The addition study in general practice:

Protocol, ADDITION-study, November 24.2005 The ADDITION-study
Anglo-Danish-Dutch Study in General Practice of Intensive Treatment and
Complication Prevention in Type 2 Diabetic Patients Identified by Screening.
Principal Investigators: Professor Torsten Lauritzen, GP, DMSc., Department of General Professor Knut Borch-Johnsen, Medical director, DMSc., Steno Diabetes Centre, and University of Aarhus, Denmark. Professor Nicholas Wareham, FRCP, Director, PhD MRC Epidemiology Unit, University of Cambridge, United Kingdom Dr Simon Griffin, DMSc., FRCGP, Programme Leader, MRC Epidemiology Unit, University of Cambridge, United Kingdom Dr Kamlesh Khunti, MD, FRCGP, Department of Health Sciences, University of Leicester, United Kingdom Professor Melanie Davies, MD FRCGP, Department of Cardiovascular Medicine University Hospital of Leicester, United Kingdom. Professor Guy Rutten, MD PhD, Julius Center for Health Sciences and Primary Care, University of Utrecht, the Netherlands. ProfessorDr Ronald P Stolk, PhD, Department of Epidemiology, University Medical Center Groningen, the Netherlands International project coordinator: University Lecturer, Annelli Sandbæk, MD PhD, Department of General Practice University of Aarhus, Denmark Protocol, ADDITION-study, November 24.2005

