Introduction
Methods
Literature Search Strategy
Study Eligibility Criteria
Study Selection
Data Extraction
Risk of Bias Assessment
Compliance with Ethics Guidelines
Results
Literature Search Results
Characteristics of Included Studies
First author (or study identifier), [reference], and countries | Study design Duration | Treatment groups | HbA1c changea
| FBG/FPG changea
| PBG/PPG changea
| Hypoglycemia definition and incidence | Body weight/BMI changea
|
---|---|---|---|---|---|---|---|
Mix50 vs. low mix
| |||||||
Chen [14] China, Japan | RCT, OL, subgroup analysis of Watada [31] 26 weeks | Lispro 50 BID (n = 160) vs. Lispro 25 BID (n = 168) | LS mean change (%) CHO intake ≥ median (≥ 230.8 g): −1.67 vs. −1.35 (P = 0.024) CHO intake ≥ median (≥ 54% of energy): −1.79 vs. −1.43 (P = 0.009) Fat intake ≥ median (≥ 56.5 g): −1.83 vs. −1.48 (P = 0.013) Fat intake ≥ median (≥ 31% of energy): −1.87 vs. −1.51 (P = 0.014) Protein intake ≥ median (≥ 66.0 g): −1.82 vs. −1.50 (P = 0.027) Protein intake ≥ median (≥ 15% of energy): −1.79 vs. −1.45 (P = 0.022) Energy intake < median (< 1714.5 kcal): −1.77 vs. −1.45 (P = 0.026) Treatment differences for CHO, fat, or protein intake < median and energy intake ≥ median P = NS | NR Pre-morning meal SMBG (mg/dL) LS mean change −39.51 vs. −44.67 (P = 0.079) | NR | Symptomatic or asymptomatic with PG ≤ 3.9 mmol/L or probably symptomatic without PG measurement Total: 61.3% vs. 59.5% Nocturnal: 10.6% vs. 11.9% Severe (requiring assistance): 0% vs. 0% | LS mean change in BW (kg) + 2.08 vs. + 2.17 (P = 0.796) |
Domeki [16] Japan | RCT, OL 48 weeks | Lispro 50 (n = 36) vs. BIAsp30 (n = 36) Before dinner + injections before breakfast and before lunch after 16 and 32 weeks, respectively, if HbA1c ≥ 7.4% | Baseline/end point mean values (%) 9.6 (n = 36)/7.7 (n = 13) vs. 9.9 (n = 36)/8.2 (n = 9), P = NS | Baseline/end point mean FPG (reported as mol/L) 130 (n = 36)/90 (n = 13) vs. 138 (n = 36)/105 (n = 9), P = NS | NR | Symptomatic overall: 8.3% vs. 8.3% Severe: 0% vs. 0% | Baseline/end point mean BMI (kg/m2) 24.5 (n = 36)/27.2 (n = 13) vs. 24.4 (n = 36)/30.5 (n = 9), P = NS |
Su [29] China | RCT, OL, subanalysis of Watada [31] 26 weeks | Lispro 50 BID (n = 76) vs. Lispro 25 BID (n = 80) | LS mean change (%) −1.99 vs. −1.58 (P < 0.001) Subgroup analysis: Men: −2.11 vs. −1.65 (P = 0.017) Women: − 1.91 vs. −1.44 (P = 0.014) Age < 65 years: −2.08 vs. −1.62 (P = 0.006) Age ≥ 65 years: −1.92 vs. −1.31 (P = 0.018) Baseline HbA1c ≥ 8.4%: −2.92 vs. − 2.11 (P < 0.001) Baseline PPG ≥ 13.5 mmol/L: −2.60 vs. −1.84 (P < 0.001) Baseline mean BG excursion ≥ 4.4 mmol/L: −2.31 vs. − 1.66 (P = 0.001) Baseline FPG ≥ 9.0 mmol/L: −2.65 vs. − 1.94 (P = 0.001) Treatment differences for baseline HbA1c < 8.4%, baseline PPG < 13.5 mmol/L, baseline mean BG excursion < 4.4 mmol/L, and baseline FPG < 9.0 mmol/L, P = NS | LS mean change in FBG (mmol/L) − 2.12 vs. −2.50 (P = 0.180) | NR LS mean change in SMBG was significantly greater in the Lispro 50 group vs. Lispro 25 after morning (P = 0.028) and evening (P = 0.001) meals | Symptomatic or asymptomatic with PG ≤ 3.9 mmol/L or probably symptomatic without PG measurement Episodes per person per year Total: 3.45 vs. 2.97 Nocturnal: 0.43 vs. 0.30 Severe (requiring assistance): no events in either group | LS mean difference (Lispro 50–Lispro 25) in change in BW (kg) 0.07 kg (P = 0.896) |
