1) − 0.3 ± 0.3 vs. − 0.3 ± 0.1 (p = NS) | 9-point SMBG performed weekly from diagnosis to 38 weeks gestation (1) Mean (± SD) 1-h post-breakfast BG (2) Mean BG 1-h post-lunch BG (3) Mean BG 1-h post-evening meal BG (4) Mean total BG 1-h postprandial BG (5) Mean total preprandial BG (6) Mean total 2-h postprandial BG | (1) post-BF: 5.93 ± 0.62 vs. 6.84 ± 0.7 (p < 0.002) (2) post-lunch: 5.91 ± 0.66 vs. 6.63 ± 0.88 (p < 0.01) (3) post-dinner: 6.21 ± 0.49 vs. 6.71 ± 0.62 (p < 0.05) (4) total: 6.02 ± 0.59 vs. 6.72 ± 0.73 (p < 0.01) (5) 4.08 ± 0.45 vs. 4.13 ± 0.73 (p = NS) (6) 5.20 ± 0.62 vs. 5.44 ± 0.69 (p = NS) | NR | NR | (1) Neonates with cranial-thoracic circumference (CC/CT) ratio 10-25th centile, % (b) Neonatal anthropometry (BW, ponderal index) and complications | (1) 12% vs. 37.5% (p < 0.05) (2) No difference between groups |
Di Cianni, 2007 [16] | Aspart (31) vs. lispro (33) vs. RHI (32) | NR | NR | 5-point SMBG (1) Mean (± SD) 1-h post-breakfast BG | (1) 6.75 ± 1.12 vs. 6.6 ± 1.05 vs. 7.5 ± 1.3 (p < 0.05) | Number of patients experiencing any hypo | 0 vs. 0 vs. 0 | (1) Neonatal anthropometry: BW, CC/CT ratio (2) Macrosomia | (1) Higher BW in RHI than aspart/lispro groups (2) Macrosomia: 9.6%, 12.1%, 15.6% (p = NS) CC/CT ratio lower in RHI than other two groups (p = 0.03) |
Pettitt, 2007 [18] | Aspart (14) vs. RHI (13) | Tested at diagnosis of GDM and delivery (1) Diagnosis (2) Delivery (both groups combined) | (1) 5.1 ± 0.4 vs. 5.3 ± 0.3 (2) 5.4 | Measured on standardized mixed meal test after 6 weeks (1) Time-adjusted mean (± SD) glucose (2) Time-adjusted mean change in glucose from baseline (no insulin) (3) Mean glucose at 30 min time point of meal test (4) Mean glucose at 60 min time point of meal test | (1) 4.2 ± 0.57 vs. 4.8 ± 0.86 (2) − 1.09 ± 0.55 vs. − 0.54 ± 0.74 (p = 0.003) (3) 4.7 ± 0.19 vs. 5.1 ± 0.23 (p = 0.03) (4) 5.4 ± 0.21 vs. 6.2 ± 0.33 (p < 0.01) | Self-reported diary (1) % of subjects (number of events) experiencing symptomatic hypo (2) % of subjects (number of events) experiencing minor hypo | (1) 71 (53) vs. 69 (23) (2) 79 (52) vs. 39 (9) | (1) Insulin-specific antibodies (2) Cross-reactive antibody binding (± SD) at 36/40 and 6/52 post-partum (%) (3) Mean neonatal birth weight (± SD) (kg) (4) Mean birth length (± SD) (cm) | (1) Low insulin-specific antibodies in both groups (2) 1.4 ± 3.0 vs. 1.5 ± 2.3 and 2.3 ± 5.4 vs. 6.5 + 13.7 (3) 3.1 (0.5) vs. 3.0 (0.5) (p = NS) (4) 49 (2.3) vs. 48 (2.4) (p = NS) |
Jovanovic, 1999 [19] | Lispro (19) vs. RHI (23) | Tested at baseline and 6 weeks after randomization (1) Mean (± SEM) at baseline (%) (2) Mean at 6 weeks (3) Mean change from baseline to 6 weeks (% reduction) | Mean (± SEM) HbA1c at: (1) 5.47 ± 0.09 vs. 5.24 vs. 0.09 (p = NS) (2) 5.12 ± 0.11 vs. 5.16 ± 0.12 (3) − 0.35 (5.7%) vs. − 0.07 (2.8%) (p = 0.002) | 6-point SMBG (1) Mean (± SEM) post-breakfast hyperglycemia rate (individual patient % of all readings ≥ 6.67 mmol/L), (%) (2) Mean post-lunch hyperglycemia rate (3) Mean post-evening meal hyperglycemia rate (4) Mean total postprandial hyperglycemia rate | (1) 5.5 ± 0.30 vs. 7.3 ± 0.4 (p = NS) (2) 4.5 ± 1.1 vs. 6.8 ± 0.86 (p = NS) (3) 2.0 ± 0.51 vs. 2.6 ± 0.54 (p = NS) (4) 4.0 ± 0.49 vs. 5.5 ± 0.47 (p < 0.05) | Self-reported diary and meter check (1) Mean (± SEM) pre-breakfast hypo rate (individual patient % of all readings < 3.1 mmol/L) (%) (2) Mean pre-lunch hypo rate (3) Mean post-evening meal hypo rate (4) Mean total preprandial hypo rate | (1) 0.65 ± 0.13 vs. 0.93 ± 1.04 (p < 0.05) (2) 0.78 ± 0.37 vs. 1.98 ± 0.81 (3) 1.26 ± 0.43 vs. 1.43 ± 0.86 (4) 0.88 ± 0.25 vs. 2.20 ± 0.86 | (1) Change in insulin-specific and cross-reactive response from baseline to delivery (2) Neonatal anthropometry (3) Neonatal glucose | (1) No difference in maternal antibody response (2) No difference in neonatal anthropometry and outcomes (3) No neonatal hypo- or hyperglycemia |
