Edward W. Gregg

Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes

BACKGROUND Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. METHODS In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. RESULTS The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P=0.51). CONCLUSIONS An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.).

Prevalence of Diabetes and Impaired Fasting Glucose in Adults in the U.S. Population National Health and Nutrition Examination Survey 1999–2002

OBJECTIVE—The purpose of this study was to examine the prevalences of diagnosed and undiagnosed diabetes, and impaired fasting glucose (IFG) in U.S. adults during 1999–2002, and compare prevalences to those in 1988–1994. RESEARCH DESIGN AND METHODS—The National Health and Nutrition Examination Survey (NHANES) contains a probability sample of adults aged ≥20 years. In the NHANES 1999–2002, 4,761 adults were classified on glycemic status using standard criteria, based on an interview for diagnosed diabetes and fasting plasma glucose measured in a subsample. RESULTS—The crude prevalence of total diabetes in 1999–2002 was 9.3% (19.3 million, 2002 U.S. population), consisting of 6.5% diagnosed and 2.8% undiagnosed. An additional 26.0% had IFG, totaling 35.3% (73.3 million) with either diabetes or IFG. The prevalence of total diabetes rose with age, reaching 21.6% for those aged ≥65 years. The prevalence of diagnosed diabetes was twice as high in non-Hispanic blacks and Mexican Americans compared with non-Hispanic whites (both P < 0.00001), whereas the prevalence of undiagnosed diabetes was similar by race/ethnicity, adjusted for age and sex. The prevalence of diagnosed diabetes was similar by sex, but prevalences of undiagnosed diabetes and IFG were significantly higher in men. The crude prevalence of diagnosed diabetes rose significantly from 5.1% in 1988–1994 to 6.5% in 1999–2002, but the crude prevalences were stable for undiagnosed diabetes (from 2.7 to 2.8%) and IFG (from 24.7 to 26.0%). Results were similar after adjustment for age and sex. CONCLUSIONS—Although the prevalence of diagnosed diabetes has increased significantly over the last decade, the prevalences of undiagnosed diabetes and IFG have remained relatively stable. Minority groups remain disproportionately affected.

The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study.

BACKGROUND Intensive lifestyle interventions can reduce the incidence of type 2 diabetes in people with impaired glucose tolerance, but how long these benefits extend beyond the period of active intervention, and whether such interventions reduce the risk of cardiovascular disease (CVD) and mortality, is unclear. We aimed to assess whether intensive lifestyle interventions have a long-term effect on the risk of diabetes, diabetes-related macrovascular and microvascular complications, and mortality. METHODS In 1986, 577 adults with impaired glucose tolerance from 33 clinics in China were randomly assigned to either the control group or to one of three lifestyle intervention groups (diet, exercise, or diet plus exercise). Active intervention took place over 6 years until 1992. In 2006, study participants were followed-up to assess the long-term effect of the interventions. The primary outcomes were diabetes incidence, CVD incidence and mortality, and all-cause mortality. FINDINGS Compared with control participants, those in the combined lifestyle intervention groups had a 51% lower incidence of diabetes (hazard rate ratio [HRR] 0.49; 95% CI 0.33-0.73) during the active intervention period and a 43% lower incidence (0.57; 0.41-0.81) over the 20 year period, controlled for age and clustering by clinic. The average annual incidence of diabetes was 7% for intervention participants versus 11% in control participants, with 20-year cumulative incidence of 80% in the intervention groups and 93% in the control group. Participants in the intervention group spent an average of 3.6 fewer years with diabetes than those in the control group. There was no significant difference between the intervention and control groups in the rate of first CVD events (HRR 0.98; 95% CI 0.71-1.37), CVD mortality (0.83; 0.48-1.40), and all-cause mortality (0.96; 0.65-1.41), but our study had limited statistical power to detect differences for these outcomes. INTERPRETATION Group-based lifestyle interventions over 6 years can prevent or delay diabetes for up to 14 years after the active intervention. However, whether lifestyle intervention also leads to reduced CVD and mortality remains unclear.