Watada [31] China, Korea, Japan, and Turkey | RCT, OL 26 weeks | Lispro 50 BID (n = 196) vs. Lispro 25 BID (n = 207) | LS mean change (%) −1.69 vs. −1.52 Lispro 25 was noninferior to Lispro 50 and Lispro 50 was noninferior to Lispro 25 Subgroup analysis: Baseline HbA1c ≥ median (≥ 8.4%): −2.35 vs. −2.05 (P = 0.026) Baseline PPG ≥ median (≥ 13.30 mmol/L): −2.26 vs. −1.94 (P = 0.027) CHO intake ≥ median (≥ 230.8 g): −1.67 vs. −1.35 (P = 0.024) CHO intake ≥ median (≥ 54% of energy): −1.79 vs. −1.43 (P = 0.009) Treatment differences for baseline HbA1c, baseline PPG, baseline FPG, and CHO intake < median and baseline FPG ≥ median P = NS | LS mean change in FBG (mmol/L) −1.99 vs. −2.37
P = 0.046 | Improvement in PBG was significantly greater with Lispro 50 than Lispro 25 after morning (P = 0.038) and evening (P < 0.001) meals | Symptomatic or asymptomatic with PG ≤ 3.9 mmol/L or probably symptomatic without PG measurement Incidence per person per year Total: 6.343 vs. 5.661, P = 0.463 Nocturnal:, 0.731 vs. 0.828, P = 0.688 Severe (requiring assistance): 0.073 vs. 0 (no events), P value ND | LS mean change in BW (kg) + 2.32 vs. + 2.31, P = 0.975 |
Zafar [32] China | RCT, OL 12 weeks | Lispro 50 BID (n = 73) vs. Lispro 25 BID (n = 73) | Mean change (%) −4.2 vs. −3.6 (P < 0.05) | Mean change in FBG (mmol/L) −2.6 vs. −1.1 (P < 0.05) | Mean change in PBG (mmol/L) −4.2 vs. −2.0 (P < 0.05) | Minor (BG ≤ 3.9 mmol/L; self-treatable): 6.84% vs. 5.48% (P = NS) Nocturnal: 0% vs. 2.74% (P = NS) Major (neurological symptoms; requiring assistance): 0% vs. 0% | Mean change in BW (kg) + 1.92 vs. + 2.03 (P = NS) |
Mix50 vs. basal
| |||||||
Jacober [19] United States | RCT, OL, crossover 8 months | Lispro 50/Lispro 25 TID (Lispro 50 before breakfast and lunch, Lispro 25 before dinner) vs. glargine OD (n = 60 crossover) | LS mean change from pretherapy (%): −1.01 vs. −0.75 (P = 0.0068) | Mean FBG at end point (mg/dL) Approx. 125 for both groups (P = NS) (presented in figure, data NR; change values NR) | NR | Symptomatic and/or BG ≤ 4.0 mmol/L; self-reported Mean episodes per patient/30 days: 4.71 vs. 2.31 (P = 0.0010) Nocturnal: 0.94 vs. 0.93 (P = 0.9701) | LS mean change in BW from pretherapy (kg) 1.98 vs. 1.52 (P = 0.457) |
Kazda [22] Germany | RCT, OL 24 weeks | Lispro 50 TID (n = 54) vs. insulin lispro TID (n = 52) vs. glargine OD (n = 53) | Mean change (%) −1.2 vs. −1.1 vs. −0.3 (P < 0.001 Lispro 50 vs. glargine; P = 0.001 insulin lispro vs. glargine) | Mean change in FBG (mmol/L): −0.9 vs. −0.9 vs. −2.6 (P < 0.001 Lispro 50 vs. glargine; P < 0.001 insulin lispro vs. glargine) | Mean change in PBG (mmol/L): −2.8 vs. −3.0 vs. −2.6 (P = 0.43 Lispro 50 vs. glargine; P < 0.01 insulin lispro vs. glargine) Mean change in PBG excursions (mmol/L): −1.8 vs. −2.1 vs. −0.1 (P < 0.001 Lispro 50 vs. glargine; P < 0.001 insulin lispro vs. glargine) | Symptomatic and/or BG < 3.0 mmol/L; self-reported Mean episodes per 100 patient-days: 1.5 vs. 1.4 vs. 1.0 Severe: none in any group | Mean change in BW (kg): + 1.8 vs. + 2.3 vs. + 0.7 Mean change in BMI (kg/m2): + 0.6 vs. + 0.9 vs. + 0.2 (P = 0.19 Lispro 50 vs. glargine; P = 0.048 insulin lispro vs. glargine) |
