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Evidence Summary

Other Supporting Document for Abnormal Blood Glucose and Type 2 Diabetes Mellitus: Screening

Preface

By Shelley Selph, MD, MPH; Tracy Dana, MLS; Ian Blazina, MPH; Christina Bougatsos, MPH; Hetal Patel, MD; and Roger Chou, MD


The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was published online first at www.annals.org on April 14, 2015.

Abstract

Background: Screening for type 2 diabetes mellitus could lead to earlier identification and treatment of asymptomatic diabetes, impaired fasting glucose (IFG), or impaired glucose tolerance (IGT), potentially resulting in improved outcomes.

Purpose: To update the 2008 U.S. Preventive Services Task Force review on diabetes screening in adults.

Data Sources: Cochrane databases and MEDLINE (2007 through October 2014) and relevant studies from previous Task Force reviews.

Study Selection: Randomized, controlled trials; controlled, observational studies; and systematic reviews.

Data Extraction: Data were abstracted by 1 investigator and checked by a second; 2 investigators independently assessed study quality.

Data Synthesis: In 2 trials, screening for diabetes was associated with no 10-year mortality benefit versus no screening (hazard ratio, 1.06 [95% CI, 0.90 to 1.25]). Sixteen trials consistently found that treatment of IFG or IGT was associated with delayed progression to diabetes. Most trials of treatment of IFG or IGT found no effects on all-cause or cardiovascular mortality, although lifestyle modification was associated with decreased risk for both outcomes after 23 years in 1 trial. For screen-detected diabetes, 1 trial found no effect of an intensive multifactorial intervention on risk for all-cause or cardiovascular mortality versus standard control. In diabetes that was not specifically screen-detected, 9 systematic reviews found that intensive glucose control did not reduce risk for all-cause or cardiovascular mortality and results for intensive blood pressure control were inconsistent.

Limitation: The review was restricted to English-language articles, and few studies were conducted in screen-detected populations.

Conclusion: Screening for diabetes did not improve mortality rates after 10 years of follow-up. More evidence is needed to determine the effectiveness of treatments for screen-detected diabetes. Treatment of IFG or IGT was associated with delayed progression to diabetes.

Primary Funding Source: Agency for Healthcare Research and Quality.

Introduction

In the United States, approximately 21 million persons received diabetes diagnoses in 2010, and an estimated 8 million cases were undiagnosed; roughly 90% to 95% of them have type 2 diabetes mellitus.1, 2 Prevalence of diabetes among U.S. adults has increased, from approximately 5% in 1995 to 8% in 2010.3 Diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and blindness; a major cause of heart disease and stroke; and the seventh-leading cause of death in the United States.1

Risk factors for diabetes include obesity, physical inactivity, smoking, and older age.1 Diabetes is more common among certain ethnic and racial minorities.1, 3 Type 2 diabetes is caused by insulin resistance and relative insulin deficiency, resulting in the inability to maintain normoglycemia. Diabetes typically develops slowly,4, 5 although microvascular disease, such as retinopathy and neuropathy, may be present at the time of diagnosis due to vascular damage during the subclinical phase.4, 6

Screening asymptomatic persons (those without signs or symptoms of hyperglycemia and no clinical sequelae) may lead to earlier identification and earlier or more-intensive treatments, potentially improving health outcomes.2 Strategies for screening include routine screening or targeted screening based on the presence of risk factors, such as obesity or hypertension. In 2008, the U.S. Preventive Services Task Force (USPSTF) recommended diabetes screening in asymptomatic adults with sustained blood pressure (BP) (treated or untreated) greater than 135/80 mm Hg (B recommendation). Although direct evidence on benefits and harms of screening was not available, the recommendation was based on the ability of screening to identify persons with diabetes and evidence that more-intensive BP treatment was associated with reduced risk for cardiovascular events, including cardiovascular mortality, in patients with diabetes and hypertension. The USPSTF found insufficient evidence to assess the balance of benefits and harms of screening in adults without elevated BP (I statement). It also found that lifestyle and drug interventions for impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), defined as a hemoglobin A1c level of 5.7% to 6.4% or a fasting blood glucose level between 5.55 and 6.94 mmol/L (100 and 125 mg/dL),2 were associated with reduced risk for progression to diabetes.7–14 Other groups also recommend screening persons with risk factors.15–20

This article updates previous USPSTF reviews21–23 on diabetes screening in nonpregnant adults.

Methods

Scope of the Review

We developed a review protocol and analytic framework (Appendix Figure 1) that included the following key questions:

  1. Is there direct evidence that screening for type 2 diabetes, IFG, or IGT among asymptomatic adults improves health outcomes?
  2. What are the harms of screening for type 2 diabetes, IFG, or IGT?
  3. Do interventions for screen-detected or early diabetes, IFG, or IGT provide an incremental benefit in health outcomes compared with no interventions or initiating interventions after clinical diagnosis?
  4. What are the harms of interventions for screen-detected or early diabetes, IFG, or IGT?
  5. Is there evidence that more-intensive glucose, BP, or lipid control interventions improve health outcomes in adults with type 2 diabetes, IFG, or IGT compared with traditional control? Is there evidence that aspirin use improves health outcomes in these populations compared with nonuse?
  6. What are the harms of more-intensive interventions compared with traditional control in adults with type 2 diabetes, IFG, or IGT?
  7. Do interventions for IFG or IGT delay or prevent the progression to type 2 diabetes?

The full report,24 on which this article is based, provides detailed methods and data for the review, including search strategies, evidence tables, and quality ratings of individual studies (available at www.uspreventiveservicestaskforce.org). The full report includes an additional key question on whether the effects of screening or interventions for screen-detected or early diabetes, IFG, or IGT vary by subgroups; effects of treatments on microvascular outcomes; and evidence on effects of more- versus less-intensive lipid control and aspirin use.24

Data Sources and Searches

A research librarian searched the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews and MEDLINE (2007 to October 2014). We supplemented electronic searches by reviewing previous USPSTF reports and reference lists of relevant articles.

Study Selection

At least 2 reviewers independently evaluated each study to determine inclusion eligibility using predefined inclusion and exclusion criteria (Appendix Figure 2). Because of the limited evidence on treatment of screen-detected diabetes (key question 5), we also included studies of treatment of early diabetes (defined as a pharmacologically untreated hemoglobin A1c level <8.5% or diabetes diagnosis in the past year) that was not specifically screen-detected. Appendix Figure 3 summarizes the selection of literature.

Data Abstraction and Quality Rating

One investigator abstracted details about the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results. A second investigator reviewed data abstraction for accuracy. Two investigators independently applied criteria developed by the USPSTF25 to rate the quality of each study as good, fair, or poor. Discrepancies were resolved through a consensus process.

Data Synthesis and Analysis

We conducted meta-analyses to calculate risk ratios (RRs) on effects of interventions with the DerSimonian–Laird random-effects model using Stata, version 12 (StataCorp). Statistical heterogeneity was assessed using the I2 statistic.26 When statistical heterogeneity was present, we performed sensitivity analyses using the profile likelihood method because the DerSimonian–Laird model results in overly narrow 95% CIs.27 Two studies28–30 that used a 2 × 2 factorial design reported no interaction between treatments and were analyzed as a 2-group parallel group trial for the comparison of interest. When studies evaluated several lifestyle strategies, we combined the lifestyle groups. We included all studies in meta-analyses, regardless of event rates. For rare events (incidence <1%), we calculated the Peto odds ratio.31 We stratified results by drug class or lifestyle intervention and performed additional sensitivity analyses based on study quality and presence of outlier trials. We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) using methods developed by the USPSTF, based on the quality of studies, precision of estimates, consistency of results, and directness of evidence.25

Role of the Funding Source

This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic framework, and key questions; resolve issues arising during the project; and finalize the report. AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. It also performed a final review of the manuscript to ensure that the analysis met methodological standards. The investigators are solely responsible for the content and the decision to submit the manuscript for publication.

Results

Benefits of Screening

Two randomized, controlled trials (ADDITION [Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen Detected Diabetes in Primary Care]–Cambridge [Cambridge, United Kingdom] trial [n = 19,226],32 rated good-quality, and a trial conducted in Ely, United Kingdom [n = 4936],33 rated fair-quality) evaluated effects of diabetes screening versus no screening on mortality (Appendix Table 1). The ongoing ADDITION trial includes sites in Cambridge, the Netherlands, and Denmark on intensive versus standard treatment of screen-detected diabetes; however, only the Cambridge site had a no-screening component.34 Mean age ranged from 51 to 58 years, 36% to 54% of participants were women, and follow-up was 10 years in both studies.32, 33 In ADDITION-Cambridge, persons at high risk for diabetes, based on known risk factors, were randomly assigned in clusters by clinic site to screening or no screening.32 The Ely study randomly enrolled participants (not selected based on high risk for diabetes) to screening or no screening from a single practice site.33 Seventy-eight percent of participants (11,737 of 15,089) invited to screening had screening in the ADDITION trial;32 68% of participants in the Ely study were screened.33 Methodological shortcomings in the Ely study included unclear randomization and allocation concealment methods, with baseline differences between groups.

Screening was not superior to no screening in reducing risk for all-cause mortality in either the ADDITION (hazard ratio [HR], 1.06 [95% CI, 0.90 to 1.25])32 or Ely (unadjusted HR, 0.96 [CI, 0.77 to 1.20]; adjusted HR, 0.79 [CI, 0.63 to 1.00])33 trial, with point estimates close to 1. The ADDITION trial also found that screening was not associated with reduced risk for cardiovascular mortality (HR, 1.02 [CI, 0.75 to 1.38]), cancer-related mortality (HR, 1.08 [CI, 0.90 to 1.30]), or diabetes-related mortality (HR, 1.26 [CI, 0.75 to 2.10]).32 Neither study reported nonmortality health outcomes.

Harms of Screening

A fair-quality pilot study of 116 persons invited for screening in the ADDITION trial found that a new diagnosis of diabetes was associated with increased short-term anxiety 6 weeks after screening, compared with no new diagnosis, based on short-form Spielberger State-Trait Anxiety Inventory scores (46.7 vs. 37.0; P = 0.031).35 Studies lasting longer than the ADDITION and Ely trials (≥1 year) found no negative psychological effects associated with invitation to screening or notification of positive diabetes status.36, 37 We identified no studies estimating the rate of false-positive test results, psychological effects, or other harms associated with a diagnosis of IFG or IGT.

Benefits of Treating Screen-Detected or Early Diabetes, IFG, or IGT

A randomized trial conducted in Da Qing, China, of overweight (mean body mass index [BMI], 25.8 kg/m2) persons with IGT found that, versus usual care, a 6-year lifestyle intervention was associated with reduced risk for all-cause (HR, 0.71 [CI, 0.51 to 0.99]) and cardiovascular (HR, 0.59 [CI, 0.36 to 0.96]) mortality after 23 years of follow-up.38 The trial was rated fair-quality because of unclear randomization and allocation concealment methods. This study had previously reported no difference in these outcomes after 20-year follow-up.39 Other trials of lifestyle interventions in persons with IFG or IGT and elevated BMI40, 41 or newly diagnosed diabetes42–44 with shorter follow-up also reported no beneficial effects on all-cause or cardiovascular mortality (Appendix Table 2).