Women with Pre-Existing T1D
Women with GDM
Meta-Analysis
Children and Adolescents
First Author, year | Analog (n) vs. comparator (n) | HbA1c outcomes | BG levels | Hypoglycemia | Secondary outcomes | ||||
---|---|---|---|---|---|---|---|---|---|
Definition | Results | Definition | Results (mmol/L) | Definition | Results | Measures | Results | ||
Philotheou, 2011 [29] | Glulisine (275) vs. lispro (295) | Tested at baseline and endpoint (1) Adjusted mean change (± SD) from baseline to endpoint (2) Difference between treatments in adjusted means (95% CI) for difference from baseline to endpoint (3) % achieving ADA age-specific HbA1c targets at endpoint | (1) + 0.10 ± 0.08 vs. + 0.16 ± 0.07 (2) − 0.06 (− 0.24; 0.12) (3) 38.4 vs. 32.0 (p = 0.0039) | 3-point SMBG at endpoint (1) Adjusted mean (± SEM) of pre-breakfast BG (p value for difference between groups) (2) Adjusted mean (± SEM) of pre-main meal BG (3) Adjusted mean (± SEM) of 2-h post main meal | (1) 8.77 ± 0.21 vs. 9.46 ± 0.21 (p = 0.014) (2) 9.76 ± 0.24 vs. 9.80 ± 0.23 (p = 0.894) (3) 9.20 ± 0.22 vs. 9.04 ± 0.21 (p = 0.564) | Reported from month 4 to treatment end (1) Severe hypo (± SD): BG < 2.0 mmol/L and third-party assistance required or prompt recovery following glucose treatment, number of episodes per patient-month (2) Nocturnal hypo (3) Any hypo | (1) 0.06 ± 0.24 vs. 0.07 ± 0.27 (2) 0.21 ± 0.50 vs. 0.20 ± 0.80 (3) 3.10 ± 4.33 vs. 2.91 ± 4.35 | Mean (± SD) increase total daily dose of insulin from baseline, units/day | 2.53 ± 0.68 vs. 4.91 ± 0.65 (p = 0.007) |
Pańkowska, 2010 [28] | Aspart (20) vs. RHI (21) | Tested at baseline, midpoint and endpoint (1) Mean HbA1c (± SD) at 13 weeks after treatment (2) Mean HbA1c at 26 weeks after treatment | (1) 7.4 ± 0.9 vs. 7.6 ± 1.1 (2) 7.6 ± 0.9 vs. 7.6 ± 1.0 | 24-h glycemic control measured using CGMS for 72 h at endpoint (1) Mean (± SD) of area under glucose curve, mmol/h/L (2) Difference between maximum and minimum glucose levels over 24 h | (1) 219.8 (12.8) vs. 211.8 (10.9) (p = 0.55) (2) 4.0 vs. 4.0 (p = NS) | Self-reported by parent during CGM period (1) Severe hypo: BG < 2.8 mmol/L accompanied by CNS symptoms requiring external help, number of episodes per patient-year of exposure (2) Minor hypoglycemia: BG < 2.8 mmol/L that were asymptomatic or self-treatable (3) Symptoms-only hypoglycemia | (1) 0.1 vs. 0.0 (1/20) vs. (0/21) (2) 18 vs. 20 18/20 vs. 19/21 (3) 1.1 vs. 1.4 | Treatment satisfaction: SD values for mean change in treatment satisfaction score at end of study | 5.6 vs. 4.4 (p = 0.04) |
Cherubini, 2006 [22] | Aspart (NR) vs. RHI (NR) | Tested at baseline and 6-weekly during study (1) Change in HbA1c (± SD) over the study period | (1) 7.5 ± 0.8 to 7.0 ± 0.4 vs. 7.5 ± 1.4 to 7.4 ± 0.5 (p = 0.018) | 7-point SMBG during study period (1) Mean 2-h postprandial BG (2) Mean fasting BG (3) Mean afternoon BG at endpoint (4) Decrease in mean daily BG variability from baseline | (1) 7.38 ± 1.0 vs. 7.94 ± 1.06 (p = 0.175) (2) Analog < RHI, p = 0.012 (3) 8.89 ± 2.89 vs. 9.17 ± 2.72 (p = 0.113) (4) Analog = RHI, p > 0.237 | Self-reported (1) Severe hypo: BG < 2.8 mmol/L, number of episodes per patient per day (2) Any hypo: BG < 3.9 mmol/L | (1) 0.045 vs. 0.035 (p = 0.209) (2) 0.214 vs. 0.18 (p = 0.117) | NR | NR |
