Raskin 2009

Methods	RANDOMISED CONTROLLED CLINICAL TRIAL (RCT): Yes. RANDOMISATION RATIO: 2:1. NON‐INFERIORITY DESIGN: Yes. EQUIVALENCE DESIGN: No. PARALLEL / CROSSOVER / FACTORIAL RCT: Parallel. CONTROLLED CLINICAL TRIAL (CCT): Yes.
Participants	WHO PARTCIPATED: SEX (female% / male%): 175 (45.5%) / 210 (54.5%). AGE (mean years (SD)): Insulin det: 55.8 (10.0); Insulin glargine: 55.9 (11.0); All: 55.8 (10.3). ETHNIC GROUPS (%): Insulin detemir: 193 (76.0%) Caucasian, 37 (14.6%) African‐American, 7 (2.8%) Asian, 4 (1.6%) American Indian or Alaskan Native, 13 (5.1%) other; Insulin glargine: 108 (82.4%) Caucasian, 14 (10.7%) African‐American, 3 (2.3%) Asian, 0 (0%) American Indian or Alaskan Native, 6 (4.6%) other; All: 301 (78.2%) Caucasian, 51 (13.2%) African‐American, 10 (2.6%) Asian, 4 (1.0%) American Indian or Alaskan Native, 19 (4.9%) other. DURATION OF DISEASE (mean years (SD)): Insulin detemir: 12.5 (6.8); Insulin glargine: 11.9 (7.4); All: 12.3 (7.0). INCLUSION CRITERIA: Patients with type 2 diabetes, who were at least 18 years old, with a BMI of ≤ 40 kg/m2, an HbA1c ranging from 7% to 11% and who had previously received any OGLD, insulin, or insulin + OGLD treatment regimens. Novo Nordisk A/S web site: Type 2 diabetes ≥ 12 months, currently on any OGLD therapy or on any insulin in any regimen with or without OGLDs ≥ 4 months, age ≥ 18 years, BMI ≤ 40 kg/m2 and HbA1c ≥ 7.0% and ≤ 11.0%. EXCLUSION CRITERIA: Proliferative retinopathy or maculopathy that required acute treatment 6 months before the start of the study, recurrent major hypoglycaemia, anticipated change in medication known to interfere with glucose metabolism, impaired hepatic or renal function believed to interfere with study participation, cardiac problems or uncontrolled hypertension. DIAGNOSTIC CRITERIA: Not specified. CO‐MORBIDITIES: Not reported. CO‐MEDICATIONS: Insulin detemir: 9 (3.5%) OGLD monotherapy, 42 (16.5%) OGLD combination therapy, 83 (32.7%) insulin without OGLDs, 120 (47.2%) insulin with OGLDs; Insulin glargine: 6 (4.6%) OGLD monotherapy, 20 (15.3%) OGLD combination therapy, 41 (31.3%) insulin without OGLDs, 64 (48.9%) insulin with OGLDs; All: 15 (3.9%) OGLD monotherapy, 62 (16.1%) OGLD combination therapy, 124 (32.2%) insulin without OGLDs, 184 (47.8%) insulin with OGLDs.
Interventions	NUMBER OF STUDY CENTRES: 68. COUNTRY/ LOCATION: Canada (8 sites) and United States (60 sites). SETTING: Not reported. INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY): Insulin detemir: Initiated once‐daily in the evening at the same time each day, titrated according to structured algorithm to FPG ≤ 6.0 mmol/L and (if needed) to pre‐dinner PG ≤ 6.0 mmol/L without significant hypoglycaemia, additional morning insulin dose if titration of evening dose did not result in pre‐dinner PG ≤ 6.0 mmol/L, but only if FPG ≤ 6.0 mmol/L and after optimisation of bolus doses. Pen‐injector (Flexpen), between 1 hour before dinner and bedtime. Insulin aspart injected in abdomen (Flexpen). CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY): Insulin glargine: Initiated once‐daily in the evening at the same time each day, titrated according to structured algorithm to FPG ≤ 6.0 mmol/L without significant hypoglycaemia. Syringes and vials, between 1 hour before dinner and bedtime. Insulin aspart injected in abdomen (Flexpen). TREATMENT BEFORE STUDY: Insulin secretagogues and α‐glucosidase inhibitors were discontinued prior to initiating trial drug, thiazolidinediones and metformin were continued unchanged. TITRATION PERIOD: 26 weeks, 9 visits and 13 telephone contacts. "Basal insulin was titrated at the instruction of the investigator according to titration guidelines". Titration algorithm is given but the titration frequency is not reported.
