Screening for type 2 diabetes

Systematic screening for type 2 diabetes aims to identify people in the general population who have undiagnosed diabetes, based on the premise that earlier treatment may help prevent or delay the onset of diabetic complications. Screening may also extend to people at high risk of developing diabetes or be linked to cardiovascular risk assessment. Many schemes use a two-step strategy in which a preliminary risk evaluation is followed by diagnostic testing in those who score positive. Diabetes screening programmes should be evaluated within a local context, since the cost-benefit ratio may vary from one setting to another. Current evidence on screening, obtained in countries with highly organised healthcare systems, shows this to be feasible in primary care and not to induce long term harm. Intensive treatment of people with screen-detected diabetes improves risk factor management, but there is no evidence that long-term outcomes are affected; a large UK randomised controlled trial found that screening in high risk patients did not affect all-cause, cardiovascular, or diabetes-related mortality over 10 years. Type 2 diabetes meets many of the criteria for screening, but there is currently little justification for screening at the population level.

## Introduction

The justification for screening in any disease rests upon certain standard criteria. These relate to the nature of the condition, the quality of the test, the availability of effective treatment, and evidence that a screening programme is effective and cost-effective. This article summarizes evidence from the diabetes screening literature as judged against the most recent UK National Screening Committee (NSC) criteria[1].

There are many different approaches to screening. At present, diabetes screening around the world is largely opportunistic; i.e. health services are invited to check everyone in certain age groups or risk categories who comes their way for diabetes, but few if any health services currently set out to apply systematic screening to the entire adult population.

Most studies into the value of screening have been carried out in well-developed health care settings in which baseline awareness of and care for diabetes is already relatively high. In other health care settings, especially where resources are limited, different cost and benefit ratios apply: it might for example be more cost-effective to channel resources towards improving care for known patients within the system rather than simply increasing the workload.

Evidence summarized in this overview page of Diapedia shows that type 2 diabetes satisfies most of the formal criteria for a disease for which screening is justified. Notwithstanding, there is still little or no evidence that implementation of screening programmes can change the natural history of diabetes. This paradox is outlined here and explored in more detail in the daughter pages that follow.

Criteria for Screening

1. The Condition

  • "The condition should be an important health problem"

    The International Diabetes Federation estimates that 285 million people around the world have diabetes, and this figure is expected to rise to 439 million within 20 years. The condition is frequently asymptomatic, with the true onset occurring several years before diagnosis. While detection of the condition may be improving, around 30–50% of people with diabetes remain undiagnosed, and when patients are diagnosed, around 20–30% have evidence of diabetic complications. This suggests a potential window for earlier detection and treatment. Diabetes is undoubtedly an important health problem.

  • "The epidemiology and natural history of the condition, including development from latent to declared disease, should be adequately understood and there should be a detectable risk factor, disease marker, latent period or early symptomatic stage".

The risk factors for type 2 diabetes are well established, glucose and cardiovascular risk markers are well understood, and type 2 diabetes is typically preceded by years of asymptomatic hyperglycaemia. These criteria are therefore satisfied.

  • "All available cost-effective primary prevention interventions should have been implemented as far as practicable".

Elements of a national plan for diabetes have been in place for several years, including guidelines by the National Institute for Health and Clinical Excellence (NICE), and financial incentives to primary care physicians to screen and treat diabetes more actively. This suggests that primary care interventions in the UK have been implemented. To take one example, recent work suggests that the yield of treatable retinopathy in newly diagnosed patients within the existing system is already too low to justify more aggressive screening[2].

2. The Test

  • "There should be a simple, safe, precise and validated screening test".

