Treating To Target in Type 2 Diabetes 4-T slides are copyright and remain the property of the University of Oxford Diabetes Trials Unit 4-T slides are.

Treating To Target in Type 2 Diabetes

• 4-T slides are copyright and remain the property ofthe 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 ([email protected])

Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapyin Type 2 Diabetes

Rury R. Holman, Kerensa I. Thorne, Andrew J. Farmer, Melanie J. Davies, Joanne F. Keenan, Sanjoy Paul, Jonathan C. Levy, for the 4-T Study Group

N Engl J Med 2007; 357: 1716-30

One-year ResultsOne-year Results43rd EASD Meeting, Amsterdam, 200743rd EASD Meeting, Amsterdam, 2007

Treating To Target in Type 2 Diabetes

The 4-T trial is designed, run and reported by an independent academic group

Funded by Novo Nordisk

Continuous glucose monitoring sub study funded by Diabetes UK

Controlled Clinical Trials number: 51125379Controlled Clinical Trials number: 51125379

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RATIONALE AND DESIGN

Rationâle

Type 2 diabetes is a progressive condition with the majority of patients requiring insulin therapy in the longer term

The rapidly rising diabetes prevalence means that insulin initiation will increasingly be undertaken in primary care

There is no evidence-based consensus about how best to initiate insulin therapy, in particular which insulin formulation should be used.

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Trial Design

Three-arm trial in 708 patients with type 2 diabetes from 58 UK and Irish centres

Evaluating addition of three different analogue insulin regimens to dual oral antidiabetic therapy

Open-label randomisation to:

• Twice a day biphasic insulin (NovoMix 30)

• Three times a day prandial insulin (NovoRapid)

• Once a day basal insulin (Levemir) before bed, with a morning injection added if necessary

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Sample Size and Analysis Methods

Sample Size

700 patients required to detect a 0.4% difference in achieved HbA1c, allowing for 15% loss to follow up

Statistical Methods

Missing data handled by multiple imputation

Analyses by intention to treat (ITT)

Mixed-effect regression or logistic models used to compare treatment groups overall

Closed-test procedure allows pair wise comparisons when overall treatment effect was significant

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Outcomes at One Year

Primary To compare HbA1c levels achieved by the three regimens

Secondary outcomes include: Proportion with HbA1c ≤6.5%

Proportion with unacceptable hyperglycemia i.e. HbA1c >10% or two successive values >8.5% at or after 24 weeks

Hypoglycaemia rates Impact on body weight Quality of Life (EQ-5D) Eight-point self-measured capillary glucose profiles Proportion requiring a morning basal insulin injection

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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 four months or more

HbA1c 7.0% to 10.0% inclusive

Body mass index not more than 40 kg/m2

Written informed consent

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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

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Patient Disposition936

Patients screened

708 Underwent randomization

219 excluded

235Assigned to

biphasic insulin

234Assigned to basal

insulin

239Assigned to

prandial insulin

13 Discontinued

10Discontinued

17Discontinued

222 (94%)Completedone year

224 (96%)Completedone year

222 (93%)Completedone year

9 refused to participate

Patients recruited between1st November 2004 and 31st July 2006N Engl J Med 2007; 357: 1716-30

Demographic Characteristics

Biphasic Prandial BasalN=235 N=239 N=234

Male 68% 64% 61%White Caucasian 94% 90% 93%Asian 5% 6% 4%Black 1% 2% 1%Other or mixed <1% 2% 2%

Retinopathy 15% 19% 18%Neuropathy 17% 23% 17%Nephropathy 9% 10% 10%Macroangiopathy 22% 18% 19%

On sulfonylurea 98% 100% 99%On metformin 96% 95% 97%

No significant differences between groups

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Baseline Characteristics

Biphasic Prandial BasalN=235 N=239 N=234

Age (years) 61.7 ±8.9 61.6 ±10.5 61.9±10.0Diabetes duration (years)* 9 (6-2) 9 (6-4) 9 (6-12)

Body weight (kg) 86.9 ±16.8 84.9 ±14.4 85.5 ±16.3Body mass index (kg/m2) 30.2 ±4.8 29.6 ±4.5 29.7 ±4.6

HbA1c (%) 8.6 ±0.8 8.6 ±0.8 8.4 ±0.8Fasting plasma glucose (mmol/l) 9.7 ±2.8 9.6 ±2.7 9.5 ±2.6

LDL cholesterol (mmol/l) 2.5 ±0.7 2.4 ±0.7 2.3 ±0.7HDL cholesterol (mmol/l) 1.0 ±0.3 1.0 ±0.2 1.0 ±0.3Triglycerides (mmol/l)* 1.6 (1.2-2.1) 1.5 (1.2-2.3) 1.5 (1.1-2.2)