Fairchild, 2000 [25] | Lispro (35) vs. RHI (35) | Tested at baseline and 6-weekly during study (1) Mean HbA1c (± SD) at endpoint | (1) 8.33 ± 0.89 vs. 8.14 ± 0.77 (p = NS) | 7-point SMBG done weekly or 2-weekly (1) Mean BG (± SD) at 03:00 h (2) Mean difference (95% CI) in 03:00 h BG between groups | (1) 10.57 ± 0.26 vs. 9.02 ± 0.46 (p = 0.001) (2) 2.35 (−3.98; − 0.72) p = 0.01 | Self-reported and BG meter analysis (1) Severe hypos: hypo associated with convulsion or coma (2) Total recorded hypos, number of episodes per patient per 3 months (3) Total recorded hypos from 06:00 to 12:00 h (4) Hypos with BG < 3.0 mmol/L | (1) 0.032 vs. 0.065 (p = NS) 1/35 vs. 2/35 (2) 13.47 vs. 10.77 (p = NS) (3) 5.69 vs. 3.31, difference 2.4 ± 5.1 (p = 0.02) (4) analog = comparator (p = NS) | Treatment satisfaction questionnaire Number (%) preferring this type of insulin over the other one | 28 (80) vs. 7 (20) |
Ford-Adams, 2003 [26] | Lispro (23) vs. RHI (23) | Tested at baseline and 4-monthly during study (1) Mean HbA1c (± SD) at crossover (2) Mean HbA1c at endpoint | (1) 8.9 ± 0.3 vs. 8.4 ± 0.3 (p = 0.14) (2) 8.5 ± 0.2 vs. 8.8 ± 0.3 (p = 0.47) | Overnight metabolic study (1) Mean BG (± SD) at start of overnight profile (2) Mean fasting BG (3) AUC of BG (± SD) from post-EM to bedtime, mmol/min/L (4) AUC of BG from 22:00 to 04:00 h | (1) 6.5 ± 1.0 vs. 7.1 ± 1.1 (p = 0.5) (2) 6.1 ± 0.8 vs. 6.3 ± 0.9 (p = 0.8) (3) 138 ± 12 vs. 170 ± 13 (p = 0.03) (4) 158 ± 13 vs. 145 ± 12 (p = 0.3) | Self-reported (1) Severe hypo: convulsions or requiring glucagon, number of episodes (2) Symptomatic hypoglycemia, number of episodes per patient per week (± SD) Overnight metabolic profile (3) Prevalence of low BG from post-EM to 22:00 h: BG < 3.5 mmol/L, % (4) Prevalence of low BG from 22:00 to 04:00 h (5) Prevalence of low BG from 04:00 to 07:00 h | (1) 2/23 vs. 1/23 (2) 1.6 ± 0.3 vs. 1.7 ± 0.3 (p = 0.2) (3) 9 vs. 6 (p = 0.06) (4) 8 vs. 13 (p = 0.01) (5) 27 vs. 22 (p = 0.11) | Mean (range) total daily insulin dose, units/kg | 0.97 (0.68–1.26) vs. 0.96 (0.53–1.22) (p = 0.2) |
Holcombe, 2002 [27] | Lispro (457) vs. RHI (457) | Tested at baseline and 2-monthly during study (1) Mean HbA1c (± SD) at baseline (2) Mean HbA1c at endpoint | (1) 8.41 ± 1.4 vs. 8.80 ± 1.5 (p = NS) (2) 8.69 ± 1.52 vs. 8.70 ± 1.65 (p = NS) | 8-point BG profiles on 2 days at baseline and end of each treatment period (1) Mean (± SD) BG concentrations at 03:00 h (2) Mean fasting BG concentrations (3) Mean BG 2-h post-breakfast (4) Mean BG 2-h post-dinner (5) Mean BG 2-h post-mid-day meal | (1) 9.7 ± 3.9 vs. 8.8 ± 3.7 (p < 0.001) (2) 10.2 ± 3.5 vs. 9.6 ± 3.4 (p = 0.005) (3) 9.7 ± 4.0 vs. 10.6 ± 4.3 (p < 0.001) (4) 8.6 ± 3.5 vs. 9.3 ± 3.7 (p = 0.003) (5) 8.1 ± 3.4 vs. 8.5 ± 3.4 (p = NS) | Self-reported (1) Severe hypo: needing third-party assistance or intravenous glucose or glucagon injection, number of patients (2) Nocturnal hypoglycemia: from midnight to 06:00 h (3) Any hypoglycemia: symptoms present or measured BG < 3.0 mmol/L, number of episodes per patient per month | (1) 5 vs. 5 5/457 vs. 5/547 (2) 1.0 ± 1.9 vs. 1.7 ± 2.6 (p < 0.001) (3) 4.02 ± 4.5 vs. 4.37 ± 4.5 (p = 0.023) | (1) Mean (± SD) total daily insulin dose, units/kg (2) Mean (± SD) daily dose of short-and rapid-acting insulin | (1) 1.08 ± 0.32 vs. 1.05 ± 0.30 (p < 0.001) (2) 0.54 ± 0.24 vs. 0.53 ± 0.20 (p = NS) |