Trials of pharmacologic interventions (alone28–30, 45–49 or in combination with lifestyle modification50 vs. placebo or usual care) for early diabetes, IFG, or IGT found few differences in health outcomes, including all-cause and cardiovascular mortality (Appendix Table 2). Mean age ranged from 45 to 64 years, and studies enrolled persons who were overweight (BMI >25.0 kg/m2) or obese (BMI >30.0 kg/m2). Five studies were rated good-quality and 3 were rated fair-quality; common methodological shortcomings in the fair-quality studies included unclear randomization and allocation concealment methods. Although individual studies were generally underpowered to detect these outcomes and few events were reported in most studies, pooled estimates were close to 1. Based on 8 studies10, 28, 45–48, 51, 52 of glucose-lowering agents, including 310, 51, 52 from the previous USPSTF review,22 the pooled odds ratio for all-cause mortality was 1.01 (CI, 0.87 to 1.18; I2 = 28%) (Appendix Figure 4). For cardiovascular mortality, the pooled odds ratio was 1.06 (CI, 0.84 to 1.35; I2 = 7%) based on 5 studies28, 48, 52–54 of glucose-lowering agents, including 3 studies52–54 involved in the previous USPSTF review22 (Appendix Figure 5).

Harms of Treating Screen-Detected or Early Diabetes, IFG, or IGT

Of 4 good-quality and 5 fair-quality trials that reported harms associated with interventions,28–30, 40, 43–49 1 study was conducted in persons with screen-detected or early diabetes and the others enrolled persons with IFG or IGT. No study was specifically designed to assess harms. There were few differences between medications or lifestyle modification versus placebo or usual care in risk for harms (Appendix Table 2). One trial found that, compared with placebo, acarbose was associated with greater risk for withdrawal because of adverse events.47 Rosiglitazone was associated with increased congestive heart failure in 1 trial, although the estimate was imprecise (HR, 7.04 [CI, 1.60 to 31]).30 One study found that nateglinide was associated with increased risk for hypoglycemia versus placebo (RR, 1.73 [CI, 1.57 to 1.92]), and valsartan was associated with increased risk for hypotension-related adverse events (RR, 1.16 [CI, 1.11 to 1.23]).28, 29

Benefits of More Intensive Treatment Versus Standard Treatment

The treatment phase of the ADDITION-Europe trial evaluated effects of more-intensive multifactorial treatment of screen-detected diabetes.55–57 It was rated fair-quality because of unclear methods of randomization and allocation concealment. The mean hemoglobin A1c level was 6.5%, approximately one fourth of participants were smokers, mean BMI was 31.5 kg/m2, and 6% to 7% of participants had a previous myocardial infarction (MI). Participants were randomly assigned to a multifactorial intervention that included use of intensive glucose-, BP-, and lipid-lowering targets (hemoglobin A1c level <7.0%, BP <135/85 mm Hg, and total cholesterol level ≤4.5 to 5.0 mmol/L [≤173.7 to 193.1 mg/dL]) plus a lifestyle education component (n = 1678) versus treatment to standard targets according to local guidelines (n = 1379). Participants were followed for 5 years or until their first cardiovascular event (cardiovascular mortality, nonfatal MI or stroke, revascularization, or [nontraumatic] amputation).55

After adjustment for country, intensive treatment was not associated with reduced risk for first cardiovascular event (HR, 0.83 [CI, 0.65 to 1.05]),55 all-cause (HR, 0.83 [CI, 0.65 to 1.05]) or cardiovascular (HR, 0.88 [CI, 0.51 to 1.51]) mortality, stroke (HR, 0.98 [CI, 0.57 to 1.71]), MI (HR, 0.70 [CI, 0.41 to 1.21]), or revascularization (HR, 0.79 [CI, 0.52 to 1.18]), although most estimates favored intensive therapy. Mortality and cardiovascular event rates were lower than anticipated, with little difference between groups in final hemoglobin A1c and total cholesterol levels and BP.55 There was also no difference in self-reported measures of general and diabetes-specific quality of life.57

In persons with diabetes that was not specifically screen-detected, 9 good-quality systematic reviews found consistent evidence that intensive glucose lowering to a target hemoglobin A1c level less than 6.0% to 7.5% was not associated with decreased risk for all-cause or cardiovascular mortality compared with less-intensive therapy (Appendix Table 3).58–66 One of the largest and most recent reviews60 analyzed evidence from 14 trials (n = 28,614), including several large, good-quality trials67–69 published since the previous USPSTF report. Intensive glucose-lowering therapy was consistently associated with reduced risk for nonfatal MI in 6 reviews (RR range, 0.83 to 0.87).58, 60, 61, 63, 64, 66

Intensive BP-lowering was associated with reduced risk for all-cause mortality (RR, 0.90 [CI, 0.82 to 0.98]; I2 = 0%) and stroke (RR, 0.83 [CI, 0.73 to 0.95]; I2 = 27%) in 1 good-quality systematic review,70 but individual trials defined intensive BP control differently and some trials showed inconsistent effects (Appendix Table 4). One recent large trial (n = 4732)71 found no difference between a systolic BP target of 140 mm Hg and 120 mm Hg in risk for all-cause (RR, 1.11 [CI, 0.89 to 1.38]) or cardiovascular (RR, 1.04 [CI, 0.73 to 1.48]) mortality, whereas another (n = 11,140)72, 73 found that, compared with placebo, the addition of an angiotensin-converting enzyme inhibitor plus a diuretic was associated with decreased risk for all-cause (RR, 0.87 [CI, 0.76 to 0.98]) and cardiovascular (RR, 0.33 [CI, 0.15 to 0.74]) mortality. Results from older studies22 were also mixed and characterized by variability in antihypertensive treatments and baseline, target, and achieved BP levels.74–79

Harms of More Intensive Treatment Versus Standard Treatment

The ADDITION-Netherlands study found no difference between intensive multifactorial treatment versus standard treatment in risk for severe hypoglycemia after 1 year of follow-up, but the event rate was low and the estimate was imprecise (0.4% vs. 0.0%; RR, 2.86 [CI, 0.12 to 70]).80

In persons with diabetes not specifically screen-detected, intensive glucose control was associated with increased risk for severe hypoglycemia and serious nonhypoglycemia adverse events requiring medical intervention (Appendix Table 3).59, 60, 63, 65 Harms of other interventions, including intensive BP-lowering and intensive multifactorial interventions, were mixed.71, 72, 81, 82

Benefits of Treatment in IFG or IGT on the Delay or Prevention of Progression to Diabetes

We identified 14 randomized, controlled trials,28, 29, 38–40, 45–47, 49, 83–89 1 quasi-randomized trial,48 and 1 cohort study90 on the effects of interventions for IFG or IGT on risk for progression to diabetes (Appendix Table 5).28, 29, 38–40, 45–49, 83–90 Three trials were rated good-quality,28, 29, 46, 49 and the remainder were fair-quality. Methodological shortcomings in the fair-quality studies included unclear randomization and allocation concealment methods, unblinded design, and lack of intention-to-treat analysis. The studies assessed lifestyle interventions (6 studies),38, 40, 84, 86–88 pharmacologic interventions (8 studies in 9 publications),28, 29, 45–49, 89, 90 and multifactorial interventions (2 studies).83, 85 Treatment duration ranged from 6 months to 6 years, with follow-up extending up to 23 years. Mean age ranged from 45 to 65 years. In all but 1 study,86 participants were overweight or obese. Mean total cholesterol levels ranged from 4.3 to 5.9 mmol/L (166 to 228 mg/dL) (Appendix Table 5).

Lifestyle Interventions

Lifestyle interventions were associated with decreased risk for progression to diabetes, based on 6 studies,38, 40, 84, 86–88 including 47–10 that were in the previous USPSTF review22 (pooled RR, 0.55 [CI, 0.43 to 0.70]; I2 = 77%; profile likelihood estimate, 0.57 [CI, 0.43 to 0.70]) (Appendix Figure 6). After exclusion of the Da Qing trial, an outlier study with very long (23-year) follow-up,38 we found similar results (pooled RR, 0.53 [CI, 0.44 to 0.63]; I2 = 25%).

Pharmacologic Interventions

Eight studies published since the previous USPSTF review assessed the effect of pharmacologic interventions.28, 45–49, 89, 90 Thiazolinediones were associated with decreased risk for progression to diabetes (3 studies; pooled RR, 0.50 [CI, 0.28 to 0.92]; I2 = 92%) (Appendix Figure 7).45, 48, 52 Statistical heterogeneity was substantial, and the estimate was no longer statistically significant using the profile likelihood method (RR, 0.51 [CI, 0.23 to 1.06]). Excluding the Indian Diabetes Prevential Programme-2 trial,48 which was conducted in India among mostly male participants, eliminated much of the heterogeneity (RR, 0.42 [CI, 0.37 to 0.47]; I2 = 36%). A similar effect was found in 4 studies of α-glucosidase inhibitors (RR, 0.64 [CI, 0.45 to 0.90]; I2 = 67%; profile likelihood method, 0.65 [CI, 0.44 to 0.91]) (Appendix Figure 8).46, 47, 51, 91 Other studies found that valsartan29 and a combination of low-dose metformin and rosiglitazone,49 but not nateglinide28 or glimepiride,89 was associated with reduced risk for progression to diabetes.

Multifactorial Interventions

Two trials examined the multifactorial interventions consisting of intensive glucose, BP, and lipid control, in addition to lifestyle counseling and aspirin.83, 85 The ADDITION-Denmark trial (n = 1510) found that the multifactorial intervention was associated with a decreased risk for progression to diabetes that was nearly statistically significant (RR, 0.89 [CI, 0.78 to 1.02]).85 Effects were greater in the subgroup that also received motivational interviewing (RR, 0.83 [CI, 0.68 to 1.00]) than in those that did not (RR, 0.95 [CI, 0.80 to 1.14]). A smaller (n = 181) Chinese study reported a lower incidence of progression to diabetes in the intervention than the control group, but the estimate was imprecise (0.0% vs. 5.8%; RR, 0.08 [CI, 0.00 to 1.42]).83

Discussion

The Table summarizes the evidence reviewed for this update. In 2 trials, 1 of which focused on persons at greater risk for diabetes, screening was not associated with decreased risk for mortality versus no screening after 10 years of follow-up.32, 33 Point estimates from both trials were close to 1 and did not indicate a trend toward benefit in the good-quality trial, although the CIs encompass potentially meaningful effects (for example, 10% and 37% reduction in risk for all-cause mortality). Possible explanations for the lack of a mortality effect include limited screening uptake, increased mortality among nonattendees invited to screening (potentially attenuating estimates based on intention-to-treat analyses), increased diabetes screening across groups outside of the study protocol, improved management of cardiovascular disease risk factors and diabetes contributing to decreased mortality, and inadequate length of follow-up to adequately assess mortality. In addition, screening trials did not report nonmortality clinical outcomes, which may require less lengthy follow-up to detect clinically relevant effects. Evidence on harms associated with screening is sparse, although limited evidence showed no clear long-term negative effects on psychological measures.35–37

Lifestyle and pharmacologic interventions both seem to be effective in delaying or preventing progression from IFG or IGT to diabetes in persons with high BMI.7–10, 39, 40, 45–47, 51, 52, 84, 86, 88, 89, 91 Effects of interventions on long-term clinical outcomes are less clear. The study with the longest follow-up (23 years) found that lifestyle modification for 6 years for early diabetes, IFG, or IGT was associated with a mortality benefit.38 Studies with shorter duration of follow-up found no beneficial effects of treatment on mortality, although evidence for improvement in microvascular outcomes was limited, as discussed in more detail in the full report.24

Pharmacologic treatment of screen-detected or early diabetes, IFG, or IGT was associated with increased risk for withdrawal because of adverse events versus placebo in 1 study,47 with no clear increased risk for serious adverse events. In general, trials were not designed or powered to specifically assess the risk for serious but uncommon or rare adverse events, although studies not restricted to persons with screen-detected or early diabetes did not show a clear increase in risk for such events, such as lactic acidosis with metformin.92

Since the previous USPSTF review, there is now evidence from a large, good-quality trial that an intensive multifactorial intervention for screen-detected diabetes aimed at decreasing glucose and lipid levels and BP was not associated with a statistically significant reduction in risk for all-cause or cardiovascular mortality or morbidity versus standard treatment, although estimates favored intensive treatment.56 For diabetes not specifically identified by screening, systematic reviews consistently found no association between intensive versus less-intensive glucose-lowering therapy and reduced risk for all-cause or cardiovascular mortality.58–66 Intensive glucose-lowering therapy was associated with reduced risk for nonfatal MI but increased risk for severe hypoglycemia. Other outcomes, such as retinopathy and neuropathy (discussed in the full report24) were found less frequently in these reviews, and pooled risk estimates were inconsistent, precluding reliable conclusions.

