Endocrinology Metabolism

Diabetes Screening and Prevention

Arguments to screen for prediabetes and undiagnosed type 2 diabetes

Prediabetes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) and type 2 diabetes (defined in Table I) represent a pathophysiological and clinical continuum.

Table I.

American Diabetes Association diagnostic criteria for impaired fasting glucose, impaired glucose tolerance and diabetes
Tests Impaired fasting glucose Impaired glucose tolerance Diabetes
Fasting plasma glucose 100–125 mg/dl (5.6–6.9 mmol/l) < 126 mg/dl (7.0 mmol/l) if measured ≥126 mg/dl (7 mmol/l)or
2 hour plasma glucose after ingestion of a 75g glucose load 199 mg/dl (<7.8 mmol/l) if measuredor 140 –199 mg/dl (7.8–11.0 mmol/l) or ≥200 mg/dl (11.1 mmol/l) or
HbA1c 5.7–6.4% 5.7–6.4% ≥6.5%

Although these conditions meet many criteria of suitability of screening, there is no direct evidence on the cost-effectiveness of screening from a randomized controlled trial. Such evidence would ideally be obtained from a trial comparing people invited to screen with those not invited to screen. However, conducting such a trial might be logistically and ethically challenging, for many reasons.

First, recommendations have for many years promoted opportunistic screening for prediabetes and type 2 diabetes in high-risk people; it may therefore prevent the conduct of a rigorous randomized controlled trial of diabetes screening as it would be difficult to have a control group that is not screened, unless a trial was done solely in people at lower risk than prediabetes. Second, such a trial would require a very large number of participants and a lengthy follow-up to detect differences in hard endpoints; thus, it would be exorbitantly costly and possible contamination may threaten the validity of the results.

Fortunately, there is robust evidence on the beneficial effects of early treatment of prediabetes, and similar evidence is accumulating on early treatment for undiagnosed diabetes. Also, many economic modeling studies have suggested that targeted opportunistic screening for prediabetes and/or type 2 diabetes would be cost effective. There is therefore a strong rationale for undertaking screening for prediabetes and undiagnosed diabetes among high-risk people in clinical settings.

Scope of the problem - burden of hyperglycemia

Regarding prediabetes, the global prevalence of impaired glucose tolerance among adults was 6.4% in 2011, and is projected to increase to 7.1% by 2030. Almost 30% of adult Americans have prediabetes, and over 40% have hyperglycemia (prediabetes or diabetes). Prediabetes is associated with an 8%-60% higher risk of mortality compared to normoglycemia, and a 20% increase in macrovascular disease compared to normoglycemia. Microvascular complications are also associated with prediabetes, including retinopathy (7%-10% ); neuropathy (11%-25% for peripheral neuropathy, and 13%-21% for neuropathic pain), and chronic kidney disease (7% higher prevalence compared to normoglycemia).

The economic burden of prediabetes and diabetes is very high. Annual global health expenditures related to diabetes are projected to total at least USD 376 billion (12% of all health expenditures) in 2010 and USD 490 billion in 2030. Approximately 1 in 5 health care dollars in the US is spent caring for someone with diagnosed diabetes. These estimates would be much higher if disease-related medical costs for people with undiagnosed diabetes were recognized and accounted for. Prediabetes is also associated with higher medical costs than normoglycemia.

Identifiable preclinical phases

Hyperglycemic conditions (prediabetes and type 2 diabetes) span a spectrum. Their natural history includes an asymptomatic phase comprised of prediabetes and preclinical diabetes. Prediabetes includes asymptomatic intermediate states of abnormal glucose regulation that precede overt diabetes, and is associated with a high risk of progression to type 2 diabetes. The estimated annual relative risk of progression from prediabetes to diabetes is 4.7%-12%, and the annual absolute risk is 5%-10%, relative to normal glucose tolerance. The estimated annual relative risk of regression of IGT to normoglycemia is low ~ 0.33. The average annual risk of developing diabetes among people with normoglycemia is 0.7%.

The early stages of type 2 diabetes after biological onset are also frequently asymptomatic. The duration of this latency period could be as long as 9-12 years. Several studies showing that up to 50% of peoplewith newly diagnosed, or screen-detected diabetes already exhibit diabetes-related macrovascular (e.g., ischemic heart disease or myocardial infarction) and microvascular complications (e.g., retinopathy, chronic kidney disease and neuropathy) at diagnosis have provided evidence of tissue damage during this preclinical stage.

For example, in the Hoorn screening study, the prevalence of myocardial infarction, ischemic heart disease (39.5% vs. 24.1%) and retinopathy (7.6% vs. 1.9%) were higher in screen-detected patients than in newly conventionally-diagnosed patients. In the Anglo Danish Dutch Study of Intensive Treatment In peOple with screeN detected diabetes in primary care (ADDITION), screen-detected people had high estimated 10-year absolute risks of coronary disease events (11% in women and 21% in men) and composite cardiovascular disease (38.6% in men and 24.6% in women).

