PREVENTIVE CARDIOLOGY SPRING 200378

The prevalence of type 2 diabetes is rising rapidlyworldwide. Evidence suggests that between onethird and one half of cases are undiagnosed andpatients may have preclinical disease for as longas 12 years. At diagnosis, 50% of patients havemicrovascular complications (retinopathy, neu-ropathy, or nephropathy) and patients have twicethe risk of macrovascular disease compared to thebackground population. Screening for type 2 dia-betes would allow earlier recognition of cases,with the potential to intervene earlier in the dis-ease course, but whether this would result inimproved long-term outcomes is unknown. Thedebate continues about who should be consideredfor screening, how we should screen, and whetherwe should screen for diabetes at all. The authorsreview the evidence, particularly in light of therecent position statement on diabetes screeningpublished by the American Diabetes Association.If we do start screening for diabetes, one of themajor challenges ahead is to ensure resources arein place to allow optimization of treatment forthe increasing number of patients. This is impor-tant both in those found to have diabetes and inthose with lesser degrees of glucose intolerancewho are at high risk of developing diabetes andare at increased risk of macrovascular disease.(Prev Cardiol. 2003;6:78–84) ©2003 CHF, Inc.

Worldwide, more than 100 million people havediabetes with the prediction that this number

will double over the next decade.1 In 1997, it was esti-mated that nearly 16 million people had diabetes inthe United States, with somewhere between one thirdand one half of these cases being undiagnosed.2

Undiagnosed diabetes is not a benign condition. Atinitial clinical presentation, patients frequently haveevidence of complications associated with diabetes.Retinopathy is present in 10%–29% of patients, pro-teinuria is present in 10%–37% and neuropathy ispresent in 9%.3 In the second National Health andNutrition Examination Survey (NHANES II), theprevalence of macrovascular disease in undiagnosedtype 2 diabetes was about equal to that found in diag-nosed diabetes and was twice that in people withoutdiabetes.4 Both patients with undiagnosed and diag-nosed diabetes have increased mortality, with abouttwice the risk of death of the background population.Risk factors for both microvascular and macrovascu-lar disease are very common in undiagnosed type 2diabetes and occur as frequently as in diagnosed type2 diabetes (Table I).

Based on the foregoing findings, it would be rea-sonable to suggest that recognizing and treating thelarge number of patients with undiagnosed diabetesearlier would be beneficial, with the aim of inter-vening earlier and potentially reducing long-termcomplications. However, there is currently a lack offirm evidence for the benefit of early detection ofdiabetes through screening. Nonetheless, severalhealth care organizations have drawn up guidelinesfor screening for type 2 diabetes.5–7 In this reviewwe will present the evidence for screening and con-sider the current strategy proposed by the Ameri-can Diabetes Association (ADA).

The aim of screening is recognition of individuals atrisk of a particular disease in whom diagnostic testingshould be carried out. Before deciding on the appropri-ateness of screening for a particular disease, it is impor-tant to consider a number of questions and these will bepresented with relation to diabetes.

Does the Disease Represent an Important HealthProblem That Imposes an Important Burden onthe Population?As previously noted, diabetes is increasingly commonin the United States and around the world. It accountsfor 50% of all nontraumatic amputations, 15% of allblindness, and 35% of all end-stage renal disease.3Coronary heart disease prevalence in diabetics is atleast twice that in the background population8,9 and

Screening for Diabetes in General PracticeJames Lawrence, BSc, MRCP;1 Anthony Robinson, MD, FRCP1,2

REVIEWS

From the Royal United Hospital, Bath;1 and theUniversity of Bath,2 Bath, United KingdomAddress for correspondence:James Lawrence, BSc, MRCP, Diabetes and LipidResearch, Wolfson Centre, Royal United Hospital, Bath,United KingdomE-mail: mpsjml@bath.ac.ukManuscript received March 20, 2002;revised April 21, 2002;accepted May 8, 2002