The 2008 USPSTF review22 found that effects of intensive BP control were greater in persons with diabetes versus those without it, based on subgroup analyses from trials that were generally less successful at achieving lower BP than recent studies.71, 72 Since then, there is more evidence on the benefits of more effective, intensive BP control versus standard therapy, specifically in persons with diabetes. Although a good-quality systematic review found that intensive BP control in persons with diabetes was associated with reduced risk for all-cause mortality versus less-intensive BP control,70 results from individual studies, including those from the recent, large, well-conducted trials,71, 72 were inconsistent.

Our review has limitations. We only included English-language articles, although a recent review found that this limitation did not introduce bias into systematic review findings.93 We identified only 2 screening studies, and only 1 treatment study was conducted in a screen-detected population. We included evidence on intensive treatment from studies of persons with early diabetes that was not specifically screen-detected because studies in screen-detected populations were lacking, which could limit applicability to screening settings.

We identified many important research gaps. Screening studies in U.S. populations, in which the prevalence of undiagnosed diabetes (and IFG or IGT) is likely to be greater than the 3% identified in the ADDITION-Cambridge and Ely studies, would be more applicable for informing U.S. screening decisions. As detailed in the full report, there is also little evidence on the effect of screening on ethnic and racial minorities, in whom the prevalence of diabetes is greater than in persons of white, European ancestry.24 Longer-term follow-up of the treatment phase of the ADDITION trial is needed to determine whether beneficial trends become statistically significant as more events occur.56 Studies of the effect of interventions for early diabetes, IFG, or IGT, particularly studies of lifestyle interventions with long-term (>20 years) follow-up, are needed to confirm the findings of the Da Qing study.38

In conclusion, screening for diabetes did not improve mortality rates after 10 years of follow-up in 2 trials32, 33 but was found to decrease mortality rates in a lifestyle intervention study with 23 years of follow-up.38 More evidence is needed to determine the effectiveness of treatments for screen-detected diabetes. Treatment of IFG or IGT was associated with delayed progression to diabetes.

Copyright and Source Information

Source: This article was published online first at www.annals.org on April 14, 2015.

Acknowledgment: The authors thank AHRQ Medical Officer Quyen Ngo-Metzger, MD, MPH.

Grant Support: By the Agency for Healthcare Research and Quality (contract no. HHSA 290-2007-10057-I, Task Order No. 13).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2221.

Requests for Single Reprints: Shelley Selph, MD, MPH, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, selphs@ohsu.edu.

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Table. Summary of Evidence

Main Findings From Previous USPSTF Report Number and Type of Studies Identified for Update* Limitations Consistency Applicability Summary of Findings Overall Quality
KQ 1. Is there direct evidence that screening for type 2 diabetes, IFG, or IGT among asymptomatic adults improves health outcomes?
No RCTs on the effects of screening for diabetes on clinical outcomes

1 case–control study found no association between screening and improvement in microvascular outcomes

2 RCTs Mortality outcomes limited to 10 y Consistent Both trials in the United Kingdom; ADDITION in high-risk population; Ely trial in average-risk population 2 RCTs found no effect on all-cause or CV mortality with screening vs. no screening after 10 y Fair
KQ 2. What are the harms of screening for type 2 diabetes, IFG, or IGT?
No evidence on serious psychological or other adverse effects associated with a new diagnosis of diabetes 3 RCTs Small sample size in study showing that short-term anxiety was associated with invitation to screening Consistent All trials in the United Kingdom; 2 studies in high-risk population; 1 study in average-risk population In the short term, being invited to screening increased anxiety vs. not being invited; in longer-term follow-up (>1 y), anxiety or depression did not differ between persons with negative screening results for diabetes and those unscreened or in those with positive screening results for diabetes vs. those with negative screening results Fair
KQ 3. Do interventions for screen-detected or early type 2 diabetes, IFG, or IGT provide an incremental benefit in health outcomes compared with no interventions or initiating interventions after clinical diagnosis?
No clear evidence on the benefit of treatment in the screen-detected diabetes population or comparing treatment effects in persons with screen- and clinically- detected diabetes, although 1 trial found that acarbose was associated with reduced risk for MI 13 RCTs (16 publications) Most studies underpowered to evaluate mortality and other CV outcomes and were limited to 3-y follow-up with few events; evidence often limited to a single study per drug Consistent Few studies in a nonwhite population; some studies required patients to have CVD or risk factors for diabetes or CVD; others excluded patients with CVD Most studies found no benefit on all-cause or CV mortality with glucose-lowering or antihypertensive medications or with lifestyle modification, although 1 study of lifestyle modification found reduced risk for all-cause and CV mortality after 23-y follow-up Fair
KQ 4. What are the harms of interventions for screen-detected or early type 2 diabetes, IFG, or IGT?
No studies reported serious harms

No studies done in persons with screen-detected diabetes reported harms

Studies done in persons with IFG or IGT included in the previous report found no differences in withdrawal rates between lifestyle or pharmacologic interventions and control

9 RCTs (11 publications) Few studies in screen-detected or early diabetes, IFG, or IGT populations; studies not designed to evaluate harms Consistent Few studies in a nonwhite population; some studies required patients to have CVD or risk factors for diabetes or CVD; others excluded patients with CVD

Little difference between active medication or lifestyle modification vs. placebo or usual care in risk for harms

Acarbose was associated with greater withdrawal rates; single-study evidence was available for increased risk for any adverse event with pioglitazone and voglibose, increased hypoglycemia with nateglinide, and increased hypotension with valsartan

Fair
KQ 5. Is there evidence that more intensive glucose, BP, or lipid control interventions improve health outcomes in adults with type 2 diabetes, IFG, or IGT compared with traditional control? Is there evidence that aspirin use improves health outcomes in these populations compared with nonuse?
No evidence in screen-detected diabetes population Persons with screen-detected diabetes: 1 RCT (3 publications)

Persons with diabetes not specifically screen-detected: 9 systematic reviews and 2 RCTs (3 publications)

Some studies were underpowered because event rates were lower than anticipated

Limited evidence in persons with IFG, IGT, and screen-detected diabetes

Persons with screen-detected diabetes: Consistent

Persons with diabetes not specifically screen-detected:

Glucose control: Consistent

BP control: Inconsistent

Only 1 fair-quality trial enrolled persons with screen-detected diabetes; other studies enrolled persons with established diabetes Persons with screen-detected diabetes: Use of an intensive multifactorial glucose-, BP-, and lipid-lowering intervention did not significantly reduce risk for all-cause or CV mortality, MI, stroke, or revascularization after 5-y follow-up

Persons with diabetes not specifically screen-detected: Intensive glucose-lowering did not significantly decrease risk for all-cause or CV mortality but was associated with a significant reduction in risk for nonfatal MI in systematic reviews

Intensive BP lowering reduced risk for all-cause mortality and stroke in a good-quality systematic review; however, results from recently published trials were mixed on the effect on health outcomes, although different interventions and BP targets were used in these studies

Good
KQ 6. What are the harms of more intensive interventions compared with traditional control in adults with type 2 diabetes, IFG, or IGT?
Not assessed 4 systematic reviews and 6 RCTs Trials generally not designed to assess harms; interventions and targets varied Consistent for effects of glucose-lowering therapy; inconsistent for BP-lowering therapy Unclear; no evidence in screen-detected population No clear differences in harms of intensive multifactorial intervention compared with standard care in persons with screen-detected diabetes

In persons with diabetes not specifically screen-detected, intensive glucose lowering was consistently associated with increased risk for severe hypoglycemia; evidence on harms of intensive BP lowering was mixed

Fair
KQ 7. Do interventions for IFG or IGT delay or prevent the progression to type 2 diabetes?
6 studies of lifestyle interventions and 8 studies of pharmacologic interventions found some evidence that intervention delays or prevents progression Lifestyle interventions: 6 RCTs

Pharmacologic interventions: 8 RCTs (9 publications)

Multifactorial interventions: 2 RCTs

Some studies underpowered; lack of blinding in many studies; content of interventions varied widely Lifestyle interventions: Consistent

Pharmacologic interventions: Consistent

Multifactorial interventions: Consistent

Few studies reported race/ethnicity, but effects were largely consistent among studies in various countries 6 studies of lifestyle interventions found significantly reduced progression to diabetes compared with usual care when pooled with 4 older studies

Pharmacologic interventions reduced progression to diabetes on the basis of pooled results of 3 studies of thiazolidinediones and 4 studies of α-glucosidase inhibitors; other studies found that valsartan and a combination of low-dose metformin and rosiglitazone but not nateglinide or glimepiride reduced progression to diabetes 2

Studies of multifactorial interventions found no effect on risk for progression to diabetes, although the estimate of 1 study was imprecise

Good

ADDITION = Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen Detected Diabetes in Primary Care; BP = blood pressure; CV = cardiovascular; CVD = cardiovascular disease; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; KQ = key question; MI = myocardial infarction; RCT = randomized, controlled trial; USPSTF = U.S. Preventive Services Task Force.
* Additional studies, including an additional KQ on subgroups, may be found in the full version of the report.24
† Based on new evidence identified for this update plus previously reviewed evidence.

Appendix Figure 1. Analytic framework.

DM = diabetes mellitus; IGF = impaired fasting glucose; IGT = impaired glucose tolerance; KQ = key question; MI = myocardial infarction.

Text Description.

This figure depicts the analytic framework, which outlines the evidence areas covered in the review, including the population, intervention and related harms, and outcomes. The population includes asymptomatic, nonpregnant adults. Screening of these individuals separates the population into high and average risk, and harms of screening are assessed. Diagnosis of either diabetes or impaired fasting glucose/impaired glucose tolerance follows. Arrows from these boxes represent drug and/or lifestyle interventions on the following health outcomes: mortality, cardiovascular morbidity (including myocardial infarction, stroke, and congestive heart failure), quality of life, and other outcomes. The incidence of diabetes is also examined as an outcome for those with impaired fasting glucose/impaired glucose tolerance. Subsequent arrows from the interventions examine any harms of interventions. In addition, an overarching arrow from screening to the health outcomes represents the direct effect of screening on these health outcomes.

Appendix Figure 2. Inclusion and exclusion criteria per KQ.

