12 August 2011
The ADDITION-Europe study looked at the effect of early intensive multifactorial management (of HbA1c, blood pressure, cholesterol; and prescription of aspirin) on 5-year cardiovascular outcomes in people with type 2 diabetes that had been detected by screening. Whilst some small reductions in disease-oriented outcomes (HbA1c, blood pressure, total and LDL-cholesterol) were seen with intensive management compared with usual care, no statistically significant differences were found in any patient-oriented cardiovascular outcome.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Patients should continue to be managed according to NICE guidance on type 2 diabetes. This recommends a multifactorial but more individualised (rather than intensive), approach to management, addressing lifestyle issues, blood glucose, blood pressure (BP) and blood lipids. For example, when managing blood glucose, individual targets for HbA1c should be agreed with each individual patient, taking into account the patient’s own preferences for care and the balance of likely benefits and harms. The results of this study do not support routine screening of the population for type 2 diabetes, which is not current practice in the UK anyway.
What is the background to this?
Several randomised controlled trials (RCTs) have shown that managing individual cardiovascular (CV) risk factors in people with type 2 diabetes is worthwhile. A review by John Yudkin and colleagues summarised the effects from meta-analyses of BP lowering, cholesterol lowering and blood glucose lowering on coronary heart disease and CV outcomes. It reported a number needed to treat (NNT) to prevent one CV event over 5 years of 34 for BP lowering, 44 for cholesterol lowering, and 119 for blood glucose lowering, suggesting that blood glucose control appears to be less effective in reducing CV disease than controlling either BP or blood lipids. This is discussed in more detail in MeReC Bulletin Vol 21 No 5. Most patient populations included in these meta-analyses had more advanced disease compared with those included in the study discussed in this article.
In terms of multifactorial management, the STENO-2 RCT suggested that intensive multifactorial management of patients with long-standing type 2 diabetes and microalbuminura can reduce the risk of CV events. However, this was a very small study with just 160 patients.
The ADDITION-Europe study discussed in this Rapid Review, is the first published RCT to assess the effect of early intensive multifactorial management on CV outcomes in people with type 2 diabetes detected by screening. 3,057 (of 3,233 patients identified with type 2 diabetes in the initial screening phase) agreed to take part in the RCT, which compared routine diabetes care (n=1,379 patients) with intensive multifactorial treatment (n=1,678). Intensive treatment consisted of blood glucose, blood pressure and lipid control to intensive targets, and aspirin if not contraindicated for those receiving antihypertensives (see study details below).
What does this study claim?
At 5 years, there was no statistically significant difference between routine care and intensive treatment in the primary endpoint, a composite of first CV event, including CV mortality, CV morbidity (non-fatal MI and non-fatal stroke), revascularisation and non-traumatic amputation. The incidence of first CV event was 7.2% (13.5 per 1,000 person-years) in the intensive treatment group and 8.5% (15.9 per 1,000 person years) in the routine care group (hazard ratio [HR] 0.83, 95%CI 0.65 to 1.05; p=0.12). Neither were there any statistically significant differences in the individual constituents of the primary endpoint (the secondary endpoints).
Statistically significant reductions were found in some disease-oriented outcomes (HbA1c, systolic and diastolic BP and total and LDL-cholesterol, but these differences were generally small (see study details below).
This study does not support a case for routine screening for type 2 diabetes, or for early intensive multifactorial management of macrovascular and microvascular risk factors in people with type 2 diabetes. No statistically significant differences between routine and intensive multifactorial treatment of type 2 diabetes identified by screening were found in any patient-oriented CV outcome at 5 years.
Neither does it support the suggestion from the 10-year follow up of UKPDS and a subgroup analysis of the CONTROL meta-analysis that intensive blood glucose control in people with early disease might lead to a greater reduction of CV risk than in people with more advanced type 2 diabetes.
However, the authors of this study have questioned whether 5 years is long enough to show a difference between treatment approaches as the event rate was lower than expected and the event rates appeared to diverge after 4 years follow-up. In addition, usual management of type 2 diabetes has improved with time and this is likely to have narrowed the actual differences between the two interventions as the study progressed. As mentioned in the accompanying editorial, by the end of the trial, the treatment groups were similar in terms of allocated treatments such as statins, and the reductions in smoking were similar. The GP surgeries involved were motivated to participate in the study and, therefore, their routine care might not represent routine care elsewhere.
This study does not give any information on the effect of early intensive multifactorial treatment on microvascular outcomes, apart from amputation, which was not reported as a first event in anyone. However, the authors are analysing the data to assess microvascular endpoints, as well as quality of life, functional status and health service costs.
An advantage of the approach considered in this study, is that is specifically focussed on a global/multifactorial approach to managing type 2 diabetes, rather than just one intervention. This is in line with NICE guidance on type 2 diabetes which recommends a multifactorial, but a more individualised, rather than intensive, approach to management, addressing lifestyle issues, blood glucose, BP and blood lipids. For example, when managing blood glucose, individual targets for HbA1c should be agreed with each individual patient, taking into account the patient’s own preferences for care and the balance of likely benefits and harms. Also, the targets for blood glucose, BP and lipids adopted by this study in the intensive treatment arm were generally more intensive than those currently recommended by NICE for patients with type 2 diabetes (MeReC Rapid Review No. 2726) have found that although more-intensive blood glucose control does have some CV benefit, it does not reduce mortality and it increases the risk of severe hypoglycaemia. Observational data has also shown that reducing HbA1c levels too low may actually increase mortality (particularly when treatment is intensified with insulin). A large retrospective cohort study by Currie CJ, et al (see MeReC Rapid Review 1017) identified a ‘U-shaped’ relationship between HbA1c levels and mortality in type 2 diabetes. It found that an HbA1c of about 7.5% (59mmol/mol) was associated with the lowest risk of all-cause mortality, with higher or lower levels associated with greater risk. MeReC Bulletin Vol 21 No 5 discusses how best to manage blood glucose in the overall context of preventing both macrovascular and microvascular diabetic complications in detail.