SPRING 2003 PREVENTIVE CARDIOLOGY 79

life expectancy is reduced by one third from the age ofdiagnosis.10 Perhaps not surprisingly, health careexpenditure on diabetes is enormous with one recentstudy suggesting that diabetes consumes 15% of healthcare expenditure (disease prevalence approximately5%). The total cost of diabetes to the US economy maybe as high as $100 billion per year.2,11

Is the Natural History of the Disease Known andDoes It Have a Recognizable Preclinical PhaseDuring Which It Could Be Diagnosed?Glucose intolerance progresses through a numberof well-recognized stages prior to the developmentof diabetes. The initial defect is most commonlypostprandial hyperglycemia with fasting hyper-glycemia occurring later. In Caucasians withimpaired glucose tolerance (IGT) (2-hour glucoseon an oral glucose tolerance test of 140–200mg/dL), the average annual rate of progression todiabetes is 4.7%, with higher rates in some ethnicminority groups.7 In patients with impaired fastingglucose (fasting glucose between 110–126 mg/dL),the annual rate of progression to diabetes isbetween 1% and 2.2%.12,13

The duration of preclinical disease has been esti-mated at 10–12 years by extrapolating back fromthe prevalence of complications at diagnosis.14,15 Inone study, the prevalence of retinopathy at diagno-sis was estimated to be 20%. Assuming a linearincrease in the prevalence of retinopathy over time,the interval between prevalence of no retinopathyand clinical diagnosis was estimated at 4–7 years.Assuming that the time between onset of diabetesand the appearance of retinopathy is 5 years, thetime between onset of disease and clinical diagnosismay be as long as 12 years.14 Clearly, this 12-yearwindow is an interval during which diabetes couldpotentially be recognized by screening.

Does Treatment After Early Detection of theDisease Give Benefits Above and Beyond ThoseObtained When Treatment Is Delayed? The United Kingdom Prospective Diabetes study(UKPDS)16,17 has established that intensive controlof blood glucose in type 2 diabetes reduces the

long-term risk of microvascular complications. Fora 0.9% difference in hemoglobin A (HbA1c)between the intensively treated and nonintensivelytreated groups at the end of follow-up (median 10years) there was a 12% reduction in all diabetes-related end points (p=0.029) and a 25% reductionin microvascular end points (p<0.01), particularlythe risk of progression of retinopathy. In additionthere was a 16% reduction in the risk of myocardialinfarction, although this was not statistically signif-icant (p=0.052).16 Although this study includedpatients newly diagnosed with diabetes, it must beremembered that these were not identified by dia-betes screening but rather by usual medical care. Itwould be anticipated that patients identified byscreening would accrue similar benefit for the samechange in HbA1c, although very little work has beencarried out in this area.

As previously discussed, diabetes is associatedwith a high risk of macrovascular disease and bothnewly diagnosed and long-standing patients oftenhave a cluster of potentially modifiable risk factors.Clearly, these could be recognized and potentiallytreated without knowing that someone had dia-betes. However, current guidelines for treatment ofhypertension, hypercholesterolemia and use ofaspirin are different for patients with diabetes.18–21

Recognizing diabetes by screening could result inearlier, more aggressive intervention to reducemacrovascular risk with potential long-term bene-fits. However, to date there is no evidence thatscreening and recognizing diabetes earlier doesalter use of these therapies, and they are extensive-ly underused even in the highest risk groups.22

In considering the potential benefits of early detec-tion and treatment of diabetes it is important to con-sider the potential risks associated with screening, par-ticularly the potential physical, social, and psychologi-cal harm. Screening may increase worry and reducehealth-related quality of life, and a positive test mayinfluence employment and health insurance. Somepatients will be incorrectly diagnosed, either beinginappropriately labelled as having diabetes or con-versely receiving false reassurance. The potentialimpact of these effects on diabetes screening programs

Table I. Risk Factors for Macrovascular Disease in Undiagnosed Diabetes4

RISK FACTOR NONDIABETIC UNDIAGNOSED PREVIOUSLY DIAGNOSED

Hypertension* 36% 61% 69%

ObesityMen (BMI >27)Women (BMI >25)

34%47%

50%82%

42%73%

Cholesterol >240 mg/dL 38% 49% 40%

Triglycerides >250 mg/dL 9% 28%

BMI=body mass index; *defined as blood pressure >160/95 mm Hg in the Second National Health and NutritionExamination Survey

has not been extensively studied and clearly mayreduce the potential benefits of screening.2

Are There Tests That Can Detect PreclinicalDisease That Are Reliable and Acceptable?A variety of different tests have been proposed forscreening for type 2 diabetes, including: 1) ques-tionnaires based on diabetes risk factors; 2) fastingand random blood glucose; 3) fasting, random andpostprandial urine glucose; and 4) HbA1c. All thesetests have their advocates but none are ideal.