Category Include Exclude
Populations KQs 1, 2: Asymptomatic, nonpregnant adults
KQs 3, 4: Asymptomatic, nonpregnant adults with screen-detected or mild type 2 DM (based on untreated A1c levels), IFG, or IGT
KQ 5: Asymptomatic, nonpregnant adults with screen-detected or mild type 2 DM (based on untreated A1c levels), IFG, or IGT, as well as abnormal BP and/or lipid levels
KQ 6: Asymptomatic, nonpregnant adults with IFG or IGT
KQ 7: All of the above
KQs 1–7: Children, adolescents, and pregnant women and persons with symptomatic type 2 DM, IFG, or IGT
Interventions KQs 1, 2: Screening (targeted or universal) for IFG, IGT, or DM
KQs 3, 4, 6: Any intervention for glycemic control; lifestyle modification
KQ 5: Any intervention for more stringent BP or lipid control or aspirin; more intensive lifestyle modification
KQ 7: All of the above
 
Comparison KQ 1: No screening or alternative screening strategies
KQs 3, 4: No intervention/usual care or interventions in individuals with advanced DM
KQ 5: Conventional intervention
KQ 6: No intervention or usual care
KQ 7: All of the above
 
Outcomes KQs 1, 3, 5: Mortality, cardiovascular morbidity (including myocardial infarction, stroke, congestive heart failure), chronic kidney disease, amputations, skin ulcers, visual impairment (including blindness), periodontitis (including tooth loss), moderate-severe neuropathy, quality of life
KQ 2: Labeling, anxiety, and false-positive results
KQ 4: Serious side effects from treatments, including death, heart attack, stroke, cancer, and hypoglycemic events requiring medical attention
KQ 6: Development of type 2 DM
KQ 7: All of the above
 
Settings KQs 1–7: Applicable to primary care  
Study designs KQs 1, 3, 5, 6: Randomized, controlled trials and controlled observational studies, systematic reviews
KQ 2: Any
KQ 4: Randomized, controlled trials and controlled observational studies, systematic reviews, and large longitudinal studies
KQ 7: All of the above
 

BP = blood pressure; DM = diabetes mellitus; IGF = impaired fasting glucose; IGT = impaired glucose tolerance; KQ = key question; MI = myocardial infarction.

Appendix Figure 3. Summary of evidence search and selection.

KQ = key question.
* Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews.
‡ Other sources include previous reports, reference lists of relevant articles, and systematic reviews. An additional 27 publications are included in the full report.23
§ Some studies have several publications and some are included for more than 1 KQ.

Text Description.

This figure is a literature flow diagram depicting the search and selection of articles for the review. The figure shows that 7,771 abstracts of potentially relevant articles were identified through MEDLINE, Cochrane, and other sources. After excluding 7,198 non-relevant abstracts and background articles, 573 articles were reviewed at the full-text level. Of these, 485 articles were excluded for the following reasons: wrong population (34), wrong intervention (15), wrong outcomes (129), wrong study design (70), wrong publication type (39), wrong population due to diabetic status (113), systematic review not directly used (33), wrong comparison (32), duplicate data (8), or review used as a source document only (12). 88 publications were included in the review, as follows: 2 studies (in 3 publications) for Key Question 1; 3 studies for Key Question 2; 13 studies (in 16 publications) for Key Question 3; 9 studies (in 11 publications) for Key Question 4; 3 studies (in 6 publications) and 9 systematic reviews for Key Question 5; 6 studies (in 6 publications) and 4 systematic reviews for Key Question 6; 16 studies (in 17 publications) for Key Question 7. A footnote indicates that some studies are included for more than one Key Question.

Appendix Figure 4. Meta-analysis of the effect of pharmacologic interventions on all-cause mortality.


M-H = Mantel–Haenszel fixed-effects model; OR = odds ratio.
* Included in the 2008 report.22

Text Description.

This figure is a meta-analysis forest plot. Risk ratios of the effect of glucose-lowering drugs on all-cause mortality in persons with screen-detected or early type 2 diabetes mellitus, impaired fasting glucose, or impaired glucose tolerance were calculated for 8 studies, with a pooled risk ratio of 1.07, 95% CI of 0.86 to 1.17, and an I-squared value of 0%.

Appendix Figure 5. Meta-analysis of the effect of pharmacologic interventions on cardiovascular mortality.


M-H = Mantel–Haenszel fixed-effects model; OR = odds ratio.
* Included in the 2008 report.22

Text Description.

This figure is a meta-analysis forest plot. Risk ratios of the effect of glucose-lowering drugs on cardiovascular mortality in persons with screen-detected or early type 2 diabetes mellitus, impaired fasting glucose, or impaired glucose tolerance were calculated for 5 studies, with a pooled risk ratio of 1.07, 95% CI of 0.84 to 1.35, and an I-squared value of 0%.

Appendix Figure 6. Meta-analysis of the effect of lifestyle interventions on incidence of progression to DM.


DM = diabetes mellitus; D+L = DerSimonian–Laird random-effects model; PL = profile likelihood model.
* Included in the 2008 report.22

Text Description.

This figure is a meta-analysis forest plot. Risk ratios of the effect of lifestyle interventions on the incidence of progression to diabetes from impaired fasting glucose or impaired glucose tolerance were calculated for 10 studies, with a pooled risk ratio of 0.53, 95% CI of 0.39 to 0.72, and an I-squared value of 88%.

Appendix Figure 7. Meta-analysis of the effect of thiazolidinediones on incidence of progression to DM.

DM = diabetes mellitus; D+L = DerSimonian–Laird random-effects model; PL = profile likelihood model.
* Included in the 2008 report.22

Text Description.

This figure is a meta-analysis forest plot. Risk ratios of the effect of thiazolidinediones on the incidence of progression to diabetes from impaired fasting glucose or impaired glucose tolerance were calculated for 3 studies, with a pooled risk ratio of 0.50, 95% CI of 0.27 to 0.92, and an I-squared value of 92%.

Appendix Figure 8. Meta-analysis of the effect of alpha-glucosidase inhibitors on incidence of progression to DM.

DM = diabetes mellitus; D+L = DerSimonian–Laird random-effects model; PL = profile likelihood model.
* Included in the 2008 report.22
† Included in the 2003 report.21

Text Description.

This figure is a meta-analysis forest plot. Risk ratios of the effect of alpha-glucosidase inhibitors on the incidence of progression to diabetes from impaired fasting glucose or impaired glucose tolerance were calculated for 4 studies, with a pooled risk ratio of 0.64, 95% CI of 0.45 to 0.90, and an I-squared value of 66%.

Appendix Table 1. Effect of Screening for Diabetes on Health Outcomes

Author, Year Study Name Quality Study Design Setting Country Interventions Population Duration of Follow-up Results
Simmons 201232
ADDITION-Cambridge
Good

 

Cluster RCT
33 general practices
United Kingdom
A. Invited to stepwise screening of high-risk participants with random capillary blood glucose and HbA1c (n=15,089; 27 sites)
A1. Invited to and attended screening (n=11,737/15,089; 78%)
A2. Did not attend screening (n=3,352/15,089; 22%)
B. No screening (n=4,137; 5 sites)
A vs. B
Mean age: 58 vs. 58 years
64% vs. 64% male
Race not reported
Mean BMI: 30.6 vs. 30.5 kg/m2
Median diabetes risk score: 0.34 vs. 0.35*
Index of Multiple Deprivation score: 12.9 (SD, 7.7) vs. 16.1 (SD, 9.0)
10 years All-cause mortality: HR, 1.06 (95% CI, 0.90 to 1.25)
Cardiovascular mortality: HR, 1.02 (95% CI, 0.75 to 1.38)
Cancer mortality: HR, 1.08 (95% CI, 0.90 to 1.30)
DM-related mortality: HR, 1.26 (95% CI, 0.75 to 2.10)
Other mortality: HR, 1.10 (95% CI, 0.87 to 1.39)
A1 vs. A2
All-cause mortality: HR, 2.01 (95% CI, 1.74 to 2.32)
Simmons 201133
Ely cohort
Fair
RCT
1 general practice
United Kingdom
Phase 1 (1990 to 1999)
A. Invited to screening with OGTT; rescreening at 5 and 10 years (n=1,705)
A1. Attended screening (n=1,157/1,705; 68%)
A2. Did not attend screening (n=548/1,705; 32%)
B. No screening (n=3,231)
Phase 1
A vs. B
Mean age: 53 vs. 51 years
45% vs. 51% male
Race not reported
Townsend Index of Deprivation Score: −1.3 vs. −1.5
Phase 1
10 years
Phase 1
A vs. B
All-cause mortality: HR, 0.96 (95% CI, 0.77 to 1.20); aHR,§ 0.79 (95% CI, 0.63 to 1.00)
A1 vs. B
All-cause mortality: HR, 0.64 (95% CI, 0.47 to 0.86); aHR, 0.54 (95% CI, 0.40 to 0.74)
A2 vs. B
All-cause mortality: HR, 1.68 (95% CI, 1.27 to 2.22); aHR, 1.36 (95% CI, 1.01 to 1.82)

ADDITION = Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen Detected Diabetes in Primary Care; aHR = adjusted HR; BMI = body mass index; DM = diabetes mellitus; HbA1c = hemoglobin A1c; HR = hazard ratio; OGTT = oral glucose tolerance test; RCT = randomized, controlled trial.
* Risk score determined using a previously validated model incorporating age, sex, BMI, use of steroids or antihypertensives, family history, and smoking history.67 A risk score of 0.35 was estimated to have 41% sensitivity, 86% specificity, 12% positive predictive value, and 96% negative predictive value.
† Higher score=higher level of deprivation.
‡ Score >0=greater deprivation than the mean, <0=less deprivation than the mean.
§ Adjusted for age, sex, and Index of Deprivation Score.

Appendix Table 2. Health Outcomes in Studies of Interventions for Screen-Detected/Early DM, IFG, or IGT

