Swinnen 2010a

Methods	RANDOMISED CONTROLLED CLINICAL TRIAL (RCT): Yes. RANDOMISATION RATIO: 1:1. NON‐INFERIORITY DESIGN: Yes. EQUIVALENCE DESIGN: No. PARALLEL / CROSSOVER / FACTORIAL RCT: Parallel. CONTROLLED CLINICAL TRIAL (CCT): Yes.
Participants	WHO PARTCIPATED: SEX (female% / male%): 437 (45.3%) / 527 (54.7%). AGE (mean years (SD)): Insulin detemir: 58.0 (8.0); Insulin glargine: 58.7 (8.5); All: 58.4 (8.3). ETHNIC GROUPS (%): Insulin detemir: 382 (78.6%) white, 80 (16.5%) asian/oriental, 6 (1.2%) black, 9 (1.9%) multiracial, 9 (1.9%) other; Insulin glargine: 368 (77.0%) white, 77 (16.1%) asian/oriental, 12 (2.5%) black, 7 (1.5%) multiracial, 14 (2.9%) other; All: 750 (77.8%) white, 157 (16.3%) asian/oriental, 18 (1.9%) black, 16 (1.7%) multiracial, 23 (2.4%) other. DURATION OF DISEASE (mean years (SD)): Insulin detemir: 9.7 (5.6); Insulin glargine: 10.1 (5.9); All: 9.9 (5.8). INCLUSION CRITERIA: Insulin‐naive people, aged 40 to 75 years, with type 2 diabetes for ≥ 1 year and treated for ≥ 3 months prior to study start with stable doses of OGLDs (including at least metformin ≥ 1 g/day), BMI < 40.0 kg/m2, HbA1c between 7.0% and 10.5% and ability and willingness to perform home glucose monitoring and to use a patient diary. EXCLUSION CRITERIA: Exclusion criteria included previous use of insulin, treatment with GLP‐1 analogues or DPP‐4 inhibitors, active proliferative retinopathy, pregnancy or lactation, treatment with systemic corticosteroids in the preceding 3 months, treatment with investigational products in the preceding 2 months, impaired hepatic or renal function or any major somatic or mental condition that might preclude implementation of the study protocol. Study protocol: Type 1 diabetes, history of hypersensitivity to the study drugs or to drugs with a similar chemical structure, likelihood of requiring treatment during the study period with drugs not permitted by the clinical trial protocol, clinically relevant cardiovascular, hepatic, neurological, endocrine, or other major disease making implementation of the protocol or interpretation of the study results difficult, history of drug or alcohol abuse in the last year or mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study. DIAGNOSTIC CRITERIA: Not used. CO‐MORBIDITIES: Insulin detemir: 79 (16.3%) macroangiopathy, 48 (9.9%) nephropathy, 123 (25.3%) neuropathy, 92 (18.9%) retinopathy; Insulin glargine: 84 (17.6%) macroangiopathy, 71 (14.9%) nephropathy, 134 (28.0%) neuropathy, 105 (22.0%) retinopathy; All: 163 (16.9%) macroangiopathy, 119 (12.3%) nephropathy, 257 (26.7%) neuropathy, 197 (20.4%) retinopathy. CO‐MEDICATIONS: Insulin detemir: 486 (100%) metformin, 417 (85.8%) sulfonylureas, 89 (18.3%) thiazolidinediones, 28 (5.8%) α‐glucosidase inhibitors, 22 (4.5%) glinides, 1 (0.2%) other; Insulin glargine: 478 (100%) metformin, 410 (85.8%) sulfonylureas, 74 (15.5%) thiazolidinediones, 32 (6.7%) α‐glucosidase inhibitors, 27 (5.6%) glinides, 0 (0%) other; All: 964 (100%) metformin, 827 (85.8%) sulfonylureas, 163 (16.9%) thiazolidinediones, 60 (6.2%) α‐glucosidase inhibitors, 49 (5.1%) glinides, 1 (0.1%) other.