Full Accounting of Diabetes and Pre-Diabetes in the U.S. Population in 1988–1994 and 2005–2006

OBJECTIVE—We examined the prevalences of diagnosed diabetes, and undiagnosed diabetes and pre-diabetes using fasting and 2-h oral glucose tolerance test values, in the U.S. during 2005–2006. We then compared the prevalences of these conditions with those in 1988–1994. RESEARCH DESIGN AND METHODS—In 2005–2006, the National Health and Nutrition Examination Survey included a probability sample of 7,267 people aged ≥12 years. Participants were classified according to glycemic status by interview for diagnosed diabetes and by fasting and 2-h glucoses measured in subsamples. RESULTS—In 2005–2006, the crude prevalence of total diabetes in people aged ≥20 years was 12.9%, of which ∼40% was undiagnosed. In people aged ≥20 years, the crude prevalence of impaired fasting glucose was 25.7% and of impaired glucose tolerance was 13.8%, with almost 30% having either. Over 40% of individuals had diabetes or pre-diabetes. Almost one-third of the elderly had diabetes, and three-quarters had diabetes or pre-diabetes. Compared with non-Hispanic whites, age- and sex-standardized prevalence of diagnosed diabetes was approximately twice as high in non-Hispanic blacks (P < 0.0001) and Mexican Americans (P = 0.0001), whereas undiagnosed diabetes was not higher. Crude prevalence of diagnosed diabetes in people aged ≥20 years rose from 5.1% in 1988–1994 to 7.7% in 2005–2006 (P = 0.0001); this was significant after accounting for differences in age and sex, particularly in non-Hispanic blacks. Prevalences of undiagnosed diabetes and pre-diabetes were generally stable, although the proportion of total diabetes that was undiagnosed decreased in Mexican Americans. CONCLUSIONS—Over 40% of people aged ≥20 years have hyperglycemic conditions, and prevalence is higher in minorities. Diagnosed diabetes has increased over time, but other conditions have been relatively stable.

Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: Four-year results of the look AHEAD trial

BACKGROUND Lifestyle interventions produce short-term improvements in glycemia and cardiovascular disease (CVD) risk factors in individuals with type 2 diabetes mellitus, but no long-term data are available. We examined the effects of lifestyle intervention on changes in weight, fitness, and CVD risk factors during a 4-year study. METHODS The Look AHEAD (Action for Health in Diabetes) trial is a multicenter randomized clinical trial comparing the effects of an intensive lifestyle intervention (ILI) and diabetes support and education (DSE; the control group) on the incidence of major CVD events in 5145 overweight or obese individuals (59.5% female; mean age, 58.7 years) with type 2 diabetes mellitus. More than 93% of participants provided outcomes data at each annual assessment. RESULTS Averaged across 4 years, ILI participants had a greater percentage of weight loss than DSE participants (-6.15% vs -0.88%; P < .001) and greater improvements in treadmill fitness (12.74% vs 1.96%; P < .001), hemoglobin A(1c) level (-0.36% vs -0.09%; P < .001), systolic (-5.33 vs -2.97 mm Hg; P < .001) and diastolic (-2.92 vs -2.48 mm Hg; P = .01) blood pressure, and levels of high-density lipoprotein cholesterol (3.67 vs 1.97 mg/dL; P < .001) and triglycerides (-25.56 vs -19.75 mg/dL; P < .001). Reductions in low-density lipoprotein cholesterol levels were greater in DSE than ILI participants (-11.27 vs -12.84 mg/dL; P = .009) owing to greater use of medications to lower lipid levels in the DSE group. At 4 years, ILI participants maintained greater improvements than DSE participants in weight, fitness, hemoglobin A(1c) levels, systolic blood pressure, and high-density lipoprotein cholesterol levels. CONCLUSIONS Intensive lifestyle intervention can produce sustained weight loss and improvements in fitness, glycemic control, and CVD risk factors in individuals with type 2 diabetes. Whether these differences in risk factors translate to reduction in CVD events will ultimately be addressed by the Look AHEAD trial. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00017953.