Mix50 vs. basal–bolus
| |||||||
Giugliano [18] Brazil, Canada, Egypt, India, Mexico, Portugal, Romania, Spain, and Turkey | RCT, OL 48 weeks | Lispro 50 and/or Lispro 25 OD, BID, or TID, titrated with algorithm (n = 171) vs. glargine OD + insulin lispro OD, BID, or TID, titrated with algorithm (n = 173) | LS mean change (%): −1.65 vs. −1.57 (P = 0.556) | NR | NR | Symptomatic and/or BG ≤ 4.2 mmol/L; self-reported Mean incidence per patient per year: 9.63 vs. 8.13 (P = 0.435) Nocturnal: 1.91 vs. 1.09 (P = 0.068) Severe: 0.09 vs. 0.12 (P = 0.852) | Mean change in BW (kg): + 2.31 vs. + 2.32 (P = 0.819) |
Jain [20] Australia, Canada, France, Greece, India, Republic of Korea, Mexico, Russia, and Spain | RCT, OL 36 weeks | Lispro 50 OD, BID, or TID, titrated with algorithm (n = 242) vs. glargine OD + insulin lispro OD, BID, or TID, titrated with algorithm (n = 242) | LS mean change (%): −1.76% vs. −1.93% (P = 0.097) Noninferiority of Lispro 50 to G + L not achieved | LS mean FBG at week 36 (mmol/L): 7.0 vs. 6.5 (P = 0.010; change values NR) | LS mean post-dinner PBG at week 36 (mmol/L): 9.3 vs. 9.8 (P = 0.010; change values NR) For post-breakfast and post-lunch PBG, P = NS (presented in figure, change values NR) | Symptomatic and/or BG < 3.9 mmol/L, % patients with episodes: 74.5% vs. 74.6% (P = NS) Nocturnal: 46.9% vs. 46.7% (P = NS) Severe (requiring assistance): 3.4% vs. 2.1% (P = NS) | LS mean change in BW (kg): + 3.09 vs. + 3.19 (P = 0.803) |
First author (or study identifier), [reference], and countries | Study design Duration | Treatment groups | HbA1c changea
| FBG/FPG changea
| PBG/PPG changea
| Hypoglycemia incidence | Body weight/BMI changea
|
---|---|---|---|---|---|---|---|
Mix50 vs. low mix
| |||||||
Cucinotta [15] Europe (18 countries) | RCT, OL 36 weeks | BIAsp50 TID (n = 201) vs. BIAsp30 BID (n = 200) vs. BIAsp70 TID (n = 198) | Mean change (%): −1.9 vs. −1.6 vs. −1.6 (P = 0.004 BIAsp50 vs. BIAsp30) | FPG at 36 weeks was higher for BIAsp70 (P < 0.05) but not for BIAsp50 (P = NS) compared with BIAsp30 (presented in figure; change values NR) | Mean PPG increment significantly lower with both BIAsp50 (P = 0.0002) and BIAsp70 (P < 0.0001) vs. BIAsp30 (presented in figure; data NR) | Symptomatic and/or BG < 3.1 mmol/L; self-reported Episodes per year: Over 24 h Major (requiring assistance): 0.0 vs. 0.0 vs. 0.1 Minor: 9.3 vs. 7.9 vs. 13.3 Nocturnal Major: 0.0 vs. 0.0 vs. 0.0 Minor: 1.3 vs. 1.6 vs. 1.6 RR of 24-h minor episodes significantly higher with BIAsp70 vs. BIAsp30 (P = 0.0002), but not with BIAsp50 vs. BIAsp30 (P = 0.2185) | Baseline-adjusted change in BW (kg): ~ + 4 vs. ~ + 3.5 vs. ~ + 4 (P = NS) |
Farcasiu [17] Hungary, Croatia, Poland, Romania, South Africa, and Turkey | RCT, OL 16 weeks (+ 2-week lead-in with previous Lispro 25 or BIAsp30 BID) | Lispro 50 TID (n = 151) vs. Lispro 25/BIAsp30 BID (n = 151) | Mean change (%): −1.0 vs. −0.82 (P = NS) | FPG at 16 weeks (mg/dL): 161.1 vs. 153.9 (P = 0.0129) | Mean change in post-lunch PBG (mg/dL):−64.8 vs. −41.5 (P < 0.05) Mean change in post-lunch BG excursion (mg/dL): −38.4 vs. −9.2 (P < 0.001) | Symptomatic and/or PG ≤ 70 mg/dL LS mean episodes/patient/30 days: Overall: 0.56 vs. 0.61 (P = 0.7230) Nocturnal: 0.04 vs. 0.13 (P = 0.0063) Severe (requiring assistance): 0.00 vs. 0.01 (P = 0.8876) | Mean change in BW (kg): + 1.3 vs. + 0.4 (P = 0.0009) |