In 2011, diabetes affected approximately 8.3% of adults globally (366 million of people). In the US, 40% of people with diabetes remained undiagnosed in 2009. In less-developed regions of the world, the proportion of people with undiagnosed diabetes could be 50% or higher. The risk of death among people with diabetes is about twice that of persons without diabetes. In 2009, the excess deaths attributable to diabetes worldwide was 6.8% among adults. In the US, diabetes was the seventh cause of death in 2007.

Close to 40% of US adults with diabetes have cardiovascular disease. Diabetes accounts for up to 40% of cases of end-stage renal disease in the US. Approximately 25% of Americans with diabetes report visual impairment. People with diabetes have significantly higher prevalence of peripheral arterial disease (8.0% vs. 3.9%); peripheral neuropathy (18.5% vs. 10.5%) and lower-extremity diseases defined as arterial disease, neuropathy, foot ulcer or amputation (26.3% vs. 15.5%), than those without diabetes. Diabetes is associated with a significant excess risk of a number of disabling conditions; about 2-fold for depression; 1.2 to 1.7-fold for cognitive decline; 1.6-fold for dementia; 1.7-fold for hip fracture and 2 to 3-fold for physical disability.

Prediabetes and type 2 diabetes are large, growing, and costly health problems worldwide.

Screening tests

Screening tests for diabetes include risk scoring tools and the biochemical tests: urine glucose, random blood glucose (RBG), fasting plasma glucose (FPG) and glycated hemoglobin (HbA 1c), fructosamine, and the 50-g oral glucose tolerance test (CGT).

Risk scores

Various tools based on known risk factors for type 2 diabetes have been developed to identify people at high risk of prediabetes or type 2 diabetes. These instruments can help to identify the minority of the population that account for the majority of people with prediabetes and type 2 diabetes. The risk appraisal tools involve use of self-reported questionnaires, health service data or collected anthropometric, lifestyle or biochemical data. The use of questionnaires or existing health service data can limit the proportion of persons that need to undergo blood glucose measurements to 20%-25% of the entire population, but this may be limited by the availability of data on key variables.

In general, the inclusion of blood glucose measurements improves the performance of a risk tool. However, adding complex indices of glucose or insulin metabolism to simple clinical measurements does not seem to further improve the prediction of type 2 diabetes. Similarly, adding genetic information to common phenotypic risk factor data does not improve risk prediction in adults.

Risk scores are pragmatic, but compared to the OGTT, none of these tools are optimal. Discriminatory performance is more heterogeneous and generally weaker in external populations, which suggests that risk scores may need to be validated within the population in which they are intended to be used.

In the U.S., the most widely validated and simple-to-use risk screening tool is the American Diabetes Association (ADA) risk questionnaire. This tool combines information on age, body mass index, ethnicity, history of hypertension, family history of diabetes, and history of gestational diabetes mellitus to estimate the risk of prediabetes or diabetes. It is available for download at: (http://www.diabetes.org/diabetes-basics/prevention/diabetes-risk-test/?loc=DropDownDB-RiskTest.

Biochemical tests

The practical advantages and limitations of the biochemical tests that have been used for hyperglycemia screening are summarized in Table II.

Table II.

Practical advantages and limitations of biochemical screening tests for prediabetes and diabetes
Test Advantages Limitations Recommendations
Urine glucose Does not require a blood sample; can be tested in fasting, random or postprandial state; rapid processing time; inexpensive Unable to measure glucose above the renal threshold; variable renal threshold; affected by fluid intake and urine concentration; not fully quantitative Not recommended
Random blood glucose Easy to obtain; no fasting required; inexpensive Requires prompt processing (<2 hours) thus the potential for error; point measurement can be affected by several factors (short-term lifestyle changes, time since prior meal, etc.) Not recommended
Fasting plasma glucose Relatively cheap and simple; single plasma glucose level measured; highly correlated with presence of complications Requires the patient to fast overnight (at least 8 hours), potential for processing error; point measurement can be affected by short-term lifestyle changes, risks of phlebotomy Can be used
75-g oral glucose tolerance test Current gold standard for the diagnosis of diabetes; most sensitive test for impaired glucose tolerance Requires 8-hour fast, lengthy and requires commitment of nurse staff, overall test-retest reproducibility lower than with other tests Can be used
Glycated hemoglobin (HbA1c) Stable marker of long-term glycemic level; no fasting required, can be completed at any time; not affected by short-term lifestyle changes; requires only venous blood or a point-of-care testing capillary sample, lower intraindividual variability (<2%) than fasting plasma glucose Value may vary with assay method used; possible non-glycemic causes of error such as hemoglobinopathies and anemia; may be insensitive for detection of impaired fasting glucose or impaired glucose tolerance; high cost (more expensive than glucose testing); limited availability in some areas of the world Can be used
50-g glucose challenge test No fasting required; not influenced by the time of the day Cumbersome to administer; test-retest reproducibility unclear Not recommended
Capillary blood glucose measurement (point-of-care testing) Simple; cheap; no phlebotomy required Imprecision may be high; not standardized Not recommended
Fructosamine Marker of glycemic level over several weeks; may be an alternative to HbA1c in case of hemoglobinopathy Can be influenced by serum protein or albumin levels; no clear association between the concentration and chronic complications of diabetes; performance may be limited Not recommended

Urine glucose - The sensitivity and positive predictive values of urine glucose testing are low, 16%-64% and 11%-37%, respectively. Thus, glycosuria appears to be a poor screening instrument for diabetes; as large proportions of individuals with diabetes would be misclassified and remain undetected.

