4-T Final Three-year Results Slides © University of Oxford Diabetes Trials Unit  4-T slides are copyright and remain the property of the University of Oxford Diabetes Trials Unit  4-T slides are made freely available to non-profit organisations on the understanding that the contents are not altered in any way, other than for translation into other languages  Commercial organisations wishing to use 4-T slides should contact the 4-T Administrator Three-Year Efficacy of Complex Insulin Regimens in Type 2 Diabetes N Engl J Med 2009;361:

Treating-To-Target in Type 2 Diabetes The 4-T trial  Three-year study in 708 people with type 2 diabetes from 58 UK and Irish centres  Sponsored and funded by Novo Nordisk  Independently designed, run and reported by an academic group  Two sub studies funded by Diabetes UK  One-year results were published in 2007 Current Controlled Trials no: ISRCTN

N Engl J Med 2009;361: Rationale for 4-T  Type 2 diabetes is a progressive condition with the majority of patients requiring insulin therapy in the longer term  Approaches to insulin therapy for type 2 diabetes vary considerably across the world, but large-scale direct comparisons of complex insulin regimens have not been performed  There is no evidence-based consensus about which insulin formulation should be used to initiate insulin therapy, or which complex insulin regimen might be most appropriate

N Engl J Med 2009;361: Aims First Phase  One-year head-to-head comparison of the efficacy of three different types of analogue insulins, when given in addition to dual oral antidiabetic therapy Second Phase  Evaluation over two further years of the need for more complex insulin regimens, and the overall efficacy of three different randomized insulin treatment strategies

N Engl J Med 2009;361: Statistical Methods  A sample size of 700 patients was calculated to detect a 0.4% difference in achieved HbA 1c, allowing for a loss-to-follow up of 15%  Missing data are handled by multiple imputation  Medians are presented with 95% confidence intervals  Analyses are by intention to treat  Mixed-effect regression or logistic models are used to compare treatment groups overall  A prespecified closed-test procedure, which adjusts p values appropriately, allows for three pair-wise comparisons between groups

N Engl J Med 2009;361: Major Inclusion Criteria  Aged 18 years or more  Male and female  Type 2 diabetes for one year or more  On maximal tolerated doses of metformin and sulfonylurea for at least four months  HbA 1c 7.0% to 10.0% inclusive  Body mass index not more than 40 kg/m 2  Written informed consent

N Engl J Med 2009;361: Major Exclusion Criteria  Taking insulin therapy  Taking oral antidiabetic therapies, other than sulfonylurea and/or metformin  Plasma creatinine >130 µmol/l  ALT ≥2x upper limit of normal  Life threatening cardiovascular disease  Lactating or potentially pregnant females

N Engl J Med 2009;361: Patient Disposition 235 Assigned to biphasic insulin (biphasic aspart) 234 Assigned to basal insulin (detemir) 239 Assigned to prandial insulin (aspart) 34 Discontinued 45 Discontinued 51 Discontinued 201 (86%) Completed three years 189 (81%) Completed three years 188 (79%) Completed three years  Overall, 18.4% of patients did not complete three years  No difference in proportions between groups (p=0.15)  No difference in baseline characteristics between those who completed or did not complete three years follow up

N Engl J Med 2009;361: Demographic Characteristics Biphasic N=235 Prandial N=239 Basal N=234 Male68%64%61% White Caucasian94%90%93% *Diabetes duration (yrs)9 (6-12)9 (6-14)9 (6-12) Taking sulfonylurea98%100%99% Taking metformin96%95%97% Age (years)61.7± ± ±10.0 Body mass index (kg/m 2 )30.2 ± ± ±4.6 HbA 1c (%)8.6 ± ±0.8 *interquartile range No significant differences between groups

N Engl J Med 2009;361: Visit Schedule in Year One  The visit schedule was designed to mirror a primary care setting  Visits were undertaken at two weeks, six weeks and three months after starting insulin therapy  Visits were then three-monthly  In addition, eight interim telephone contacts were scheduled

N Engl J Med 2009;361: Hypoglycaemia Categorised as  Grade 1 - Symptoms only with glucose (if measured) ≥3.1 mmol/l (≥56 mg/dl)  Grade 2 - Symptoms plus glucose <3.1 mmol/l (<56 mg/dl)  Grade 3 - Third party assistance required

N Engl J Med 2009;361: Glycaemic targets and Insulin Injections Fasting and pre-meal: mmol/l (72-99 mg/dl)‏ Two-hours post meal: mmol/l ( mg/dl)‏ Biphasic Basal Prandial * * Twice a day if required

N Engl J Med 2009;361: Transition to a Complex Insulin Regimen * Intensify to a complex insulin regimen in year one if unacceptable hyperglycaemia 708 T2DM on dual oral agents Add biphasic insulin* twice a day Add prandial insulin* three times a day R First Phase Add basal insulin* once (or twice) daily Add prandial insulin at midday Add basal insulin before bed Second Phase Add prandial insulin three times a day From one year onwards, if HbA 1c levels were >6.5%, sulfonylurea therapy was stopped and a second type of insulin was added