Deeb, 2001 [24] | Lispro before meals (analog 1, 53) vs. lispro after meals (analog 2, 55) vs. RHI (57) | Tested at baseline and 3-monthly during study (1) Mean (± SD) HbA1c at endpoint | (1) 8.40 ± 1.1 vs. 8.54 ± 1.0 vs. 8.43 ± 1.0 (p = NS) | 7-point SMBG profiles on 2 days at baseline and end of each treatment period (1) Overall mean BG (± SD) (2) Mean BG 2-h post-breakfast (3) Mean BG pre-lunch (4) Mean BG 2-h post-lunch (5) Mean BG 2-h post-dinner BG | (1) 9.6 ± 1.6 vs. 10.1 ± 1.6 vs. 10.0 ± 1.7 (p = 0.007 analog 1 vs. analog 2 (p = 0.024 for trend) (2) 11.7 ± 4.4, 13.5 ± 5.5, 15.0 ± 5.4 (p < 0.001 analog 1 vs. comparator; p = 0.023 analog 1 vs. analog 2) (3) 8.7 ± 3.9 vs. 8.3 ± 3.1 vs. 8.3 ± 3.1 vs. 9.5 ± 4.1 (p = NS analog 1 vs. analog 2, p = 0.037 analog 1 vs. RHI) (4) Analog 1 = analog 2 = RHI (p = NS) (5) 8.8 ± 5.0 vs. 9.9 ± 4.7 vs. 10.8 ± 5.4 (p = NS analog 1 vs. analog 2, p = 0.006 analog 1 vs. RHI) | Self-reported (1) Severe hypo: needing third-party assistance, resulting in a coma, or requiring intravenous glucose or glucagon, number of patients (2) Any hypoglycemia: symptomatic or measured BG < 3.5 mmol/L, number of episodes per 30 days | (1) 2 vs. 3 vs. 6 (p = NS) 5/108 vs. 6/57 (2) 14.7 ± 11.9 vs. 13.6 ± 9.3 vs. 13.8 ± 9.8 (p = NS) | Mean total daily insulin dose, units/kg | 0.21 vs. 0.23 vs. 0.25 (p = NS) |
Tupola, 2001 [30] | Lispro (22) vs. RHI (22) | Tested at baseline and 3-monthly during study (1) Mean (± SD) change in HbA1c from baseline to endpoint | (1) 0.2 ± 0.8 vs. − 0.4 ± 0.7 (p = 0.1) | 7-point SMBG profiles on 1 day per month over study period (1) Mean BG (± SD) pre-breakfast (2) Mean BG pre-dinner (3) Mean BG at bedtime (4) 1-h and 2-h postprandial BG excursions | (1) 11.5 ± 4.5 vs. 8.4 ± 3.8 (p = 0.02) (2) 11.7 ± 6.0 vs. 9.6 ± 5.7 (p = 0.4) (3) 11.5 ± 5.0 vs. 10.6 ± 6.0 (p = 0.8) (4) Analog = RHI (p = NS) | Self-reported and BG meter analysis (1) Severe hypo: loss of consciousness during a hypoglycemic episode (2) Nocturnal hypoglycemia: from 11:00 to 06:00 h (3) Hypoglycemia: symptoms present or BG < 3 mmol/L, number of episodes per patient per month | (1) 2 vs. 2 (p = NS) (2) 34 vs. 41 (p = 0.6) (3) 4.9 vs. 4.4 (p = 0.3) | (1) Total daily insulin dose (2) Patient satisfaction: number (%) of patients/families who wanted to continue this type of insulin | (1) Analog = RHI (p = NS) (2) 18 (82) vs. 4 (18) |
Danne, 2007 [23] | Aspart (23) vs. RHI (25) | Tested at baseline and 3-monthly during study (1) HbA1c at endpoint | (1) Analog = RHI (p = NS) | 7-point SMBG during study period (1) Daily BG variations | (1) Analog = RHI (p = NS) | Self-reported (1) Major hypoglycemia: those that parents could not handle on their own, number of episodes (2) Any hypoglycemia, number of episodes per week (3) Relative risk of hypoglycemia (95% CI): relative risk for analog/RHI | (1) 2 vs. 3 (2) 2.75 vs. 2.74 (3) 1.06 (0.96;1.17) (p = 0.225) | WHO–DTSQs (1) Mean score (± SD) for question on continuing present form of insulin (2) Mean score (± SD) for question on recommending this form of insulin to others | (1) 4.8 ± 1.5 vs. 3.7 ± 1.8 (p = 0.045) (2) 5.0 ± 1.4 vs. 4.2 ± 1.8 (p = 0.051) |
Meta-Analysis
Patients Treated with CSII
First author, year | Analog (n) vs. comparator (n) | HbA1c outcomes | BG levels | Hypoglycemia | Secondary outcomes | ||||
---|---|---|---|---|---|---|---|---|---|
Definition | Results | Definition | Results (mmol/L) | Definition | Results | Measures | Results | ||