Changes in Diabetes-Related Complications in the United States, 1990–2010

BACKGROUND Preventive care for adults with diabetes has improved substantially in recent decades. We examined trends in the incidence of diabetes-related complications in the United States from 1990 through 2010. METHODS We used data from the National Health Interview Survey, the National Hospital Discharge Survey, the U.S. Renal Data System, and the U.S. National Vital Statistics System to compare the incidences of lower-extremity amputation, end-stage renal disease, acute myocardial infarction, stroke, and death from hyperglycemic crisis between 1990 and 2010, with age standardized to the U.S. population in the year 2000. RESULTS Rates of all five complications declined between 1990 and 2010, with the largest relative declines in acute myocardial infarction (-67.8%; 95% confidence interval [CI], -76.2 to -59.3) and death from hyperglycemic crisis (-64.4%; 95% CI, -68.0 to -60.9), followed by stroke and amputations, which each declined by approximately half (-52.7% and -51.4%, respectively); the smallest decline was in end-stage renal disease (-28.3%; 95% CI, -34.6 to -21.6). The greatest absolute decline was in the number of cases of acute myocardial infarction (95.6 fewer cases per 10,000 persons; 95% CI, 76.6 to 114.6), and the smallest absolute decline was in the number of deaths from hyperglycemic crisis (-2.7; 95% CI, -2.4 to -3.0). Rate reductions were larger among adults with diabetes than among adults without diabetes, leading to a reduction in the relative risk of complications associated with diabetes. When expressed as rates for the overall population, in which a change in prevalence also affects complication rates, there was a decline in rates of acute myocardial infarction and death from hyperglycemic crisis (2.7 and 0.1 fewer cases per 10,000, respectively) but not in rates of amputation, stroke, or end-stage renal disease. CONCLUSIONS Rates of diabetes-related complications have declined substantially in the past two decades, but a large burden of disease persists because of the continued increase in the prevalence of diabetes. (Funded by the Centers for Disease Control and Prevention.).

A diabetes report card for the United States: Quality of care in the 1990s

Context There are no recent national evaluations of diabetes care in the United States. Contribution Using data from two national surveys, this study documents a substantial gap between the recommended and actual care of diabetes in the United States between 1988 and 1995. Many participants had hemoglobin A1c levels greater than 9.5% (18.0%), poorly controlled blood pressure (34.3%), and elevated cholesterol levels (58.0%). Implications As a nation, the United States is falling short in caring for patients with diabetes. A periodic national report card may help us to gauge the success of future efforts to improve. The Editors Diabetes, a typical example of chronic disease, currently affects 16 million people in the United States, causes considerable morbidity and mortality, and costs the nation almost

Improvements in diabetes processes of care and intermediate outcomes: United States, 1988-2002.