NCT00627445 [24] China | RCT, OL 16 weeks (+ 4-week lead-in with previous insulin) | BIAsp50 before breakfast and lunch + BIAsp30 before dinner (n = 219) vs. BIAsp30 BID (n = 222) | LS mean change (%): −1.790 vs. −1.517 (P < 0.001) BIAsp50/BIAsp30 was non-inferior to, and also superior to, BIAsp30 | LS mean change in pre-breakfast SMBG (mmol/L): −2.52 vs. −2.43 (P = 0.516) | LS mean change in PBG (mmol/L): Post-breakfast: −3.92 vs. −4.00 (P = 0.716) Post-lunch: −4.37 vs. −3.15 (P < 0.001) Post-dinner: −3.46 vs. −3.37 (P = 0.746) | Symptomatic and/or PG < 3.1 mmol/L; self-reported Episodes per person per year Total: 11.1 vs. 10.3 (P = 0.1976) Nocturnal: 2.04 vs. 1.23 (P = 0.0130) Major (requiring assistance): 1 vs. 0 events | LS mean change in BW (kg): + 1.188 vs. + 0.817 (P = 0.0851) |
NCT00834262 [40] Israel | Prospective, nonrandomized, OL, observational 13 weeks | BIAsp50 (n = 91) vs. BIAsp30 (n = 106) vs. BIAsp70 (n = 14) vs. combinations (n = 127) Dose and frequency at physician’s discretion | Mean change (% [SD]):b −0.6 (1.5) vs. −0.7 (1.3) vs. −0.6 (0.9) vs. −0.9 (1.4) | Mean change (mg/dL [SD]):b −17.6 (77.0) vs. −17.5 (52.3) vs. −50.3 (57.6) vs. −23.5 (74.2) | Mean change in PPG (mg/dL [SD]):b
Post-breakfast: −44.4 (70.0) vs. −25.1 (53.6) vs. −72.8 (60.2) vs. −35.1 (71.0) Post-lunch: − 43.7 (73.1) vs. −27.6 (51.0) vs. -56.9 (58.8) vs. − 36.9 (80.3) Post-dinner: − 45.3 (71.5) vs. − 25.2 (56.2) vs. − 75.5 (56.8) vs. − 34.4 (86.1) | Symptomatic and/or PG < 3.1 mmol/L; self-reported Episodes per patient-year: 3.8 vs. 2.5 vs. 0.3 vs. 4.1 | Mean change in BW (kg): + 0.4 vs. + 0.8 vs. −0.8 vs. + 0.7 |
Roach [25] India | RCT, OL, DB for pre-breakfast insulin, crossover 16 weeks (+ 4-week lead-in with human insulin 30/70 BID) | Lispro 50 before breakfast + Lispro 25 before dinner vs. Lispro 25 BID (n = 116; crossover) | Mean at 16 weeks (%): 8.14 vs. 8.14 (P = 0.919; change values NR) | Mean FBG at 16 weeks (mmol/L): 9.5 vs. 8.9 (P = 0.129; change values NR) | Mean PBG after CHO-rich breakfast at 16 weeks (mmol/L): 10.9 vs. 12.4 (P = 0.0012; change values NR) | Symptomatic; self-reported % patients with episodes: 32.4% vs. 26.1% (P = 0.078) Severe (requiring assistance): no episodes | NR |
Shimizu [41] Japan | Prospective, nonrandomized, interventional 24 weeks | Lispro 50 BID (PPG > 200 mg/dL; n = 20) vs. Lispro 25 BID (PPG < 200 mg/dL; n = 20) | Mean (%) at baseline: 8.3 vs. 8.1 Mean (%) at 24 weeks: 7.5 vs. 7.9 | Mean FPG at baseline (mg/dL): 143.0 vs. 150.7 Mean FPG at 24 weeks (mg/dL): 134.8 vs. NR (not significantly changed from baseline) | Mean PPG at baseline (mg/dL): 228.8 vs. 181.8 (P < 0.05) Mean PPG at 24 weeks (mg/dL): 182.5 vs. NR (not significantly changed from baseline) | Not defined No severe episodes in either group | Mean BW at baseline (kg): 59.1 vs. 59.1 Mean BW at 24 weeks (kg): 60.0 vs. 59.3 |
