StudyDesignParticipantsInterventionsOutcome measures
insulin-naïve, oral antihyperglycaemics – glargine versus NPH insulin
Pan 2007 (LEAD study)179
China, France, Korea
focus: effect of insulin glargine versus NPH insulin on metabolic control and safety in Asian patients with type 2 diabetes, inadequately controlled on oral antihyperglyceamic agents
design: non- inferiority study; open-label, parallel group randomised trial
multi-centre duration: 24 weeks
follow-up: no post- intervention follow- up
setting:
funding: Sanofi- Aventis Korea
total number: 443
N glargine: 220; 198 completed the trial
N NPH: 223; 201 completed the trial
inclusion criteria: insulin-naïve; Asian; aged ≥40 and ≤80 years; type 2 diabetes according to WHO criteria plus specified blood glucose criteria; poorly controlled on oral hypoglycaemic agents for ≥3 months before study entry; BMI 20–35 kg/m2; HbA1c ≥7.5 and ≤10.5%, fasting blood glucose levels >120 mg/dL (>6.7 mmol/L)
exclusion criteria: pregnancy; history of ketoacidosis; likelihood of requiring treatment with drugs prohibited by the protocol (e.g. non- selective beta-blockers, systemic corticosteroids)
age: glargine: 55.6 SD8.4 years; NPH: 56.6 SD8.7 years
gender: glargine: 59.6% female; NPH: 55.6% female
BMI: glargine: 24.8 SD3.1 kg/m2; NPH: 25.1 SD3.3 kg/m2
ethnicity: n=126 China, 26 Hong Kong, 19 Indonesia, 112 South Korea, 16 Malaysia, 36 Pakistan, 24 Philippines, 32 Taiwan, 48 Thailand, 4 Singapore
diabetes duration: glargine: 10.3 SD6.3 years;
NPH: 10.0 SD5.4 years
previous medication: not reported, duration of treatment with oral antihyperglycaemic agents:
glargine: 9.1 SD6.0 years; NPH: 8.6 SD5.2 years
comorbidities: not reported
subgroups: none
glargine: insulin glargine once daily at bedtime (21–23 h), once daily glimepiride (3 mg) in the morning (7–9 h)
NPH: NPH insulin once daily at bedtime (21–23 h), once daily glimepiride (3 mg) in the morning (7–9 h)
both: insulin glargine/NPH insulin titrated to a target FBG ≤120 mg/dL (≤6.7 mmol/L), starting at insulin dose of 0.15 U/kg/day
co-interventions: none
adherence assessment: no
screening phase: 3–4 weeks, oral treatments standardised to 3 mg glimepiride, patients were given training in self-administration of insulin and self-monitoring of blood glucose levels
primary: change in HbA1c level from baseline to endpoint
HbA1c: HbA1c, proportion of patients with HbA1c <7.5%, proportion of combined responders (both HbA1c <7.5% and FBG levels ≤120 mg/dL)
hypoglycaemia: proportion of patients with hypoglycaemia; severe hypoglycaemia (symptoms consistent with hypoglycaemia, BG <50 mg/dL or prompt recovery after oral carbohydrate, intravenous glucose or glucagons administration and the requirement of third party assistance); nocturnal hypoglycaemia (while patient was asleep)
glycaemic excursions: yes, blood glucose profiles
total daily dose: yes
weight change: BMI
complication rates: no
adverse events: yes
health-related quality of life: no
other: none
timing of assessment: baseline, 2, 4, 6, 8, 12, 16, 20 and 24 weeks after randomisation
Wang 2007185
China
focus: effect of insulin glargine as basal insulin replacement versus NPH insulin in patients with type 2 diabetes, in whom blood glucose was not well controlled with sulphonylureas
design: randomised controlled trial
single centre duration: 12 weeks
follow-up: no post- intervention follow- up
setting: unclear
funding: not reported
total number: 24
N glargine: 16
N NPH: 8
inclusion criteria: type 2 diabetes for six months; age 30 to 70 years; blood glucose not well controlled (FBG ≥7.0 mmol/L and <13.0 mmol/L); treatment with sulphonylurea (equivalent to 7.5 mg/day glibenclamide) or combination treatment with oral agents for >3 months
exclusion criteria: obvious renal, liver or heart disease
age: glargine: 57 SD6 years; NPH: 56 SD8 years
gender: glargine: 43.8% female; NPH: 50% female
BMI: glargine: 24.2 SD2.8 kg/m2; NPH: 24.6 SD2.5 kg/m2
ethnicity: not reported, presumably all Chinese
diabetes duration: glargine: 10.4 SD4.3 years;
NPH: 9.5 SD4.9 years
previous medication: not reported
comorbidities: not reported
subgroups: none
glargine: insulin glargine plus extended-release glipizide (glucotrol XL)
NPH: NPH insulin plus extended-release glipizide (glucotrol XL)
both: extended-release glipizide (glucotrol XL) 5 mg/day before breakfast; glargine or NPH injected at bedtime, initial dose 0.15 IU/kg/day; dose titrated every 3 days by the patient with instructions from researchers until FBG was <6.7 mmol/L.
