. 2013 Feb 20;30(3):276–288. doi: 10.1111/dme.12019

Table 1.

Clinical trials investigating the stepwise addition of bolus insulin to basal insulin

Trial	Duration of randomized treatment period	Trial arms	Population size	HbA_1c change (%)	Target HbA_1c [mmol/mol (%)]	Proportion achieving target HbA_1c (%)	Severe hypoglycaemia rate (events/patient-year)	Weight change, kg
OPAL study ²⁰	24 weeks	Insulin glargine + OADs + insulin glulisine at breakfast	162^*	−0.36^†	≤ 48 (≤ 6.5)	27.8	0.01 ± 0.15^‡	+1.0
OPAL study ²⁰	24 weeks	Insulin glargine + OADs + insulin glulisine at main mealtime	154^*	−0.31^†	≤ 48 (≤ 6.5)	33.8	0.04 ± 0.30^§	+0.9
‘Proof of Concept’ study ³³	3 months	Insulin glargine + OADs	51^*	−0.11^†	< 53 (< 7)	8.8	0.2 ± 1.1	−0.4
‘Proof of Concept’ study ³³	3 months	Insulin glargine + OADs + insulin glulisine at main mealtime	45^*	−0.37^†	< 53 (< 7)	22.4	0.0 ± 0.0	+0.7
1.2.3. study ³⁴	24 weeks	Insulin glargine + OADs + once-daily insulin glulisine	115^‖	−0.44^†	< 53 (< 7)	30	0.28^¶	+3.8^†
		Insulin glargine + OADs + twice-daily insulin glulisine	113^‖	−0.36^†	< 53 (< 7)	33	0.89^**	+4.1^†
		Insulin glargine + OADs + thrice-daily insulin glulisine	115^‖	−0.43^†	< 53 (< 7)	46	0.64^¶	+3.9^†
OSIRIS study ³⁵	12 months	Insulin glargine + metformin + thrice-daily insulin glulisine	144^*	−0.72 ± 1.25^†	NA	NA	NA	+2.03 ± 3.21
		Insulin glargine + metformin + stepwise addition of insulin glulisine (1–3 times daily)^††	197^*	−0.47 ± 1.05^†	NA	NA	NA	+1.30 ± 3.17
		Insulin glargine + metformin + sulphonylurea + stepwise addition of insulin glulisine (1–3 times daily)^††	123^*	−0.40 ± 1.11^†	NA	NA	NA	+1.90 ± 3.38
STEPWise ²¹	3 × 12 weeks treatment periods	Insulin detemir + OADs + stepwise addition of insulin aspart to largest meal (based on pre-meal glucose values): SimpleSTEP	150	−1.1 ± 1.1	< 53 (< 7)	31	0.04^‡‡	+2.7 ± 3.9^§§
STEPWise ²¹	3 × 12 weeks treatment periods	Insulin detemir + OADs + stepwise addition of insulin aspart to meal with largest prandial glucose increment (based on post-meal glucose values): ExtraSTEP	146	−1.3 ± 1.2	< 53 (< 7)	27	0.01^‡‡	+2.0 ± 3.8^§§
ELEONOR ⁴⁰	24 weeks	Insulin glargine + metformin + once-daily insulin glulisine titrated using SMBG	126^‖‖	−0.7 ± 0.06^†	< 53 (< 7)	54.8	0.02	+0.4 ± 5.1
ELEONOR ⁴⁰	24 weeks	Insulin glargine + metformin + once-daily insulin glulisine titrated using telecare	115^‖‖	−0.7 ± 0.06^†	< 53 (< 7)	45.2	0.04	+0.4 ± 3.4
All To Target ⁴³	60 weeks	Twice-daily premixed insulin (70/30 protamine-aspart/aspart) + 2–3 OADs	192	−1.8 ± 0.1^¶¶	< 53 (< 7)	39	0.2 ± 0.1^***	NA
		Insulin glargine + once-daily glulisine + 2–3 OADs	189	−2.1 ± 0.1^¶¶	< 53 (< 7)	49	0.1 ± 0.0^***	NA
		Insulin glargine + stepwise addition of insulin glulisine + 2–3 OADs	191	−2.2 ± 0.1^¶¶	< 53 (< 7)	45	0.2 ± 0.1^***	NA

Per-protocol population.

^†

Adjusted mean change from baseline.

^‡

Safety population n = 196.

^§

Safety population n = 197.

^‖

Modified intention-to-treat population.

^¶

Safety population n = 115.

^**

Safety population n = 113.

^††

The first dose of insulin glulisine was added to the meal with the highest postprandial glucose excursion.

^‡‡

Major hypoglycaemic episodes—patients unable to treat the episode themselves.

^§§

Data expressed as mean ± standard deviation.

^‖‖

Intention-to-treat population.

^¶¶

Last observation carried forward.

^***

Data expressed as adjusted event-rates per patient/year ± standard error.

ELEONOR, Evaluation of Lantus Effect on Optimization of Use of Single Dose Rapid Insulin; NA, data not available; OAD, oral anti-diabetic drug; OPAL, Orals Plus Apidra and Lantus; OSIRIS, Opposing Step-by-Step Insulin Reinforcement to Intensified Strategy; SMBG, self-monitoring of blood glucose.