Random blood glucose (RBG) - The use of RBG as a screening tool, is somewhat limited by its low performance. At a cut-off of ≥6.9 mmol/l, the specificity of RBG is about 93% specificity and the sensitivity 41%. For identification of prediabetes, the specificity has been estimated at ~ 94%, and the sensitivity at 23%. An expert panel has recommended a RBG cut-off of ≥7.2 mmol/l (sensitivity of 63% and specificity of 87%), based on validation against OGTT.

Fasting plasma glucose (FPG) - FPG screening may have modest sensitivity for hyperglycemia screening. A threshold of ≥ 7mmol/l may detect only 55.7% of people with diabetes based on diagnosis by OGTT, with 100% specificity. A cut-off for FPG of > 6.1 mmol/l may be optimal with a sensitivity of 85.2% but a specificity of 88.5%. FPG may not be sensitive for the diagnosis of IGT as compared to OGTT, a threshold of > 5.6 mmol/l only detects 28.9% of IGT cases whereas OGTT would identify 87.4% of cases.

Glycated hemoglobin (HbA 1c) - As a screening tool for undiagnosed diabetes, an HbA 1c value between 5.8% and 6.3% to screen for diabetes would have 6%-95% sensitivity and 97%-98% specificity, while 6.1%-6.2% is optimal in terms of sensitivity. HbA 1c ≥6.1% would have a 63.2% sensitivity and 97.4% specificity for screening for type 2 diabetes; this value corresponds most closely with a two-hour post-prandial glucose concentration of 11.1 mmol/1, and would include about 41% of non-diabetic subjects and 21% of subjects with IGT.

For detecting prediabetes, HbA 1c ≥6.1% generally has a sensitivity of 50% at most for the detection of IGT (47); HbA 1c ≥5.8% may only detected about 30% of people with prediabetes (50), HbA 1c of ≥5.7% may have a sensitivity of 59.4% and a specificity of 73.9%, HbA 1c of ≥5.6 % may be was optimal for prediabetes detection with an area under the receiver-operating-characteristic curve (AUC) of 0.63 to 0.71.

In combination with either RBG or FPG, HbA 1c may add value in identifying the subgroups of individuals that need to undergo an OGTT.

The 50-g oral glucose challenge test – An evaluation of the 50-g oral glucose challenge test (GCT) for screening in non-pregnant adults estimated AUCs of 0.90, 0.82 and 0.79 for detection of undiagnosed diabetes, undiagnosed diabetes or dysglycemia, and dysglycemia, respectively, by plasma GCT. However, these results need confirmation in further studies with a larger and more ethnically diverse population.

Effectiveness of screening for hyperglycemia

Impact of screening for hyperglycemia on morbidity and mortality

Ideally, randomized trials of screening comparing people offered and those not offered screening would provide the highest level of evidence on the effect of screening for diabetes on morbidity and mortality. However, the results of such a trial have not yet been published; the ongoing ADDITION-Cambridge study may provide an answer to the question. Nevertheless, the ADDITION trial, which compared intensive treatment vs. routine care, showed beneficial effects of early treatment among people with screen-detected diabetes.

There are also suggestions from observational studies of a possible beneficial effect of screening on morbidity and mortality. A 10-year retrospective matched case-control study suggested that screen-detected diabetes was associated with a 13% (95% CI: -62, 98) relative reduction in microvascular outcomes compared with routine diagnosis. Another study showed that over 12 years, people with diabetes detected by glycosuria lost 1.96 years of life and people with conventionally diagnosed diabetes, 3.42 years, compared with age- and sex-matched controls without diabetes (P<0.005). Unfortunately, these observational studies may be plagued by biases and confounding that limit their validity. Besides, they either focused on microvascular outcomes or conducted glycosuria screening, which has a very limited performance.

There is also no direct trial evidence of benefit in health outcomes from screening for prediabetes. Nonetheless, intensive programs of lifestyle modification (diet, exercise, and behavior), and metformin do reduce the incidence of diabetes among screen-detected people in the US Diabetes Prevention Program, with collateral benefits on cardiovascular risk factors.

Psychosocial impact of screening for hyperglycemia

Observational studies have found limited or no psychological effect of screening on newly-detected people with type 2 diabetes. This includes no effect on the screen-detected patients’ perceived health status and well-being after notification of the results, no significant impact on anxiety levels in screen-detected patients, and no short-term (2 weeks) or long-term (6-12 months) adverse or positive effects on quality of life after diagnosis. This suggests that diabetes screening has little or no labeling effect. However, observational data is susceptible to misinterpretation because of biases, and it mainly focuses on people with screen-detected diabetes, ignoring those who screened negative but may still be affected psychologically.