No significant differences between groups *interquartile range

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Randomisation

* Intensify to a combinationinsulin regimen in year one if unacceptable hyperglycaemia

708T2DM

on dual OAD

Add biphasic insulintwice a day

Add prandial insulinthree times a dayR

Year 1Comparison of three

single insulin regimens,added to OADs*

Add basal insulinonce (or twice) daily

Add prandial insulinat midday

Add basal insulinbefore bed

Years 2 and 3If HbA1c >6.5%, stop

sulfonylurea and add a second insulin formulation

Add prandial insulinthree times a day

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Study Visits

Week

0Randomisation

2Two-week visit

6Six-week visit

12Three-month visit

24Six-month visit

38Nine-month visit

52One-year visit

With eight interim telephone contacts

The frequency of contacts was designed to be appropriate for insulin initiation in a primary care setting

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Hypoglycaemia and Safety Measures

Hypoglycaemia Categorised as:

• Grade 1: symptoms only (glucose 3.1 mmol/l or more)

• Grade 2: symptoms with glucose <3.1 mmol/l

• Grade 3: third party assistance required

Safety Measures Unexpected and/or serious adverse events Plasma ALT, creatinine and lipid levels Blood pressure Metformin discontinued if plasma creatinine rose to

150 µmol/l or more on two successive occasions Data Safety Monitoring Board

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Individual Starting Insulin Doses

*Diabetic Medicine 1985; 5: 45-53

Starting doses in rank order

Advised dose : range 2 to 76 IU/day: median 16 (10–25) IU/day

No grade 3 hypoglycaemic episodes occurred within two weeks of starting insulin

Dose taken : median 15 (10–24) IU/day 77% given >10 IU/day 37% given >20 IU/day

5% given >40 IU/day

Estimated from fasting plasma glucose, body weight and gender*

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Insulin Injections & Glucose Measurements

Injection * Self-measured glucose

* *Biphasic

* * ** ** *Prandial

< >Basal* *

Glucose targets

Fasting and pre-meal: 4.0-5.5 mmol/l

Two-hour post meal: 5.0-7.0 mmol/l

6 6 1212 624186 6 1212 624186 6 1212 62418

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Insulin Titration

The online Trial Management System suggested dose adjustments using a common algorithm for all groups

Doses increased if 1/3 or more of glucose values were above target, and in proportion to the gap from target

Doses reduced in the presence of hypoglycaemia

Investigators encouraged to amend suggested doses, as necessary, on clinical grounds in consultation with patients

Patients also educated how to modify doses between visits

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ONE YEARRESULTS

Insulin Dose Adjustments

Morning injection of basal insulin 34% (n=79) of patients randomised to pre-bedtime

basal insulin required, per protocol, an additional morning injection by one year

Adherence to dose adjustment suggestions (±10%) Biphasic 89.7% Prandial 80.4% Basal 90.2%

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Need for a Second Insulin Formulation

Patients with “unacceptable” hyperglycaemia (HbA1c values above 10%, or above 8.5% on two successive occasions, at or after 24 weeks therapy) given a second type of insulin were:

Biphasic 8.9% (n=21)

Prandial 4.2% (n=10)

Basal 17.9% (n=42), P<0.001 vs. biphasic or prandial

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Primary Outcome: HbA1c at One Year

— Biphasic— Prandial— Basal

Mean ±SD at 1 year (%)7.3±0.9

Baseline to 1 year (%)-1.3±1.1

7.2±0.9, p=0.08 vs. biphasic7.6±1.0, p<0.001 vs. biphasic or prandial -0.8±1.0

-1.4±1.0

Months since randomisation

Gly

cate

d ha

emog

lobi

n (%

)

P<0.001

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Distribution of HbA1c Values

— At baseline

HbA1c (%)

— Biphasic— Prandial— Basal

De

nsi

ty23.9%, p=0.08 vs. biphasic 8.1%, p=0.001 vs. biphasic, <0.001 vs. prandial

Proportion <6.5%17.0%

4 6 8 10

0.1

0.2

0.3

0.4

0.5

0.0

Proportion <7.0%41.7%

27.8%48.7%

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Likelihood of Achieving HbA1c ≤6.5%

Odds ratio, 95% CI p

Baseline HbA1c >8.5%

Basal vs. Biphasic 0.21, 0.07-0.65 0.007

Prandial vs. Biphasic 1.24, 0.62-2.51 0.54

Baseline HbA1c ≤8.5%

Basal vs. Biphasic 0.50, 0.24-1.03 0.06

Prandial vs. Biphasic 1.76, 0.96-3.26 0.07

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Glucose Profiles Before & After Starting Insulin

