Table 3.

Summary of outcomes from additional studies of Mix50

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]	Post-hoc analysis of ethnicity, including 2 RCTs involving Lispro 50 [26, 27]	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]	SR of 7 RCTs, including 3 RCTs involving Lispro 50 [19, 22, 26]	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]	SR, MA of 45 trials, including 3 RCTs involving Lispro 50 [19, 22, 26]	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)

AUC area under the curve, BG blood glucose, BIAsp30 30% soluble insulin aspart, 70% protamine-crystallized insulin aspart, BIAsp50 50% soluble insulin aspart, 50% protamine-crystallized insulin aspart, BIAsp70 70% soluble insulin aspart, 30% protamine-crystallized insulin aspart, BID twice daily, BMI body mass index, BW body weight, CI confidence interval, FBG fasting blood glucose, FPG fasting plasma glucose, G + L insulin glargine + insulin lispro, HbA1c glycated hemoglobin, Lispro 25 25% insulin lispro, 75% insulin lispro protamine suspension, Lispro 50 50% insulin lispro, 50% insulin lispro protamine suspension, MA meta-analysis, NPH neutral protamine Hagedorn, NR not reported, NS not significant, OD once daily, OHAs oral hypoglycemic agents, OR odds ratio, PBG postprandial blood glucose, PPG postprandial plasma glucose, RCT randomized controlled trial, SD standard deviation, SMBG self-monitored blood glucose, SR systematic review, SU sulfonylurea, TID three times daily, T2D type 2 diabetes