Interventions	NUMBER OF STUDY CENTRES: 122. COUNTRY/ LOCATION: 20 countries (Australia, Brazil, Canada, Europe, India, Korea, Russia, Serbia, Taiwan, Turkey). SETTING: Hospitals and diabetes centres (endocrinologists and diabetologists). INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY): Insulin detemir: Initiated twice‐daily, at breakfast and dinner, using NovoPen3 injector pen, starting dose 0.2 units/kg/day. Titrated to FPG and pre‐dinner PG < 5.6 mmol/L, increase both doses by 1 unit every 2 days until fasting and pre‐dinner PG ≤ 6.9 mmol/L, subsequently increase evening dose by 2 units every 2 days until FPG < 5.6 mmol/L, finally increase breakfast dose by 2 units every 2 days until pre‐dinner PG < 5.6 mmol/L. CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY): Insulin glargine: Initiated once‐daily, at dinner or bedtime, but at the same time every day throughout the study, using OptiClik injector pen, starting dose 0.2 units/kg/day. Titrated to FPG < 5.6 mmol/L, increase dose by 2 units every 2 days until FPG < 5.6 mmol/L. TREATMENT BEFORE STUDY: Insulin‐naive, treated for ≥ 3 months prior to study start with stable doses of OGLDs (including at least metformin ≥ 1 g/day), GLP‐1 analogues and DPP‐4 inhibitors were exclusion criteria. Metformin continued at stable dose throughout study, thiazolidinediones stopped at randomisation, insulin secretagogues stopped at randomisation or continued at stable dose throughout (decision made by site‐investigator, considering local guidelines). TITRATION PERIOD: 24 weeks, 8 clinical visits and 8 telephone contacts. Insulin detemir: Increase both doses by 1 unit every 2 days until FPG and pre‐dinner PG ≤ 6.9 mmol/L, subsequently increase evening dose by 2 units every 2 days until FPG < 5.6 mmol/L, finally increase breakfast dose by 2 units every 2 days until pre‐dinner PG < 5.6 mmol/L; Insulin glargine: Increase insulin dose by 2 units every 2 days until FPG < 5.6 mmol/L.
Outcomes	PRIMARY OUTCOME(S) (as stated in the publication): Percentage of patients reaching HbA1c < 7% at the end of the treatment period without symptomatic hypoglycaemia confirmed by PG ≤ 3.1 mmol/L during these 24 weeks. SECONDARY OUTCOMES (as stated in the publication): Secondary outcomes included proportions of patients achieving HbA1c < 7% and < 6.5%, changes in HbA1c, FPG, 8‐point PG profiles and weight, hypoglycaemia, insulin dose, adverse events and quality of life and treatment satisfaction. Incidence and rates for all symptomatic, symptomatic daytime, symptomatic nocturnal (both with PG ≤3.1 mmol/L and ≤3.9 mmol/L), asymptomatic ≤3.1 mmol/L, and severe (an event with symptoms consistent with hypoglycaemia, requiring the assistance of another person, and associated with measured PG <2.0 mmol/L or recovery after carbohydrate or glucagon administration) hypoglycaemia were assessed. ADDITIONAL OUTCOMES: Statistical analysis plan: Day‐to‐day FPG variability, change in waist circumference, change in hip circumference, change in BMI, change in waist‐to‐hip ratio, HbA1c < 7% without symptomatic hypo ≤ 3.1 mmol/L in last 12 weeks, and mean and SD of 24‐hour profiles.
Study details	DURATION OF INTERVENTION: 24 weeks. DURATION OF FOLLOW‐UP: Study protocol: 25 weeks (1 telephone contact to be made within the week after the completion visit). RUN‐IN PERIOD: No (1‐ to 4‐week screening phase).
Publication details	LANGUAGE OF PUBLICATION: English. COMMERCIAL FUNDING: Yes: "This study was sponsored by sanofi‐aventis, Paris, France". NON‐COMMERCIAL FUNDING: No. PUBLICATION STATUS (PEER REVIEW JOURNAL): No. PUBLICATION STATUS (JOURNAL SUPPLEMENT): Yes, Diabetologia 2009 Supplement 1. PUBLICATION STATUS (ABSTRACT): Yes, abstract only.