Type 2 diabetes (T2D) is a characterised by substantial loss in life expectancy, and a high
risk of developing complications1. Two of three patients will die from cardiovascular disease
(CVD)2. The recent guidelines for prevention of CVD by the European Society of Cardiology3
recommend targeted intervention in those at highest risk. T2D is a major risk factors for
development of CVD, and Finnish data show that the risk of dying from CVD is the same in
diabetic patients without CVD as in non-diabetic post-MI patients4. In patients hospitalised
with acute MI or unstable angina the prevalence of diabetes is 25-40%5. Diabetic patients
developing acute MI have a case fatality rate and risk of re-infarction twice as high as non-
diabetic patients2. T2D is also one of the fastest growing chronic diseases world wide
together with obesity6, and up to 50 % of individuals suffering from T2D are unaware of the
condition7. With two thirds of the patients dying from CVD, prevention of CVD is the key to an
improved prognosis. Prevention of CVD is more effective in patients with diabetes, and
treatment targets are stricter than in patients without diabetes3. Most patients have had
diabetes for 5-10 years before clinical diagnosis8, years where they are not offered relevant
treatment, and 50% of all newly diagnosed patients have one or more complications9.
Evidence is increasing that early detection and treatment of T2D is beneficial. Hyperglyc-
aemia is associated with the development of microvascular and macrovascular disease. The
risk of complications can be reduced by intensive treatment of hyperglycaemia10-13,
hypertension14-16 and dyslipidaemia17;18 in people with clinically diagnosed disease. Thus, the
relevance of screening for and early intervention in T2D is intensively debated19. A recent
Danish Health Technology Assessment Report20 concluded that general, population based
screening can not be recommended, but randomised trials should be performed studying the
effectiveness and cost-effectiveness of screening and intervention together with the potential
side effects of screening. Thus, trials are needed that can quantify the potential benefits and
harms associated with screening for early, intensive, multifactorial treatment of type 2
Type 2 diabetes is typically diagnosed and managed in primary care21;22, and there is
evidence that family practitioners may provide standards of care as well as that achieved in
hospital outpatient departments23. Recent changes in treatment regimens with
polypharmacological treatment targeted at multiple risk factors, however, complicates the
treatment regiment24, and it may be questioned whether this is feasible in general practice. If
this is not the case, this would have tremendous impact on the organisation of future
diabetes care not only in Denmark, UK and The Netherlands.
Diabetes is more common in people originating from the Indian Sub-Continent compared to
those from the United Kingdom or Europe and the age at presentation of diabetes is earlier in
South Asians25 and since duration of diabetes is a strong risk factor for complications, this
group is at high risk. Mortality from heart disease is approximately three times higher in
South Asian patients with diabetes compared to those with diabetes born in England and
Wales26 and South Asians with Type 2 diabetes are more likely to develop premature
coronary heart disease compared to their white British counterparts27.
Based on this the ADDITION-study was established with the following aims:
• To develop and evaluate strategies for early detection of type 2 diabetes in different • To study whether a multifactorial treatment strategy can reduce CVD-mortality and reduce the incidence of macro- and microvascular complications. The treatment strategy consist of motivational interviewing, encouraging behavioural changes (dietary advises, physical activity, smoking cessation) and intensive pharmacological treatment of blood pressure, blood glucose, and serum lipids • To identify genetic markers predicting development of diabetic complications • To evaluate health economical consequences screening and early intervention for Protocol, ADDITION-study, November 24.2005
Design and methods
The study is an investigator initiated and designed study, initiated in Denmark by the two
principal investigators, planned and conducted in collaboration between the four centers in
Denmark, UK and the Netherlands. The study has two elements: a screening study and a
subsequent intervention study.
In the screening study, the feasibility and results of country specific models to identify
undiagnosed individuals with Type 2 diabetes will be evaluated.
In the treatment study the effects of routine care in general practice according to local and
national guidelines will be compared with an intensive ADDITION protocol, including
structured lifestyle education (dietary modification, increased physical activity and smoking
cessation) and intensive treatment of blood glucose, blood pressure and lipids, and
prophylactic aspirin with or without motivational interviewing, on mortality, macrovascular and
microvascular disease. Furthermore the impact of treatment on health status, treatment
satisfaction and health service costs will also be assessed.
Methodology: screening study
In Denmark, primary care physicians from 5 different counties (Copenhagen, Aarhus,
Ringkøbing, Ribe and Sønderjylland) participate in the study. Diabetes-related information is
sent to all individuals aged 40–69 years enrolled in their practice. A questionnaire (diabetes
risk score28) including age, gender, family history of type 2 diabetes; obesity; physical activity
and previously diagnosed hypertension was used. Individuals scoring high on the
questionnaire are encourages to contact their physician for an examination of random blood
glucose (RGB) and HbA1c. A step-wise strategy based on RBG, HbA1c, FPG and OGTT is
used to diagnose diabetes
In the Netherlands all people aged 50-69 years and listed with the participating primary care
physicians is invited to fill in a diabetes risk questionnaire based on the same risk factors as
in Denmark. Those at high risk of having type 2 diabetes are requested to come fasting for a
screening visit at a centre set up near the general practice. A stepwise screening strategy
based on RBG, FPG and OGTT is used to diagnose diabetes.
In UK, different strategies are used in Cambridgeshire and Leicester. In Cambridgeshire a
search of computerised general practice records is performed, using a simple validated risk
score, based on routine general practice data (age, gender, prescribed medication and body
mass index), to identify people in the age of 40-69 years at high risk of having undiagnosed
diabetes29. Those with a high score undergo a stepwise screening strategy based on RBG,
FPG and OGTT is used to diagnose diabetes.
In Leicester all white European subjects aged 40-75 years and asian, black or Chinese
subjects aged 25-75 years are invited in a restricted geographical region within Leicester. All
attendant undergo an OGTT as the first screening step (unless FPG > 7.0 mmol/l)
Diagnostic procedures
The diagnostic procedure includes a stepwise procedure minimising the work-load on the
general practitioner and includes the questionnaire, random capillary blood glucose and
HbA1c as screening instruments followed by fasting capillary blood glucose (FCBG) and an
oral glucose tolerance test in everyone with marginally elevated FCBG. The diagnostic
criteria follow the most recent World Health Organization guidelines30 and is based on two
diagnostic glucose values measured on independent days.

Exclusion criteria

Participants are excluded if they already have diabetes, are pregnant or lactating or have a
severe psychotic illness are house bound or have an illness with a likely survival of less than
one year.
Outcome measures
Outcome measures from the screening study include measures of the efficacy of the
screening campaign, the objective health status of patients newly identified by the campaign,
Protocol, ADDITION-study, November 24.2005 feasibility as reported by the primary care physician, and the economic impact or benefit of
the programme. Furthermore a substudy explores the psycho-social and ethical aspects of
the screening programme.
Methodology: intervention study
All patients diagnosed as part of the screening programme are invited to enter the
ADDITION-study. The study will include a minimum of 3000 patients with screen detected
diabetes. The general practices are randomised to the routine care group (standard care as
given by the GP) or to the intervention group which features a target driven, intensive
multifactorial approach to treatment. The study is an open, multicentre, parallel group trial
with randomisation of general practices. Patients are screened and recruited during the
period January 1st 2000 and June 30th 2006. The end follow-up is by july 1st 2009.
Participation is based on informed consent in accordance with the Declaration of Helsinki.