co-interventions: none
adherence assessment: no
screening phase: diabetes education; previous oral antihyperglycaemic therapy stopped and patients treated with extended-release glipizide 5mg/day before breakfast for 2 weeks
primary: unclear
HbA1c: HbA1c
hypoglycaemia: yes; hypoglycaemic event defind as a sensor glucose value of <3.5 mmol/L for >15 min.
glycaemic excursions: yes, continuous glucose monitoring system
total daily dose: yes
weight change: yes; weight and BMI
complication rates: no
adverse events: no
health-related quality of life: no
other: none
timing of assessment: baseline and week 12
previous insulin – detemir versus NPH insulin
Montanana 2008 (PREDICTIVE- BMI trial)178
Spain
focus: weight change caused by detemir or NPH used as part of basal-bolus regimen in already overweight type 2 diabetes patients
design: open parallel group randomised controlled trial
multi-centre duration: 26 weeks
follow-up: no post- intervention follow- up
setting: unclear
funding: Novo Nordisk
total number: 271
N detemir: 126; 125 completed the trial
N NPH: 151; 146 completed the trial
inclusion criteria: men or women ≥18 years, type 2 diabetes, had been receiving 2 daily doses (at least one premix) for ≥3 months; HbA1c between 7.5 and 11%; BMI between 25 and 40 kg/m2
exclusion criteria: patients receiving oral glucose-lowering drugs (other than metformin); daily insulin dose ≥2 IU/kg; any condition rendering the patient unsuitable to participate; anticipated changes in concomitant medications known to interfere with glucose metabolism; proliferative retinopathy or maculopathy requiring acute treatment in the preceding 6 months; uncontrolled hypertension; pregnancy and breastfeeding
age: detemir: 62.1 SD9.3 years; C: 61.8 SD8.3 years
gender: detemir: 62.4% female; C: 56.8% female
BMI / weight: detemir: 31.6 SD4.3 kg/m2 / 79.5 SD11.9 kg; C: 32.0 SD4.2 kg/m2 / 82.2 SD12.2 kg
ethnicity: 99% white
diabetes duration: detemir: 16.2 SD8.7 years; C: 16.4 SD7.4 years
previous medication: detemir: 50.4% metformin use; C: 57.5% metformin use
comorbidities: not reported
subgroups: none
detemir: once daily (evening) detemir
NPH: once daily (evening) NPH
both: basal insulin continually and individually titrated, aiming for pre-breakfast plasma glucose of ≤6.1 mmol/L without levels of hypoglycaemia considered unacceptable to the patient
co-interventions: all patients received insulin aspart at main meals (individually titrated aiming for postprandial glucose levels of ≤10.0 mmol/L); concomitant treatment with metformin also allowed
adherence assessment: not reported
primary: weight change
HbA1c: yes
hypoglycaemia: yes; all, major (third-party assistance required), minor (self-managed, plasma glucose confirmed ≤3.0 mmol/L), nocturnal hypoglycaemic events
glycaemic excursions: no
total daily dose: yes
weight change: yes
complication rates: no
adverse events: yes
health-related quality of life: no
other: none
timing of assessment: five clinic visits after randomisation
insulin-naïve – detemir versus NPH insulin
Philis-Tsimikas 2006180
Denmark, France, Italy, The Netherlands, Norway, Spain, USA
focus: effectiveness and tolerability of detemir versus NPH once daily with one or more oral anti-diabetic in people with poorly controlled type 2 diabetes
design: multi- centre, randomised, open-label, 3-arm parallel trial
multi-centre duration: 20 weeks
follow-up: no post- intervention follow- up
setting: outpatient clinic
funding: Novo Nordisk
total number: 504 enrolled, 498 in ITT analysis
N morning detemir: 165, 149 completed the trial
N evening detemir: 169, 154 completed the trial
N evening NPH: 164, 149 completed the trial
inclusion criteria: age ≥18 years, BMI ≤40 kg/m2, diagnosis of type 2 diabetes since at least 12 months, insulin-naïve, HbA1c between 7.5 and 11% after at least 3 months’ treatment with one or more oral anti-diabetic agent (OAD); OAD therapy was therapy with metformin or an insulin secretagogue or a combination of the two, at least half the recommended maximum dose; at US centres, concomitant treatment with thiazolidinediones (TZD) was permitted throughout study period, at European centres TZD was to be discontinued before initiation of insulin treatment; use of alpha-glucosidase inhibitor was permitted but only in combination with another OAD