Zinmann, 1997 [41] | Lispro (30) vs. RHI (30) | Tested monthly (1) Mean (± SE) baseline HbA1c in all patients (2) Mean endpoint HbA1c (3) Difference in endpoint HbA1c between treatments | (1) 8.03 ± 0.13 (2) 7.66 ± 0.13 vs. 8.00 ± 0.16 (3) − 0.34 (p = 0.0041) | 8 point-SMBG profile done weekly (1) Mean fasting BG (2) Mean post-prandial BG | (1) No significant difference between treatments (2) Lower with lispro than with RHI (p < 0.05) | Self-reported diary (1) Any hypo at baseline: BG < 3 mmol/L or compatible symptoms, episodes per 30 days (± SE) (2) Any hypo during treatment (3) Biochemical hypo at baseline: BG < 3 mmol/L only (4) Biochemical hypo during treatment (5) Severe hypo | (1) 12.7 ± 1.6 (2) 8.6 ± 1.4 vs. 10.8 ± 1.8 (lispro p = 0.035 vs. baseline, RHI p = NS) (3) 8.4 ± 1.3 (4) 6.0 ± 0.9 vs. 7.6 ± 1.3 (lispro p = 0.03 vs. baseline, RHI p = NS) (5) 0/30 vs. 0/30 | (1) 5-h meal test on subgroup of six patients for postprandial insulin glucose and FFA (2) BW (3) Infusion-set occlusion | (1) Peak free plasma insulin at 45 min for lispro (287 ± 69 pmol/L) vs. 150 min for RHI (294 ± 56). Plasma glucose and FFA markedly reduced for lispro vs. RHI (2) No difference in BW from baseline or between treatments at endpoint (3) No occlusions with either treatment |
Melki, 1998 [35] | Lispro (38) vs. RHI (38) | Tested at end of first 3 months (1) Baseline (2) Endpoint (3) Change from baseline to endpoint | (1) 7.74 ± 0.20 vs. 7.97 ± 0.13 (2) 7.11 ± 0.15 vs. 7.88 ± 0.16 (3) − 0.62 ± 0.13 vs. − 0.09 ± 0.15 (p = 0.01) | 7 point-SMBG profile done daily during last 30 days of each treatment period (1) Mean BG ± SE (2) Mean preprandial BG (3) Mean 2-h postprandial BG | (1) 7.93 ± 0.15 vs. 8.61 ± 0.18 (p < 0.0001) (2) 7.70 ± 0.17 vs. 7.75 ± 0.21 (p = NS) (3) 8.26 ± 0.19 vs. 9.90 ± 0.20 (p < 0.0001) | Self-reported diary recorded in last 30 days of first treatment period (1) Hypo event: BG < 3 mmol/L, episodes per month (± SD) (2) Very low BG measurement: BG < 2 mmol/L (3) Severe hypo: third-party assistance required | (1) 7.03 ± 0.94 vs. 7.94 ± 0.88 (p = NS) (2) 0.05 ± 0.05 vs. 0.47 ± 0.19 (p < 0.05) (3) 3 vs. 7 (3/38 vs. 4/38) | (1) Ketoacidosis (2) BW (3) Glucose variability (4) Patient preference (5) Technical problems | (1) No episodes in either group (2) No difference (3) Significantly lower overall mean and postprandial glycemic fluctuation with lispro than RHI, SD of BG in mmol/L (± SE): 3.44 ± 0.10 vs. 3.80 ± 0.10 (p < 0.001) and 3.58 ± 0.10 mmol/L vs. 3.84 ± 0.10 (p < 0.02) (4) All seven questions on non-validated questionnaire in favor of lispro (p < 0.0001) (5) Insulin precipitation in catheter, one vs. four episodes; catheter obstruction, nine episodes each |
Schmauss, 1998 [38] | Lispro (11) vs. RHI (11) | Tested 3-monthly (1) Baseline (2) End of first 3 months (3) End of study | Lispro then RHI vs. RHI then lispro (1) 6.3 ± 0.2 vs. 6.7 ± 0.4 (p = NS) (2) 5.7 ± 0.3 vs. 6.5 ± 0.3 (p = NS) (3) 6.2 ± 0.2 vs. 6.3 ± 0.3 (p = NS) | 3-day BG profile done 3-monthly (1) Mean fasting BG (2) Mean 2-h postprandial BG | (1) 6.5 ± 0.4 vs. 7.5 ± 0.4 (p = NS) (2) 6.8 ± 0.3 vs. 8.3 ± 0.3 (p = 0.03) | Self-reported (1) Hypo: BG < 3.5 mmol/L and/or symptoms, episodes per 30 days (± SD) (2) Severe hypo: requiring IV glucose or glucagon | (1) 4.0 ± 0.9 vs. 3.2 ± 0.7 (p = NS) (2) 0 vs. 0 (0/11 vs. 0/11) | (1) Basal and bolus insulin requirements (2) BMI change (3) Treatment satisfaction | (1) No difference (2) No change in BMI (3) No difference in treatment satisfaction |