— Biphasic— Prandial— Basal

Change in FPG (mmol/l))-2.5±3.1

Change in PPG (mmol/l)-3.8±3.5

-1.3±2.7-3.3±2.9 -2.6±3.0

-4.6±3.0p<0.001 vs. biphasicp<0.001 vs. biphasic or prandial

0

— At baseline

Body Weight Over One Year

Months since randomisation

Bod

y w

eigh

t (k

g)

P<0.001

— Biphasic— Prandial— Basal

Baseline to 1 year (kg)+4.7±4.0+5.7±4.6, p<0.005 vs. biphasic+1.9±4.2, p<0.001 vs. biphasic or prandial

N Engl J Med 2007; 357: 1716-30

Insulin Doses Over One Year

Months since randomisation

Insu

lin d

ose

(U/k

g/da

y)

P=0.04

— Biphasic— Prandial— Basal

Median at 1 year (U/kg/day)0.53 (0.36 to 0.70)

Total per day (U)48 (30 to 71)

0.61 (0.37 to 0.88), p<0.006 vs. biphasic0.49 (0.34 to 0.73), p<0.02 vs. prandial 42 (28 to 72)

56 (34 to 78)

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Hypoglycaemia (≥ Grade 2) Over One Year

Months since randomisation

Pro

port

ion

with

eve

nts

(%)

P=0.001

— Biphasic— Prandial— Basal

Mean at 1 year (events/patient/year) 5.712.0, p<0.002 vs. biphasic 2.3, p=0.01 vs. biphasic, p<0.001 vs.prandial

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Serious Adverse Events

Biphasic Prandial Basal p(N=235) (N=239) (N=234)

All 41 30 30 0.25

Gastro intestinal and abdominal pain 4 0 0 0.02

Lower respiratory & lung infection 4 0 0 0.02

Ischaemic & coronary artery disorder 3 4 3 0.99

Abdominal and gastrointestinal infection 3 0 2 0.21

Other infection 1 3 1 0.63

Deaths

3 Biphasic (heart failure, myocardial infarction, ischaemic heart disease)

1 Prandial (myocardial infarction)0 Basal

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Adverse events

No clinically relevant changes in albumin creatinine ratio, ALT or plasma creatinine were observed

Biphasic Prandial Basal pN=235 N=239 N=234

All 209 203 207 0.37

Upper respiratory tract infection 81 74 91 0.19

Reaction at injection or infusion site 37 33 52 0.04

Musculoskeletal/connective-tissue 43 37 35 0.59

Lower respiratory/lung infection 36 40 29 0.40

Nausea and vomiting 36 32 32 0.83

Diarrhoea 27 26 34 0.45

Headache 16 27 20 0.23

Upper respiratory tract symptom 17 20 26 0.33

Cough 22 26 17 0.39

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Quality of Life

Baseline Change at one year

Biphasic 0.81 (0.78 to 0.84) 0 (-0.15 to 0.03)

Prandial 0.79 (0.76 to 0.82) 0 (-0.08 to 0.03)

Basal 0.78 (0.75 to 0.82) 0 (-0.09 to 0.04)

p=0.48

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Mean One-year Changes

Biphasic Prandial Basal

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SUMMARY AND CONCLUSIONS

Biphasic Insulin Summary

Two injections a day, with two capillary glucose tests for dose titration

HbA1c lowering equivalent to Prandial insulin

Greater weight gain and more hypoglycaemia than with Basal insulin but less for both than with Prandial insulin

No change in QoL as assessed by EQ-5D

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Prandial Insulin Summary

Three injections a day, with up to seven capillary glucose tests for dose titration

HbA1c lowering equivalent to Biphasic insulin

Greater weight gain and more hypoglycaemia than with Biphasic or Basal insulin

No change in QoL as assessed by EQ-5D

Basal Insulin Summary

One injection a day, with two capillary glucose tests for dose titration

One third of patients require a morning insulin injection in addition

More patients require a second insulin formulation than with Biphasic or Prandial insulin

Less HbA1c lowering than with Biphasic or Prandial insulin

Less weight gain and less hypoglycaemia than with Biphasic or Prandial insulin

No change in QoL as assessed by EQ-5D

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Conclusions

Addition of a single analogue insulin formulation to metformin and sulfonylurea can lower HbA1c by between 0.8 and 1.4%, and sustain these values over one year

Regimens using biphasic or prandial insulin reduced HbA1c to a greater extent than basal, but were associated with greater risks of hypoglycemia and more weight gain

The one-year results of the 4-T study suggest that most patients are likely to need more than one type of insulin to achieve target glucose levels in the longer term

The final two years of the trial will examine specifically the use of complex insulin regimens in these patients

N Engl J Med 2007; 357: 1716-30