100 billion per year (1, 2). Fortunately, several efficacious treatment strategies to prevent or delay diabetes complications have emerged during the past decade, including control of glycemia, lipids, and hypertension; early detection and treatment of diabetic retinopathy, nephropathy, and foot disease; therapy with aspirin and angiotensin-converting enzyme inhibitors; and influenza and pneumococcal vaccines (3-12). Many of these treatments are cost-effective (13-17). However, their implementation in the United States remains suboptimal and varied (18-22). There is considerable pressure on U.S. health care systems to improve this situation and to deliver high-quality care while controlling costs. Influential bodies, such as the Institute of Medicine, have recently emphasized the need for strategies to improve the current quality of all medical care in the United States (23). Federal agencies are also increasingly responding with initiatives to address quality of care (24, 25). One powerful quality initiative in the United States is the Diabetes Quality Improvement Project (DQIP), which is designed to influence the care of millions of U.S. patients with diabetes (26). The standard measures of quality of diabetes care proposed by DQIP were incorporated into the National Committee for Quality Assurance (NCQA) Health Plan Employer and Data Information Set. In contrast to guidelines or clinical goals for individual care, DQIP measures are designed to assess the performance of health care systems for a population, and they offer a wayto make comparisons across health care systems. Several public and private health care systems, including the Indian Health Service (27), the Veterans Administration, the U.S. Department of Defense, and numerous managed care organizations, have adopted these indicators. Currently, there is no national reference for assessing the quality of diabetes care using a standard set of measures. Such a reference could help health care systems using DQIP measures to compare their own performance against population norms rather than the norms of other health systems. This reference could be a benchmark for assessing population changes in quality of diabetes care after implementation of national quality improvement initiatives recommended by the Institute of Medicine and NCQA. Furthermore, the use of a standard set of measures to assess the quality of diabetes care at a national level can facilitate international comparison. For this report, we used U.S. national data to provide a reference and benchmark of the quality of diabetes care as measured by the DQIP indicators. Methods Surveys We used two federally funded, nationally representative population-based surveys, the Third U.S. National Health and Nutrition Examination Survey (NHANES III) (19881994) and the Behavioral Risk Factors Surveillance System (BRFSS) (1995). Data from these two surveys were analyzed separately. Some measures came exclusively from NHANES III, and others came from BRFSS. We included adults 18 to 75 years of age who reported receiving a previous diagnosis of diabetes from a physician. Women with gestational diabetes were excluded. The two survey groups were similar in demographic characteristics, household income, health insurance coverage, and prevalence of diabetes. In NHANES III compared with BRFSS, more persons did not have a high school education (41.5% vs. 27.1%) and fewer persons used insulin (30.9% vs. 39.8%) (Table 1). Table 1. Characteristics of Persons with Self-Reported Diabetes in the Third U.S. National Health and Nutrition Examination Survey (19881994) and the Behavioral Risk Factors Surveillance System1995 The methods for NHANES III are described elsewhere (28). Briefly, the NHANES III survey used a nationally representative sample of the civilian noninstitutionalized population obtained through a complex multistage cluster sampling design, with oversampling of non-Hispanic black persons, Mexican-American persons, and elderly persons. During a household interview, data were collected on sociodemographic characteristics and medical and family history. Within 4 weeks, this was followed by a clinical examination at a mobile examination center. The procedures for blood collection and processing have also been described elsewhere (29, 30). Low-density lipoprotein (LDL) cholesterol level was calculated by using the Friedwald equation for persons who fasted more than 8 hours (n = 302). Data from NHANES III were self-reported (demographic and clinical variables) or were obtained during clinical examination (hemoglobin A1c level, cholesterol level, triglyceride level, and blood pressure). The survey included 16 705 participants 18 to 75 years of age, 1026 of whom reported receiving a diagnosis of diabetes from a physician before the survey. The BRFSS is an annual random-digit telephone survey of state populationbased samples of the civilian noninstitutionalized population of adults ( 18 years of age) in each of the 50 states and the District of Columbia. Its purpose, methods, and data analyses have been described in detail elsewhere (31). A diabetes-specific BRFSS module was used to collect data on clinical characteristics and preventive care practices from respondents with diabetes. Data from BRFSS were self-reported (dilated eye examination, lipid test, foot examination, and demographic and clinical variables). The survey included 103 929 participants 18 to 75 years of age, 3059 of whom completed the diabetes module and reported receiving a diagnosis of diabetes from a physician. We used the 1995 BRFSS so that the time frame would correspond with NHANES III. Quality-of-Care Measures We assessed the quality of diabetes care using indicators from the DQIP measurement set for which data were available. The DQIP began under the sponsorship of a coalition that included the American Diabetes Association, the Foundation for Accountability, the Health Care Financing Administration, and NCQA. The American Academy of Physicians, the American College of Physicians, the Veterans Administration, and the Centers for Disease Control and Prevention later joined the coalition. A committee of experts in diabetes care was responsible for developing the DQIP measure set. The DQIP classified the proposed indicators into three categories: accountability indicators, quality improvement indicators, and indicators under field-testing. The accountability measures, which are well grounded in evidence, have received consensus support from the scientific and medical community and have been extensively field-tested in a variety of health care settings. These measures are used to compare health systems and plans or providers. The quality improvement measures are not considered appropriate for comparing systems and plans or providers but were recommended by the NCQA for assessing internal performance. Table 2 shows all of the analyzed quality indicators and their data sources. The DQIP measures are a combination of process and outcome measures. In this paper, we use DQIP terminology and DQIP accountability and quality improvement measures. Table 2. Diabetes Quality Improvement Project Indicators and Related Data Sources Statistical Analysis All analyses were conducted by using SAS software (SAS Institute, Inc., Cary, North Carolina) for data management and SUDAAN (Research Triangle Institute, Research Triangle Park, North Carolina) to account for the complex sampling scheme, the unequal probability of selection, the oversampling of certain demographic groups, and nonresponse factors (32, 33). Level of care was estimated by the percentage, with corresponding 95% CIs, of respondents who reported each preventive care practice. We estimated prevalence by groups of sex, age, ethnicity, education, health insurance, type of treatment, and duration of diabetes. Multiple logistic regression and computation of predictive margins were used to estimate the probability of receiving DQIP indicators when we controlled for all other independent variables. Predictive margins are a type of direct standardization in which the predicted values from the logistic regression models are averaged over the covariate distribution in the population (34). Predictive margins and their standard errors from logistic regression models are provided by the current version of SUDAAN (33). Taylor linearization is used in SUDAAN for calculating these standard errors. Odds ratios are usually used to display the result from logistic regression models. However, predictive margins are easier to interpret than odds ratios, and they do not require designating one of the groups as the referent group. Results Diabetes Quality Improvement Project Accountability and Quality Improvement Measures Among adults 18 to 75 years of age with diabetes, 28.8% had had hemoglobin A1c levels tested in the past year, and 18.0% had a hemoglobin A1c level greater than 9.5%. Biannual lipid testing was done in 85.3% of participants, but only 42.0% had an LDL cholesterol level less than 3.4 mmol/L (<130 mg/dL). Only 65.7% had blood pressure less than 140/90 mm Hg, 63.3% had an annual dilated eye examination, an

