follow-up data from the UKPDS reported reduction in both microvascular and macrovascular complications in the intensive treatment arm. 11 A meta-analy

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1 COMMENTARY SCREENING FOR TYPE 2 DIABETES MELLITUS Back to Wilson and Jungner: 10 Good Reasons to Screen for Type 2 Diabetes Mellitus ANN M. SHEEHY, MD, MS; DOUGLAS B. COURSIN, MD; AND ROBERT A. GABBAY, MD, PHD The US Preventive Services Task Force (USPSTF) operates under the Agency for Healthcare Research and Quality, one of 11 divisions of the US Department of Health and Human Services. A panel of preventive medicine and health care experts, the USPSTF reviews existing literature and evidence to make recommendations regarding preventive care measures. 1 Primary care practitioners rely on such guidelines to make medical decisions, and insurance companies and government agencies use this information to determine payment for services rendered and for credentialing of institutions. Recently, the USPSTF updated its guidelines on screening adults for type 2 diabetes mellitus 2,3 (Table 1). 4 This report was based on a literature review of the existing data in both MEDLINE and the Cochrane Library databases. Members of the USPSTF concluded that screening for diabetes in asymptomatic individuals with hypertension (blood pressure >135/80 mm Hg) was merited. Unfortunately, they did not recommend or highlight the importance of screening other at-risk populations who would be screened under the American Diabetes Association (ADA) guidelines, citing lack of direct or indirect evidence supporting population screening. 2 However, the authors acknowledge that direct evidence, such as a randomized trial that compared treated vs untreated persons in whom screening detected diabetes, will not be available because withholding treatment from persons with known diabetes is unethical. The ADA also concluded that a study of this type is unlikely to occur and developed guidelines based on existing data and expert opinion that recommend screening for diabetes mellitus in a much wider population because of the epidemic in the United States. 4 In addition, the criteria used to develop these new USPSTF recommendations have been a subject of interest. Although USPSTF states its guidelines are based on explicit criteria, 1 experts have questioned its more restrictive screening criteria used to develop its diabetes screening From the Department of Medicine (A.M.S., D.B.C.) and Department of Anesthesiology (D.B.C.), University of Wisconsin School of Medicine and Public Health, Madison; and Penn State Diabetes and Obesity Institute, Penn State College of Medicine, Hershey, PA (R.A.G.). Individual reprints of this article are not available. Address correspondence to Ann M. Sheehy, MD, MS, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, H6/169, Madison, WI (asr@medicine.wisc.edu) Mayo Foundation for Medical Education and Research guidelines compared with that used for another chronic disease, obesity. 5 This query has merit considering the impact USPSTF guidelines have on population health. Clearly, screening for disease must meet certain criteria to be medically and financially acceptable. Perhaps the most recognized criteria were determined by Wilson and Jungner 6 in These principles (Table 2), which the World Health Organization follows, define the basis of preventive medicine 40 years later and are largely considered the standards by which screening tests are judged and determined. Because of the potential far-reaching implications of the new USPSTF guidelines, it is important to examine the merits of diabetes screening using the 10 criteria of Wilson and Jungner since national screening recommendations profoundly affect health care delivery and outcomes. IMPORTANT HEALTH PROBLEM Diabetes mellitus has reached epidemic proportions, and the number of people with this condition continues to increase. The National Health and Nutrition Examination Survey identified 9.3% of the US population 20 years or older (19.3 million people) as having diabetes, with approximately two-thirds diagnosed as having diabetes and one-third not diagnosed. An additional 26.0% of the population had impaired fasting glucose (IFG), making the burden of disease estimate at 73.3 million people. 7 A predicted 48.3 million people in the United States will have diabetes by 2050, 8 with a lifetime risk of disease being 32.8% and 38.5%, respectively, for US males and females born in Estimated quality-adjusted life years lost in men and women diagnosed as having diabetes at age 50 years is 14.5 and 18.0 years, respectively, with greater years lost at younger age of diagnosis because such individuals have more years of life to lose. 9 ACCEPTED TREATMENT FOR RECOGNIZED DISEASE Many treatment options are available for diabetes that improve glycemic control and reduce risks of complications, particularly microvascular disease. Numerous studies have shown that treatment is effective. The UK Prospective Diabetes Study (UKPDS) found improved microvascular outcomes for patients with a hemoglobin A 1c (HbA 1c ) value of 7.0% compared with the group that had a mean HbA 1c value of 7.9%. 10 The recently published 10-year 38

