Table 1

Overview of the identified clinical studies including a basal-plus arm (according to the PICO scheme)

Clinical studyPatient populationBasal-plus dosage InterventionComparatorPrimary endpointKey outcomes
B+ combination: IGlar + IGlu
OPAL8
Open-label RCT; 24-week FU
Outpatient; T2D; age ≥18 years; HbA1c >6.5%–9.0%; FBG ≤6.7 mmol/L; IGlar + OADs for ≥3 months B+ (breakfast): IGlar + OADs + IGlu before breakfast (n=162) B+ (main meal): IGlar + OADs + IGlu before main meal of the day (n=154)Change in HbA1c from baseline to endpoint
  1. Regimens comparable for HbA1c reduction and HbA1c <7% target achievement.

  2. Hypoglycemia rare and comparable between groups.

Davidson et al 9
Open-label RCT; 24-week FU
Outpatient; T2DM ≥6 months, age 18–79 years, HbA1c ≥8%, stable dose of 2–3 OADs B+ 1: IGlar + OADs + IGlu before the largest meal of the day (n=101)
B+ 2: IGlar + OAD + IGlu before the two largest meals of the day (n=102)
BB: IGlar +OADs + IGlu before all three meals (n=100)Change in HbA1c from randomization to study end (week 24)
  1. HbA1c reduction non-inferior with B+ 1 and B+ 2 vs BB.

  2. HbA1c <7% target achievement more frequent with BB vs B+ 1 and B+ 2.

  3. Severe hypoglycemia nominally more common with BB vs B+ 1 and 2.

POC21
Open-label RCT; 6-month FU
Outpatient; T2D; age 18–75 years; BMI 25–45 kg/m2; HbA1c 7.5%–9.5%; treatment with basal insulin + Met ≥1 g/day for >3 months B+ : IGlar + OADs + IGlu before main meal of the day (n=45) BOT: IGlar + OADs only (n=51)Proportion of patients achieving HbA1c <7% at endpoint
  1. HbA1c <7% more common and reduction in HbA1c greater with B+ vs BOT.

  2. Hypoglycemia and weight change comparable between groups.

Choe et al 13
Retrospective chart review; 6-month FU
Outpatient; T2D; in Severance Hospital Diabetes Insulin Education Registry; IGlar ≥6 months; recent addition of IGlu 1×/day B+ : IGlar + IGlu 1×/day (n=87)n.a.Changes in glycemic and clinical parameters
  1. HbA1c reduced by 0.8% and PPBG by 48.7 mg/dL at 6 months (p<0.001).

ELEONOR15
Open-label RCT; 24-week FU
Outpatient; T2DM ≥12 months; age 30–70 years; BMI>25 kg/m2; HbA1c 7.5%–11%; maximum dose OADs for ≥3 months B+ (telecare): IGlar + Met 1 g 2×/day + IGlu 1×/day at dinner time with telecare monitoring (n=115) B+ (SMBG): IGlar + Met 1 g 2×/day + IGlu 1×/day at dinner time with SMBG (n=126)Change in HbA1c from baseline to end of treatment phase
  1. HbA1c reduction and achievement of FBG ≤7 mmol/L comparable between groups.

  2. Weight change and hypoglycemia similar between groups.

OSIRIS20
Open-label RCT; 12-month FU
Outpatient; T2D; age 18–75 years; BMI ≤40 kg/m2; HbA1c >7%; treated with basal insulin and ≥2 OADs B+ : IGlar + Met + IGlu before main meal; subsequent stepwise addition of IGlu (n=165)
B+ (+IS): IGlar + Met + insulin secretagogue + IGlu before main meal; subsequent stepwise addition of IGlu (n=100)
BB: IGlar + IGlu 3×/day before meals + Met (n=120)To show non-inferiority in terms of efficacy between the treatment arms as measured by HbA1c
  1. B+ not non-inferior to BB for adjusted HbA1c reduction (0.228; 95% CI: −0.018 to 0.473).

  2. Weight gain lower with B+ than BB.

  3. Symptomatic hypoglycemia comparable between groups. Nocturnal symptomatic hypoglycemia more common with B+ (+IS) than B+.