Trial data also suggest no adverse psycho-social effect of screening for diabetes. In the short- and long-term, the anxiety level, illness perception and self-rated health of participants invited to screening (with or without diabetes at screening) do not differ from that of those not invited, be it immediately after the test, at 6 weeks, at 3-6 months or at 12-15 months. Furthermore, negative screening test results do not promote false reassurance (expressed as lower perceived risk, lower intentions for health-related behavioral change, or higher self-rated health); or negatively affect behaviors (smoking, alcohol consumption, dietary intake, or physical activity), at least, in the first year after screening.

The psychological effect of receiving a diagnosis of prediabetes largely remains unclear. However, there are suggestions that participation in a diabetes prevention program would not be associated with higher levels of anxiety, depression or overall psychological distress than that of the general population.

Cost-effectiveness of screening for hyperglycemia

A systematic review of economic studies of diabetes screening indicates that (i) screening for hyperglycemia would be cost-effective, (ii) targeted screening of high-risk groups would be more cost-effective than universal screening and (iii) treatment is the key determinant of cost-effectiveness. Screening for IGT followed by lifestyle modification or metformin treatment was also cost-effective, with the lifestyle having a better cost-effectiveness ratio.

The detection and treatment for people with prediabetes appeared to be much more cost-effective than detection and treatment limited to individuals with both IGT and IFG. Screening for diabetes and IGT, followed by lifestyle intervention in persons with IGT, would be more cost-effective than screening for type 2 diabetes alone or screening for type 2 diabetes and IGT followed by metformin therapy.

A recent US-based simulation of nine screening strategies found that screening for undiagnosed diabetes would be most cost-effective if started in the age range 30-45 years and repeated every 3-5 years. Another US-based comparison of five opportunistic screening strategies (plasma or capillary RBG, HbA 1c, plasma or capillary GCT and subsequent OGTT) for both prediabetes and type 2 diabetes such an approach to be cost saving method from a health care perspective and cost-neutral to society.

Screening intervals

The exact frequency of screening for hyperglycemia is not known, as there are no compelling data from which to decide the optimum frequency. An optimal interval between screening rounds would be one at which the prevalence of undiagnosed cases reaches the prevalence of such cases at the previous screening, and the cost-effectiveness is the same for each screening. A recent US-based simulation suggested that targeted screening for type 2 diabetes would be most cost-effective if repeated every 3-5 years. Based on expert opinions, professional organizations have generally favored a 3-year interval.

Management or treatment of screen-detected prediabetes or undiagnosed diabetes

Therapies for undiagnosed diabetes

Multifactorial intervention for screen-detected diabetes - The ADDITION study compared intensive treatment to standard therapy in exclusively screen-detected patients. The ADDITION intensive intervention was modeled after the regimen used in the Steno-2 trial, which showed that intensified multifactorial intervention (lifestyle modification and multidrug therapy) to control cardiovascular risk factors is more cost-effective (reduction in macrovascular and microvascular complications, and all-cause mortality) than standard therapy among people with longstanding type 2 diabetes and microalbuminuria.

In ADDITION, intensive multifactorial treatment (targeting several cardiovascular risk factors) of screen-detected people over five years provided a non-significant 17% reduction in a composite cardiovascular primary endpoint compared with routine care, but greater improvements in levels of cardiovascular risk factors, reductions in cardiovascular death (12%), nonfatal myocardial infarction (30%), and revascularization (21%). These results may partly be explained by secular improvements in the quality of diabetes care during the trial period, a phenomenon that is likely to happen in any screening trial. Nonetheless, ADDITION showed some macrovascular benefits of early treatment for screen-detected diabetes.

The long term follow-up of the ADDITION study will provide a more definite answer on the effect of early treatment in people with screen-detected diabetes. While waiting for more direct evidence for treatment among screen-detected patients, data from intervention studies comparing the effects of individual treatment to lower blood glucose, blood pressure and serum cholesterol in conventionally diagnosed diabetic populations (ideally newly diagnosed) can inform the practice of early treatment.

Glycemic control - The United Kingdom Prospective Diabetes Study (UKPDS), a study involving newly-diagnosed type 2 diabetes patients, provides estimates of the likely effect of glycemic control during the lead-time. The 10-year post-trial monitoring results showed that tight glycemic control reduced myocardial infarction by 15% (P=0.01) and 33% (P=0.005) in the sulfonylurea-insulin and metformin groups, respectively, compared with the control group. However, there were no reductions in stroke, heart failure, angina and all-cause mortality associated with tight glycemic control.

Lipid-lowering therapy - There is clear evidence that lowering lipids in people with diabetes is beneficial. A meta-analysis of 12 trials (statins and fibric acid derivatives studies) showed that lipid-lowering therapy is equally efficacious in people with and without diabetes for primary and secondary cardiovascular disease prevention. In both primary and secondary primary prevention, the use of lipid-lowering drugs was associated with a significant 21% reduction in major coronary events in patients with diabetes, respectively.