2 follow-up data from the UKPDS reported reduction in both microvascular and macrovascular complications in the intensive treatment arm. 11 A meta-analysis by Selvin et al 12 found better macrovascular outcomes in patients with type 2 diabetes mellitus who achieve tighter glycemic control. These and other studies suggest improved outcomes with treatment that results in moderate reduction in HbA 1c values. Recently, the glucose arm of the Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD) 13 (a randomized controlled study that evaluated multiple cardiovascular risk factors simultaneously) was terminated early because of increased mortality in the tightly controlled group. However, the absolute HbA 1c value achieved (6.4% vs 7.5%) may be less important than the rate of change (1.4% in 4 months in the intensive group) or overall magnitude of change ( 1.9% vs 0.8%). Additionally, hypoglycemia in the intensive treatment arm may have contributed to adverse outcomes, as well as the number and/or types of medication used and amount of weight gain (27.8% vs 14.1% in the intensive vs standard therapy groups, respectively, had >10-kg weight gain). The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), 14 published in parallel to ACCORD, achieved a similar HbA 1c value (6.5%) but did so more gradually and from a lower starting point (7.5%-6.5%; 1.0). In contrast to ACCORD, AD- VANCE showed an improved combined end point of microvascular and macrovascular events in the intensive therapy arm. Given these findings, ADVANCE, as well as previous studies such as the UKPDS, still confirms benefit in reducing HbA 1c values from the higher ranges, such as from 8%, indicating mean glucose value of 183 mg/dl (to convert to mmol/l, multipy by ), to 7%, mean glucose level of 154 mg/dl. 4,15,16 Although primary care practitioners who treat patients with cardiovascular disease or those with several risk factors for cardiovascular disease should use judgment in achieving glycemic targets in light of the ACCORD data, this study should not in general discourage practitioners from recommending the current ADA target of an HbA 1c of 7.0%, as compelling data exist to support this glycemic goal. 10 AVAILABILITY OF FACILITIES FOR DIAGNOSIS AND TREATMENT General practitioners in nearly any clinic can diagnose and manage diabetes. Although access to health care and medical insurance in the United States is a problem for certain patient populations, it is not a problem specific or unique to patients with diabetes mellitus. 17 TABLE 1. ADA and USPSTF Criteria to Screen for Diabetes Mellitus a ADA 1. Testing should be considered in all adults who are overweight (BMI 25 kg/m 2 ) and have the following additional risk factors Physical inactivity First-degree relative with diabetes Member of high-risk ethnic populations Women who were delivered of a baby weighing >4.1 kg or were diagnosed as having gestational diabetes mellitus Hypertension HDL cholesterol level <35 mg/dl b or triglyceride level >250 mg/dl b Women with polycystic ovarian syndrome Impaired glucose tolerance or impaired fasting glucose on previous testing Other clinical conditions associated with insulin resistance History of cardiovascular disease 2. In the absence of the above criteria, testing for diabetes and prediabetes should begin at age 45 y 3. If results for diabetes or prediabetes are normal, testing should be repeated at least at 3-y intervals, with consideration of more frequent testing depending on initial results and risk status USPSTF 1. Screening is recommended for asymptomatic adults with sustained blood pressure >135/80 mm Hg 2. No recommendation for asymptomatic adults with blood pressure 135/80 mm Hg a ADA = American Diabetes Association; BMI = body mass index; HDL = high-density lipoprotein; USPSTF = US Preventive Services Task Force. b SI conversion factors: To convert cholesterol values to mmol/l, multiply by ; to convert triglyceride values to mmol/l, multiply by Adapted from Ann Intern Med 3 and Diabetes Care, 4 with permission. RECOGNIZABLE LATENT OR EARLY SYMPTOMATIC STAGE Diabetes is the classic disease model for screening because clinical disease is typically preceded by a lengthy asymptomatic phase. 4 Several studies support the importance of identifying the preclinical phase. For example, the Nurses Health Study showed that women who eventually developed diabetes had a higher risk of myocardial infarction (relative risk, 3.75; 95% confidence interval, ) even before their diagnosis of diabetes compared with women who never developed diabetes, with an increased risk likely beginning as many as 15 years before actual diagnosis of diabetes. 18 In a Wisconsin cohort, Harris et al 19 found a TABLE 2. Wilson and Jungner Criteria for Disease Screening (Adopted by the World Health Organization) 1. The condition sought should be an important health problem 2. There should be an accepted treatment for patients with recognized disease 3. Facilities for diagnosis and treatment should be available 4. There should be a latent or early symptomatic stage 5. There should be a suitable test or examination 6. The test should be acceptable to the population 7. The natural history of the condition, including development from latent to declared disease, should be adequately understood 8. There should be an agreed policy on who to treat as patients 9. The cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole 10. Case finding should be a continuing process and not a once and for all project From World Health Organization. 6 39