Intensive Treatment strategy
The intensive multifactorial treatment includes lifestyle advices (concerning diet, physical
activity, medication adherence and tobacco cessation), prescription of aspirin and stepwise
increases in pharmacological treatment of blood glucose, blood pressure and lipids,
according to strict targets (appendix 1): The treatment targets are as follows:
• HbA1c < 7.0 • Total cholesterol < 5.0 mmol/l (4.5 mmol/l if CVD present) but statin to everyone with • Aspirin 75-150 mg/day to everyone on antihypertensive treatment • Healthy diet (low fat, 600g of fruit and vegetables/day) The treatment targets may be intensified during the study according to the results of other clinical trials published during the study period, as the aim is to strive for treatment targets based on the most intensive guidelines available. Within the intensive group a further randomisation allocates 50% of the patients to country specific interventions concerned with motivating adherence to lifestyle changes and medication. This intervention, including the use of motivational interviewing, is delivered either by a trained facilitator (UK and The Netherlands) or through training of practitioners (Denmark), and is based on a client-centred non-directive counselling style to help patients explore and resolve ambivalence and stimulate lifestyle changes, appropriate diabetes self-care and adherence to medical treatment31;32. Pharmacological treatment The decision on which pharmaceutical drug to use for the individual patients which is made by the clinician as the study is target driven and not a trial comparing different specific drugs. The GP is provided with recommendations for a treatment strategy (appendix 1), which should be based on balancing treatment effect, side-effects and cost. The main priority is achievement of treatment targets with a flexible lifestyle and low rates of side effects such as hypoglycaemia and weight gain. Therapies are adjusted at 2 to 4-weekly intervals until targets are reached, thereafter every 3 months. HbA1c is taken every third month, in between antidiabetic drugs are adjusted according to blood glucose measurements in the interim. Outcome measures The primary aim of the study is to study whether intensive treatment of people with screen detected type 2 diabetes can prevent or delay development of major late diabetic complications. Cardiovascular disease is the most frequent complication and cause of death Protocol, ADDITION-study, November 24.2005 and this is reflected in the distinction between primary and secondary endpoints as listed below. 6.2 Quality of life
6.3 Patient satisfaction
6.4 Health utility

Sample size and statistical power
Based on levels of risk in the conservative-treatment arm of the UKPDS, the expected
event rate is 3% per year for the combined endpoint (all-cause mortality, nonfatal myocardial
infarction, stroke, revascularisation or amputation). With a sample size of 1350 patients in
each arm (standard versus intensive treatment) the study will allow the detection of a 30%
risk reduction in the intervention group at a significance level of 5% with a mean duration of
follow-up of 5 years.
The screening study began in late 2000 and will end by December 31st 2004. Patients are
enrolled into the treatment study following diagnosis in the screening study: thus the
treatment study proceeds along with the evaluation phase of the screening study. The follow-
up will continue until July 1st 2009.
Ethics and safety
The Scientific Ethics Committee in the involved counties in Denmark and the Multipractice
Study Committee have accepted the project, and the study has been approved by the ethical
committees in UK and the Netherlands.
A data safety and monitoring committee will have access to all end point data (unblinded)
after 1, 3 and 5 years , and the study will be terminated if the composite end point (including:
Cardiovascular death, non-fatal MI, non-fatal stroke, revascularisation and amputation)
should demonstrate a clear advantage of intensive versus standard treatment (p<0.001) or a
clear advantage of the standard versus intensive treatment (p<0.01).
Collaborating centres