Outcomes	PRIMARY OUTCOME(S) (as stated in the publication): HbA1c after 26 weeks. SECONDARY OUTCOMES (as stated in the publication): FPG during the trial and body weight. Safety endpoints were the incidence of hypoglycaemic events and adverse events. Nocturnal hypoglycaemia = between 23:00 and 06:00 hour; Daytime hypoglycaemia = between 06:00 and 23:00 hour. ADDITIONAL OUTCOMES: Novo Nordisk A/S web site: Proportion of subjects achieving HbA1c ≤ 7% after 26 weeks, proportion of subjects with HbA1c ≤ 7% without symptomatic hypoglycaemia confirmed by PG < 4.0 mmol/L or any single PG < 3.1 mmol/L in the last 3 months of the treatment, FPG, within‐subject variation of self‐measured FPG and pre‐dinner PG, 9‐point PG profiles, body weight, difference in weight change, basal and bolus insulin doses, time to start detemir twice‐daily, proportion of detemir‐treated subjects on once‐daily basal insulin, insulin treatment satisfaction (ITSQ), incidence of hypoglycaemia (all, minor, major, symptoms only, nocturnal and during the day), adverse events, laboratory assessments, physical examination, fundoscopy, vital signs and ECG.
Study details	DURATION OF INTERVENTION: 26 weeks. DURATION OF FOLLOW‐UP: 26 weeks. RUN‐IN PERIOD: Not specified.
Publication details	LANGUAGE OF PUBLICATION: English. COMMERCIAL FUNDING: Yes: "This trial was funded and monitored by Novo Nordisk". NON‐COMMERCIAL FUNDING: No. PUBLICATION STATUS (PEER REVIEW JOURNAL): Yes. PUBLICATION STATUS (JOURNAL SUPPLEMENT): No. PUBLICATION STATUS (ABSTRACT):No.
Stated aim of study	Quote: "The current study compared the efficacy and safety of the basal insulin insulin detemir and insulin glargine used in combination with insulin aspart as bolus insulin in patients with type 2 diabetes".
Notes	Trialnumbers: NN304‐2175 and NCT00106366. Contact information: Philip Raskin (Philip.Raskin@UTSouthwestern.edu).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "were randomised 2:1 to insulin detemir and insulin glargine treatment groups". Comment: Besides this quote the paper gives no information about the randomisation process.
Allocation concealment (selection bias)	Unclear risk	Quote: "were randomised 2:1 to insulin detemir and insulin glargine treatment groups". Comment: Besides this quote the paper gives no information about the randomisation process.
Blinding (performance bias and detection bias) All outcomes	High risk	Quote: "open‐label". 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	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 on the Novo Nordisk A/S web site are reported (time to start insulin detemir twice‐daily, insulin treatment satisfaction, and hypoglycaemia with symptoms only are not reported).
Other bias	High risk	Quote: "For patients randomised to insulin detemir, an optional second daily morning dose could be added at the discretion of the investigator". Also, patients randomised to insulin detemir used a pen‐injector, whereas patients randomised to insulin glargine used syringes and vials. Comment: The study has a potential source of bias related to the specific study design used, i.e. different frequency of injection and different injection devices across treatments.