The fasting plasma glucose (FPG) has the advan-tage of reproducibility from day to day and can becombined with other pathology tests such as fastinglipids, but has the disadvantage that patients must bein the fasting state. As with other tests, the sensitiv-ity and specificity of the FPG depends on the cutpoint selected for a positive screening test (Table II).A cut point between 99 mg/dL and 108 mg/dLseems to offer the optimal sensitivity and specificityfor recognizing diabetes in studies where all patientshave oral glucose tolerance tests to diagnose dia-betes. In a study by Costa et al.23 involving 616 non-diabetic bank employees, all of whom had an oralglucose tolerance test, the optimal sensitivity andspecificity for FPG were seen at a cut point of 97mg/dL. Similar results were seen in a study byModan and Harris.24 Although they considered nocut point to be ideal, they found that an FPG of 100

mg/dL offered the best combination of sensitivity(83%) and specificity (76%). In the DiabetesEpidemiology: Collaborative Analysis of DiagnosticCriteria in Europe (DECODE) study,25 data wasanalyzed from a number of European studies involv-ing 29,108 people who had a glucose tolerance test.A cut point of 99 mg/dL for FPG identified 93% ofpeople with diabetes and 69% of people with IGTand a cut point of 110 mg/dL identified 82% withdiabetes and 29% with IGT. Perhaps not surprising-ly, the lower the cut point for FPG accepted as apositive screening test, the greater the number ofpeople requiring diagnostic testing. In the DECODEstudy 46% of patients had an FPG greater than 99mg/dL while only 12% had an FPG ≥110 mg/dL.25

Similar results were seen in the Rancho Bernardostudy of US Caucasians aged 50–79, with 41.4%having an FPG >99 mg/dL and 17.9% having anFPG ≥110 mg/dL.26

Measurement of a random blood glucose has theadvantage that it can be undertaken opportunisti-cally; however, it is less reproducible than FPG andnot standardized. Although some authors favorurine glucose testing for screening for diabetes,27,28

the general consensus is its sensitivity is too low forthis purpose.2,6,7

HbA1c has been proposed for screening. Its majoradvantage is that the patient requires no preparation.However, there is still not universal standardization

PREVENTIVE CARDIOLOGY SPRING 200380

Table II. Sensitivity and Specificity of Urine and Blood Glucose Testing in Screening for Diabetes

TEST

CUT POINT FOR

POSITIVE SCREENING TEST SENSITIVITY SPECIFICITY

Urine glucose—fasting49 ≥trace 16 98

≥trace50 23 99Urine glucose—random

≥trace51 64 99

Urine glucose—1 hr postprandial27,28 ≥trace 43 98

≥10452 85 84

≥1103 65 93

≥11053 80 96

≥12154 32 97

≥12655 56 98

≥12656 59 96

Venous glucose—fasting(mg/dL)

≥12657 40 99

≥9949 90 94

≥12158 65 94

Capillary glucose—fasting(mg/dL)

≥12159 90 90

Capillary glucose—random(mg/dL)

Age and postprandialtime specific60

50–60 90

of the test, which makes generalization of thresholdsfor positive screening tests problematic. There is alsoa large overlap in HbA1c between patients identifiedas having diabetes on an oral glucose tolerance test(OGTT) and those with normal glucose tolerance,clearly limiting the utility of this approach. InNHANES III, 60% of patients with diabetes diag-nosed by an FPG of 126–140 mg/dL had normalHbA1c and one third had results within 1% of theupper limit of normal.29