Tanaka [42] Japan | Prospective, non-comparative, OL, switching study 2 days | Switched from low-mix to Lispro 50 BID (n = 13) | NR | NR | Post-breakfast PBG lower with Lispro 50 than before switch (P < 0.01) | Symptomatic No hypoglycemic symptoms | NR |
Mix50 vs. basal
| |||||||
Hirsch [34] Australia, Greece, India, The Netherlands, Poland, Puerto Rico, and United States | Post-hoc analysis of Robbins [26] 24 weeks (+ 6-week lead-in with Lispro 25 BID) | Lispro 50 TID (n = 157) vs. glargine OD (n = 158) | Mean change (%): −0.72 vs. −0.35 (P < 0.001) | Mean FBG change (mg/dL): −10.4 vs. −34.9 (P < 0.001) | NR | Symptomatic or BG < 3.5 mmol/L; self-reported Episodes per patient per 30 days: All: 0.65 vs. 0.28 (P = 0.017) Nocturnal: 0.19 vs. 0.16 (P = 0.017) | BW at end point (kg): 89.96 vs. 87.64 (P < 0.001) |
Robbins [26] Australia, Greece, India, The Netherlands, Poland, Puerto Rico, and United States | RCT, OL 24 weeks (+ 6-week lead-in with Lispro 25 BID) | Lispro 50 TID (n = 158) vs. glargine OD (n = 159) | Mean change (%): −0.7 vs. −0.4 (P < 0.001) | Mean FBG at 24 weeks (mmol/L): 8.1 vs. 6.5 (P < 0.001) (change values NR) | Mean change in daily 2-h PBG excursion (mmol/L): −1.0 vs. + 0.6 (P < 0.001) | Symptomatic or BG < 3.5 mmol/L; self-reported Episodes per patient per 30 days: entire treatment period: all: 0.8 vs. 0.5 (P = 0.07) Nocturnal: 0.2 vs. 0.3 (P = 0.30) At end point: all: 0.7 vs. 0.3 (P = 0.02) Nocturnal: 0.2 vs. 0.2 (P = 0.62) | Mean change in BW (kg): + 1.2 vs. −0.5 (P < 0.001) |
Mix50 vs. basal–bolus
| |||||||
Ito [36] Japan | Prospective, observational 16 weeks | Lispro 50 or BIAsp50 switched to glargine OD + glulisine BID (n = 28) | Mean change (%): −0.1 (change P = 0.64) | NR | NR | No severe hypoglycemia (symptomatic, requiring assistance) | Mean BW, baseline/end point (kg): 69.3/69.6 (P = 0.38) Mean BMI, baseline/end point (kg/m2): 25.5/25.6 (P = 0.31) |
Jia [21] China, Taiwan, Korea | RCT, OL 24 weeks | Lispro 50 before breakfast and lunch + Lispro 25 before dinner (n = 199) vs. glargine OD + lispro TID (n = 203) | LS mean change (%): −1.1 vs. −1.1 Noninferiority demonstrated | LS mean change in FBG (based on SMBG morning pre-meal) (mmol/L): −0.8 vs. −1.2 (P = 0.002) | LS mean change in PBG (mmol/L): Post-lunch: −3.5 vs. −3.0 (P = 0.005) Post-breakfast and post-dinner: P = NS (presented in figure, values NR) | Symptomatic and PG ≤ 3.9 mmol/L Mean episodes per patient per 30 days: 0.47 vs. 0.41 (P = 0.148) Nocturnal: 0.03 vs. 0.05 (P = 0.235) Severe (requiring assistance): no episodes in either group | Change in BW (kg): + 0.8 vs. + 0.7 (P = NR) |
Miser [23] Argentina, Australia, Brazil, Canada, Greece, Hungary, India, the Netherlands, Romania, Spain, and United States | RCT, OL, substudy 6 months (substudy, after 6 months main study) | Lispro 50 TID (n = 174) vs. glargine OD + insulin lispro TID (n = 171) (Arm B only; received Lispro 25 in main study) | Mean HbA1c (%) at 6 months: 8.2 vs. 8.2 (P = 0.990) Noninferiority of Lispro 50 to G + L was shown | No significant differences in PG at end point (data NR) | NR | Symptomatic or PG ≤ 70 mg/dL; self-reported Mean episodes per patient per year: Overall: 11.1 vs. 12.1 (P = 0.623) Nocturnal: 2.5 vs. 2.4 (P = 0.949) Severe (events; requiring assistance): 2 vs. 0 (P = 0.188) | Mean change in BW (kg): 0.6 vs. 0.9 (P = 0.345) |