The ACCORD BP and lipid trials add to the message regarding glycaemic control, that over-intensification of treatment in type 2 diabetes provides limited or no overall benefit, and may increase the risk of adverse events. The ACCORD BP study conducted in patients with type 2 diabetes at high risk for CV disease found that intensive BP control to a target systolic blood-pressure of 120mm Hg, as compared with a target of 140mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major CV events. However, there were significantly more serious adverse events attributed to antihypertensive treatment in the intensive-therapy group compared with the standard-therapy group; NNH 50 over 5 years (see MeReC Rapid Review No 1296).
The ACCORD lipid trial in patients with type 2 diabetes concluded that intensifying lipid modification therapy through combination use of fenofibrate and simvastatin (at a daily dose of 40mg or less) did not reduce the rate of fatal CV events, non-fatal myocardial infarction or stroke, as compared with simvastatin alone (see MeReC Rapid Review No.1306).
In conclusion, as the authors of this study point out, the extent to which the complications of type 2 diabetes can be reduced by earlier detection and treatment remains uncertain. Further study is needed to determine whether screening patients for type 2 diabetes and early intensive multifactorial management is beneficial and NICE guidance on type 2 diabetes should continue to be followed.
Study details –
Griffin SJ, et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial. Lancet 2011;378:156–67
Consisted of two phases: a screening phase and a pragmatic, cluster-randomised, parallel-group trial.
Aged 40 to 69 years (50 to 69 years in the Netherlands) from 343 general practices in Denmark, the Netherlands, and the UK (Cambridge and Leicester) without known type 2 diabetes were screened. 3,057 (of 3,233 patients identified with type 2 diabetes) agreed to take part in the RCT.
Intervention and comparison
Initial screening phase between April 2001 and December 2006: included calculation of a risk score for type 2 diabetes (using information from medical records in Cambridge, or from self-completed questionnaires in Denmark and the Netherlands), followed by capillary glucose testing. In Leicester, patients were invited for an oral glucose tolerance test, without previous risk assessment.
Practices were randomly assigned to provide routine diabetes care (1,379 patients) or intensive multifactorial treatment (1,678 patients). Intensive treatment was added to usual care and promoted to participating practices by educational meetings. This included management of HbA1c, blood pressure and cholesterol to intensive targets, and prescription of aspirin in patients without contraindications receiving antihypertensives (see table below).
A summary of intensive multifactorial treatment
|Treatment target||Treatment threshold||Approach at baseline if threshold passed||Action at each of 3 reviews (see paper for specific detail)|
|HbA1c||<7.0%||>6.5%||Diet||Prescribe metformin and increase dose or add further hypoglycaemics if value > threshold|
|BP||<135/85 mmHg*||>120/80 mmHg||If CVD+, prescribe an ACE inhibitor titrated to maximum dose||Add further antihypertensives if value > target|
|Total cholesterol without IHD||<5.0 mmol/L||>3.5 mmol/L||Prescribe a statin||Increase dose and consider adding fibrate if value > target|
|Total cholesterol with IHD||<4.5 mmol/L||>3.5 mmol/L||Prescribe a statin||Increase dose and consider adding fibrate if value > target|
|Aspirin**||None||None||75 to 80mg daily||75 to 80mg daily|
CVD+= CV event or presence of CV risk factor other than diabetes
*<130/80 mmHg in the Leicester cohort
** All patients receiving antihypertensives and without specific contraindications
IHD= ischaemic heart disease
Outcomes and results
The primary endpoint was a composite of first CV event, including CV mortality, CV morbidity (non-fatal MI and non-fatal stroke), revascularisation and non-traumatic amputation over 5 years. There was no statistically significant difference between routine care and intensive treatment (8.5% versus 7.2%; HR 0.83, 95%CI 0.65 to 1.05%; p=0.12). Neither were there any statistically significant differences in the individual constituents of the primary endpoint (secondary endpoints). The HRs favoured intensive treatment but the 95%CIs crossed one. No amputations were reported as a first event in any group. Small but statistically significant reductions from baseline in HbA1c (mean -0.08%, 95%CI -0.14 to -0.02), systolic BP (-2.86 mmHg, 95%CI -4.51 to -1.20), diastolic BP (-1.44 mmHg, 95%CI -2.30 to -0.58), total cholesterol (-0.27 mmol/L, 95% CI -0.34 to -0.19) and LDL-cholesterol (-0.20 mmol/L, 95%CI -0.26 to -0.13) in favour of intensive treatment were seen at 5 years. No statistically significant differences were seen between groups in the proportion of patients reporting hypoglycaemia in a questionnaire.
Supported by unrestricted grants from several drug companies and health organisations in the UK, Denmark and the Netherlands.
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