Author, Year
Study Name Quality
Intervention and Comparison Population Health Outcomes Quality
Lifestyle interventions
Andrews, 201142
217 sites + community
recruitment in the United
Kingdom
RCT
Early ACTID
Treatment duration and follow-up: 1 year
A. Intensive dietary advice and exercise (n=246)
B. Intensive dietary advice (n=248)
C. Usual care (n=99)
Patients with newly diagnosed DM
A vs. B vs. C
Mean age: 60 vs. 60 vs. 60 years
Female sex: 36% vs. 34% vs. 37%
Race: 94% vs. 96% vs. 97% white; other races NR
Mean HbA1c: 6.7% vs. 6.6% vs. 6.7%
Mean BMI: 31.6 vs. 31.5 vs. 32.3 kg/m2
Mean BP: NR; >180/100 mm Hg at baseline excluded
Mean total cholesterol: 4.3 vs. 4.3 vs. 4.4 mmol/L
Proportion of smokers: 7% vs. 10% vs. 8%
A vs. B vs. C
All-cause mortality: 0% (0/246) vs. 0% (0/248) vs. 1% (1/99); A vs. C: RR, 0.14 (95% CI, 0.01 to 3.31); B vs. C: RR, 0.14 (95% CI, 0.01 to 3.29)
Good
Davies, 200843 and Khunti, 201244
13 sites in the United Kingdom
Cluster RCT
DESMOND
Treatment duration: One 6-hour education session
Follow-up: 3 years
A. Single, 6-hour group education session focusing on lifestyle, food, physical activity, and CV risk factors + standard clinical management (n=437)
B. Usual care (n=387)
Patients with newly diagnosed DM
A vs. B
Mean age: 60 vs. 60 years
Female sex: 47% vs. 43% (p<0.05)
Race: 94% vs. 94% white; other races NR
Mean HbA1c: 8.3% vs. 7.9% (p<0.05)
Mean BMI: 32.3 vs. 32.4 kg/m2
Mean BP: 141/82 vs. 140/81 mm Hg
Mean total cholesterol: 5.4 vs. 5.4 mmol/L
Proportion of smokers: 14% vs. 16%
A vs. B
Quality of life, WHOQOL-BREF*
Overall satisfaction with quality of life: 4.0 vs. 4.0; p=0.48
Overall satisfaction with health: 4.0 vs. 4.0; p=0.94
Fair
Li, 200839 and Li, 201438
33 centers
China
Cluster RCT
Da Qing DPS
Treatment duration: 6 years
Follow-up: 23 years
A. Interventions: Combined lifestyle, diet, or lifestyle + diet
Diet intervention: Increase vegetable intake and lose weight by decreasing calories from sugar and alcohol; increase leisure time physical activity (n=438)
B. Control (n=138)
Patients with IGT
A vs. B
Mean age: 45 vs. 47 years
Female sex: 47% vs. 43%
Race: NR
Mean fasting glucose: 5.6 vs. 5.5 mmol/L
Mean BMI: 25.7 vs. 26.2 kg/m2
Mean BP: 132/87 vs. 134/89 mm Hg
Mean total cholesterol: 5.2 vs. 5.3 mmol/L
Proportion of smokers: NR
A vs. B: 20-year results
All-cause mortality: 25% vs. 29%; HR, 0.96 (95% CI, 0.65 to 1.41)
CV mortality: 12% vs. 17%; HR, 0.83 (95% CI, 0.48 to 1.40)
CV events: 41% vs. 44%; HR, 0.98 (95% CI, 0.71 to 1.37)
A vs. B: 23-year results
All-cause mortality: 28% (121/430) vs. 38% (53/138); HR, 0.71 (95% CI, 0.51 to 0.99)
CV mortality: 12% (51/430) vs. 20% (27/138); HR, 0.59 (95% CI, 0.36 to 0.96)
Fair
Saito, 201140
38 centers in Japan
RCT
Treatment duration: 3 years
Follow-up: 3 years
A. Individual lifestyle counseling session aimed at decreasing body weight and increasing physical activity with follow-up at 1, 3, 6, 12, 18, 24, 30, and 36 months (n=330)
B. Usual care (n=311)
Patients with IFG
A vs. B
Mean age: 50 vs. 48 years
Female sex: 28% vs. 29%
Race: NR
Mean HbA1c: 5.4% vs. 5.4%
Mean BMI: 26.9 vs. 27.1 kg/m2
Mean BP: 130/81 vs. 131/81 mm Hg
Mean total cholesterol: 5.5 vs. 5.5 mmol/L
Proportion of smokers: 25% vs. 28%
A vs. B
All-cause mortality: 0.3% (1/311) vs. 0% (0/330); RR, 3.18 (95% CI, 0.13 to 78)
Fair
Uusitupa, 200941
Finnish DPS
5 centers in Finland
RCT
Mean follow-up: 11 to 14 years (varied by intervention group)
A. Intensive diet and counseling group (n=257)
B. Control group (n=248)
Patients with IGT and BMI >25 kg/m2
A vs. B
Mean age: 55 vs. 55 years
Female sex: 66% vs. 68%
Race: NR
Mean fasting glucose: 6.1 vs. 6.2 mmol/L
Mean BMI: 31.4 vs. 31.2 kg/m2
Mean BP: 140/88 vs. 136/86 mm Hg
Mean total cholesterol: 5.6 vs. 5.6 mmol/L
Proportion of smokers: 7% vs. 7%
A vs. B
All-cause mortality: 2.2 vs. 3.8 events/1,000 person-years; HR, 0.57 (95% CI, 0.21 to 1.58)
CV events: 22.9 vs. 22.0 events/1,000 person-years; HR, 1.04 (95% CI, 0.72 to 1.51)
Fair
Pharmacologic interventions
DeFronzo, 201145
8 centers in United States
RCT
Median follow-up: 2.4 years
A. Pioglitazone 30 mg/day for 1 month, increased to 45 mg/day (n=303)
B. Placebo (n=299)
Patients with IGT, BMI >25 kg/m2, and ≥1 other DM risk factor
A vs. B
Mean age: 53 vs. 52 years
Female sex: 58% vs. 58%
Race: 51% vs. 57% white; 26% vs. 25% Hispanic; 19% vs. 15% black; 3% vs. 3% other
Mean HbA1c: 5.5% vs. 5.5%
Mean BMI: 33.0 vs. 34.5 kg/m2
Mean BP: 127/74 vs. 128/74 mm Hg
Mean total cholesterol: 4.3 vs. 4.5 mmol/L
Proportion of smokers: NR
A vs. B
All-cause mortality: 1% (3/303) vs. 0.3% (1/299); OR, 2.96 (95% CI, 0.31 to 28.62)
CV events: 9% (26/303) vs. 8% (23/299); RR, 1.11 (95% CI, 0.65 to 1.91)
Fair
DREAM Trial Investigators, 200830
191 centers in 21 countries
RCT
Mean follow-up: 3 years
A. Ramipril 15 mg/day (n=2,623)
B. Placebo (n=2,646)
C. Rosiglitazone 0.8 mg/day (n=2,635)
D. Placebo (n=2,634)
Patients randomized twice, to ramipril or placebo and rosiglitazone or placebo
Patients with IFG or IGT
A vs. B and C vs. D
Mean age: 55 vs. 55 years and 55 vs. 55 years
Female sex: 60% vs. 59% and 58% vs. 60%
Race: NR
Median fasting plasma glucose: 5.9 vs. 5.9 and 5.8 vs. 5.8 mmol/L
Mean BMI: 30.9 vs. 30.9 and 30.8 vs. 31.0 kg/m2
Mean BP: 136/83 vs. 136/83 and 136/83 vs. 136/84 mm Hg
Mean total cholesterol: NR; A vs. B: 36% and 35% history of dyslipidemia; C vs. D: 15% vs. 15% statin or fibrate use
Proportion of current or former smokers: 44% vs. 45% and 44% vs. 45%
A vs. B
Total mortality: 1% (31/2623) vs. 1% (32/2646); HR, 0.98 (95% CI, 0.60 to 1.61)
CV mortality: 0.5% (12/2623) vs. 0.4% (10/2646); HR, 1.21 (95% CI, 0.52 to 2.80)
CV events: 3% (69/2623) vs. 2% (64/2646); HR, 1.09 (95% CI, 0.78 to 1.53)
C vs. D
Total mortality: 1% (30/2635) vs. 1% (33/2634); OR, 0.91 (95% CI, 0.56 to 1.49)
CV mortality: 0.5% (12/2635) vs. 0.4% (10/2634); OR, 1.20 (95% CI, 0.52 to 2.78)
CV events: 3% (77/2635) vs. 2% (56/2634); HR, 1.38 (95% CI, 0.98 to 1.95)
Good
Kawamori, 200946
103 centers in Japan
RCT
Treatment duration: 5 years
Mean follow-up: 3 years
A. Voglibose, 0.2 mg/day (n=897)
B. Placebo (n=881)
Patients with IFG
A vs. B
Mean age: 56 vs. 56 years
Female sex: 40% vs. 40%
Race: NR
Mean fasting plasma glucose: 5.8 vs. 5.9 mmol/L
Mean BMI: 25.8 vs. 25.9 kg/m2
Mean BP: NR; 59% vs. 58% history of hypertension
Mean total cholesterol: NR; 77% vs. 76% history of dyslipidemia
Proportion of smokers: NR
A vs. B
All-cause mortality: 0.7% (6/897) vs. 0% (0/881); OR, 12.77 (95% CI, 0.72 to 226.99)
Good
NAVIGATOR, 201028
806 centers in 40 countries
RCT
Median follow-up: 5 years
A. Nateglinide 60 mg/3 times daily (n=4,645)
B. Placebo (n=4,661)
Patients also randomized in 2x2 factorial design to receive valsartan or placebo
Patients with IGT and at least 1 CV risk factor or known CVD
A vs. B
Mean age: 64 vs. 64 years
Female sex: 51% vs. 50%
Race: 83% vs. 83% white; 3% vs. 3% black; 7% vs. 8% Asian; 8% vs. 8% other
Mean HbA1c: 5.8% vs. 5.8%
Mean BMI: 30.5 vs. 30.5 kg/m2
Mean BP: 140/83 vs. 140/83 mm Hg
Mean total cholesterol: 5.4 vs. 5.4 mmol/L
Proportion of smokers: 11% vs. 11%
A vs. B
All-cause mortality: 7% (310/4645) vs. 7% (312/4661); OR, 1.00 (95% CI, 0.85 to 1.17)
CV mortality: 3% (126/4645) vs. 4% (118/4661); OR, 1.07 (95% CI, 0.83 to 1.38)
Stroke: 4% (111/4645) vs. 3% (126/4661); HR, 0.89 (95% CI, 0.69 to 1.15)
Good
NAVIGATOR, 201029
806 centers in 40 countries
RCT
Median follow-up: 5 years
A. Valsartan 160 mg/once daily (n=4,631)
B. Placebo (n=4,675)
Patients also randomized in 2x2 factorial design to receive nateglinide or placebo
Patients with IGT and at least one CV risk factor or known CVD
A vs. B
Mean age: 64 vs. 64 years
Female sex: 50% vs. 51%
Race: 83% vs. 83% white; 2% vs. 3% black; 6% vs. 7% Asian; 8% vs. 8% other
Mean HbA1c: 5.8% vs. 5.8%
Mean BMI: 30.4 vs. 30.6 kg/m2
Mean BP: 139/83 vs. 140/83 mm Hg
Mean total cholesterol: 5.4 vs. 5.4 mmol/L
Proportion of smokers: 11% vs. 11%
A vs. B
All-cause mortality: 6% (295/4631) vs. 12% (327/4675); OR, 1.00 (95% CI, 0.85 to 1.17)
CV mortality: 3% (128/4631) vs. 3% (116/4675); OR, 1.07 (95% CI, 0.83 to 1.38)
MI: 3% (138/4631) vs. 3% (140/4675); HR, 0.97 (95% CI, 0.77 to 1.23)
Heart failure requiring hospitalization: 2% (91/4631) vs. 2% (94/4675); HR, 0.97 (95% CI, 0.72 to 1.29)
Stroke: 2% (105/4631) vs. 3% (132/4675); HR, 0.79 (95% CI, 0.61 to 1.02)
Good
Nijpels, 200847
1 center in the Netherlands
RCT
DAISI
Treatment duration: 3 years
A. Acarbose 50 mg/3 times daily (n=60)
B. Placebo (n=58)
Patients with IGT
A vs. B
Mean age: 59 vs. 57 years
Female sex: 49% vs. 50%
Race: NR
Mean HbA1c: 5.9% vs. 5.6%
Mean BMI: 28.4 vs. 29.5 kg/m2
Mean BP: NR
Mean total cholesterol: NR
Proportion of smokers: 25% vs. 23%
A vs. B
All-cause mortality: 2% (1/60) vs. 5% (3/58); OR, 0.32 (95% CI, 0.03 to 3.19)
Fair
Ramachandran, 200948
India
RCT
IDPP-2
Mean follow-up: 3 years
A. Pioglitazone (n=181)
B. Placebo (n=186)
Patients with IGT
A vs. B
Mean age: 45.1 vs. 45.5 years
Female sex: 13% vs. 14%
Race: NR
Mean HbA1c: 5.8% vs. 5.8%
Mean BMI: 26.0 vs. 26.2 kg/m2
Mean BP: 118/75 vs. 118/76 mm Hg
Mean total cholesterol: 5.2 vs. 5.3 mmol/L
Proportion of smokers: 37% vs. 47%
A vs. B
All-cause mortality: 1% (2/203) vs. 0.5% (1/203); OR, 2.00 (95% CI, 0.18 to 22.23)
CV mortality: 0.9% (2/204) vs. 0% (0/203); OR, 4.98 (95% CI, 0.24 to 104.28)
Fair
Zinman, 201049
2 centers in Canada
RCT
CANOE
Treatment duration: NR
Median follow-up: 3.9 years
A. Metformin 500 mg plus rosiglitazone 2 mg/twice daily as a fixed-dose combination (n=103)
B. Placebo (n=104)
Patients with IGT and/or IFG and ≥1 risk factor for DM
A vs. B
Mean age: 50 vs. 55 years
Female sex: 65% vs. 68%
Race: 75% vs. 74% white; 8% vs. 7% South Asian; 7% vs. 7% Latino; 11% vs. 13% other
Mean fasting glucose: 5.4 vs. 5.4 mmol/L
Mean BMI: 31.3 vs. 32.0 kg/m2
Mean BP: 130/80 vs. 128/82 mm Hg
Mean total cholesterol: 4.9 vs. 5.4 mmol/L
Proportion of smokers: NR
A vs. B
MI: 0% (0/103) vs. 1% (1/104); RR, 0.34 (95% CI, 0.01 to 8.17)
Congestive heart failure: 0% (0/103) vs. 1% (1/104); RR, 0.34 (95% CI, 0.01 to 8.17)
Good
Lifestyle and pharmacologic interventions
Florez 201250
27 centers in the United States
RCT
Diabetes Prevention Program
Treatment duration: 3 years
A. Intensive lifestyle intervention, including diet and exercise to achieve modest weight reduction (n=1,048)
B. Metformin 850 mg/twice daily (n=1,043)
C. Placebo (n=1,041)
Patients with IGT and BMI ≥24 kg/m2 (≥22 kg/m2 in Asian Americans)
A vs. B vs. C
Mean age: 51 vs. 51 vs. 50 years
Female sex: 68% vs. 66% vs. 69%
Race: 54% vs. 56% vs. 54% white; 19% vs. 21% vs. 20% black; 17% vs. 15% vs. 16% Hispanic; 9% vs. 8% vs. 10% other
Mean HbA1c: 5.9% vs. 5.9% vs. 5.9%
Mean BMI: 33.9 vs. 33.9 vs. 34.2 kg/m2
Mean blood pressure: NR
Mean total cholesterol: NR
Proportion of smokers: NR
A vs. C
Quality of life, SF-36 score* changes from baseline, mean between-group difference:
SF-6D: 0.0084 (SD, 0.0041; p<0.05)
PCS: 1.57 (SD, 0.30; p<0.01)
MCS: −0.29 (SD, 0.32; p=NS)
Physical function: 3.58 (SD, 0.66; p<0.01)
Body pain: 1.93 (SD, 0.78; p<0.01)
General health: 3.23 (SD, 0.66; p<0.01)
Vitality: 2.05 (SD, 0.77; p<0.01)
B vs. C
Quality of life, SF-36 score* changes from baseline, mean between-group difference:
SF-6D: 0.0019 (SD, 0.0041; p=NS)
PCS: 0.15 (SD, 0.30; p=NS)
MCS: 0.22 (SD, 0.32; p=NS)
Physical function: 0.13 (SD, 0.71; p=NS)
Body pain: 0.50 (SD, 0.78; p=NS)
General health: 0.06 (SD, 0.66; p=NS)
Vitality: 0.09 (SD, 0.76; p=NS)
Good