3 20.8% incidence of retinopathy at the time diabetes was diagnosed. Using linear regression and statistical modeling, onset of diabetes was estimated at 4 to 7 years before clinical diagnosis. Taken together, these studies suggest that both microvascular and macrovascular disease are occurring before clinically apparent disease and formal diagnosis. Formal definitions exist for the prediabetic states IFG and impaired glucose tolerance (IGT). These states are detected with the same screening test as for diabetes. 4 Recognition of patients with prediabetes in and of itself is important because of evidence of preclinical vascular disease (as aforementioned) and also because of the potential to prevent or delay onset of actual diabetes mellitus with lifestyle and pharmacological intervention. SUITABLE TEST OR EXAMINATION The fasting plasma glucose (FPG) is a simple, inexpensive test with essentially no adverse effects or risk. 2 Although the FPG is the recommended screening test, patients may also be screened with a 75-g oral glucose tolerance test or with a glucose value obtained randomly when patients are symptomatic (Table 3). 4 In most cases, an abnormal test result should be confirmed on a subsequent day. Hemoglobin A 1c is used as a marker of long-term glycemic control and therefore is used to assess efficacy of therapy, but it is not currently endorsed by the ADA, American College of Endocrinology, or World Health Organization to diagnose diabetes. However, data from the National Health and Nutrition Examination Survey revealed that an HbA 1c value of 5.8% had optimal sensitivity (86%) and specificity (92%) for detecting undiagnosed diabetes. The authors suggest that this value could be used as a trigger to formally screen with FPG. 20 Others have independently recommended using an HbA 1c value of 6.0% as a trigger to screen and have suggested that values greater than 6.5% could be used in certain diagnostic criteria. 21 This value, if standardized, could also be useful to further characterize and stratify risk in certain populations, such as hospitalized patients, in whom the prevalence of undiagnosed diabetes is high; however, FPG values, elevated by counterregulatory hormone surge, cannot typically be used for diabetes screening and diagnosis. 22 ACCEPTABLE TEST TO THE POPULATION As described in the USPSTF position statement, no data suggest serious adverse outcomes to screening. 2 The ADA recommends a FPG (with abnormal result confirmed on a subsequent day) as the screening method of choice, an intervention that is less invasive and less time-consuming than other readily acceptable screening tests such as mammography and colonoscopy. TABLE 3. Criteria for Diagnosis of Diabetes Mellitus a,b 1. Fasting plasma glucose level 126 mg/dl OR 2. Symptoms of hyperglycemia and a casual plasma glucose level 200 mg/dl OR 3. 2-h plasma glucose level 200 mg/dl during a 75-g oral glucose tolerance test a In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeated testing on a different day. b SI conversion factors: To convert glucose values to mmol/l, multiply by Adapted from Diabetes Care, 4 with permission. NATURAL HISTORY OF THE CONDITION UNDERSTOOD Not every person at risk will develop diabetes, and not everyone who develops diabetes will have progressive complications. The direct mechanism by which dysglycemia translates to vascular disease is an area of active research 23 and is most likely multifactorial and polygenic. Screening for disease is beneficial only if discovering earlier or preclinical disease improves outcome. In both type 1 and type 2 diabetes mellitus, periods of hyperglycemic exposure can cause long-term adverse effects, the socalled legacy effect. 24 Because glycemic control cannot be achieved in patients in whom diabetes has not been diagnosed, screening plays an important role in preventing long-term complications. In patients with type 1 diabetes, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC) study group showed that the benefit of tighter glycemic control (HbA 1c, 7.4% vs 9.1%) for an average of 6.5 years was still apparent 11 years later even though glycemic control had equalized (7.9% vs 7.8%) during the 11- year follow-up. 25 Patients with diabetes whose glycemia was more tightly controlled during the 6.5 years of study had significantly fewer cardiovascular events after the 11 years of follow-up. Importantly, 10-year follow-up data from the UKPDS cohort, originally a group of 4209 persons with newly diagnosed type 2 diabetes mellitus, were recently published. 11 Like the DCCT/EDIC study, lasting benefits of tighter glycemic control during the intervention period were seen despite equalization of HbA 1c values in the follow-up period (8.0% vs 8.1%). These benefits were apparent for both microvascular and macrovascular end points. These studies suggest that glycemic effects are lasting and irreversible and therefore advocate for early diagnosis via screening so early and consistent glycemic control can be achieved. CONSENUS FOR TREATMENT All patients with prediabetes and diabetes should be treated. The ADA recommends that people with IFG or IGT modify their lifestyle (5%-10% weight loss and 30 minutes of exercise daily). 4 For individuals with both IGF 40