Umpierrez et al 18 19
Open-label RCT; 8-day FU
Inpatient; hospitalized, non-ICU, general medicine and surgery patients; T2DM >3 months; age 18–80 years; FBG 140–400 mg/dL; preadmission management with diet, OADs or daily insulin ≤0.4 U/kg B+ : IGlar + corrective IGlu before meals and at bedtime only when BG >140 mg/dL (n=133) BB: IGlar + IGlu before all meals + corrective IGlu when BG >140 mg/dL (n=144)
SSI: Sliding scale regular insulin when BG >140 mg/dL (n=74)
Difference in glycemic control, as measured by daily BG concentrations
  1. Reduction in BG after day 1 similar between BB and B+. and worse with SSI.

  2. Treatment failure lower with BB and B+ vs SSI.

  3. Severe hypoglycemia comparable between groups.

All To Target16
Open-label RCT; 60-week FU
Outpatient; T2D; age 30–80 years; BMI <45 kg/m2; HbA1c >7.5%; 2–3 OADs for ≥3 months; <1 week insulin use in past 12 months Basal+ 1: IGlar + IGlu 1×/day with main meal; ±OADs (n=194)
Basal+ ≤ 3: IGlar + IGlu up to 3×/day; ±OADs (n=194)
Premix: IAsp/IAsp protamine 30/70 2×/day at breakfast and dinner time; ±OADs (n=194)Non-inferiority of treatment options based on the reduction of HbA1c from baseline to week 60
  1. Basal+ 1 non-inferior to premix for HbA1c reduction and basal+ ≤3 superior to premix for achievement of HbA1c <7.0%.

  2. Hypoglycemia <2.8 mmol/L more frequent with premix vs basal+ 1 and basal+ ≤3.

LanScape23
Open-label RCT; 24-week FU
Outpatient; T2D; aged 18–75 years; HbA1c ≥7.5% and ≤11%; BMI ≤40 kg/m2; basal insulin for ≥3 months; no prior GLP-1 RA, DPP-4i, biphasic, short-acting or rapid-acting insulin B+ : IGlar + IGlu with largest meal; no OADs (except Met) (n=170) Premix: IAsp/IAsp protamine 30/70 2×/day at breakfast and dinner time; no OADs (except Met) (n=165)Change in HbA1c
  1. B+ non-inferior to premix for HbA1c.

  2. Treatment satisfaction higher for B+.

  3. Hypoglycemia similar between groups and nocturnal hypoglycemia more common with B+.

Jin et al 22
Open-label RCT; 24-week FU
Outpatient; T2D; age ≥20 years; BMI <30 kg/m2; HbA1c 7.0%–10.0%; FPG <130 mg/dL; IGlar ≥12 weeks B+: IGlar + IGlu before largest meal for 12 weeks; subsequently, second IGlu bolus before second largest meal, where HbA1c> 7.0%; ±OADs (n=78) Premix: IAsp/IAsp protamine 30/70 before breakfast and dinner;±OAD (n=82)Change in HbA1c after 24 weeks
  1. Mean-adjusted HbA1c reduction comparable between groups.

  2. Rate of hypoglycemia and total daily insulin dose similar between groups.

GetGoal Duo-224
Open-label RCT; 26-week FU
Outpatient; T2DM ≥1 year; BMI >20 and <40 kg/m2; basal insulin for ≥6 months; HbA1c ≥7% and ≤9%; FBG ≤140 mg/dL; ≤3 OADs B+ : IGlar + IGlu before main meal; ±Met (n=298)
BB: IGlar + IGlu 3×/day before meals; ±Met (n=295)
Lixisenatide: IGlar + lixisenatide 20 mg before main meal; ±Met (n=297)HbA1c reduction with the treatment options
  1. HbA1c improved comparably in all groups.

  2. Symptomatic hypoglycemia less common with lixisenatide vs B+ and BB.

  3. Change in bodyweight negative for lixisenatide and positive for B+ and BB groups.

  4. GI events more common with lixisenatide.

B+ combination: IGlar + ILis
Tinahones et al 26
Open-label RCT; 24-week FU
Outpatient; T2D; age ≥18 and ≤75 years; BMI ≤45 kg/m2; HbA1c ≥7.5% and ≤10.5%; FPG ≤6.7 mmol/L; Met≥ 1500 mg/day for ≥8 weeks and/or pioglitazone ≥30 mg/day for ≥12 weeks; IGlar for ≥90 days B+ : Bedtime IGlar+ ILis before largest meal; +Met/pioglitazone (n=240) Premix: LM25 before breakfast and dinner; +Met/pioglitazone (n=236)Change in HbA1c after 24 weeks
  1. Premix superior to B+ for HbA1c reduction

