The value of early detection of type 2 diabetes remains controversial because of a lack of an established evidence base. Randomized trials have established the benefits of interventions to prevent or delay diabetes [1,2] and reduce diabetes-related complications . However, no randomized controlled trial has established the benefit of early detection of diabetes, although one, the Anglo-Danish-Dutch Study of Intensive Treatment and Complication (ADDITION) study (ClinicalTrials.gov identifier: NCT00237549) [4••], is currently in progress. This article reviews the value of early detection of type 2 diabetes from the perspective of potential benefits and harms to the individual, and also from the perspective of the health system.
Case detection can be justified if a disease represents an important health problem, is present at a high enough prevalence within the target population, has a relatively long asymptomatic phase, interventions are available that have a proven beneficial effect on clinically meaningful outcomes and the test procedures are safe, acceptable and have adequate sensitivity and specificity. Ideally, any case detection program should be assessed in randomized controlled trials measuring health outcomes and costs in screened and unscreened populations. In the absence of such information, case finding is considered worthwhile if all or most of the above requirements are fulfilled. As discussed below, diabetes fulfils most of the above criteria.
Diabetes is clearly an important global health problem. It was estimated to affect 246 million people worldwide (6.0% of the population) in 2007, with 380 million people (7.3% of the population) expected to have diabetes in the year 2025 . Diabetes was responsible for an estimated 3.8 million deaths globally (∼6% of total world mortality) in adults aged 20–79 years in 2007, with over two-thirds of the diabetes-attributable deaths occurring in developing countries. The estimated cost of treatment and prevention of diabetes and its complications worldwide in 2007 was US$232 billion, which is expected to rise to US$302.5 billion in 2025.
Worldwide, approximately 50% of all people with diabetes are undiagnosed . Undiagnosed diabetes is associated with increased risk of death. For example, the Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study on over 25 000 people from a range of European countries  showed that during a mean follow-up of 7.3 years, the hazards ratio for death for people with type 2 diabetes diagnosed through a case detection program was approximately two compared with people with normal glucose tolerance. The Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Asia (DECODA) study  similarly reported increased cardiovascular mortality in people with screen-detected diabetes over a mean 5.9-year period. This adverse outcome may be modulated by age at diagnosis of diabetes. Barnett et al.  performed a systematic review of observational studies reporting all-cause mortality in people with type 2 diabetes diagnosed after age 60 years. The combined relative risk [95% confidence interval (CI)] of increased mortality for men diagnosed between the ages of 60 and 70 was 1.38 (1.08–1.76), and 1.13 (0.88–1.45) for men diagnosed aged 70 years or older. For women in the same age groups, the combined relative risks were 1.40 (1.10–1.79) and 1.19 (0.93–1.52), respectively.
Complications are commonly present at the time of diagnosis of type 2 diabetes. The Australian Diabetes, Obesity and Lifestyle (AusDiab) study found that in people with newly diagnosed diabetes, the prevalence of retinopathy was 6.2%, peripheral neuropathy 7.1%, peripheral vascular disease 6.9% , while 10.6% had microalbuminuria and 2.0% had macroalbuminuria . Other studies have reported higher rates. Spijkerman et al.  found retinopathy in 7.6% of people with screen-detected diabetes, impaired foot sensitivity in 48.1% and microalbuminuria in 17.2%. Macrovascular complications were also common with the prevalence of myocardial infarction being 13.3%, ischemic heart disease 39.5% and peripheral arterial disease 10.6% .
Studies that have examined the relationship of diabetes complications and the diagnosis of diabetes indicate that type 2 diabetes commonly has a lengthy asymptomatic phase. On the basis of extrapolations of prevalence of retinopathy plotted against duration of diabetes, Harris et al.  estimated that undiagnosed diabetes may exist for as long as 12 years before clinical diagnosis.
Value to the individual
The major unanswered question for case detection in diabetes is whether early intervention in people with screen-detected diabetes is beneficial. It is well established that improving metabolic control in people with newly diagnosed type 2 diabetes improves outcomes [3,14]. However, there are no reported randomized controlled trials on the effects of early intervention in people with screen-detected diabetes. One such study, the ADDITION study, is in progress and is examining cardiovascular and microvascular outcomes of intensive treatment, 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, compared with conventional treatment according to local and national guidelines in people with screen-detected diabetes [4••]. The study includes 3233 people aged 40–69 years with screen-detected diabetes who are being followed up over 5 years and the study findings are due to be reported in 2010 [15••].