ACTID = Activity in Diabetes; BMI = body mass index; BP = blood pressure; CANOE = Canadian Normoglycemia Outcomes Evaluation; CV = cardiovascular; CVD = cardiovascular disease; DAISI = Dutch Acarbose Intervention Study in Persons With Impaired Glucose Tolerance; DESMOND = Diabetes Education and Self Management for Ongoing and Newly Diagnosed; DM = diabetes mellitus; DPS = Diabetes Prevention Study; DREAM = Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; HbA1c = hemoglobin A1c; HR = hazard ratio; IDPP-2 = Indian Diabetes Prevention Program-2; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; MCS = SF-36 Mental Health Component Summary; MI = myocardial infarction; NAVIGATOR = Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; NR = not reported; NS = not significant; OR = odds ratio; PCS = SF-36 Physical Component Summary; RCT = randomized, controlled trial; RR = relative risk; SF = short form; WHOQOL-BREF = World Health Organization Quality of Life Assessment, short version.
* Scale 1 to 5 for each domain; higher score = higher quality of life.

Appendix Table 3. Good-Quality Systematic Reviews of Intensive vs. Standard Glucose Control in People With DM Reporting Health Outcomes and Harms

Author, Year Intensive vs. Standard Control
Number of Studies; RR, 95% CI; I2 (if Reported)*
All-Cause Mortality CV Mortality Stroke MI Harms
Buehler, 201358 6 studies; 1.03, 0.90 to 1.17; I2=50% 6 studies; 1.04, 0.83 to 1.29; I2=60% Nonfatal stroke: 5 studies; 1.02, 0.88 to 1.17; I2=0% Nonfatal MI: 5 studies; 0.85, 0.76 to 0.95; I2=0% Severe hypoglycemia: 5 studies; 2.39, 1.79 to 3.18; I2=62%
Hemmingsen, 201359 18 studies; 1.01, 0.9 to 1.13; I2=40% 18 studies; 1.06, 0.9 to 1.26; I2=37% Nonfatal stroke: 11 studies; 0.96, 0.80 to 1.16; I2=20% Nonfatal MI: 12 studies; 0.87, 0.76 to 1.00; I2=28% Severe hypoglycemia: 12 studies; 1.76, 1.46 to 2.13; I2=95%
Boussageon, 201161 9 studies; 1.04, 0.91 to 1.19; I2=42% 10 studies; 1.11, 0.86 to 1.43; I2=61% Fatal or nonfatal stroke: 8 studies; 0.96, 0.83 to 1.13; I2=0% Nonfatal MI: 8 studies; 0.85, 0.74 to 0.96; I2=0%
Fatal or nonfatal MI: 8 studies; 0.90, 0.81 to 1.01; I2=0%
 
Hemmingsen, 201160 12 studies; 1.02, 0.91 to 1.13; I2=30% 12 studies; 1.11, 0.92 to 1.35; I2=46%   Nonfatal MI: 8 studies; 0.85, 0.76 to 0.95; I2=0% Severe hypoglycemia: 9 studies; 2.39, 1.71 to 3.34; I2=73%
Wu, 201062 6 studies; 0.95, 0.80 to 1.12 5 studies; 1.10, 0.79 to 1.53      
Kelly, 200963 5 studies; 0.98, 0.84 to 1.15; I2=72% 5 studies; 0.97, 0.76 to 1.24; I2=76% Fatal or nonfatal stroke: 5 studies; 0.98, 0.86 to 1.11
Nonfatal stroke: 5 studies; 0.98, 0.82 to 1.17
Fatal stroke: 5 studies; 0.87, 0.63 to 1.20
Nonfatal MI: 5 studies; 0.84, 0.75 to 0.94
Fatal MI: 5 studies; 0.94, −0.75 to 1.18
Severe hypoglycemia: 5 studies; 2.03, 1.46 to 2.81; I2=85%
Ma, 200965 3 studies; 1.02, 0.98 to 1.07   3 studies; 0.97, 0.84 to 1.12   Severe hypoglycemia: 2 studies; 2.34, 1.64 to 3.35; I2=89%
Mannucci, 200966 5 studies; OR 1.01, 0.88 to 1.15 5 studies; OR 1.01, 0.82 to 1.26 Fatal or nonfatal stroke: 5 studies; OR 0.94, 0.83 to 1.06 Fatal or nonfatal MI: 5 studies; OR 0.85, 0.78 to 0.93  
Ray, 200964 5 studies; OR 1.02, 0.87 to 1.19 5 studies; OR 1.01, 0.82 to 1.26   Nonfatal MI: 5 studies; OR 0.83, 0.75 to 0.93  

CV = cardiovascular; DM = diabetes mellitus; MI = myocardial infarction; OR = odds ratio; RR = relative risk.
* Results for other outcomes are summarized in the full report.24

Appendix Table 4. Trials of Variably Defined Intensive vs. Standard BP Control in People With DM

Study n Duration of Follow-up Interventions BP: Baseline; Target; Achieved (mm Hg) Intensive vs. Standard BP Lowering, RR (95% CI)
All-Cause Mortality CV Mortality Stroke Myocardial Infarction Other Outcomes

ABCD (H)*79
n=470
5 years

Intensive: Nisoldipine or enalapril, plus open-label antihypertensives to achieve target DBP
Standard: Nisoldipine or enalapril
Baseline
  Intensive: 156/98
  Standard: 154/98
Target
   Intensive: DBP ≤75
  Standard: DBP 80 to 89
Achieved
  Intensive: 132/78
  Standard: 138/86
6% (13/237) vs. 10% (25/233); 0.51 (0.27 to 0.97)     7% (16/237) vs. 6% (14/233); 1.12 (0.56 to 2.25) Nephropathy: 7% (16/237) vs. 10% (23/233); 0.68 (0.37 to 1.26)
ABCD (N)*78
n=480
5 years
Intensive: Nisoldipine 10 to 60 mg/day or enalapril 5 to 40 mg/day
Standard: Placebo
Baseline
   Intensive: 136/84
   Standard: 137/84
Target
   Intensive: DBP decrease of ≥10
  Standard: No DBP decrease (DBP, 80 to 89)
Achieved
   Intensive: 128/75
   Standard: 137/81
8% (18/237) vs. 8% (20/243); 0.92 (0.50 to 1.70) 5% (13/237) vs. 4% (9/243); 1.48 (0.65 to 3.40) 2% (4/237) vs. 5% (13/243); 0.32 (0.10 to 0.95) 8% (19/237) vs. 6% 15/243); 1.30 (0.68 to 2.50) Congestive heart failure: 5% (12/237) vs. 5% (11/243); 1.12 (0.50 to 2.49)
ACCORD71
n=4,732
5 years
Intensive: Use of antihypertensives necessary to reach target according to a prespecified treatment algorithm
Standard: Usual care
Baseline
   Intensive:139/76
   Standard: 139/76
Target
   Intensive: SBP <120
  Standard: SBP <140
Achieved
   Intensive: 119/64
   Standard: 134/71
6% (150/2,363) vs. 6% (144/2,371); 1.11 (0.89 to 1.38) 3% (60/2,363) vs. 2% (58/2,372); 1.04 (0.73 to 1.48) 2% (36/2,363) vs. 3% (62/2,371); 0.58 (0.39 to 0.88) 5% (126/2,362) vs. 6% (146/2,371); 0.87 (0.69 to 1.09) Fatal or nonfatal heart failure: 4% (83/2,363) vs. 4% (90/2,371); 0.93 (0.69 to 1.24)
Loss of visual acuity: 35% (819/2,339) vs. 36% (849/2,352); 0.97 (0.90 to 1.05)
Score >2 on Michigan Neuropathy Screening Instrument: 53% (722/1,353) vs. 56% (781/1,388); 0.95 (0.89 to 1.02)
ADVANCE72
n=11,140
4 years
Intensive: Addition to existing BP regimen of fixed-dose combination of perindoprilindapamide; no target set
Standard: Existing BP regimen with addition of placebo
Baseline
   Intensive: 145/81
   Standard: 145/81
Target
   Intensive: No target
   Standard: No target
Achieved
   Intensive: 136/73
   Standard: 140/73
7% (408/5,569) vs. 9% (471/5,571); 0.87 (0.76 to 0.98) 4% (211/5,569) vs. 5% (257/5,571); 0.82 (0.69 to 0.98)     Renal events: 22% (1,243/5,569) vs. 27% (1,500/5,571); 0.83 (0.78 to 0.89)
New or worsening retinopathy: 5% (289/5,569) vs. 5% (286/5,571); 1.01 (0.86 to 1.19)
New or worsening nephropathy: 3% (181/5,569) vs. 4% (216/5,571); 0.84 (0.69 to 1.02)
HOT*74
n=1,501 with DM
4 years
Intensive: Felodipine + others added incrementally if needed to reach target
Standard: Felodipine
Baseline
   Intensive: 170/105
   Standard: 170/105
Target
   Intensive: DBP ≤80
   Standard: DBP ≤85 or 90
Achieved
   Intensive: 140/81
   Standard: 143/84
3% (17/499) vs. 6% (59/1,002); 0.58 (0.34 to 0.94) 1% (7/499) vs. 4% (42/1,002); 0.33 (0.15 to 0.74) 2% (12/499) vs. 3% (30/1,002); 0.80 (0.41 to 1.56) 3% (15/499) vs. 3% (34/1,002); 0.89 (0.49 to 1.61)  
UKPDS*75
n=1,148
8 years
Intensive: Captopril or atenolol + others added incrementally if needed to reach target
Standard: No use of ACE inhibitors or β-blockers
Baseline
   Intensive: 160/93
   Standard: 160/93
Target
   Intensive: <150/85
   Standard: <180/105
Achieved
   Intensive: 143/79
   Standard: 152/22
18% (134/758) vs. 21%
(83/390); 0.83 (0.65 to 1.06)
  5% (38/758) vs. 9% (34/390); 0.58 (0.37 to 0.90) 14% (107/758) vs. 18% (69/390); 0.80 (0.60 to 1.05) DM-related death: 11% (82/758) vs. 16% (62/390); 0.68 (0.50 to 0.92)
UKPDS76
n=1,148
16 years (8 years on trial + 8 years post-trial monitoring)
Intensive: Captopril or atenolol + others added incrementally if needed to reach target
Standard: No use of ACE inhibitors or β-blockers
Baseline
   Intensive: 160/93
   Standard: 160/93
Target
   Intensive:
   Standard:
Achieved
   Intensive: 143/79
   Standard: 152/22
49% (373/758) vs. 54% (211/390); 0.89 (0.75 to 1.06)   12% (90/758) vs. 15% (58/390); 0.77 (0.55 to 1.07) 27% (205/758) vs. 29% (115/390); 0.90 (0.71 to 1.13) DM-related death: 27% (203/758) vs. 31% (122/390); 0.84 (0.67 to 1.05)