  2. Mean BG, glycemic variability, tolerability and hypoglycemic episodes not significantly different.

Gracia-Ramos et al 25
Open-label RCT; follow-up during hospital stay
Inpatient; hospitalized, non-ICU patients; T2DM >3 months; BG >140 and <400 mg/dL on admission; treatment with diet, OADs or low-dose insulin (≤0.4 U/kg) before admission; consumption of ≥75% of indicated diet B+ : IGla + ILis before meals when BG >140 mg/dL; no OADs (n=25) Premix: LM75/25 + ILis before meals when BG >140 mg/dL; no OADs (n=25)To compare the safety and efficacy of the study treatments
  1. Premix and B+ comparable for BG after day 1 (166.6 vs 173.0 mg/dL; p=0.470), final BG (131.3 vs 143.8 mg/dL; p=0.153) and achievement of BG <140 mg/dL (72% vs 56%; p=0.239).

  2. Hypoglycemia comparable between groups.

Gross et al 14
Post hoc analysis of Tinahones et al 26; 24-week FU
Outpatient; T2D; age ≥18 and ≤75 years; BMI ≤45 kg/m2; HbA1c ≥7.5 and ≤10.5%; FPG ≤6.7 mmol/L; Met ≥1500 mg/day for ≥8 weeks and/or pioglitazone ≥30 mg/day for ≥12 weeks; IGlar for ≥90 days B+ : Bedtime IGlar+ ILis before main meal; +Met/pioglitazone
Main meal timing: breakfast (n=40); lunchtime (n=107); evening (n=93)
Premix: LM25 before breakfast and dinner; +Met/pioglitazone.
Main meal timing: breakfast (n=51); lunchtime (n=71); evening (n=114)
To compare the safety and efficacy of the study treatments
  1. HbA1c decreased in all main meal subgroups in both insulin regimens.

  2. Evening main meal: greater weight gain and more hypoglycemia with premix vs B+.

  3. Lunchtime main meal: higher nocturnal hypoglycemia with premix vs B+.

B+ combination: IDet + IAsp
STEPWise28
Open-label RCT; 48-week FU
Outpatient; T2DM ≥6 months; age ≥18 years; HbA1c 7.5%–10%; receiving basal insulin +1–3 OADs B+ (simpleSTEP): IDet + OAD + stepwise addition of IAsp at largest meal based on premeal glucose (n=150) B+ (ExtraSTEP): IDet + OAD + stepwise addition of IAsp at meal with largest prandial glucose increment based on postmeal glucose (n=146)Change in HbA1c levels at 36 weeks after randomization
  1. HbA1c reduction comparable between groups.

  2. Adverse events and hypoglycemia rare and comparable between groups.

FullSTEP27
Open-label RCT; 32-week FU
Outpatient; T2DM ≥12 months; age ≥18 years; HbA1c 7%–9%; BMI <40.0 kg/m²; NPH, IGlar or IDet for ≥6 months B+ : IDet + IAsp before largest meal for 11 weeks; subsequent stepwise addition of IAsp up to 3×/day; ±OADs (n=201) BB: IDet + prandial IAsp 3×/day; ±OADs (n=200)Change in HbA1C from baseline to week 32
  1. HbA1c reduction not significantly different between groups.

  2. Fewer hypoglycemic events with B+ than BB.

  • LM25: insulin lispro protamine suspension 75% and insulin lispro solution 25%; B+, basal plus; BB, basal-bolus; BG, blood glucose;BMI, body mass index; BOT, basal-supported oral therapy; FBG, fasting blood glucose; FU, follow-up; GI, gastrointestinal;GLP-1 RA, glucagon-like peptide-1 receptor agonist; IAsp, insulin aspart; IDet, insulin detemir; IGlar, insulin glargine; IGlu, insulin glulisine; ILis, insulin lispro;LOS, length of stay; Met, metformin;n.a., not applicable; OAD, oral antidiabetic drug; PPBG, postprandial blood glucose; RCT, randomized controlled trial; SMBG, self-monitored blood glucose; T2D, type 2 diabetes.