Except for the Collaborative Atorvastatin Diabetes Study (CARDS), the trials included in the aforementioned meta-analysis were not specifically aimed at people with diabetes and only demonstrated these results in post-hoc analyses of sub-populations with diabetes. CARDS, a primary prevention trial conducted exclusively in patients with type 2 diabetes, showed a 37% (95% CI: 17, 52) relative reduction in cardiovascular events. This reduction was independent of the baseline level of cholesterol. Similar findings were reported in the Heart Protection Study (HPS) demonstrating a 22% (95% CI 13, 30) relative reduction in cardiovascular events in the sub-population with diabetes.

Antihypertensive treatment - In UKPDS, a study of people with newly diagnosed diabetes, tight blood pressure control compared with less tight control significantly reduced macrovascular and microvascular risks in patients with newly diagnosed diabetes. This indicates the potential beneficial effects of blood-pressure-lowering therapy among screen-detected patients with undiagnosed diabetes.

Aspirin therapy - Aspirin has been shown to be effective for secondary prevention of cardiovascular disease in people with diabetes. A meta-analysis confirmed that aspirin allocation yielded greater absolute reductions in serious vascular events (6·7% vs. 8·2% per year, P<0.0001), total stroke (2·08% vs. 2·54% per year, P=0.002) and coronary events (4·3% vs. 5·3% per year, P<0.0001). Regarding primary prevention in individuals with diabetes, several meta-analyses have shown no significant beneficial effects of aspirin for primary prevention of cardiovascular events among people with diabetes, resulting in the ADA and the American Heart Association (AHA) not recommending the blanket use of aspirin in all patients with diabetes, but rather a use guided by an assessment of their absolute global cardiovascular risk.

Lifestyle modification - Compared to routine diabetes education and support, intensive lifestyle modification has been shown to independently affect cardiovascular risk factors in people with type 2 diabetes over a 4-year period in the Look AHEAD (Action for Health in Diabetes) study. Participants had a greater percentage of weight loss than diabetes support and education participants (–6.15% vs –0.88%; P< 0.001) and greater improvements in fitness (12.74% vs 1.96%; P< 0.001), HbA 1c level (–0.36% vs –0.09%; P < 0.001), systolic (–5.33 vs –2.97 mm Hg; P< 0.001) and diastolic (–2.92 vs –2.48 mm Hg; P = 0.01) blood pressure, and levels of high-density lipoprotein cholesterol (3.67 vs 1.97 mg/dL; P< 0.001) and triglycerides (–25.56 vs. –19.75 mg/dL; P<0.001). However, the independent effect of intensive lifestyle modification on cardiovascular events remains unknown.

Therapies for prediabetes

Screen-detected prediabetes can be managed with lifestyle intervention and/or pharmacotherapy, as there is robust trial evidence on the efficacy of each of these therapies, which is stronger for lifestyle intervention.

Lifestyle intervention (dietary and physical activity recommendations to achieve weight loss) has been shown to reduce the progression from IGT to diabetes by 30%-60% in several randomized controlled trials. Lifestyle interventions have been efficacious across a broad range of ethnic groups, with a persistence of the beneficial effects of lifestyle modification in reducing diabetes incidence several years after discontinuation of the active intervention. Sustained relative reductions (34% to 43%) in diabetes incidence were evident 3 to 14 years after the termination of the active lifestyle intervention in three landmark trials.

In addition to effects on diabetes incidence, lifestyle modification improved cardiovascular risk factors (blood pressure, serum cholesterol, and serum triglycerides) in people with prediabetes; however, hard cardiovascular outcomes were not reduced. Lifestyle intervention also has beneficial effects on microvascular outcomes; 14 years after the active phase of the Da Qing study, the lifestyle intervention group exhibited a 47% lower incidence of severe retinopathy than the control group. Regarding the translation of these results into practice, group delivery of the lifestyle intervention in community settings has the potential to be significantly less expensive while still achieving weight loss similar to that observed with individually-based intervention used in landmark trials.

Several drugs have been shown to prevent the progression of the impaired glucose tolerance to type 2 diabetes; these include metformin, troglitazone, rosiglitazone, arcabose, orlistat, voglibose, and valsartan. However, for most drugs concerns regarding their costs, side effects, and the lack of persistence of effect level of efficacy, limit their use, including acarbose despite its collateral positive effects on cardiovascular events (49% reduction) and hypertension (34% decreased incidence). Consequently, the only drug with the best safety profile and efficacy that has been recommended for use in practice for preventing diabetes is metformin, which was shown to be most effective compared to lifestyle in persons with a body mass index ≥35 kg/m², and in younger patients (less than 60 years of age).

Recommendations for screening

Recommendations of various US professional organizations

The currently available evidence does not support universal screening; consequently, most professional organizations advocate a selective and opportunistic approach in high-risk populations.