A number of questionnaires have been devel-oped to be used as screening tools for type 2 dia-betes. In general, these have been shown to per-form less well than biochemical testing and havenot been rigorously tested.5,30–33

The FPG is currently favored in guidelines forscreening for type 2 diabetes, although it isacknowledged that on occasion other tests may beappropriate (including random glucose in the USguidelines, a postprandial urine test in the diabetesUnited Kingdom guidelines and possible use of theOGTT as a screening test in both). Perhaps not sur-prising in view of the incomplete nature of theavailable evidence, there is no consensus on theappropriate threshold above which further diag-nostic testing is considered appropriate in patientsafter screening for diabetes. In the recently pub-lished Australian guidelines on screening for type 2diabetes, an FPG of 99 mg/dL is considered a posi-tive screening test.7 This compares with a thresholdfor an FPG of 110 mg/dL in the diabetes UnitedKingdom guidelines6 and a threshold of 126 mg/dLin the US guidelines.5 Suggested follow-up of a pos-itive screening test also varies between countries. Inthe United States, the United Kingdom, andAustralia, if a patient has an FPG ≥126 mg/dL theadvice is to repeat this to confirm diabetes. In theUnited States, no suggestion is made about follow-up of other patients although patients with an FPGof ≥110 mg/dL and <126 mg/dL on screening aregiven the diagnostic label of impaired fasting glu-cose. In the United Kingdom, it is suggested that allscreened patients with an FPG ≥110 mg/dL and<126 mg/dL should have an OGTT to exclude dia-betes and in Australia it is suggested that all

screened patients with an FPG >99 mg/dL shouldhave an OGTT to exclude diabetes. Clearly, thiswill result in a greater number of diagnostic tests inscreen-positive patients in the United Kingdom andeven more in Australia with the likelihood of rec-ognizing a greater proportion of the patients withundiagnosed diabetes as well as those with IGT.

Is Screening for the Disease Cost Effective?Treatment of hyperglycemia in patients withknown type 2 diabetes is considered cost effective,with a cost estimated at $16,000 per quality-adjust-ed life year (QALY).34 Whether screening for andtreating patients with screen-detected diabetes iscost effective, is largely unknown as very little workhas been carried out in this area. Perhaps the mostwidely quoted study used a Monte Carlo simula-tion model to compare the lifetime benefits associ-ated with the early detection and treatment of type2 diabetes based on one-time opportunistic screen-ing with diagnosis as and when it occurs in usualclinical practice. The identified cost per case of dia-betes was $1200. Diabetes was diagnosed on aver-age 5.5 years earlier with an estimated average costof treating a newly diagnosed patient of $1007.The lifetime cost of diabetes was $3400 higher withscreening. Overall, the cost per life-year gained was$236,400 and the cost per QALY was $56,000.35

This estimate is less than that for breast screeningwith annual mammography for women aged 50–65($150,000 per QALY) but is more than cervicalscreening with four yearly smears for women aged20–75 ($16,000 per QALY).36

DiscussionOverall, evidence for screening for type 2 diabetes isincomplete, particularly with regard to the benefits ofearly treatment and cost effectiveness.2,37 Population-wide screening is felt to be inappropriate because it hasa very low pick-up rate of new cases in those with lowrisk. Cowie et al.38 reported data from 19,680 patientsshowing the prevalence of diabetes in people with noestablished risk factors for diabetes to be 0.4%. A num-ber of factors have been identified which clearlyincrease the risk of diabetes in an individual (Table III).In the study by Cowie et al.38 the prevalence of undi-agnosed diabetes was 11.7% in those with three riskfactors (older age, family history, and obesity). We havefound similar results in a recent study screeningpatients for diabetes in general practice in the UnitedKingdom.39 Current expert consensus is that efforts toidentify undiagnosed diabetes should focus on thosewith risk factors for the disease. This potentially limitsthe number of patients requiring screening andenhances the pick-up rate of new cases. The ADA hasstated that “screening for diabetes as part of routinecare may be appropriate if the patient has one or morerisk factors.... Based on the lack of high-quality cost-benefit studies, it is premature to recommend screen-ing all high-risk individuals.... The decision to screen