Professor Torsten Lauritzen, GP, DMSc.
Department of General Practice University of Aarhus, Denmark Professor Knut Borch-Johnsen, Medical director, DMSc. Steno Diabetes Centre, and University of Aarhus, Denmark. Professor Nicholas Wareham, FRCP, Director, PhD MRC Epidemiology Unit, University of Cambridge, United Kingdom Dr Simon Griffin, DMSc., FRCGP, Programme Leader, MRC Epidemiology Unit, University of Cambridge, United Kingdom Department of Health Sciences, University of Leicester, United Kingdom Department of Cardiovascular Medicine, Leicester, United Kingdom. Protocol, ADDITION-study, November 24.2005 Julius Center for Health Sciences and Primary Care, University of Utrecht, the Netherlands. Department of Epidemiology, University Medical Center Groningen, the Netherlands International project coordinator: University Lecturer, Annelli Sandbæk, MD PhD, Department of General Practice University of Aarhus, Denmark
Perspectives of the trial

The results of the study will be of immediate national and international relevance to policy
decisions about screening for diabetes, and subsequent intensive treatment. If the study
shows that screening and early intervention markedly reduces the risk of developing
premature CVD, then the study will have potential important impact at the individual patient
level as well as on the societal level. If the study fails to show an effect of screening and
early intensive treatment then this would have direct impact on future recommendations for
screening and treatment regimens, and the study could lead to significant savings if it shows
that strict treatment targets are not essential in the early phase of the disease. The results of
the sub-study will inform approaches to health promotion to the management of chronic
disease and risk, and to strategies to support adherence applicable not only to diabetes but
also to other chronic diseases.
Protocol, ADDITION-study, November 24.2005 References
(1) Laakso M, Lehto S. Epidemiology of macrovascular disease in diabetes. Diabetes Rev 1997; (2) Sprafka JM, Burke GL, Folsom AR, McGovern PG, Hahn LP. Trends in prevalence of diabetes mellitus in patients with myocardial infarction and effect of diabetes on survival. The Minnesota Heart Survey. Diabetes Care 1991; 14(7):537-543. (3) Backer GD, Ambrosioni E, Borch-Johnsen K, Brotons C. European guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal 24, 1601-1610. 2003. European Society of Cardiology. Ref Type: Magazine Article (4) Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339(4):229-234. (5) Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendic S, Ryden L et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002; 359(9324):2140-2144. (6) King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabet Care 1998; 21(9):1414-1431. (7) Glumer C, Jorgensen T, Borch-Johnsen K. Prevalences of diabetes and impaired glucose regulation in a Danish population: the Inter99 study. Diabet Care 2003; 26(8):2335-2340. (8) Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabet Care 1992; 15(7):815-819. (9) UK Prospective Diabetes Study 6. Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res 1990; 13(1):1-11. (10) UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. (11) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group [published erratum appears in Lancet 1999 Aug 14;354(9178):602] [see comments]. Lancet 1998; 352(9131):837-853. (12) Guillausseau PJ, Massin P, Charles MA, Allaguy H, Guvenli Z, Virally M et al. Glycaemic control and development of retinopathy in type 2 diabetes mellitus: a longitudinal study. Diabet Med 1998; 15(2):151-155. (13) Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years [see comments]. Diabet Care 1999; 22(2):233-240. (14) Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group [see comments]. Lancet 1998; 351(9118):1755-1762. (15) Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group [see comments] [published erratum appears in BMJ 1999 Jan 2;318(7175):29]. BMJ 1998; 317(7160):703-713. (16) Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint Protocol, ADDITION-study, November 24.2005 reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359(9311):1004-1010. (17) Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S) [see comments] [published erratum appears in Diabetes Care 1997 Jun;20(6):1048]. Diabet Care 1997; 20(4):614-620. (18) Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361(9374):2005-2016. (19) Wareham NJ, Griffin SJ. Should we screen for type 2 diabetes? Evaluation against national screening committee criteria. BR MED J 2001; 322(7292):986-988. (20) Type 2-diabetes: medicinsk teknologivurdering af screening, diagnostik og behandling. 2003. København, Sundhedsstyrelsen. Medicinsk Teknologivurdering; 2003; 5(1). Ref Type: Report (21) Khunti K, Baker R, Rumsey M, Lakhani M. Quality of care of patients with diabetes: collation of data from multi-practice audits of diabetes in primary care. Fam Pract 1999; 16(1):54-59. (22) Kinmonth AL, Griffin S, Wareham NJ. Implications of the United Kingdom Prospective Diabetes Study for general practice care of type 2 diabetes [editorial] [see comments]. Br J Gen Pract 1999; 49(446):692-694. (23) Griffin S. Diabetes care in general practice: meta-analysis of randomised control trials [see (24) Gaede P, Vedel P, Larsen N, Jensen G, Parving H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348(5):383-93. (25) Simmons D, Williams DR, Powell MJ. The Coventry Diabetes Study: prevalence of diabetes and impaired glucose tolerance in Europids and Asians. Q J Med 1991; 81(296):1021-1030. (26) Chaturvedi N, Fuller JH. Ethnic differences in mortality from cardiovascular disease in the UK: do they persist in people with diabetes? J Epidemiol Community Health 1996; 50(2):137-139. (27) Greenhalgh PM. Diabetes in British south Asians: nature, nurture, and culture. Diabet Med (28) Glumer C, Carstensen B, Sandbaek A, Lauritzen T, Jorgensen T, Borch-Johnsen K. A Danish diabetes risk score for targeted screening: the Inter99 study. Diabet Care 2004; 27(3):727-733. (29) Griffin SJ, Little PS, Hales CN, Kinmonth AL, Wareham NJ. Diabetes risk score: towards earlier detection of type 2 diabetes in general practice. Diabetes Metab Res Rev 2000; 16(3):164-171. (30) Alberti KGMM, Zimmet P, for a WHO consultation. Definition, diagnosis and classification of diabetes mellitus and its complications; Part 1: Diagnosis and classification of diabetes mellitus. World Health Organisation . 1999. Geneva, Switzerland, World Health Organisation. Ref Type: Report (31) Rollnick S, Kinnersley P, Stott N. Methods of helping patients with behaviour change. BMJ (32) Kinmonth AL, Woodcock A, Griffin S, Spiegal N, Campbell MJ. Randomised controlled trial of patient centred care of diabetes in general practice: impact on current wellbeing and future disease risk. The Diabetes Care From Diagnosis Research Team. BMJ 1998; 317(7167):1202-1208.
Appendix 1 (March 2003)
Basic treatment
Supplementary treatment
Increase dose with 2 weeks interval; go to next treatment step when maximum daily dose is reached or if side-effects appear. See patient every 2nd week until target is reached, more frequent with start of insulin treatment. Treatment
If above target add
If still above add
If still above
< 7.0%*:
> 7.0%:
> 7.0%:
> 7.0%:
BG (eg Metformin)
PGR (eg Repaglinid)
Continue oral hypoglycaemic agent, add Insulatard 12IU at bed time, increasing with
or PGR (eg Repaglinid)
or SU (eg Gliclazin)
4-6IU every week until fbg < 7 mmol/l.
or SU (eg Gliclazin)
or BG (eg Metformin)
If more than 20 units then divide dose and quit oral drugs.