Regarding undiagnosed diabetes, the US Preventive Services Task Force (USPSTF) recommends screening for undiagnosed type 2 diabetes in adults with sustained blood pressure ≥135/80 mmHg. The American Diabetes Association (ADA) recommends opportunistic screening in adults of any age with a body mass index ≥25 kg/m² and additional risk factors, which include physical inactivity, first-degree relative with diabetes, high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander), women who delivered a baby weighing 9 lb or were diagnosed with gestatioinal diabetes mellitus, hypertension (≥140/90 mmHg or on therapy for hypertension), HDL-cholesterol level <35 mg/dl (0.90 mmol/l) and/or a triglyceride level >250 mg/dl (2.82 mmol/l), women with polycystic ovarian syndrome, HbA 1c≥5.7%, IGT, or IFG on previous testing, other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans), and history of cardiovascular disease. In adults with normal weight and without any risk factors, screening must begin at age 45. Both the USPTF and the ADA recommend using either fasting plasma glucose of HbA 1c for testing, at a 3-year frequency. The ADA further recommends the consideration of more frequent testing depending on initial results and risk.

The American Academy of Family Physicians (AAFP) recommends screening for type 2 diabetes in adults with hypertension and hyperlipidemia. The AAFP found insufficient evidence to recommend for or against adults who are at low risk for coronary vascular disease.

For prediabetes, the ADA and USPSTF recommendations are similar to that of undiagnosed diabetes, but with the use of OGTT as a screening test in addition to FPG or HbA 1c. The ADA recommends that patients detected with prediabetes or an HbA 1c of 5.7%–6.4% be referred to an effective ongoing support program targeting weight loss of 7% and increasing physical activity to at least 150 min/week of moderate activity such as walking. For those at very-high-risk of progression to type 2 diabetes (presence of both IGT and IFG or of multiple risk factors), especially if there is progression of hyperglycemia [e.g., HbA 1c ≥6.0%] despite lifestyle interventions), the ADA advises additional use of metformin therapy. Furthermore, monitoring for the development of prediabetes should be performed every year.

The Endocrine Society recommends screening for prediabetes among patients for components of metabolic syndrome, as defined by the American Heart Association/National Heart, Lung, and Blood Institute, at least every 3 years. At least 3 components in any patient puts him/her at high risk for metabolic syndrome. It also recommends that patients with previous history of diabetes be screened for diabetes every 1 to 2 years using FPG or OGTT. Also, all patients with metabolic risk should undergo global risk assessment for 10-year risk for coronary heart disease or cerebral vascular disease using the Framingham Risk Evaluation algorithm before starting preventive therapy.

The American Association of Clinical Endocrinologists (AACE) recommends testing for prediabetes among all subjects with high-risk factors for developing diabetes using the 2-hour OGTT or FPG.

The Indian Health Service recommends screening for prediabetes in high-risk patients using FPG or 2-hour OGTT to screen high-risk patients.

Of all the recommendations made by US professional organizations, the USPSTF and ADA recommendations were developed after a rigorous process of systematic review of the available evidence, and thus appear as a solid basis for clinical practice. However, the USPSTF guidelines are more restrictive in terms of the target population; consequently, these may be less appropriate for use in clinical practice.

Summary and recommendations for clinical practice

Reasons to screen for prediabetes and diabetes include the increasingly high prevalence of these conditions worldwide, recognizable pre-diabetic and long latent diabetic phases, and the availability of suitable, reliable, high performance and acceptable tests that can aid in the detection of hyperglycemic conditions. Although no trial assessing the effectiveness of screening for hyperglycemia on health outcomes (morbidity and mortality) has been published, testing for diabetes does not seem to be associated with adverse psychosocial consequences. However, the effect of attributing the label of prediabetes remains unknown. There are accepted and cost-effective treatments for recognized prediabetes, which include lifestyle modification and metformin; however, the effect of these therapies on cardiovascular outcomes remains unknown. There also seems to be an incremental benefit of intensive multifactorial therapy over current standards in people with screen-detected diabetes, which will need confirmation with additional follow-up. Furthermore, indirect evidence from studies of people with recently conventionally-diagnosed diabetes indicates potential benefits of early treatment for diabetes. Economic models strongly support the undertaking of targeted screening for both prediabetes and diabetes.

Based on the overall available evidence, it may be justifiable to undertake opportunistic screening in an organized manner for prediabetes and undiagnosed diabetes among asymptomatic high-risk people every 3 years using the ADA criteria, which are more broader, and were based on a robust derivation process. People detected as having diabetes should be treated using a multifactorial approach aiming to control blood glucose and other cardiovascular risk using existing cardioprotective cost-effective drugs, as well as lifestyle modification. People detected with prediabetes should primarily be managed by lifestyle modification, with the addition of metformin in case of need.

What’s the Evidence?/References

Arguments for screening for prediabetes and undiagnosed type 2 diabetes

Whiting, DR, Guariguata, L, Weil, C, Shaw, J. "IDF Diabetes Atlas: Global estimates of the prevalence of diabetes for 2011 and 2030". Diabetes Res Clin Pract.. vol. 94. 2011. pp. 311-2.

Roglic, G, Unwin, N. "Mortality attributable to diabetes: estimates for the year 2010". Diabetes Res Clin Pract. vol. 87. pp. 15-9.