4 and IGT and an additional risk factor (in particular, body mass index >35 kg/m 2 or age <60 years), metformin can be considered. 4 These guidelines are based on a variety of studies that have shown that these interventions delay or prevent progression from prediabetes to diabetes. 26,27 All patients with diabetes should receive education and undergo a comprehensive evaluation, including screening for known complications of diabetes. 4 Treatment is recommended to achieve glycemic goals based on an HbA 1c value of 7.0% and preprandial and postprandial glycemic targets of 70 to 130 mg/dl and less than 180 mg/dl, respectively. 4 COST OF CASE FINDING Costs of discovering cases of diabetes, including diagnosis and treatment, must make economic sense. The estimated cost of diabetes in the United States in 2007 was $174 billion: $27 billion for direct diabetes treatment, $58 billion for treatment of long-term complications of diabetes, 13 $31 billion for other medical costs, and $58 billion for lost workforce productivity. The mean health care cost of a patient with diabetes is 2.3 times the cost of a patient without diabetes. 13 Preventing diabetes in patients with IFG or managing risk factors in patients with diabetes is needed to reduce these enormous health care expenditures. 28 PROCESS OF DETERMINING CASES OF DIABETES Determining who has diabetes should be a continuing process and not a once and for all project. 6 For patients who meet criteria for testing, the ADA recommends screening every 3 years after a normal result is obtained. 4 For those with IFG and/or IGT, yearly evaluation is recommended. 4 CONCLUSION Screening for diabetes mellitus meets the Wilson and Jungner criteria for screening for disease. The specific patient population to screen may be less well defined, but clearly a more inclusive screening plan than is outlined by the USPSTF seems merited given the national diabetes epidemic, the imperfect but compelling data regarding risk reduction with glycemic control, and the ease of screening. The USPSTF cites lack of direct data to support its relatively restrictive guidelines yet acknowledges that a clinical trial to assess treatment vs observation in patients in whom diabetes has been detected by screening would be unethical. However, endorsing only a limited screening program has the same clinical outcome and effect: a large number of patients will not have diabetes diagnosed and will not be treated because their disease is not known. Long-term follow-up data from both the DCCT/EDIC and UKPDS confirm that untreated periods of hyperglycemia, as may be expected in undiagnosed (and therefore possibly uncontrolled) diabetes, has lasting effects in regard to microvascular and macrovascular disease progression. With 2.8% of the US population having undiagnosed diabetes, determining who these people are should be a top priority. Incorporating other high-risk factors in the decision to screen for diabetes, such as those recommended by the ADA (Table 1), makes clinical and economic sense. A large body of evidence shows that morbidity and mortality due to diabetes can be reduced with proper diagnosis, treatment, and even actual disease prevention, particularly microvascular complications such as nephropathy. In patients with known diabetes, cholesterol and hypertension management can be optimized to reduce risk of macrovascular disease. The USPSTF guidelines appear too restrictive and allow information that is unknown to interfere with overwhelming evidence that is known. The bottom line is that our current efforts are dismal, with one-third of persons with diabetes in the United States being undiagnosed. We need to improve our efforts in determining who has diabetes. We need to seek out newer methods to screen patients with type 2 diabetes mellitus that include risk stratification, laboratory evaluation, probability analysis, and, in the future, genomic screening. A more robust national database is required to optimize the tracking and natural history of the highest-risk patients with multiple risk factors compared with those who have no risk factors. Finally, we need to remember that in reality most clinical decision making is based on imperfect evidence; however, as summarized by British poet William Cowper ( ), Absence of proof is not proof of absence. REFERENCES 1. AHRQ. 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