There are a number of screening tests which are acceptable to those undergoing screening and have reasonable performance when evaluated against recommended diagnostic criteria. These include random glucose, fasting glucose, the glucose challenge test, 2-h post-challenge glucose and postprandial urine testing. The blood tests can be carried out using capillary finger-pricks or venous samples; they can be analysed in local laboratories or by near-patient testing. More recently, the WHO has recommended that HbA1c can be used as a diagnostic test for type 2 diabetes, with a cut-off value of ≥6.5%[3]. This simple, safe and validated test has already been used in large-scale screening programmes, although there are concerns over standardization and cost, and also performance in populations with a high prevalence of haemoglobinopathies. Furthermore, the correlation between glucose and glycated haemoglobin measures is not always good.

An example of a patient questionnaire - The Finnish Diabetes Risk Score
An example of a patient questionnaire - The Finnish Diabetes Risk Score
Risk factor questionnaires and risk scores generated from routinely available data are increasingly being used to stratify populations before inviting those at high risk to attend for blood glucose testing.

  • "The distribution of test values in the target population should be known and a suitable cut-off level defined and agreed".
  • "The test should be acceptable to the population".
  • "There should be an agreed policy on the further diagnostic investigation of individuals with a positive test result and on the choices available to those individuals".

Both glucose and glycated haemoglobin are well validated measures, and both represent a considerable deviation from the range seen in health, with a low risk of false positives (except possibly in the elderly). Choice of test is altogether more problematic when different measures are used to establish a diagnosis of "high risk of diabetes". These concerns apart, screening tests for diabetes itself are simple, well accepted and well validated, as is the subsequent diagnostic and treatment pathway. This criterion is therefore satisfied.

3: The Treatment

  • "There should be an effective treatment or intervention for patients identified through early detection, with evidence of early treatment leading to better outcomes than late treatment".

Some difficulties arise at this point. Diabetes is associated with multiple adverse outcomes, and screening programmes need to define which outcomes they are seeking to prevent, and which intervention is effective in preventing which outcome. The overall aim is typically to reduce diabetes-associated cardiovascular risk, since this is the leading cause of premature death and disability in this population.

Glucose is a good marker of cardiovascular risk, but other screening measures (BP, lipids) are also effective, and lead on to interventions that reduce cardiovascular risk more effectively than glucose lowering therapy. Screening programmes may address this issue by simultaneous evaluation and treatment of multiple risk factors. The cardio-protective effects of intensive reduction of blood pressure and cholesterol are well-demonstrated in individuals with established diabetes, as is treatment with aspirin for secondary prevention of CVD. Multifactorial treatment, encompassing blood pressure, glucose and cholesterol lowering, alongside behaviour modification, has sustained beneficial effects with respect to vascular complications and on rates of all-cause and cardiovascular death[4].

A further limitation of screening for diabetes as a means of cardiovascular risk reduction is that the diagnostic threshold for diabetes was defined in terms of threshold risk for retinopathy and (by implication) other microvascular complications. It was not designed as a cut-off for cardiovascular risk, and the association between glycaemia and cardiovascular disease (CVD) risk is continuous and extends well into the non-diabetic population[5]. Since most excess CVD is contributed by the large group of hyperglycaemic patients who fall below the threshold for diabetes, rather than the smaller number above it[6], screening for diabetes itself will miss a high proportion of the at-risk population.

Last but not least, a series of large prospective trials has failed to demonstrate that intensified glucose-lowering therapy, which is often invasive and unwelcome to older patients, brings measurable benefit in terms of cardiovascular mortality, overall mortality or quality of life. The evidence is more encouraging when tight glycaemic control is achieved early in the course of type 2 diabetes. Thus, the initial report from the UK diabetes prospective study (UKPDS) showed benefit from improved control with respect to microvascular and non-vascular complications such as cataracts and neuropathy, but the results were equivocal in terms of cardiovascular end-points[7][8].

Longer term follow-up after completion of the trial demonstrated reduced CVD risk [9], however, and is supported by subgroup analyses of the ACCORD, ADVANCE and VADT trials. These suggest that the benefits of glucose control upon CVD risk can be demonstrated in the recently diagnosed, whereas intensive treatment later in the disease course has not been associated with useful benefit.

