L ‐ LEAD 1 Marre 2009

Methods	TRIAL DESIGN: Randomised double‐blind, double dummy, active control, five armed parallel trial, multi‐centre (116 sites) DURATION OF INTERVENTION: 26 weeks DURATION OF FOLLOW‐UP: No post‐intervention follow‐up RUN‐IN PERIOD: 2 weeks SETTING: NR COUNTRY: 21 countries (mainly in Europe and Asia)
Participants	INCLUSION CRITERIA: Patients with type 2 diabetes, OADs for ≥ 3 months, aged 18 to 80 years old, HbA1c 7% to 11% (previous OAD monotherapy) or 7% to 10% (previous OAD combination therapy), BMI ≤ 45 kg/m2 EXCLUSION CRITERIA: Using insulin within 3 months, impaired liver or renal function, uncontrolled hypertension (≥ 180/100 mm Hg), cancer, use of any drug apart from OAD likely to affect glucose concentrations AGE: 54.7 SD 10.0 to 57.7 SD 9.0 years SEX: 47% to 55% female DIABETES DURATION: (median, 25th and 75th percentile) 6.5 (3.7, 10.5) to 6.7 (4.0, 10.7) years ETHNICITY: NR HbA1c (%): LIR 1.2 mg: 8.5 SD 1.1; LIR 1.8 mg: 8.5 SD 0.9; Placebo: 8.4 SD 1.0; ROS (rosiglitazone): 8.4 SD 1.0 BMI (kg/m2): LIR 1.2 mg: 29.8 SD 5.1; LIR 1.8 mg: 30 SD 5.1; Placebo: 30.3 SD 5.4; ROS: 29.4 SD 4.8 PREVIOUS THERAPY: Previously on mono‐therapy: 27% to 32%, on combination therapy: 68% to 73% NUMBERS: 1712 screened; Randomised: 1041 (1 to 37 participants per centre); LIR 0.6 mg: 233; LIR 1.2 mg: 228; LIR 1.8 mg: 234; Placebo: 114; ROS: 232
Interventions	COMPARISON: LIR (3 doses) + Glimepiride (SU) VERSUS Placebo + SU VERSUS ROS (TZD) + SU NO. OF COMPARISON GROUPS: 5 (LIR 0.6 mg not considered in the present review) DOSE LIR: 1.2 mg and 1.8 mg: LIR up‐titrated weekly in 0.6 mg increments until the allocated dose reached; injected subcutaneously once daily DOSE SU: Forced glimepiride titration for 2 weeks and then 2 weeks maintenance period; glimepiride 2 to 4 mg/day DOSE TZD: 4 mg/day rosiglitazone OTHER TREATMENT: NR
Outcomes	PRIMARY OUTCOMES:  HbA1c (change from baseline to end of treatment) SECONDARY OUTCOMES: Proportion of participants reaching targeted goals of HbA1c (≤ 7%, ≤ 6.5%), FPG (5 to ≤ 7.2 mmol/L), PPG (10 mmol/L); body weight, FPG (fasting plasma glucose), PPG (post prandial glucose), beta‐cell function, blood pressure; superiority of liraglutide to placebo and non‐inferiority to rosiglitazone was tested OTHER OUTCOMES: Hypoglycaemic episodes based on PG levels (< 3.1 mmol/L) (minor: self‐treated; major: requiring third party assistance), liraglutide antibodies including cross‐reacting and neutralizing antibodies, tolerability (gastrointestinal complaints), pulse, adverse events, vital signs, ECG, biochemical and haematological parameters, calcitonin
Notes	AIM: To compare efficacy and safety of liraglutide and glimepiride combination therapy with either placebo or rosiglitazone added to glimepiride. SOURCE OF FUNDING: Novo Nordisk OTHER: Conflict of interest: One author had received lecture fees from Novo Nordisk, Servier, MSD. The second author had received honoraria, grants and lecture fees from Novo Nordisk. The remaining authors had no conflict of interest SAMPLE SIZE: A combined power (calculated as the product of the marginal powers for HbA1c and body weight) of at least 85% was required.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information; participants were stratified according to previous treatment (monotherapy or combination therapy)
Allocation concealment (selection bias)	Unclear risk	Insufficient information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comparisons made on the intent to treat population, missing data imputed using last observation carried forward, adequate description of withdrawals and losses to follow‐up (overall 14% withdrawals, 9 to 27% in the individual groups)
Selective reporting (reporting bias)	Low risk	All pre‐specified (primary and secondary) outcomes were reported