Rosenstock [27] Puerto Rico and United States | RCT, OL 24 weeks | Lispro 50 TID (n = 187) vs. glargine OD + insulin lispro TID (n = 187) | Mean change (%): −1.87% vs. −2.09% (P = 0.021) Noninferiority of Lispro 50 to G + L was not demonstrated | Mean FBG at 24 weeks (mmol/L): 8.8 vs. 8.2 (P = 0.013) (change values NR) | Mean PBG at 24 weeks (mmol/L): Post-breakfast: 9.6 vs. 8.6 (P = 0.002) (change values NR) For post-lunch and post-dinner PBG, treatment difference NS | Symptomatic; self-reported Episodes per patient per year: Overall: 51.20 vs. 48.70 (P = 0.619) Nocturnal: 4.78 vs. 6.17 (P = 0.139) Severe (requiring assistance): 0.10 vs. 0.04 (P = 0.266) | Mean change in BW (kg): 4.0 vs. 4.5 (P = 0.224) |
First author and [reference] | Study type | Patient population | Reason for exclusion from quality assessment | Relevant efficacy outcomes | Relevant safety outcomes |
---|---|---|---|---|---|
Akahori [35] | Observational Approx. 11 months | T2D with poor glycemic control Lispro 50 (n = 19) vs. BIAsp30 (n = 20) | Combined initiation and intensification | Mean HbA1c (%): Baseline, 9.9 vs. 10.1 Week 12, 6.9 vs. 7.0 Week 48, 7.0 vs. 7.3 (P = 0.03) HbA1c < 6.9% at week 48: 60.0% vs. 25.0% (P = 0.01) Mean FBG (mg/dL): baseline, 119.4 vs. 122.6 Week 48, 127.4 vs. 132.6 (P = NS) Mean PPG after 1 week (mg/dL): Post-breakfast, 147.6 vs. 170.0 (P = 0.34) Post-lunch, 146.9 vs. 161.0 (P = 0.51) Post-dinner, 116.0 vs. 204.0 (P = 0.01) | No major and few minor (symptoms only) hypoglycemic episodes (P = NS) No significant changes in BMI in either group |
Brito [9] | Consensus statement | Patients currently on BIAsp30 who require intensification | Presents clinical evidence for use of high-mix insulin analogs (based on 4 studies of BIAsp30, BIAsp50, and BIAsp70) | Patients poorly controlled on low-mix insulin BID or TID considered most likely to benefit from switching to high-mix insulin analogs Patients with normal FPG but elevated PPG may benefit most from BIAsp70 Patients with elevated FPG and PPG levels may benefit most from BIAsp50 Provides algorithms for intensification, depending on patient’s PPG and FBG | PPG should not exceed 9 mmol/L as long as hypoglycemia is avoided Down-titration recommended if major or recurrent minor hypoglycemia occurs |
Cho [45] | Retrospective observational Approx. 2 weeks (perioperative) | Patients requiring intensive insulin treatment to stabilize glycemic control before surgery Lispro 50 TID (n = 20) vs. basal–bolus (insulin type NR; n = 27) | Perioperative | Lispro 50 TID and basal–bolus therapy were equally effective in controlling BG at 1 day before or 7 days after surgery | No differences in hypoglycemia (symptomatic or BG < 60 mg/dL), infections, or surgical complications between Lispro 50 TID and basal–bolus therapy |