ABCD = Appropriate Blood Pressure Control in Diabetes; ACCORD = Action to Control Cardiovascular Risk in Diabetes; ACE = angiotensin-converting enzyme; ADVANCE = Action in Diabetes and Vascular Disease; BP = blood pressure; CV = cardiovascular; DBP = diastolic blood pressure; DM = diabetes mellitus; H = hypertensive subgroup; HOT = Hypertensive Optimal Treatment; N = nonhypertensive subgroup; RR = relative risk; SBP = systolic blood pressure; UKPDS = U.K. Prospective Diabetes Study.
* Included in the prior U.S. Preventive Services Task Force report.22

Appendix Table 5. Studies of Interventions to Prevent or Delay Progression to DM

Author, Year
Country
Study Design
Study Name Treatment Duration Follow-up
Intervention and Comparison Population Progression to DM Quality
Lifestyle interventions
Katula, 201388
Community setting, United States
RCT
Treatment duration: 2 years
A. Intensive lifestyle intervention (n=151)
B. Usual care (n=150)
Overweight or obese patients with IFG
A vs. B
Mean age: 57.3 vs. 58.5 years
Female sex: 58% vs. 57%
Race: 73.5% vs. 74% white, 25.8% vs. 23.3% black, 0.7% vs. 2.7% other
Mean fasting glucose: 5.9 vs. 5.9 mmol/L
Mean BMI: 32.8 vs. 32.6 kg/m2
Mean blood pressure: NR
Mean total cholesterol: NR
Proportion of smokers: NR
A vs. B
Incidence: 2.6% (4/151) vs. 7.3% (11/150); RR, 0.36 (95% CI, 0.12 to 1.11)
Fair
Li, 201438 and Li, 200839
33 centers, China
Cluster RCT
Da Qing DPS
Treatment duration: 6 years
Follow-up: 20 years (mean, 9.4 years)
A. Interventions: Combined lifestyle, diet, or lifestyle + diet; diet intervention: increase vegetable intake and lose weight by decreasing calories from sugar and alcohol; increase leisure time physical activity (n=438)
B. Control (n=138)
Patients with IGT
A vs. B
Mean age: 45 vs. 47 years
Female sex: 47% vs. 43%
Race: NR
Mean fasting glucose: 5.6 vs. 5.5 mmol/L
Mean BMI: 25.7 vs. 26.2 kg/m2
Mean blood pressure: 132/87 vs. 134/89 mm Hg
Mean total cholesterol: 5.21 vs. 5.26 mmol/L
Proportion of smokers: NR
A vs. B: 20-year results
Incidence: 6.9 vs. 11.3 cases/100 person-years
Cumulative incidence: 79.7% vs. 92.8%
Adjusted HR: 0.57 (95% CI, 0.41 to 0.81)
NNT: 6
A vs. B: 23-year results
Incidence: 7.3 vs. 12.3 cases/10 person-years
Cumulative incidence: 73% (312/430) vs. 90% (124/138); RR, 0.86 (95% CI, 0.80 to 0.92)
Adjusted HR: 0.55 (95% CI, 0.40 to 0.76)
Fair
Lindahl, 200987
Single center, Sweden
Vasterbotten Intervention Programme
Treatment duration: 1 year
Follow-up: 5 years
A. Intensive lifestyle intervention, including a month-long stay in a wellness center and 4-day follow-up 1 year later (n=83)
B. Usual care (n=85)
Patients with IGT and BMI >27 kg/m2
A vs. B
Mean age: 52 vs. 54 years
Female sex: 70% vs. 61%
Race: NR
Mean fasting glucose: 5.8 vs. 6.2 mmol//L
Mean BMI: 31.2 vs. 30.2 kg/m2
Mean blood pressure: 141/84 vs. 141/86 mm Hg
Mean total cholesterol: 5.6 vs. 5.6 mmol/L
Proportion of (ever) smokers: 42% vs. 34%
A vs. B
Incidence at 1 year (end of intervention): 6% (5/83) vs. 23.5% (20/85); RR, 0.26 (95%
CI, 0.10 to 0.65)
Incidence at 3 years: 14.5% (12/83) vs. 23.5% (20/85); RR, 0.61 (95% CI, 0.32 to 1.18)
Incidence at 5 years: 20% (17/83) vs. 27% (23/85); RR, 0.75 (95% CI, 0.44 to 1.31)
Fair
Penn, 200984
United Kingdom
RCT
EDIPS
Treatment duration: Up to 5 years
Median follow-up: 3.1 years
A. Biweekly sessions for 1 month and monthly for 3 months and every 3 months for up to 5 years; motivational interview from dietician and physiotherapist with quarterly newsletter and advice to target >50% energy from carbohydrates (n=51)
B. 1 session of health promotion advice (n=51)
Patients with IGT and BMI >25 kg/m2
A vs. B
Mean age: 57 vs. 57 years
Female sex: 59% vs. 61%
Race: NR
Mean fasting glucose: 5.7 vs. 5.8 mmol/L
Mean BMI: 34.1 vs. 33.5 kg/m2
Mean blood pressure: NR
Mean total cholesterol: NR
Proportion of smokers: NR
A vs. B
Incidence: 9.8% (5/51) vs. 21.6% (11/51); RR, 0.45 (95% CI, 0.17 to 1.22)
Incidence rate per 1,000 persons: 32.7 vs. 67.1
Fair
Saito, 201140
38 centers in Japan
RCT
Zensharen Study for Prevention of Lifestyle Diseases
Treatment duration: 5 years and 3 months
Mean follow-up: 2.7 years
A. Individual session and goal to decrease weight by 5% with follow up at 1, 3, 6, 12, 18, 24, 30, and 36 months (n=330)
B. 1 session of advice to reduce weight by 5% (n=311)
Patients with IGT and BMI >24 kg/m2
A vs. B
Mean age: 50 vs.48 years
Female sex: 28% vs. 29%
Race: NR
Mean HbA1c: 5.4% vs. 5.4%
Mean BMI: 26.9 vs. 27.1 kg/m2
Mean blood pressure: 130/81 vs. 131/81 mm Hg
Mean total cholesterol: 5.5 vs. 5.5 mmol/L
Proportion of smokers: 25% vs. 28%
A vs. B
Cumulative incidence: 10.6% (35/330) vs. 16.4% (51/311); RR, 0.65 (95% CI, 0.43 to 0.97)
Fair
Sakane, 201186
32 community clinics in Japan
RCT
JDPP
Treatment duration: 6 years
Follow-up: 3 years
A. Individual and group sessions (4 group session lasting 2 to 3 hours, biannual individual session lasting 20 to 40 minutes) (n=146)
B. 1 group session (n=150)
Patients with IGT
A vs. B
Mean age: 51 vs. 51 years
Female sex: 50% vs. 49%
Race: NR
Mean fasting glucose: 5.9 vs. 6.1 mmol/L
Mean BMI: 24.8 vs. 24.5 kg/m2
Mean blood pressure: NR
Mean total cholesterol: NR
Proportion of smokers: NR
A vs. B
Incidence: 6.1% (9/146) vs. 12% (18/150); RR, 0.51 (95% CI, 0.24 to 1.11)
Fair
Pharmacologic interventions
Armato, 201290
United States
Prospective cohort
Mean follow-up: 6.9 vs. 5.5 vs. 8.9 months
A. Pioglitazone 15 mg/day and metformin 850 mg/day (n=40)
B. Pioglitazone 15 mg/day, metformin 850 mg/day, and exenatide 10 mcg/twice daily (n=47)
C. Lifestyle counseling, including weight loss 7% over 3 months, diet information, walking 30 minutes per day 7 days per week (n=18)
Patients with IFG or IGT
A vs. B vs. C
Mean age: 62 vs. 56 vs. 61 years; p=0.03
Female sex: 28% vs. 43% vs. 39%
Race: 82.5% white, 2.5% black, 15% other vs. 83% white, 2.1% black, 14.9% other vs. 100% white
Mean HbA1c: 5.8% vs. 5.7% vs. 5.6%
Mean BMI: 27.0 vs. 29.7 vs. 27.5 kg/m2
Mean blood pressure: NR
Mean total cholesterol: NR
Proportion of smokers: NR
A vs. B vs. C
Incidence: 0 vs. 0 vs. 5.6% (1/18); A vs. C: RR, 0.15 (95% CI, 0.01 to 3.62); B vs. C: RR, 0.13 (95% CI, 0.01 to 3.10)
Fair
DeFronzo, 201145
8 centers in United States
RCT
Median follow-up: 2.4 years
A. Pioglitazone 30 mg/day for 1 month, increased to 45 mg/day (n=303)
B. Placebo (n=299)
Patients with IGT, BMI >25 kg/m2, and ≥1 other risk factor for DM
A vs. B
Mean age: 53 vs. 52 years
Female sex: 58% vs. 58%
Race: 51% vs. 57% white; 26 vs. 25%
Hispanic; 19% vs.15% black; 3% vs. 3% other
Mean HbA1c: 5.5% vs. 5.5%
Mean BMI: 33.0 vs. 34.5 kg/m2
Mean blood pressure: 127/74 vs. 128/74 mm Hg
Mean total cholesterol: 4.3 vs. 4.5 mmol/L
Proportion of smokers: NR
A vs. B
Incidence: 5.0% (15/303) vs. 16.7% (50/299); RR, 0.30 (95% CI, 0.17 to 0.52)
Annual average incidence: 2.1% vs. 7.6%; p<0.001
HR: 0.28 (95% CI, 0.16 to 0.49)
NNT for duration of trial (2.2 years): 8
NNT for 1 year: 18
Fair
Kawamori, 200946
103 centers in Japan
RCT
Treatment duration: 5 years
Mean follow-up: 3 years
A. Voglibose 0.2 mg/day (n=897)
B. Placebo (n=881)
Patients with IFG
A vs. B
Mean age: 56 vs. 56 years
Female sex: 40% vs. 40%
Race: NR
Mean fasting plasma glucose: 5.8 vs. 5.9 mmol/L