exclusion criteria: proliferative retinopathy/maculopathy requiring treatment, hypoglycaemia unawareness or recurrent major hypoglycaemia, use or anticipated use of ≥1 drug likely to affect blood glucose regulation (e.g. systemic steroids, nonselective beta-blockers, monoamine oxidase inhibitors), OAD treatment not adhering to approved labelling in the respective country; any disease or condition that would make patient unsuitable for participation (e.g. renal, hepatic, cardiac disease), uncontrolled hypertension, any psychological incapacity or language barrier precluding adequate understanding or cooperation
age: morning detemir: 58.3 SD10.4 years;
evening detemir: 58.7 SD10.2 years; NPH insulin: 58.4 SD11.0 years
gender: morning detemir: 40.6% female;
evening detemir: 46.2% female; NPH insulin: 42.7% female
BMI / weight: morning detemir: 29.8 SD5.0 kg/m2; evening detemir: 29.7 SD5.1 kg/m2; NPH insulin: 30.4 SD4.8 kg/m2
ethnicity: not reported
diabetes duration: morning detemir: 10.5 SD7.6 years; evening detemir: 10.5 SD7.0 years; NPH insulin: 10.0 SD6.9 years
previous medication: morning detemir: 26.1% OAD monotherapy (9.7% metformin, 16.4% secretagogue), 73.9% combination therapy (56.4% metformin + 1 or 2 secretagogues, 5.5% metformin + secretagogue + TZD, 6.7% 2 secretagogues, 1.8% secretagogue + TZD);
evening detemir: 21.3% OAD monotherapy (8.3% metformin, 13.0% secretagogue), 78.7% combination therapy (53.8% metformin + 1 or 2 secretagogues, 8.9% metformin + secretagogue + TZD, 7.7% 2 secretagogues, 1.2% secretagogue + TZD); NPH insulin: 24.4% OAD monotherapy (9.8% metformin, 14.6% secretagogue), 75.6% combination therapy (53.0 % metformin + 1 or 2 secretagogues, 6.1% metformin + secretagogue + TZD, 9.1% 2 secretagogues, 1.2% secretagogue + TZD)
comorbidities: ~56% hypertension, ~29% hypercholesterolaemia, ~12% dyslipidaemia, ~11% diabetic retinopathy; similar occurrence in treatment groups
subgroups: none
N morning detemir: insulin detemir once daily before breakfast
N evening detemir: insulin detemir once daily in the evening (=interval 1 hour before last meal until bedtime)
N evening NPH: human NPH insulin once daily in the evening
all groups: insulin injected via pen device, participants advised to keep time of injection constant and to inject insulin subcutaneously, preferably in the thigh, but to rotate sites; initial dose of treatment was 10 IU (U), doses were titrated at clinic visits or by telephone at least once every 4 weeks based on the mean of 3 plasma glucose levels measured on 3 consecutive days; in patients receiving detemir in the morning, the dose was titrated to aim for pre-dinner plasma glucose concentration of ≤6.0 mmol/L; in patients receiving detemir or NPH in the evening, titration was aimed to achieve pre-breakfast plasma glucose concentration of ≤6.0 mmol/L
co-interventions: OAD therapy and dose was to remain unchanged; other co-interventions (similar between groups): ~21% used acetylsalicylic acid, ~19% simvastatin, ~15% atorvastatin
adherence assessment: not reported
primary: HbA1c
HbA1c: yes
hypoglycaemia: yes; major episodes (requiring third party assistance), confirmed episodes (plasma glucose reading <3.1 mmol/L, patients able to self-manage the event), nocturnal hypoglycaemia (between 11 pm and 6 am)
glycaemic excursions: 9-point self-measured plasma glucose profiles (using capillary blood and plasma-calibrated monitor): immediately before and 90 min after main meals, bedtime, 3 am; additional measurements when patients experienced symptoms indicative of hypoglycaemia
total daily dose: yes
weight change: yes (calibrated scales)
complication rates: no
adverse events: adverse events, standard laboratory analyses, fundoscopy, physical examination
health-related quality of life: no
other: none
timing of assessment: at least 9 telephone contacts and 6 clinic visits (including screening and randomisation)