Ford, ES, Zhao, G, Li, C. "Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence". J Am Coll Cardiol. vol. 55. pp. 1310-7.

Zhang, P, Zhang, X, Brown, J, Vistisen, D, Sicree, R, Shaw, J. "Global healthcare expenditure on diabetes for 2010 and 2030". Diabetes Res Clin Pract. vol. 87. pp. 293-301.

Gerstein, HC, Santaguida, P, Raina, P, Morrison, KM, Balion, C, Hunt, D. "Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies". Diabetes Res Clin Pract. vol. 78. pp. 305-12.

Harris, MI, Klein, R, Welborn, TA, Knuiman, MW. "Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis". Diabetes Care. vol. 15. pp. 815-9.

Sandbaek, A, Griffin, SJ, Rutten, G, Davies, M, Stolk, R, Khunti, K. "Stepwise screening for diabetes identifies people with high but modifiable coronary heart disease risk. The ADDITION study". Diabetologia. vol. 51. pp. 1127-34.

Echouffo-Tcheugui, JB, Sargeant, LA, Prevost, AT, Williams, KM, Barling, RS, Butler, R. "How much might cardiovascular disease risk be reduced by intensive therapy in people with screen-detected diabetes". Diabet Med. vol. 25. pp. 1433-9.

Screening tests

Buijsse, B, Simmons, RK, Griffin, SJ, Schulze, MB. "Risk assessment tools for identifying individuals at risk of developing type 2 diabetes". Epidemiol Rev. vol. 33. pp. 46-62.

Herman, WH, Smith, PJ, Thompson, TJ, Engelgau, MM, Aubert, RE. "A new and simple questionnaire to identify people at increased risk for undiagnosed diabetes". Diabetes Care. vol. 18. pp. 382-7.

Heikes, KE, Eddy, DM, Arondekar, B, Schlessinger, L. "Diabetes Risk Calculator: a simple tool for detecting undiagnosed diabetes and pre-diabetes". Diabetes Care. vol. 31. pp. 1040-5.


Echouffo-Tcheugui, JB, Ali, MK, Griffin, SJ, Narayan, KM. "Screening for type 2 diabetes and dysglycemia". Epidemiol Rev. vol. 33. pp. 63-8.

Effectiveness and cost-effectiveness of screening for hyperglycemia

Echouffo-Tcheugui, JB, Simmons, RK, Williams, KM, Barling, RS, Prevost, AT, Kinmonth, AL. "The ADDITION-Cambridge trial protocol - a cluster randomised controlled trial of screening for type 2 diabetes and intensive treatment for screen-detected patients". BMC Public Health. vol. 9. pp. 136.

Griffin, SJ, Borch-Johnsen, K, Davies, MJ, Khunti, K, Rutten, GE, Sandbaek, A. "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. vol. 378. pp. 156-67.

Schellhase, KG, Koepsell, TD, Weiss, NS, Wagner, EH, Reiber, GE. "Glucose screening and the risk of complications in Type 2 diabetes mellitus". J Clin Epidemiol. vol. 56. pp. 75-80.

Schneider, H, Ehrlich, M, Lischinnski, M. "Did the intensive glycosuria screening of the sixties and seventies in East Germany improve the survival prognosis of early dectected diabetics". Diabetes Stoffweschsel. vol. 5. pp. 33-8.

Eborall, HC, Griffin, SJ, Prevost, AT, Kinmonth, AL, French, DP, Sutton, S. "Psychological impact of screening for type 2 diabetes: controlled trial and comparative study embedded in the ADDITION (Cambridge) randomised controlled trial". BMJ. vol. 335. pp. 486.

Echouffo-Tcheugui, JB, Ali, MK, Griffin, SJ, Narayan, KM. "Screening for type 2 diabetes and dysglycemia". Epidemiol Rev. vol. 33. pp. 63-8.

Paddison, CA, Eborall, HC, Sutton, S, French, DP, Vasconcelos, J, Prevost, AT. "Are people with negative diabetes screening tests falsely reassured? Parallel group cohort study embedded in the ADDITION (Cambridge) randomised controlled trial". BMJ. vol. 339. pp. b4535.

Mai, KS, Sandbaek, A, Borch-Johnsen, K, Lauritzen, T. "Are lifestyle changes achieved after participation in a screening programme for Type 2 diabetes". Diabet Med. vol. 24. pp. 1121-8.

Cost-effectiveness of screening for hyperglycemia

Waugh, N, Scotland, G, McNamee, P, Gillett, M, Brennan, A, Goyder, E. "Screening for type 2 diabetes: literature review and economic modelling". Health Technol Assess. vol. 11. pp. 1-12.

Hoerger, TJ, Hicks, KA, Sorensen, SW, Herman, WH, Ratner, RE, Ackermann, RT. "Cost-effectiveness of screening for pre-diabetes among overweight and obese U.S. adults". Diabetes Care. vol. 30. pp. 2874-9.

Gillies, CL, Lambert, PC, Abrams, KR, Sutton, AJ, Cooper, NJ, Hsu, RT. "Different strategies for screening and prevention of type 2 diabetes in adults: cost effectiveness analysis". BMJ. vol. 336. pp. 1180-5.