Case–control studies have also examined this question of benefits from early detection. A 10-year retrospective examination of health maintenance administrative data suggested that diabetes detected through screening was associated with a 13.0% reduction in the risk of complications compared with routine diagnosis (hazard ratio 0.87, 95% CI 0.38–1.98); however, this difference was not statistically significant . Another study examined outcomes in 488 people with diabetes detected by glycosuria screening compared with people with conventionally diagnosed diabetes. Over 12 years, loss of life years compared with age-matched and sex-matched controls was 1.96 years for screen-detected diabetes and 3.42 years for conventionally diagnosed diabetes (P <0.05) .
Colagiuri et al.  performed a post-hoc analysis of the 5102 United Kingdom Prospective Diabetes study (UKPDS) participants with newly diagnosed type 2 diabetes. The cohort was divided into three groups based on their fasting plasma glucose (FPG) at presentation – low FPG group (FPG <7.8 mmol/l), intermediate FPG group (FPG 7.8 to <10 mmol/l) and high FPG group (FPG ≥10 mmol/l). The high FPG group was estimated to have developed diabetes approximately 5 years earlier and the intermediate group 2–3 years earlier than the low FPG group. Over the following 10 years, the high FPG group had significantly worse outcomes for all-cause mortality, diabetes-related deaths, myocardial infarction and microvascular complications compared with the low FPG group. The intermediate FPG group had significantly increased diabetes-related deaths and myocardial infarction compared with the low FPG group. If the assumptions of differences in duration of diabetes are correct, these data support an earlier diagnosis of type 2 diabetes being associated with improved outcomes.
Modeling has also been used to estimate the benefits of earlier diagnosis of diabetes. Attributable fraction estimates in a white male US cohort aged 45–74 years with clinically or screen-detected diabetes indicate that 20.2% of all-cause deaths and 35.7% of cardiovascular disease (CVD) deaths are attributable to delayed diagnosis of type 2 diabetes . Furthermore, population attributable risk calculations indicate that early detection and standard therapy (assuming 100% implementation and compliance) could reduce all-cause mortality and CVD mortality by 3.5 and 7.1%, respectively. Early detection and intensive therapy could reduce all-cause mortality and CVD mortality by 5.9 and 8.6%, respectively. Using a Markov chain model, Kuo et al.  assessed the efficacy of screening for type 2 diabetes in Taiwan. The model estimated that the average time between asymptomatic and symptomatic phases of type 2 diabetes was 8 years and that the 10-year survival rate for people with diabetes detected during the asymptomatic phase was 79.4%, compared with 69.5% in those with symptomatic type 2 diabetes.
Most modeling studies presume a beneficial effect of improving blood glucose control. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (ClinicalTrials.gov identifier: NCT00000620) , involving 10 251 participants (mean age 62 years; median duration of diabetes 10 years; median HbA1c 8.1%) with type 2 diabetes, recently reported a higher mortality in the intensively treated group (targeting HbA1c below 6.0%) compared with the standard treatment group (targeting HbA1c 7.0–7.9%; hazards ratio 1.22; 95%CI 1.01–1.46; P = 0.04). These results are the first to identify possible harm associated with intensive glucose lowering in high-risk people with type 2 diabetes. However, these findings were not observed in two other recent similar studies [22,23] or in the one long-term study on people with newly diagnosed diabetes .
It should be noted that screening for undiagnosed type 2 diabetes will also identify people with impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), conditions associated with increased risk of progression to diabetes and increased morbidity and premature mortality, predominantly due to cardiovascular complications . It is now well established that progression to diabetes in these people can be prevented or delayed through lifestyle modification or with a number of pharmacological agents [1,2,25–32]. Therefore, identification of people with IGT or IFG provides an opportunity to implement interventions to decrease the risk of developing diabetes.
Screening for undiagnosed diabetes is generally considered to be safe. Most screening procedures begin with a risk assessment that relies on routinely collected demographic and clinical examination information followed by blood testing in high-risk individuals [33,34]. There are also well established and accepted diagnostic criteria for making a diagnosis of type 2 diabetes .
However, there are some potential deleterious effects of screening. A diagnosis of type 2 diabetes results in the initiation of a variety of treatments (dietary, counseling and possibly medication) and follow-up visits to health professionals. If medications are used, there is the possibility of side effects. On the other hand, screening may result in a false negative result and failure to appropriately treat a person who has diabetes but in whom the diagnosis is missed.
A diagnosis of diabetes has potential implications for employment and personal insurance. Treatment with certain medications, especially insulin, precludes certain forms of employment and insurance premiums for people with diabetes are invariably higher than in people without diabetes. However, there is little evidence that people with screen-detected diabetes experience adverse effects of labeling . In 1253 patients aged 45–64 years, there were no differences in quality of life at baseline or 1 year after screening between people with screen-detected diabetes and those without diabetes.