insulin-naïve – glargine versus detemir
Rosenstock 2008177
Europe, USA
focus: comparison of clinical outcomes following supplementation of oral glucose- lowering drugs with with basal insulin analogues detemir and glargine in patients with type 2 diabetes
design: open-label, parallel group randomised controlled non- inferiority trial
multi-centre duration: 52 weeks
follow-up: no post- intervention follow- up
setting: unclear
funding: Novo Nordisk
total number: 582
N detemir: 291, 231 completed the trial
N NPH: 291, 252 completed the trial
inclusion criteria: insulin-naïve men or women ≥18 years, type 2 diabetes with ≥12 months disease duration; HbA1c between 7.5 and 10%; BMI ≤40 kg/m2; had been receiving one or two oral agents (metformin, insulin secretagogues, alpha-glucosidase inhibitors) ≥4 months on at least half of maximum recommended dose
exclusion criteria: treatment with thiazolidinediones; use of more than two oral agents within 6 months; hypoglycaemic unawareness; other medical conditions likely to interfere with trial conduct; withdrawal criteria included pregnancy, HbA1c >11% after the first 12 weeks of treatment, initiation of medication interfering with glucose metabolism
age: detemir: 58.4 SD10.2 years; glargine: 59.4 SD9.6 years
gender: detemir: 43% female; glargine: 41.2% female
BMI / weight: detemir: 30.6 SD4.8 kg/m2 / 87.4 SD16.6 kg; glargine: 30.5 SD4.6 kg/m2 / 87.4 SD17.4 kg
ethnicity: detemir: 86% White, 7.6% Black, 2.4% Asian-Pacific Islanders, 4% other;
glargine: 90.4% White, 4.1% Black, 2.4% Asian-Pacific Islanders, 3.1% other
diabetes duration: detemir: 9.1 SD6.1 years;
glargine: 9.1 SD6.4 years
previous medication: detemir: montherapy 25% (11% metformin, 14% insulin 25% (11% metformin, 14% insulin secretagogues); combination therapy 75% (97% metformin + secretagogue); glargine: montherapy 24% (11% metformin, 13% insulin secretagogues); combination therapy 76% (97% metformin + secretagogue)
comorbidities: not reported
subgroups: none
detemir: once daily (evening) detemir or twice daily (morning and evening) (55% used twice daily injections)
glargine: once daily (evening)
both: basal insulin initiated at once daily (evening) 12 U and titrated according to a structured treatment algorithm; people on detemir were allowed to receive an additional morning dose is pre- dinner PG was >7.0 mmol/L, but only if pre- breakfast PG was <7.0 mmol/L or nocturnal hypoglycaemia (major episode or PG ≤4.0 mmol/L) precluded the achievement of the fasting plasma glucose (FPG) target; injection of insulin using pen- injector; FPG target ≤6.0 mmol/L in the absence of hypoglycaemia
co-interventions: oral glucose-lowering therapy, diet and physical activity recommended to remain stable during the study; no meal-time insulin allowed
adherence assessment: not reported
primary: HbA1c
HbA1c: yes; proportion of participants achieving HbA1c ≤7.0% with and without hypoglycaemia
hypoglycaemia: yes; major (assistance from another person required), minor (confirmed by PG <3.1 mmol/L) symptoms only (PG ≥3.1 mmol/L or no measurement made), nocturnal
glycaemic excursions: within-participant variation in PG; 10- point self-measured PG profiles
total daily dose: yes
weight change: yes
complication rates: no
adverse events: yes
health-related quality of life: no
other: fasting plasma glucose
timing of assessment: 16 scheduled visits, during first 12 weeks weekly investigator contact

From: Appendix 5, Characteristics of included trials - long acting insulin analogues

Cover of Newer Agents for Blood Glucose Control in Type 2 Diabetes (Supplement)
Newer Agents for Blood Glucose Control in Type 2 Diabetes (Supplement) [Internet].
NICE Clinical Guidelines, No. 87S.
Waugh N, Cummins E, Royle P, et al.
Copyright © 2009, National Institute for Health and Clinical Excellence.

All rights reserved. This material may be freely reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the express written permission of NICE.

PubMed Health. A service of the National Library of Medicine, National Institutes of Health.