Optional first choice
< 120/80 mmHg:
> 120/80 mmHg:
> 135/85 mmHg:
> 135/85 mmHg:
> 135/85 mmHg:
ACE-inhibitor (eg Ramipril)
B-blocker (eg metroprolol)
TZD (eg bendrofluazide)
low to maximum dose
or thiazide diuretic (eg bendrofluazide)
or LD (furosemide)
Ca antag (eg amlodipine)
or B-blocker (eg metroprolol)
< 3,5 mmol/l:
> 3.5 mmol/l:
- IHD: > 5.0 mmol/l:
lipid lowering treatment (eg statin 40 mg)
diet + statin dose up to maximum
+ IHD: > 4.5 mmol/l:
diet + statin dose up to maximum
cylic acid
75 mg to all patients treated with antihypertensive agents
Outline of treatment recommendation in the intensive-therapy arm. The protocol allows for advantage to be taken of new drug development and the final decision will depend on the individual doctor and patient. BMI, body mass index (kg/m2); NPH, neutral protamine Hagedorn; PGR, prandial glucose regulator; SU, sulphonylureas; BG, biguanide; LD, loop diuretic; CVD, cardiovascular disease; fbg, fasting blood glucose. * In order to achieve the overall goal of the ADDITION Study, ie to keep the HbA1c under 7%, alterations or additions to therapy should seriously be considered when the HbA1c is > 6.5%.


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