  • "There should be agreed evidence based policies covering which individuals should be offered treatment and the appropriate treatment to be offered".

The Anglo-Danish-Dutch Study of intensive treatment of people with newly diagnosed diabetes in primary care (ADDITION) is the only trial of early intensive treatment among individuals with screen-detected diabetes [10]. The study consists of a screening phase followed by a pragmatic open-label cluster randomised controlled trial comparing the effect on cardiovascular risk of intensive multifactorial therapy with standard care. Data from the ADDITION trial show that people with screen-detected diabetes exhibit an adverse but potentially modifiable cardiovascular risk profile at diagnosis. At five years, intensive treatment was associated with slightly, but significantly increased prescription of treatments and improvements in cardiovascular risk factors [11]. There was a non-significant relative reduction in the incidence of cardiovascular events at (HR 0.83, 95% 0.65 to 1.05). The lower-than-expected event rate suggests that five years of follow-up may be an insufficient time period in which to establish a cardiovascular benefit of early treatment. Further follow-up is needed to test whether early intensive multifactorial treatment reduces cardiovascular risk in the long term, as seen in the UKPDS study [9].

  • "Clinical management of the condition and patient outcomes should be optimised in all health care providers prior to participation in a screening programme".

Another prerequisite for screening is that the clinical management of the condition and patient outcomes should be optimised by all health care providers prior to participation in a screening programme. While much progress has been made in improving care for those with diabetes in the developed world, suboptimal care persists. Given that an effective screening programme will increase the demand for diabetes care, it is clear that further work is needed to optimise clinical care before national screening programmes are introduced. Furthermore, in some countries, there are an overwhelming number of people with poorly treated diabetes. Primary and tertiary prevention strategies may be a more appropriate use of scarce health resources than screening in these settings.

4. The Screening Programme

(The full set of criteria will not be considered here - see daughter section on "Screening: the programme" for full details)

  • "There should be evidence from high quality Randomised Controlled Trials that the screening programme is effective in reducing mortality or morbidity".

Modelling studies suggest that a programme of screening for diabetes would reduce both diabetes-related and overall mortality, but a pragmatic parallel group, cluster-randomised trial of 33 general practices in eastern England found that screening for type 2 diabetes in those at high risk did not result in a reduction in all-cause, cardiovascular, or diabetes-related mortality over 10 years[12]. This critical screening criterion has therefore not been satisfied.

  • "There should be evidence that the complete screening programme (test, diagnostic procedures, treatment/ intervention) is clinically, socially and ethically acceptable to health professionals and the public".

The ADDITION-Cambridge study suggests that primary care staff and patients find it feasible and acceptable to screen for type 2 diabetes in general practice using a two-step procedure [13]. Screening required individual explanations, advice on health-related behaviours and appropriate follow-up. However, it should be noted that few participants were diagnosed with diabetes, even in the high-risk groups identified in these programmes. In ADDITION-Cambridge, some groups were hard to reach, with lower uptake in deprived areas and among males and the obese, and attendance at the first screening stage did not ensure completion of the programme.

  • "The benefit from the screening programme should outweigh the physical and psychological harm (caused by the test, diagnostic procedures and treatment)".

Potential harms, both direct and indirect, must be considered before implementing a large-scale screening programme. A small harm to the majority who tests negative could outweigh a large benefit to the minority whose diabetes is detected by screening. Almost all studies have however found that screening for type 2 diabetes in the general population is associated with limited psychological adverse effects. In a controlled trial of the psychological impact of stepwise screening for diabetes among 7,380 participants in the ADDITION-Cambridge trial, anxiety, depression, worry about diabetes and self-rated health were not significantly different in participants invited to screening and those not invited (controls) shortly after screening and 3–6 and 12–15 months later[14].

  • "The opportunity cost of the screening programme (including testing, diagnosis and treatment, administration, training and quality assurance) should be economically balanced in relation to expenditure on medical care as a whole (ie. value for money)".