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Table III. Factors Associated With Increased Risk ofDiabetes

• People with impaired glucose tolerance or impaired fasting glucose• Increasing age• Obesity• Family history of diabetes• History of macrovascular disease• Hypertension• Certain ethnic groups• Previous gestational diabetes• Women with polycystic ovarian syndrome

should be based on clinical judgement and patient pref-erence.” The risk factors included in the ADA positionstatement are shown in Table IV.5 This does not includepatients with clinical cardiovascular disease (ischemicheart disease, peripheral vascular disease, and cere-brovascular disease), a group clearly at risk of diabeteswhere case finding should be considered.

If it is accepted that case finding is appropriate inpatients at high risk for diabetes, it is important to con-sider which test to use for screening and how to followpatients. As already discussed, the ADA favors use ofthe FPG as the primary screening test with a thresholdfor a positive screening test of 126 mg/dL and a repeatfasting glucose to confirm the diagnosis of diabetes.This will clearly limit the number of patients whorequire diagnostic testing. However, it will also resultin not recognizing the significant number of patientswho have an FPG <126 mg/dL but who would bediagnosed with diabetes by virtue of having a 2-hourglucose on an OGTT of >200 mg/dL; and no patientswill be recognized with IGT. In the DECODE study,25

only 49% of patients with diabetes had an FPG >126mg/dL, so screening on the basis of an FPG >126mg/dL alone may miss over 50% of patients with dia-betes. Does this matter?

In the NHANES III study,40 patients with isolatedpostchallenge hyperglycemia (IPH) (i.e., patients diag-nosed with diabetes with an FPG <126 mg/dL and a2-hour glucose >200 mg/dL on an OGTT) had a meanHbA1c significantly lower than those with diabetesdiagnosed on the basis of FPG >126 mg/dL (5.6% vs.7.1%). Indeed the level was very close to the nondia-betic mean (5.3%). The risk of microvascular compli-

cations in diabetes rises with increasing HbA1c, andtreatment of patients with diabetes with an HbA1cnear-normal would center on diet. It could, therefore,be argued that recognizing these patients would havelittle impact on their management and that efforts torecognize diabetes should be focused on those withhigher degrees of fasting hyperglycemia where moreaggressive treatment may be appropriate. If the screen-ing interval were short enough, it would be unlikelythat patients with IPH would develop significant fast-ing hyperglycemia and complications between screen-ing visits. Currently, there is no evidence to support orrefute this assertion from clinical trials.

In the NHANES III study,40 patients with IPH alsohad a more favorable cardiovascular risk profile thanthose with a fasting glucose >126 mg/dL with a lowerbody mass index, lower triglycerides, and higher high-density lipoprotein cholesterol, although these werehigher than the normal population. However, these dif-ferences were not reflected in mortality data from theRancho Bernardo study,41 which showed mortality inthose with IPH to be twice that of the normal popula-tion—and similar to that seen in patients with diabetesdiagnosed on FPG, results reflected in a Europeanstudy.42 If diabetes screening is considered in the con-text of assessing overall coronary heart disease risk,there could be an argument for screening to recognizethose with IPH with a reduction in the threshold for apositive screening test for diabetes and inclusion of theOGTT in the diagnostic algorithm. Whether this wouldresult in greater attention to recognition and treatmentof coronary heart disease risk factors and improve long-term outcome is unknown.

Evidence is accumulating that intervening inpatients with known IGT will reduce the rate of pro-gression to diabetes.43,44 It would clearly not be pos-sible to adopt this approach if the ADA guidelines forscreening for diabetes are followed, as IGT cannot beidentified without carrying out an OGTT. This couldbe an argument for lowering the threshold for a pos-itive screening test and incorporating the OGTT intothe diagnostic algorithm. However, there are current-ly no long-term studies showing that intervention inpatients with IGT to prevent diabetes improves long-term outcome or to show that such a strategy wouldbe cost effective. It is also unclear what would be theappropriate threshold for FPG for identifyingpatients with IGT. As discussed, in the DECODEstudy an OGTT on all patients with an FPG >99mg/dL identified 69% of patients with IGT but 46%of the population had to have an OGTT.25 Loweringthe threshold would increase the sensitivity but fur-ther compromise specificity. This would clearlyinvolve a significant amount of resource input both interms of personnel and the laboratory with an uncer-tain return on the investment. Using the ADA criteriafor screening for diabetes, a large number of patientswith impaired fasting glucose will be identified. Datais currently lacking as to whether intervention in thisgroup will reduce the rate of progression to diabetes.