Guerci, 1999 [32] | Lispro (10) vs. RHI (10) | Tested monthly (1) Baseline (2) Endpoint of each treatment period | (1) 7.17 ± 0.86 vs. 7.36 ± 0.76 (p = NS) (2) 7.07 ± 0.51 vs. 6.97 ± 0.67 (p = NS) | SMBG done monthly (1) Mean baseline BG (2) Mean BG at endpoint (3) Mean baseline postprandial BG (4) Mean postprandial BG at endpoint | (1) 9.35 ± 1.17 vs. 9.07 ± 0.43 (p = NS) (2) 9.04 ± 0.89 vs. 9.32 ± 1.17 (p = NS) (3) 9.53 ± 1.98 vs. 9.92 ± 1.05 (p = NS) (4) 9.43 ± 1.39 vs. 10.49 ± 2.05 (p = 0.05) | Self-reported (1) Incidence of hypo at baseline: BG < 3.5 mmol/L, episodes per 30 days (± SD) (2) Incidence of hypo at endpoint | (1) 10.1 ± 9.7 vs. 6.9 ± 4.4 (p = NS) (2) 7.1 ± 4.6 vs. 12.6 ± 10.2 (p = 0.05) | (1) Glucose variability, mean SD of previous months’ BG After pump interruption for 5 h: (2) Mean PG (3) Plasma 3-hydroxybuturate (4) Plasma FFA | (1) No difference between treatment groups (2) Until 3 h no difference in PG between groups. From 3 to 5 h, PG higher with lispro (p < 0.01) (3) From 3 h onwards, consistently higher for lispro vs. RHI (but p = NS) (4) From 2 h onwards, consistently higher for lispro vs. RHI (p < 0.05) |
Renner, 1999 [37] | Lispro (113) vs. RHI (113) | Tested at baseline and endpoint (1) Baseline in all patients (2) Endpoint | (1) 7.24 ± 1.0 (2) 6.77 ± 0.88 vs. 6.90 ± 0.97 (p = 0.02) | 8-point daily SMBG (1) Mean fasting BG (± SD) (2) Mean post-breakfast BG (3) Mean pre-lunch BG (4) Mean post-lunch BG (5) Mean pre-dinner BG (6) Mean post-dinner BG (7) Mean 22:00 h BG (8) Mean 02:00 h BG | (1) 7.2 ± 1.7 vs. 7.8 ± 2.1 (p = NS) (2) 7.0 ± 1.9 vs. 8.6 ± 2.6 (p < 0.001) (3) 6.9 ± 1.9 vs. 7.3 ± 2.2 (p = NS) (4) 7.6 ± 1.9 vs. 8.7 ± 2.4 (p < 0.001) (5) 7.3 ± 1.9 vs. 7.5 ± 1.9 (p = NS) (p < 0.001) (6) 7.2 ± 1.9 vs. 8.3 ± 1.9 (7) 7.6 ± 1.8 vs. 8.3 ± 2.0 (p < 0.001) (8) 8.0 ± 2.7 vs. 7.7 ± 2.3 (p = NS) | Self-reported (1) BG < 3.5 mmol/L and/or symptoms, mean number of episodes (± SD) per patient per 4 months (2) BG < 3.3 mmol/L, mean number of episodes (± SD) per patient per month | (1) 12.0 ± 13.9 vs. 11.0 ± 11.2 (p = NS) (2) Lispro = RHI (p = NS) | (1) Ketosis (2) Treatment satisfaction (DTSQ) (3) Occlusion of catheter | (1) Five vs. four patients (2) Patients scored significantly higher on the treatment satisfaction when treated with lispro compared to RHI (3) Same amount in the two treatments |
Johansson, 2000 [34] | Lispro (41) vs. RHI (41) | Tested at baseline and endpoint (1) Baseline in all patients (2) Endpoint (3) Difference between treatments (95% CI) | (1) 7.7 ± 0.8 (2) 7.4 vs. 7.6 (p = 0.047) (3) − 0.2 (− 0.3; 0.0) (p = 0.047) | Last 30 days SMBG (1) Mean of pre-prandial and bedtime BG (2) Mean of postprandial BG (3) Mean of all SMBG | (1) 8.5 vs. 8.4 (p = NS) (2) 8.1 vs. 9.6 (p < 0.001) (3) 8.3 vs. 8.9 (p < 0.001) | Self-reported (1) Any hypo: BG < 3.0 mmol/L and/or symptoms, episodes per 30 days (difference between treatments [95% CI]) | (1) 9.7 vs. 8.0 [1.7 (− 1.3; 5.3)] (p = NS) | (1) Treatment satisfaction (DTSQ) | (1) No difference between the treatments |
Raskin, 2001 [36] | Lispro (58) vs. RHI (58) | Tested at baseline and endpoint (1) Baseline in all patients (2) Change from baseline | (1) 7.9 ± 1.1 vs. 7.6 ± 0.8 (p = NS) (2) − 0.34 ± 0.59 vs. − 0.09 ± 0.63 (p = 0.004) | 4-point daily SMBG done in last 2 weeks of each treatment period (1) Mean BG (± SD) PG during test meal at end of each treatment period (2) Mean PG 1 h post-meal (3) Mean PG 2 h post-meal | (1) 8.1 ± 2.0 vs. 8.1 ± 1.6, (p = NS) (2) 11.16 ± 4.29 vs. 13.20 ± 4.68 (p = 0.012) (3) 9.64 ± 4.10 vs. 12.53 ± 4.64 (p = 0.001) | Self-reported (1) Any hypo: BG < 3.0 mmol/L and/or symptoms, episodes per 12 weeks (2) Severe hypoglycemia: requiring IV glucose | (1) 8 vs. 11 (p = NS) (2) 3 vs. 3 (p = NS) 3/58 vs. 2/58 | (1) BW | (1) No difference between treatments |