Stated aim of study	Quote: "Our primary objective was to demonstrate the non‐inferiority of glargine once‐daily compared to detemir twice‐daily with respect to the percentage of patients reaching HbA1c < 7% without symptomatic hypoglycaemia confirmed by PG ≤ 3.1 mmol/L".
Notes	Trialnumbers: LANTU‐C‐00579 and NCT00405418. Contact information: Sanne Swinnen (s.g.swinnen@amc.uva.nl).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomisation was stratified by centre and treatment allocation was concealed by using an interactive voice‐response system". Comment: Probably done, as the "interactive voice‐response system" probably used a computer random number generator.
Allocation concealment (selection bias)	Low risk	Quote: "Randomisation was stratified by centre and treatment allocation was concealed by using an interactive voice‐response system". Comment: Done, as central allocation (by means of interactive voice‐response system) was used.
Blinding (performance bias and detection bias) All outcomes	High risk	Quote: "A limitation of our study was its open‐label design. This design was necessary, however, as detemir was dosed twice‐daily with a separate titration target before dinner". Comment: Neither study participants nor study personnel were blinded and this may have influenced outcome measurements.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Safety analysis: 8/486 (=1.6%) excluded from intervention group and 1/487 (=0.2%) excluded from control group. Imbalance in reasons for missing data across intervention groups. However, plausible effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size. Primary analysis: 13/486 (=2.7%) excluded from intervention group and 15/487 (=3.1%) excluded from control group. Reasons for missing data not reported. However, (virtually) no imbalance in number of missing data and plausible effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size. Quality of life analysis: Number of missing data or number of patients used for the calculation of outcomes are not reported.
Selective reporting (reporting bias)	High risk	Not all of the study's pre‐specified secondary outcomes as listed in the study protocol are reported (change in BMI, waist circumference, hip circumference, waist‐to‐hip ratio, and mean and SD of 24‐hour PG profiles and the proportions of patients achieving HbA1c < 7% without symptomatic hypoglycaemia with PG ≤ 3.1 mmol/L in the last 12 weeks of the study are not reported).
Other bias	High risk	Quote: "Insulin glargine was administered at dinner or bedtime" and "Insulin detemir was administered at breakfast and dinner" and "Patients randomised to insulin glargine were instructed to perform daily fasting home glucose measurements and to increase their insulin dose by 2 units every 2 days until they reached the titration target of fasting PG < 5.6 mmol/L. Patients randomised to insulin detemir were instructed to measure their glucose before breakfast and before dinner. The goal was to obtain both fasting and pre‐dinner PG < 5.6 mmol/L. The systematic titration of insulin detemir followed three steps. First, both doses were increased by 1 unit every 2 days until FPG and pre‐dinner PG ≤ 6.9 mmol/L. Subsequently, patients were instructed to achieve fasting PG < 5.6 mmol/L by increasing their dinner dose by 2 units every 2 days. Finally, the breakfast dose was increased by 2 units every 2 days until pre‐dinner PG < 5.6 mmol/". Comment: The study has a potential source of bias related to the specific study design used, i.e. insulin detemir was dosed twice‐daily (and insulin glargine once‐daily), patients in the insulin detemir group measured their glucose level twice‐daily (insulin glargine‐treated patients once‐daily) and the titration scheme for insulin detemir may have been more complicated than that for insulin glargine.

Anti‐GAD = anti‐Glutamic Acid Decarboxylase; BMI = body mass index; DPP‐4 = dipeptidyl peptidase‐4; FPG = fasting plasma glucose; GLP‐1 = glucagon‐like peptide‐1; HbA1c = glycosylated haemoglobin A1c; OGLD = oral glucose‐lowering drug; PG = plasma glucose; SD = standard deviation.