Kahn, R, Alperin, P, Eddy, D, Borch-Johnsen, K, Buse, J, Feigelman, J. "Age at initiation and frequency of screening to detect type 2 diabetes: a cost-effectiveness analysis". Lancet. vol. 375. pp. 1365-74.

Chatterjee, R, Narayan, KM, Lipscomb, J, Phillips, LS. "Screening adults for pre-diabetes and diabetes may be cost-saving". Diabetes Care. vol. 33. pp. 1484-90.

Treatment for screen-detected prediabetes or diabetes

Lauritzen, T, Griffin, S, Borch-Johnsen, K, Wareham, NJ, Wolffenbuttel, BH, Rutten, G. "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 . vol. 24. pp. S6-11.

Griffin, SJ, Borch-Johnsen, K, Davies, MJ, Khunti, K, Rutten, GE, Sandbaek, A. "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 . vol. 378. pp. 156-67.

Gaede, P, Vedel, P, Larsen, N, Jensen, GV, Parving, HH, Pedersen, O. "Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes". NEJM. vol. 348. pp. 383-93.

Gaede, P, Lund-Andersen, H, Parving, HH, Pedersen, O. "Effect of a multifactorial intervention on mortality in type 2 diabetes". NEJM. vol. 358. pp. 580-91.

Holman, RR, Paul, SK, Bethel, MA, Matthews, DR, Neil, HA. "10-year follow-up of intensive glucose control in type 2 diabetes". NE J M. vol. 359. pp. 1577-89.

Costa, J, Borges, M, David, C, Vaz Carneiro, A. "Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials". BMJ. vol. 332. pp. 1115-24.

Colhoun, HM, Betteridge, DJ, Durrington, PN, Hitman, GA, Neil, HA, Livingstone, SJ. "Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial". Lancet. vol. 364. pp. 685-9.

Collins, R, Armitage, J, Parish, S, Sleigh, P, Peto, R. "MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial". Lancet. vol. 361. pp. 2005-16.

"Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group". BMJ. vol. 317. 1998. pp. 703-13.

Pignone, M, Alberts, MJ, Colwell, JA, Cushman, M, Inzucchi, SE, Mukherjee, D. "Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation". Circulation. vol. 121. pp. 2694-701.

Crandall, JP, Knowler, WC, Kahn, SE. "The prevention of type 2 diabetes". Nat Clin Pract. vol. 4. pp. 382-93.

Lindstrom, J, Ilanne-Parikka, P, Peltonen, M, Aunola, S, Eriksson, JG, Hemio, K. "Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study". Lancet . vol. 368. pp. 1673-9.

Li, G, Zhang, P, Wang, J, Gregg, EW, Yang, W, Gong, Q. "The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study". Lancet. vol. 371. pp. 1783-9.

Knowler, WC, Fowler, SE, Hamman, RF, Christophi, CA, Hoffman, HJ, Brenneman, AT. "10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study". Lancet. vol. 374. pp. 1677-86.

Gong, Q, Gregg, EW, Wang, J, An, Y, Zhang, P, Yang, W. "Long-term effects of a randomised trial of a 6-year lifestyle intervention in impaired glucose tolerance on diabetes-related microvascular complications: the China Da Qing Diabetes Prevention Outcome Study". Diabetologia. vol. 54. pp. 300-7.

Current screening recommendations in the United States

"Screening for type 2 diabetes". Diabetes Care. vol. 27. 2004. pp. S11-4.

"Standards of medical care in diabetes--2011". Diabetes Care. vol. 34. 2011. pp. S11-61.

Norris, SL, Kansagara, D, Bougatsos, C, Fu, R. "Screening adults for type 2 diabetes: a review of the evidence for the U.S. Preventive Services Task Force". Ann Intern Med. vol. 148. pp. 855-68.

"Screening for type 2 diabetes mellitus in adults: U.S. Preventive Services Task Force recommendation statement". Ann Intern Med. vol. 148. 2008. pp. 846-54.

Leawood, KS. "American Academy of Family Physicians. AAFP Policy Action: Summary of Recommendations for Clinical Preventive Services". American Academy of Family Physicians. 2007.

Rosenzweig, JL, Ferrannini, E, Grundy, SM, Haffner, SM, Heine, RJ, Horton, ES. "Primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk: an endocrine society clinical practice guideline". J Clin Endocrinol Metab. vol. 93. pp. 3671-89.

Rodbard, HW, Blonde, L, Braithwaite, SS, Brett, EM, Cobin, RH, Handelsman, Y. "American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus". Endocr Pract13 Suppl. vol. 1. pp. 1-68.

Garber, AJ, Handelsman, Y, Einhorn, D, Bergman, DA, Bloomgarden, ZT, Fonseca, V. "Diagnosis and management of prediabetes in the continuum of hyperglycemia: when do the risks of diabetes begin? A consensus statement from the American College of Endocrinology and the American Association of Clinical Endocrinologists". Endocr Pract. vol. 14. pp. 933-46.

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