PREVENTIVE CARDIOLOGY SPRING 200382

Table IV. Major Risk Factors for Type 2 Diabetes inthe American Diabetes Association Position Statementon Screening for Type 2 Diabetes

• Family history of diabetes (parents or siblings with diabetes)• Race/ethnicity (e.g., African Americans, Hispanic Americans, Native Americans, Asian Americans, Pacific Islanders)• Age ≥45 years• Obesity (≥20% over desired body weight or body mass index ≥27 kg/m2)• Hypertension (≥140/90 mm Hg in adults)• High-density lipoprotein cholesterol ≤35 mg/dL or triglyceride ≥250 mg/dL• Previously identified impaired fasting glucose or impaired fasting glucose• History of gestational diabetes or delivery of babies over 9 lbs

Reprinted with permission of The American DiabetesAssociation from the American Diabetes Association.Screening for diabetes. Diabetes Care. 2002;25(suppl 1):21S–24S. Copyright 2002.

Finally, evidence regarding the most appropriateinterval between screening visits for diabetes islacking and research in this area is awaited. TheADA recommendation of screening every 3 years isbased on a consensus of expert opinion that the riskof developing significant hyperglycemia and com-plications within 3 years of a negative screening test(FPG <126 mg/dL) is low.

The current ADA position of opportunistic screen-ing and case finding in individuals at risk for diabetesfits the available evidence. There is an ongoing debateabout the appropriate screening tests, the time intervalbetween tests, appropriate thresholds above whichpatients should have diagnostic testing, and the use ofthe OGTT. It is possible to make a case for the ADAposition of undertaking further testing only in thosewith an FPG ≥126 mg/dL. Equally, a case can be madefor an OGTT in patients with an FPG >99 mg/dL (assuggested by the Diabetes Australia7 guidelines) or ≥110mg/dL (as suggested by the Diabetes UK6 guidelines).When considering whether to look for new cases ofdiabetes in primary care, it is crucially important tohave systems in place to ensure call and recall, andresources must be available to manage the increasednumber of patients with diabetes. Otherwise, anypotential benefit the patient might gain from earlierdiagnosis of diabetes will be negated. This may be a par-ticular problem for the 18% of the population in theUnited States who currently have no provision, or inad-equate provision, of medical coverage. These peoplemay be at high risk of diabetes but are likely not to beconsidered for screening; and if they are screened, theyare not likely to receive adequate ongoing diabetes care.We should be considering looking for new cases of dia-betes in at-risk groups, but we need to ensure that fol-low-up of all patients is optimized, both in terms oftreating hyperglycemia and also in terms of recognizingand treating risk factors for macrovascular disease.

The diagnostic threshold for diabetes is based onthe risk of developing microvascular complications.However, patients with raised glucose below thelevel needed to diagnose diabetes are at increasedrisk of macrovascular disease.45–48 Much of thisincreased risk is due to the clustering of establishedrisk factors, particularly hypertension and dyslipi-demia. Whether or not patients have diagnostictesting for diabetes, screening with an FPG allowsus to identify a cohort of patients who are poten-tially at increased risk of macrovascular disease. Wewould suggest that any patient found to have anFPG >5.5 µmol/L, whether or not they go on tohave further testing for diabetes, should bescreened for macrovascular disease risk factors,particularly hypertension and hypercholesterol-emia. Recognizing and treating these in appropriatepatients will have a significant impact on the preva-lence of cardiovascular disease across the popula-tion. Indeed, it may even be appropriate to usemanagement guidelines for cardiovascular diseasein these patients as if they have diabetes.

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