Tubiani-Rufi, 2004 [42] | Lispro (27) vs. RHI (27) | Tested at baseline and endpoint (1) Difference in HbA1c (± SD) from baseline to end of first treatment sequence | (1) + 0.15 ± 0.13 vs. + 0.11 ± 0.63 (p = NS) | 9-point SMBG on 2 days during each treatment (1) Change in mean post-dinner BG | (1) − 0.94 ± 5.05 vs. + 1.78 ± 5.94 (p = 0.01) | Self-reported (1) Severe hypoglycemia, episodes per 30 days (2) BG ≤ 3.3 mmol/L (3) BG ≤ 2.2 mmol/L | (1) 2 vs. 2 2/27 vs. 2/27 (2) 11.0 ± 6.4 vs. 13.8 ± 8.5 (p = NS) (3) 0.6 ± 1.1 vs. 1.0 ± 1.1 (p = NS) | (1) BW (2) Glucose variability (SD of SMBG) (3) Infusion-set occlusion (4) Parents’ treatment preference (5) Hyperglycemic episodes with ketonuria | (1) No difference between treatments (2) 6.4 ± 1.0 vs. 6.0 ± 0.95 mmol/L (p = 0.01) (3) No difference between treatments (4) 74% want to continue lispro (5) 2.5 ± 2.7 vs. 2.0 ± 3.0 episodes (p = NS) |
Hoogma, 2006 [33] | Glulisine (29) vs. aspart (30) | Tested at baseline and endpoint (1) Baseline HbA1c (2) Endpoint HbA1c (3) Between-group difference in HbA1c (95% CI) from baseline to endpoint | (1) 6.8 vs. 7.1 (p = NS) (2) 7.0 vs. 7.2 (3) 0.11 (− 0.09; 0.31) (p = NS) | NR | NR | Self-reported (1) Severe hypoglycemia: BG < 2.0 mmol/L and requiring assistance or IV glucose/glucagon, number of patients experiencing at least one in 12 weeks (2) Nocturnal hypoglycemia (3) Symptomatic hypoglycemia | (1) 2 vs. 2 (2) 20 vs. 15 (p = NS) (3) 26 vs. 24 (p = NS) | (1) Infusion-set occlusion (2) Unexplained hyperglycemia: at least one episodes of BG > 19.4 mmol/L, episodes in 12 weeks | (1) No difference between treatments (2) 6 vs. 12 (p = NS) |
Weinzimer, 2008 [43] | Aspart (198) vs. lispro (100) | Tested at baseline and endpoint (1) Baseline (2) Change in HbA1c from baseline to end of treatment (3) Percentage achieving age-specific HbA1c target at baseline (4) Percentage achieving age-specific HbA1c target at endpoint | (1) 8.0 ± 0.94 vs. 8.2 ± 0.84 (p = NS) (2) − 0.15 ± 0.05 vs. − 0.05 ± 0.07 (p = NS) (3) 50.3 vs. 40.4% (p = NS) (4) 59.7 vs. 43.8% (p = 0.04) | 8-point SMBG done on 2 days at baseline and before ending treatment (1) Mean fasting BG (± SD) at baseline (2) Mean fasting BG at endpoint (3) Mean postprandial BG at endpoint (4) Mean BG at endpoint | (1) 9.5 ± 4.3 vs. 9.9 ± 3.8 (p = NS) (2) 9.3 ± 3.7 vs. 10.0 ± 4.6 (p = NS) (3) aspart = lispro (p = NS) (4) aspart = lispro (p = NS) | Self-reported (1) Major hypoglycemia: BG < 3.1 mmol/L and requiring assistance or IV glucose/glucagon, episodes per patient per year (2) Nocturnal hypoglycemia: minor or major occurring between midnight and 06:00 h (3) Minor hypoglycemia: BG < 3.1 mmol/L with or without symptoms | (1) 0.4 vs. 0.3 (p = NS) (2) 5.7 vs. 6.2 (p = NS) (3) 77.2 vs. 66.0 (p = NS) | (1) BW (2) Hyperglycemia: BG > 16.7 mmol/L, % patients with episodes (3) DKA, number of patients with episodes | (1) No difference between treatments (2) 11 vs. 17 (p = NS) (3) 1 vs. 2 (p = NS) |
Tamborlane, 2015 [39] | Substudy 1 lispro (116) vs. aspart (116) Substudy 2 lispro (118) vs. aspart (118) | Tested at baseline and endpoint (1) Mean (± SD) HbA1c at baseline (2) Mean (± SEM) endpoint HbA1c (3) Mean change (± SEM) in HbA1c from baseline | Substudy 1 (1) 7.3 ± 0.7 (2) 7.34 ± 0.05 vs. 7.28 ± 0.05 (p = NS) (3) 0.06 ± 0.05 vs. − 0.00 ± 0.05 (p = NS) Substudy 2 (1) 7.5 ± 0.7 (2) 7.30 ± 0.04 vs. 7.14 ± 0.04 (p < 0.001) (3) − 0.15 vs. − 0.31 (p < 0.001) | 7-point SMBG done on day 6 of reservoir use (1) Mean (± SEM) BG | Substudy 1 (1) 9.34 ± 0.14 vs. 9.11 ± 0.14 (p > 0.05) Substudy 2 (1) 8.72 ± 0.10 vs. 8.54 ± 0.10 (p > 0.05) | Self-reported (1) Severe hypo: requiring third-party assistance, total number of episodes (2) Nocturnal hypo: occurring between bedtime and wake up (3) Symptomatic