Davidson [33] | Patients treated with Lispro 50, Lispro 25, basal (glargine or NPH), or basal–bolus (G + L) | Basal and basal–bolus groups combined | Lispro 50: no effect of ethnicity on change in HbA1c, % of patients achieving HbA1c targets, or FPG at end point Lispro 25: change in HbA1c significantly lower in Asian (−0.8%) and Latino/Hispanic (−0.9%) patients compared with Caucasian patients (−1.3%; P < 0.05) Significantly fewer Asian patients achieved HbA1c < 7.0% compared with Caucasian patients (2.3% vs. 23.3%; P < 0.05) Basal/basal–bolus: change in HbA1c significantly greater in Latino/Hispanic (− 0.9%) patients compared with Caucasian patients (−0.3%; P < 0.01) Significantly more Latino/Hispanic patients achieved HbA1c < 7.0% compared with Caucasian patients (36.5% vs. 14.0%; P < 0.01) | Lispro 50: no effect of ethnicity on BW or hypoglycemia (definitions varied among studies), except a higher rate of severe episodes in Asian patients compared with Caucasian patients (P < 0.01) Lispro 25: no effect of ethnicity on BW or hypoglycemia Basal/basal–bolus: no effect of ethnicity on BW or hypoglycemia | |
Ilag [12] | T2D requiring insulin initiation or intensification | Combined initiation and intensification; did not conduct MA | Changes in HbA1c, range: Lispro 50: −0.72% to −1.2% Glargine: −0.3% to −0.75% (P ≤ 0.007) More patients achieved HbA1c target with Lispro 50 vs. glargine FBG was lower with glargine vs. Lispro 50 in 2 trials and NR in 1 trial PPG was lower with Lispro 50 vs. glargine in 2 trials and similar in 1 trial Insulin doses were higher with Lispro 50 than with basal | More hypoglycemic episodes with Lispro 50 than with basal (definitions varied among studies) No significant difference in BW gain between treatments or NR | |
Mashitani [37] | Noncontrolled, interventional 24 weeks | Insulin-naive patients poorly controlled on SU Lispro 50 OD (n = 15) | Did not compare Lispro 50 with low-mix, basal, or basal–bolus | Mean (SD) HbA1c (%): Baseline, 9.0 (0.9) Week 24, 7.5 (0.9) (P < 0.01 vs. baseline) HbA1c < 7.0: 60% Significantly lower SMBG values at all time points except after dinner compared with baseline | No significant changes in BW |
Nakashima [38] | Nonrandomized, interventional 48 weeks | Patients (no insulin for ≥ 6 months) who required intensification Lispro 50 OD, increased to BID or TID if required (n = 135) | Did not compare Lispro 50 with low-mix, basal, or basal–bolus | Mean change in HbA1c (%): −1.29 (P < 0.001 vs. baseline) HbA1c < 6.9%: 18.5% HbA1c < 7.4%: 52.6% | Hypoglycemia incidence (symptomatic, self-reported): Any episode: 65.9% Daytime: 65.9% Nocturnal: 5.9% Daytime severe: 2.2% Nocturnal severe: 0.7% All severe hypoglycemic episodes (requiring assistance) occurred in patients on Lispro 50 TID who did not achieve HbA1c targets Mean change in BW (kg): + 1.3 (P < 0.001 vs. baseline) Mean change in BMI (kg/m2): + 0.48 (P < 0.001 vs. baseline) |
NCT00755833 [39] | Observational 8 weeks to 17 months | T2D treated with biphasic human insulin requiring intensification BIAsp50 TID (n = 63) vs. BIAsp50 BID (n = 43) vs. BIAsp50 BID + BIAsp30 OD (n = 65) | Compared different BIAsp50 regimens | BIAsp50 BID vs. BIAsp50 TID vs. BIAsp50/30 at 12 months Mean change (SD) in HbA1c (%): −0.6 (0.8) vs. −1.3 (1.8) vs. −1.3 (1.3) (P < 0.0001 vs. baseline for each treatment) HbA1c ≤ 6.5%: 7.0% vs. 11.1% vs. 7.7% HbA1c < 7%: 20.9% vs. 15.9% vs. 13.8% Mean (SD) change in FPG (mmol/L) for all patients combined: −1.3 (3.6) (P < 0.0001 vs. baseline) Mean (SD) change in PPG (mmol/L) for all patients combined: −2.5 (3.0) (P < 0.0001 vs. baseline) | Major hypoglycemic episodes (not defined) in last 3 months for all patients combined: 4.5% at 12 months Mean change in BW at 12 months for all patients combined (kg): + 1.1 (P < 0.0001 vs. baseline) |