The Evolving Diabetes Burden in the United States

Context As the target of many quality improvement programs, positive change in diabetes care is a good marker for progress toward better health care. Content The authors analyzed measures of diabetes care from national population-based surveys that were conducted between 1988 and 2002. Improvements occurred in the proportion of patients with hemoglobin A1c between 6% and 8%, low-density lipoprotein (LDL) cholesterol levels less than 3.4 mmol/L (<130 mg/dL), annual influenza vaccination, and aspirin use. Blood pressure did not change. Substantial proportions of patients still had poor control of LDL cholesterol levels, glycemia, and blood pressure. Implications Despite some progress, population-based measurements show that care for many Americans with diabetes falls far short of targets. The Editors Diabetes currently affects 20.8 million people in the United States (1), and that number is projected to reach 39 million by the year 2050 (2). If current trends continue, 1 in 3 Americans will develop diabetes sometime in his or her lifetime, and those with diabetes will lose, on average, 10 to 15 life-years (3). In 2002, diabetes cost the nation an estimated

Prevalence of Diabetes and High Risk for Diabetes Using A1C Criteria in the U.S. Population in 1988–2006

132 billion in direct and indirect costs (4). There is, however, a growing array of effective and cost-effective treatments to help prevent or delay diabetes complications and also diabetes itself (5-17). Diabetes care has been suboptimal and varied in the United States (18-21). The National Diabetes Quality Improvement Project, founded in 1997, developed a comprehensive set of measures of diabetes quality of care (22). These measures have been incorporated into the Health Plan Employer Data and Information Set, the American Diabetes Association Provider Recognition Program, the American Medical Association Diabetes Measures Group, the Veterans Administration performance monitoring program, and other activities. The Diabetes Quality Improvement Project partners now continue their work as a coalition of 13 influential private and public national organizations called the National Diabetes Quality Improvement Alliance. The Alliance develops, maintains, and promotes the use of an updated standardized measurement set (the Alliance measures) for quality of diabetes care (23). We previously established a national benchmark for diabetes quality of care in the United States for the years 1988 to 1995 by using the standard measurements recommended by the Diabetes Quality Improvement Project (18). On the basis of nationally representative data collected in 1999 to 2002, we report the changes in the quality of diabetes care from the 1990s to 2000s by using the standardized Alliance measures for both time periods. Methods Surveys We used data from 2 federally funded, nationally representative surveys: the National Health and Nutrition Examination Survey, 19881994 (NHANES III) and 19992002 (NHANES 19992002), and the Behavioral Risk Factor Surveillance System, 1995 (BRFSS 1995) and 2002 (BRFSS 2002). As previously explained (18), we used both BRFSS and NHANES to obtain data on all the process and intermediate outcome measures needed for the analysis. In our report, we refer to NHANES III and BRFSS 1995 as baseline surveys and NHANES 19992002 and BRFSS 2002 as recent surveys. We analyzed data from each survey separately. Table 1 presents the indicators used and their respective data source. Table 1. National Diabetes Quality Improvement Alliance and Additional Indicators of Diabetes Processes and Outcomes of Care National Health and Nutrition Examination Survey The NHANES consists of nationally representative samples of the U.S. civilian, noninstitutionalized population. Samples were obtained by using a stratified multistage probability design with planned oversampling of older and minority groups. Household interviews were conducted to ascertain sociodemographic characteristics and medical and family history. After the household interview, clinical examinations were conducted at a mobile examination center. Detailed descriptions of the design and data collection of each survey have been published elsewhere (24-27). Data from NHANES were self-reported (demographic characteristics and clinical variables) or were obtained during the clinical examination (hemoglobin A1c, cholesterol level, triglycerides level, and blood pressure level). Hemoglobin A1c measurements were standardized to the Diabetes Control and Complications Trial. Cholesterol levels were standardized by using the criteria established by the Centers for Disease Control and Prevention and the National Heart, Lung, and Blood Institute Lipid Standardization Program II. For persons who fasted for more than 8 hours and had triglyceride levels less than 4.5 mmol/L (<400 mg/dL), the Friedewald equation was applied to calculate low-density lipoprotein (LDL) cholesterol level. We log-transformed triglyceride levels because data were not normally distributed. We used the average of each persons blood pressure readings that were taken in the seated position during the clinical examination. Because we did not have data on annual testing for microalbuminuria, we assessed the absence of microalbuminuria, defined as albumin-to-creatinine ratio greater than 30 g/mg in spot urine collection (28). We analyzed the data for all indicators regardless of respective treatment status. Behavioral Risk Factor Surveillance System The BRFSS is an ongoing random-digit telephone survey of the noninstitutionalized U.S. adult population in each of the 50 states and the District of Columbia. Detailed descriptions of the design and data collection of the BRFSS have been published elsewhere (29). We used the diabetes-specific module that contains questions on clinical and preventive care practices to collect information from the participants with diabetes. Participants We included adults 18 to 75 years of age who reported a previous diagnosis of diabetes by a health care professional. We excluded women with gestational diabetes. We analyzed data from 1024 participants in NHANES III and 750 participants in NHANES 19992002 who selfreported a diagnosis of diabetes and who completed the clinical examination. We analyzed data from 3065 persons in BRFSS 1995 and 13078 persons in BRFSS 2002 who identified themselves as having diabetes. Participants reporting diabetes in all surveys were similar in age, sex, education, smoking, and insurance status at each point of time. Among participants of the recent surveys compared with those of the baseline surveys, the proportion of women and non-Hispanic white persons was lower and the proportion of participants with more than a high school education and an annual household income of