hypo: BG < 3.9 mmol/L and symptomatic, episodes per 30 days (4) Symptomatic hypo: total number of episodes (5) Asymptomatic: BG < 3.9 mmol/L and no symptoms | (1) 5 vs. 16 (2) lispro = aspart (3) Substudy 1: 9.39 vs. 10.84 (p = 0.003) Substudy 2: 7.57 vs. 8.71 (p = 0.012) (4) Substudy 1: 15.26 vs. 16.91 (p = 0.006) Substudy 2: 16.74 vs. 18.86 (p < 0.001) (5) lispro = aspart | (1) Infusion-set occlusion (2) Hyperglycemia: BG > 13.9 mmol/L (> 3 h after eating) or > 16.7 mmol/L (within 3 h after eating), episodes per 30 days (3) DKA, number of episodes | (1) No difference between treatments (2) Substudy 1: 8.20 vs. 6.79 (p = 0.029) Substudy 2: 8.05 vs. 6.54 (p = 0.003) (3) 4 vs. 0 |
Bode, 2002 [31] | Aspart (59) vs. lispro (28) vs. RHI (59) | Tested at baseline and endpoint (1) Mean (± SD) HbA1c at baseline (2) Mean change from baseline to endpoint | (1) 7.3 ± 0.7 vs. 7.3 ± 0.7 vs. 7.5 ± 0.8 (p = NS) (2) 0.00 ± 0.51 vs. 0.18 ± 0.84 vs. 0.15 ± 0.63 (p = NS) | 8-point SMBG done on 2 days at baseline and endpoint (1) Fasting and pre-meal BG (2) Post-dinner BG (3) BG at 02:00 h | (1) Aspart = lispro = RHI (2) Aspart < lispro = RHI (p = 0.019) (3) RHI < aspart = lispro (p = 0.002) | Self-reported (1) Severe hypo: BG < 2.8 mmol/L and requiring assistance or IV glucose/glucagon, mean events per patient per 30 days (± SD) (2) Nocturnal hypo: minor or major occurring between midnight and 06:00 h (3) Minor hypo: symptomatic and BG < 2.8 mmol/L (4) Minor hypo: symptoms with or without low BG | (1) 0 vs. 0 vs. 1 0/59 vs. 1/59; 0/28 vs. 1/59 (2) 0.5 ± 0.83 vs. 0.6 ± 0.61 vs. 0.9 ± 0.97 (aspart vs. lispro p = NS, aspart vs. RHI p = 0.004) (3) 3.7 ± 3.6 vs. 4.4 ± 4.7 vs. 4.8 ± 4.2 (p = NS) (4) 6.7 ± 5.4 vs. 10.5 ± 8.1 vs. 10.5 ± 8.9 (aspart vs. lispro p = 0.044, aspart vs. RHI p = 0.034) | (1) BW (2) Unexplained hyperglycemia: BG > 19.4 mmol/L, % patients with at least one episode (3) DKA | (1) No difference in any treatment group (2) 27% vs. 36% vs. 41%, (p = NS) (3) No episodes |
van Bon, 2011 [40] | Glulisine (256) vs. aspart (256) vs. lispro (256) | Tested at baseline and endpoint (1) Mean (± SD) HbA1c at baseline (2) Mean HbA1c at endpoint (3) Percentage of patients with HbA1c < 7.0 at endpoint, % | (1) 7.31 ± 0.71 vs. 7.33 ± 0.71 vs. 7.28 ± 0.71 (p = NS) (2) 7.32 ± 0.73 vs. 7.26 ± 0.76 vs. 7.31 ± 0.74 (p = NS) (3) 28 vs. 31 vs. 30 (p = NS) | 7-point SMBG 1 day before endpoint (1) Fasting and pre-meal SMBG (2) Mean post-lunch BG (3) Mean nocturnal BG | (1) glulisine = aspart = RHI (2) (glulisine vs. aspart) 9.2 vs. 8.6 (p < 0.021) (3) (glulisine vs. lispro) 8.8 vs. 8.2 (p < 0.018) | Self-reported (1) Severe hypoglycemia: BG < 2.8 mmol/L and requiring assistance or IV glucose/glucagon, episodes per patient-year (± SD) (2) Nocturnal severe hypo: severe hypo occurring at night (3) Symptomatic hypo: BG < 3.9 mmol/L and symptomatic (4) Nocturnal symptomatic hypo: symptomatic hypo occurring at night | (1) 1.63 ± 4.50 vs. 1.38 ± 7.73 vs. 1.06 ± 3.81 (p = NS) (2) 0.61 ± 2.20 vs. 0.33 ± 1.18 vs. 0.36 ± 1.40 (glulisine vs. aspart p = 0.044, glulisine vs. lispro p = 0.070) (3) 73.84 ± 82.10 vs. 65.01 ± 72.07 vs. 62.69 ± 72.87 (glulisine vs. aspart p = 0.008, glulisine vs. lispro p < 0.001) (4) 12.80 ± 18.02 vs. 9.66 ± 13.75 vs. 9.48 ± 13.28 (glulisine vs. aspart p < 0.001, glulisine vs. lispro p < 0.001) | (1) Infusion-set occlusion (2) DKA (3) Hyperketonemia, rate per month (± SD) | (1) No difference between groups (2) 1 vs. 0 vs. 0 (3) 0.14 ± 0.43 vs. 0.06 ± 0.22 vs. 0.06 ± 0.18 (glulisine vs. aspart p = 0.01, glulisine vs. lispro p = 0.02) |