Modelling studies have suggested that a programme of screening for diabetes every 4–5 years would be associated with a reduction in diabetes-related mortality of the order of 26–40%[15][16]. Kahn et al assessed the cost-effectiveness of eight simulated screening strategies compared to a no-screening control strategy using the Archimedes model[17]. Compared with no screening, all simulated screening strategies reduced the incidence of myocardial infarction and diabetes-related microvascular complications and increased the number of QALYs added over 50 years. Although encouraging, modelling studies are only as robust as their underlying assumptions, and cannot substitute data from long-term RCTs. If screening for diabetes is to be undertaken, it should be as part of a wider strategy to prevent both diabetes and CVD and include assessment of CVD risk factors other than just glucose.

  • "Evidence-based information, explaining the consequences of testing, investigation and treatment, should be made available to potential participants to assist them in making an informed choice".

The DICISION trial examined the impact of an informed choice invitation compared to a standard invitation on uptake of diabetes screening in primary care [18]. An ‘informed choice’ invitation did not reduce overall attendance or affect attendance differentially by social class. These findings suggest that there is no reason not to provide full information on the pros and cons of diabetes screening, especially in view of recent scepticism about the net benefits of established mammographic screening programmes for breast cancer. With regard to the remaining NSC criteria outlined above, there is little current evidence to inform these criteria.

The pros and cons of screening are discussed in more detail in the following sections of Diapedia..

References

  1. ^ National Screening Committee. http://www.screening.nhs.uk/criteria. 2010 [19/03/2010]

  2. ^ Looker HC et al. Diabetic retinopathy at diagnosis of type 2 diabetes in Scotland. Diabetologia. 2012;55(9):2335-42. Epub 2012/06/13

  3. ^ WHO. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Abbreviated report of a WHO consultation. Geneva: 2011

  4. ^ Gaede P et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580-91

  5. ^ Levitan EB et al. Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A meta-analysis of prospective studies. Arch Intern Med. 2004;164(19):2147-55

  6. ^ Rose G. Sick individuals and sick populations. Int J Epidemiol. 1985;14(1):32-8

  7. ^ UKPDS. 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. Lancet. 1998;352(9131):837-53

  8. ^ UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854-65

  9. ^ Holman RR et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-89

  10. ^ Lauritzen T et al. The ADDITION study: proposed trial of the cost-effectiveness of an intensive multifactorial intervention on morbidity and mortality among people with Type 2 diabetes detected by screening. Int J Obes Relat Metab Disord. 2000;24 Suppl 3:S6-11.

  11. ^ 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(9786):156-67

  12. ^ Simmons RK et al. Screening for type 2 diabetes and population mortality over 10 years (ADDITION-Cambridge): a cluster-randomised controlled trial. Lancet. 2012;380(9855):1741-8. Epub 2012/10/09

  13. ^ Graffy J et al. More than measurement: practice team experiences of screening for type 2 diabetes. Fam Pract. 2010;27(4):386-94

  14. ^ Eborall HC et al. Psychological impact of screening for type 2 diabetes: controlled trial and comparative study embedded in the ADDITION (Cambridge) randomised controlled trial. Bmj. 2007;335(7618):486

  15. ^ Kuo HS et al. A Markov chain model to assess the efficacy of screening for non-insulin dependent diabetes mellitus (NIDDM). Int J Epidemiol. 1999;28(2):233-40

  16. ^ Chang HJ et al. Evaluation of a population-based screening for type 2 diabetes: a community-based screening project in Puli, Taiwan. Prev Med. 2000;31(4):396-402

  17. ^ Kahn R et al. Age at initiation and frequency of screening to detect type 2 diabetes: a cost-effectiveness analysis. Lancet. 2010;375(9723):1365-74

  18. ^ Mann E et al. Impact of an informed choice invitation on uptake of screening for diabetes in primary care (DICISION): trial protocol. BMC Public Health. 2009;9:63

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