Mean BMI: 25.8 vs. 25.9 kg/m2
Mean blood pressure: NR; 59% vs. 58% history of hypertension
Mean total cholesterol: NR; 77% vs. 76% history of dyslipidemia
Proportion of smokers: NR
A vs. B
Incidence: 5.5% (50/897) vs. 12% (106/881); RR, 0.46 (95% CI, 0.34 to 0.64)
HR: 0.595
Good
Lindblad, 201189
23 centers in Sweden
RCT
Median follow-up: 3.7 years
A. Glimepiride 1 mg/day (n=136)
B. Placebo (n=138)
Patients with IFG
A vs. B
Mean age: 60 vs. 60 years
Female sex: 35% vs. 46%
Race: NR
Mean HbA1c: 4.9% vs. 4.9%
Mean BMI: 29.9 vs. 29.6 kg/m2
Mean blood pressure: 144/82 vs.141/82 mm Hg
Mean total cholesterol: 5.5 vs. 5.4 mmol/L
Proportion of smokers: NR
A vs. B
Incidence: 30.1% (41/136) vs. 39.9% (55/138); RR, 0.76 (95% CI, 0.55 to 1.05)
Incidence, adjusted for baseline HbA1c, proinsulin, and CRP: OR, 0.62 (p=0.028)
Fair
NAVIGATOR, 201028 (nateglinide results)
806 centers in 40 countries
RCT
Median follow-up: 5 years
A. Nateglinide 60 mg/3 times daily (n=4,645)
B. Placebo (n=4,661)
Patients also randomized in 2x2 factorial design to receive valsartan or placebo
Patients with IGT and at least 1 CV risk factor or known CVD
A vs. B
Mean age: 64 vs. 64 years
Female sex: 51% vs. 50%
Race: 83% vs. 83% white; 3% vs. 3% black; 7% vs. 8% Asian; 8% vs.8% other
Mean HbA1c: 5.8% vs. 5.8%
Mean BMI: 30.5 vs. 30.5 kg/m2
Mean blood pressure: 140/83 vs. 140/83 mm Hg
Mean total cholesterol: 5.4 vs. 5.4 mmol/L
Proportion of smokers: 11% vs. 11%
A vs. B
Incidence: 36.0% (1647/4,645) vs. 33.9% (1580/4,661); RR, 1.05 (95% CI, 0.99 to 1.11)
Absolute hazard difference: 6.18 (95% CI, 0.47 to 11.90)
HR: 1.07 (95% CI, 1.00 to 1.15)
Good
NAVIGATOR, 201029 (valsartan results)
806 centers in 40 countries
RCT
Median follow-up: 5 years
A. Valsartan 160 mg/once daily (n=4,631)
B. Placebo (n=4,675)
Patients also randomized in 2x2 factorial design to receive nateglinide or placebo
Patients with IGT and at least 1 CV risk factor or known CVD
A vs. B
Mean age: 64 vs. 64 years
Female sex: 50% vs. 51%
Race: 83% vs. 83% white; 2% vs. 3% black, 6% vs. 7% Asian, 8% vs. 8% other
Mean HbA1c: 5.8% vs. 5.8%
Mean BMI: 30.4 vs. 30.6 kg/m2
Mean blood pressure: 139/83 vs. 140/83 mm Hg
Mean total cholesterol: 5.4 vs. 5.4 mmol/L
Proportion of smokers: 11% vs. 11%
A vs. B
Incidence: 33.1% (1532/4,631) vs. 36.8%(1722/4,675); RR, 0.90 (95% CI, 0.85 to 0.95)
Absolute hazard difference: −12.6 (95% CI, −18.4 to −6.9)
HR: 0.86 (95% CI, 0.80 to 0.92)
Good
Nijpels, 200847
1 center in the Netherlands
RCT
DAISI
Treatment duration: 3 years
A. Acarbose 50 mg/3 times daily (n=60)
B. Placebo (n=58)
Patients with IGT
A vs. B
Mean age: 59 vs. 57 years
Female sex: 49% vs. 50%
Race: NR
Mean HbA1c: 5.9% vs. 5.6%
Mean BMI: 28.4 vs. 29.5 kg/m2
Mean blood pressure: NR
Mean total cholesterol: NR
Proportion of smokers: 25% vs. 23%
A vs. B
Incidence: 18.3% (11/60) vs. 24.1% (14/58); RR, 0.76 (95% CI, 0.38 to 1.53)
Attributable risk: −0.14 (95% CI, −0.46 to 0.21)
Absolute risk reduction: 6% (95% CI, −9% to 21%)
Fair
Ramachandran, 200948
India
RCT
IDPP-2
Mean follow-up: 3 years
A. Pioglitazone (n=181)
B. Placebo (n=186)
Patients with IGT
A vs. B
Mean age: 45.1 vs. 45.5 years
Female sex: 13% vs. 14%
Race: NR
Mean HbA1c: 5.8% vs. 5.8%
Mean BMI: 26.0 vs. 26.2 kg/m2
Mean blood pressure: 118/75 vs.118/76 mm Hg
Mean total cholesterol: 5.2 vs. 5.3 mmol/L
Proportion of smokers: 37% vs. 47%
A vs. B
Cumulative incidence: 29.8% (54/181) vs. 31.6% (59/186); RR, 0.94 (95% CI, 0.69 to 1.28)
Fair
Zinman, 201049
2 centers in Canada
RCT
CANOE
Treatment duration: NR
Median follow-up: 3.9 years
A. Metformin 500 mg plus rosiglitazone 2 mg/twice daily as a fixed-dose combination (n=103)
B. Placebo (n=104)
Patients with IGT and ≥1 risk factor for DM
A vs. B
Mean age: 50 vs. 55 years
Female sex: 65% vs. 68%
Race: 75% vs. 74% white; 8% vs. 7% South Asian; 7% vs. 7% Latino; 11% vs.13% other
Mean fasting glucose: 5.4 vs. 5.4 mmol/L
Mean BMI: 31.3 vs. 32.0 kg/m2
Mean blood pressure: 130/80 vs. 128/82 mm Hg
Mean total cholesterol: 4.9 vs. 5.4 mmol/L
Proportion of smokers: NR
A vs. B
Incidence: 13.6% (14/103) vs. 39.4% (41/104); RR, 0.34 (95% CI, 0.20 to 0.59)
RR reduction: 66% (95% CI, 41 to 80%)
Absolute risk reduction: 26% (95% CI, 14 to 37%)
NNT over 3.9 years: 4 (95% CI, 2.7 to 7.1)
HR: 0.31 (95% CI, 0.17 to 0.58)
Good
Multifactorial interventions
Lu, 201183
4 communities in China
RCT
Treatment duration: 2 years
A. IGT: Acarbose 50 mg/3 times daily; IFG or IGT/IFG: Metformin 250 mg/3 times daily; antihypertensives, antidyslipidemia agents, and aspirin (n=95)
B. Control: Health/diabetic education once a month (n=86)
Patients with IGT and BMI >19 kg/m2
A vs. B
Mean age: 62 vs. 65 years
Female sex: 47% vs. 48%
Race: NR
Mean HbA1c: 5.9% vs. 6.0%
Mean BMI: 27.1 vs. 26.9 kg/m2
Mean blood pressure: 130/79 vs. 130/79 mm Hg
Mean total cholesterol: 5.1 vs. 5.0 mmol/L
Proportion of smokers: NR
A vs. B
Incidence: 0% vs. 5.8% (5/86); RR, 0.08 (95% CI, 0.00 to 1.42)
Fair
Rasmussen, 200885
Multicenter, Denmark
Cluster RCT
ADDITION-Denmark
A. Intensive management, including lifestyle advice, aspirin, drug treatment of blood glucose, blood pressure, and lipids according to strict targets (n=865); subgroup received motivational interviewing training
B. Standard care (n=645)
Patients with IGT or IFG
A vs. B
IFG
Mean age: 60 vs. 60 years
Female sex: 43% vs. 43%
Race: NR
Mean BMI: 29.1 vs. 29.1 kg/m2
Proportion with hypertension: 41% vs. 49%
Mean total cholesterol: 5.7 vs. 5.7 mmol/L
Proportion of smokers: 26% vs. 27%
IGT
Mean age: 61 vs. 61 years
Female sex: 53% vs. 60% (p=0.037)
Race: NR
Mean BMI: 29.5 vs. 29.8 kg/m2
Proportion with hypertension: 53% vs. 53%
Mean total cholesterol: 5.8 vs. 5.9 mmol/L
Proportion of smokers: 28% vs. 21% (p=0.016)
A vs. B
Incidence: 14.1 vs. 15.8 cases/100 person-years; RR, 0.89 (95% CI, 0.78 to 1.02)
Subanalyses
Motivational interviewing + intensive intervention: RR, 0.83 (95% CI, 0.68 to 1.00)
Intensive treatment alone: RR, 0.95 (95% CI, 0.80 to 1.14)
IFG: RR, 0.90 (95% CI, 0.73 to 1.12)
IGT: RR, 0.90 (95% CI, 0.77 to 1.07)
Fair

ADDITION = Anglo-Dutch-Danish Study of Intensive Treatment in People With Screen Detected Diabetes in Primary Care; BMI = body mass index; CANOE = Canadian Normoglycemia Outcomes Evaluation; CRP = C-reactive protein; CV = cardiovascular; CVD = cardiovascular disease; DAISI = Dutch Acarbose Intervention Study in Persons With Impaired Glucose Tolerance; DM = diabetes mellitus; DPS = Diabetes Prevention Study; EDIPS = European Diabetes Prevention Study; HbA1c = hemoglobin A1c; HR = hazard ratio; IDPP-2 = Indian Diabetes Prevention Program-2; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; JDPP = Japanese Diabetes Prevention Program; NAVIGATOR = Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; NNT = number needed to treat; NR = not reported; OR = odds ratio; RCT = randomized, controlled trial; RR = relative risk.

Current as of: April 2015

Internet Citation: Evidence Summary: Abnormal Blood Glucose and Type 2 Diabetes Mellitus: Screening. U.S. Preventive Services Task Force. June 2015.
https://www.uspreventiveservicestaskforce.org/Page/Document/evidence-summary25/screening-for-abnormal-blood-glucose-and-type-2-diabetes

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