Perhaps the greatest concern is the false positive result and the anxiety that this may cause in the interval between the initial screening test and the diagnostic test. A recent review assessed the psychological impact of screening for type 2 diabetes and concluded that screening in the general population has no serious psychological side effects, and that a diagnosis of type 2 diabetes has no substantial effect on perceived health status and well being . Eborall et al. [37•] reported that a stepwise approach to screening for type 2 diabetes facilitated psychological adjustment, with perceptions changing as people progressed through the screening program. A randomized controlled study of 7380 people aged 40–69 years in the top 25% for risk of having type 2 diabetes [38•] showed no difference in psychological parameters (state anxiety, anxiety, depression, diabetes-specific worry and self-rated health) at 3–6 months and 12–15 months postscreening in those invited for screening and a control group which was not screened. Anxiety and beliefs related to screening for type 2 diabetes were assessed in a cohort of 1339 UK participants aged 25–75 years at high risk of developing diabetes from the Screening Those at Risk (STAR) study . The study found that screening for type 2 diabetes did not cause significant anxiety.
Value to the health system
Cost and cost-effectiveness are of primary concern when assessing value to the health system. In general, the cost of detecting undiagnosed diabetes through opportunistic screening is low but is dependent on the screening protocol. Screening procedures that use routinely available information to identify people at high risk of diabetes or are linked to other screening programs (e.g. screening for glucose and lipids on the same fasting blood sample as part of a cardiovascular screening program) are usually low cost . For example, the Australian screening protocol that involves an initial risk assessment, measurement of FPG in individuals at risk and further testing of people with an equivocal result costs US$530 per case of newly diagnosed diabetes . Another recent study  simulated screening in a US population of people aged 45–74 years over a 15-year period. Opportunistic screening every 3 years costs US$275 per case of detected diabetes.
A diagnosis of diabetes is associated with increased costs to the health system. Gulliford et al.  examined the effect of a clinical diagnosis of type 2 diabetes on healthcare utilization in the UK in 4974 people with type 2 diabetes and 9948 matched people without diabetes. A substantial increase in health-care utilization was observed following a diagnosis of diabetes, with primary care consultations increasing four-fold, specialist referrals three-fold, medications 2.5-fold and emergency and hospital care 2.5-fold. Following diagnosis, health-care utilization increased six-fold for acute myocardial infarction, five-fold for cerebrovascular disease and five-fold for peripheral nerve disorders.
As there are no definitive outcomes studies on the effectiveness of early intervention in people with screen-detected diabetes, there can be no definitive statement of its cost-effectiveness . However, a number of models have been developed to address this issue. The outcomes of modeling are dependent on the model structure and assumptions, particularly the estimated clinical benefits of the modeled scenario.
Consensus indicates that interventions having cost-effectiveness ratios less than US$20 000 per quality-adjusted life year (QALY) should be readily adopted, those having ratios between US$20 000 and US$100 000 per QALY are usually provided and those with ratios greater than US$100 000 per QALY have weak evidence for adoption . Engelgau et al.  used the US Centers for Disease Control and Prevention (CDC) model to review screening for type 2 diabetes compared with screening for other conditions and concluded that diabetes screening is less favorable than some and more favorable than others. Clinic-based opportunistic screening for undiagnosed diabetes cost US$56 649 per QALY compared with US$150 000 per QALY for screening for breast cancer and US$16 000 per QALY for screening for colon cancer in people aged 50–75 years.
A recent study in the UK [46•] examined the cost-effectiveness of four potential screening and treatment strategies for type 2 diabetes in a hypothetical cohort of adults aged 45 years with above average risk of diabetes. Compared with no screening, the cost per QALY gained for screen-detected diabetes was US$20 475.
The Australian Diabetes Cost-Benefit model was developed to estimate the health benefits and costs associated with a national diabetes screening and prevention program among Australians aged 45–74 years [47•]. Screening for undiagnosed diabetes in Australians aged 55–74 years and in those aged 45–54 years who were obese (BMI ≥30 kg/m2), had a family history of diabetes or had hypertension was modeled and resulted in a cost per disability-adjusted life year (DALY) of US$35 580.
There are many reasons why the earlier detection of diabetes could be beneficial. For the individual, there is the potential for early intervention to treat not only the hyperglycemia but also the commonly observed accompanying abnormalities of risk factors for CVD. The magnitude of the potential benefit of early detection and treatment has yet to be quantitated in a randomized controlled trial and this information will be available in 2010 when the ADDITION study reports its findings. Any improvement in outcomes in people with screen-detected diabetes will also benefit society in general through a reduction in the utilization of expensive health resources, especially hospitalizations for potentially avoidable complications. Case detection of undiagnosed diabetes is generally low cost and affordable but definitive cost-effectiveness calculations must await the results of outcome studies.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 193–194).
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