Qayyum [13] | T2D requiring insulin initiation or intensification | Combined initiation and intensification | Mean difference (95% CI) of change in HbA1c (%): glargine vs. Lispro 50 = −0.40 (−0.65, −0.15) (significant in favor of Lispro 50) Mean difference (95% CI) of change in FBG/FPG (mg/dL): glargine vs. Lispro 50 = 24.7 (19.0, 30.4) (significant in favor of glargine) Mean difference (95% CI) of change in PBG/PPG (mg/dL): glargine vs. Lispro 50 = −32.6 (−48.2, −17.1) (significant in favor of Lispro 50) | Hypoglycemia (definitions varied among studies) (OR [95% CI]): combined premixed analogs (Lispro 25, BIAsp30, Lispro 50) vs. basal insulin = 2.02 (1.35, 3.04) Pooled difference (95% CI) in change in BW (kg): combined premixed analogs (Lispro 25, BIAsp30, Lispro 50) vs. basal insulin = 2.0 (1.1, 3.0) | |
Schwartz [28] | RCT, crossover | T2D using insulin (but not glargine) N = 23 | Single-dose study | Incremental AUC of serum glucose over 4 h after test meal significantly lower with Lispro 50 than with Lispro 25 (P < 0.025) Mean 2-h PPG (mg/dL): Lispro 50 vs. Lispro 25: 159 vs. 198 (P < 0.05) Mean maximal PPG (mg/dL): Lispro 50 vs. Lispro 25: 194 vs. 222 (P = NR) | No serious adverse events |
Suzuki [30] | RCT 12 months | T2D with HbA1c ≥ 7% despite maximal OHAs Lispro 50 (n = 12) vs. Lispro 50 + SU (n = 10) | Unclear whether patients were insulin-naive or insulin-treated at baseline (mean [SD] insulin dose at baseline = 0.23 [0.18] U/kg) Does not compare Mix50 with other insulin | Mean change in HbA1c (%): Lispro 50 vs. Lispro 50 + SU = −2.02 vs. −1.55 (P = 0.16) HbA1c < 7.0%: Lispro 50 vs. Lispro 50 + SU = 66.7% vs. 50.0% (P = 0.22) HbA1c < 6.5%: Lispro 50 vs. Lispro 50 + SU = 41.7% vs. 20.0% (P = 0.14) | Incidence of slight hypoglycemia (not defined) same in both groups; no serious hypoglycemia (not defined) Mean change in BMI (%): Lispro 50 vs. Lispro 50 + SU = 7.0 vs. 4.5 (P = 0.08) |
Tanaka [43] | Observational 6 months | Patients with poor glycemic control with insulin and/or OHAs Lispro 50 TID (n = 35) | Combined initiation and intensification; did not compare Lispro 50 with low mix, basal, or basal–bolus | Mean (SD) HbA1c (%): baseline, 10.1 (1.6) 6 months, 6.8 (1.1) (P < 0.001 vs. baseline) | Mean (SD) BW (kg): baseline, 59.7 (10.8) 6 months, 61.1 (9.7) (P < 0.05 vs. baseline) |
Yamashiro [44] | Observational 24 weeks | Insulin-naive; HbA1c > 7.5%; receiving SU ± biguanides ± alpha-glucosidase inhibitors Lispro 50 (n = 15) vs. prandial insulin lispro + SU (n = 16) | Did not compare Lispro 50 with low mix, basal, or basal–bolus | Mean HbA1c (%) Baseline, 10.3 vs. 9.2 Week 24, 6.8 vs. 6.8 HbA1c < 7%: 67% vs. 69% Mean FPG (mg/dL): Baseline, 207.8 vs. 178.1 Week 24, 142.7 vs. 132.1 | Mean minor hypoglycemic episodes (symptomatic and/or BG < 70 mg/dL; self-reported) per patient/year: 0.60 vs. 4.48 (P = 0.03) No major (requiring assistance) hypoglycemic episodes Mean BW (kg): Baseline, 62.1 vs. 60.3 Week 24, range 61.2–63.3 (P < 0.05 change from baseline) vs. 58.5–59.1 (P = NS change from baseline) |