N Engl J Med 2009;361: Starting Doses for Second Type of Insulin Biphasic group  Add midday prandial insulin - 10% of current total daily biphasic insulin dose (limited to 4-6 units) Prandial group  Add basal insulin at bedtime - 10 units Basal group  Add prandial insulin at breakfast, lunch and dinner - 10% of current total daily basal insulin dose at each time point (limited to 4-6 units)

N Engl J Med 2009;361: Titrate to Target Glycaemic targets as for Phase 1 of the study  Fasting and pre-meal mmol/l (72-99 mg/dl)  Two-hours post meal mmol/l ( mg/dl)  The 4-T Online Trial Management System suggested dose adjustments using a common algorithm for all groups  Investigators encouraged to amend suggested doses on clinical grounds and in consultation with patients  Patients encouraged to modify doses between visits

N Engl J Med 2009;361: Complex Insulin Regimens Proportion eligible for a second type of insulin per protocol Proportion taking two types of insulin

N Engl J Med 2009;361: Insulin Doses Over 3 Years Median±95% confidence interval Biphasic ±prandial Prandial ±basal Basal ±prandial

N Engl J Med 2009;361: Total Daily Insulin Doses at 3 Years Median±95% confidence interval

N Engl J Med 2009;361: HbA 1c Values Over 3 Years Median±95% confidence interval Biphasic ±prandial Prandial ±basal Basal ±prandial Overall 6.9% (6.8 to 7.1)

N Engl J Med 2009;361: Primary Outcome: HbA 1c at 3 Years Median±95% confidence interval

N Engl J Med 2009;361: Distribution of HbA 1c Values at 3 Years Proportion ≤6.5% Biphasic31.9% Prandial44.8% Basal43.2% p=0.006 p=0.55 p=0.03 Biphasic ±prandial Prandial ±basal Basal ±prandial Baseline Proportion ≤7.0% Biphasic49.4% Prandial67.4% Basal63.2% p<0.001 p=0.22 p=

N Engl J Med 2009;361: Decrease in SMBG Levels Over 3 Years Mean±1SD

N Engl J Med 2009;361: Body Weight over 3 Years Median±95% confidence interval Biphasic ±prandial Prandial ±basal Basal ±prandial

N Engl J Med 2009;361: Increase in Body Weight Over 3 Years Mean±1SD

N Engl J Med 2009;361: Increase in Waist Circumference Over 3 Years Mean±1SD

N Engl J Med 2009;361: Grade 2 or 3 Hypoglycaemia Over 3 Years Biphasic ±prandial Prandial ±basal Basal ±prandial

N Engl J Med 2009;361: Grade 2 or 3 Hypoglycaemia Over 3 Years Median±95% confidence interval All patients Patients with HbA 1c ≤6.5%

N Engl J Med 2009;361: EQ-5D Quality of Life Scores at 3 Years Biphasic:0.76 (0.71 to 0.80) Prandial:0.77 (0.73 to 0.81) Basal:0.80 (0.77 to 0.83) p=0.73 p=0.86 Winzorized mean±95% confidence interval

N Engl J Med 2009;361: Adverse Events Biphasic N=235 Prandial N=239 Basal N=234 p value Any serious event105 (44.7%) 79 (33.1%) 78 (33.3%) Death from any cause7 (3.0%) 9 (3.8%) 4 (1.7%) 0.23 Cardiovascular death4 (1.7%) 9 (3.8%) 1 (0.4%) Any adverse event228 (97.0%) 235 (98.3%) 227 (97.0%) 0.58 No significant differences were seen between groups in:  Serious adverse events occurring in more than 1% in any group  Non-serious adverse events occurring in more than 10% in any group

N Engl J Med 2009;361: Safety Data No clinically relevant differences were seen between the groups with respect to changes in:  Blood pressure  Lipid profiles  Alanine aminotransferase  Plasma creatinine  Ratio of urinary albumin to creatinine

N Engl J Med 2009;361: Relative Changes over 3 Years and Hypoglycaemia Mean±1SD

N Engl J Med 2009;361: Overview of Main Results BiphasicPrandialBasal Median HbA 1c level achieved +++ HbA 1c targets achieved +++ Mean SMBG level achieved +++ Fewer hypoglycaemic episodes Less weight gain ++++ Less increase in waist circumference ++++

N Engl J Med 2009;361: Summary  Three quarters of patients added a second insulin  Those commencing therapy with a basal or prandial insulin more often achieved glycaemic targets than patients commencing with a biphasic insulin  Patients commencing therapy with basal insulin had fewer hypoglycaemic episodes and less weight gain These findings provide clear evidence in people with type 2 diabetes to support starting insulin therapy with a once a day basal insulin, and then adding a mealtime insulin if glycaemic targets are not met