Sherita Hill Golden

Meta-analysis: Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus

Context The relationship between glycosylated hemoglobin and cardiovascular disease in diabetic persons is less clear than its relationship with microvascular disease. Contribution This meta-analysis of 13 observational studies estimates that, for every 1-percentage point increase in glycosylated hemoglobin, the relative risk for any cardiovascular disease event is 1.18 for patients with type 2 diabetes mellitus and 1.15 for patients with type 1 diabetes mellitus. Cautions Although this analysis suggests that improvements in glycosylated hemoglobin level might translate into reductions in cardiovascular events, confirmation from randomized trials is necessary. The Editors Persons with diabetes mellitus are at an increased risk for cardiovascular disease; they have more than a 2-fold increased risk for cardiovascular death compared with persons without diabetes (1-3). Cardiovascular death accounts for more than 75% of all deaths among persons with diabetes mellitus (3, 4). Because this excess risk is only partially explained by traditional risk factors, such as obesity, dyslipidemia, and hypertension, diabetes is often considered an independent risk factor for cardiovascular disease. A strong body of evidence links chronic hyperglycemia to microvascular complications, such as retinopathy, neuropathy, and nephropathy, in persons with diabetes (5-10). In randomized clinical trials, improving glycemic control substantially reduces the incidence of microvascular disease in persons with diabetes (5, 6, 11). However, few randomized trials have specifically been designed to examine the influence of glycemic control on macrovascular complications, such as coronary heart disease, stroke, and peripheral arterial disease. Results from clinical trials that collected information on cardiovascular outcomes have been equivocal. In interpreting recent clinical trial data in a position statement, the American Diabetes Association stated that the role of hyperglycemia in cardiovascular complications is still unclear (12). Fasting blood glucose levels in diabetic and nondiabetic persons have been linked to an excess risk for cardiovascular disease (13-15); this link suggests an association between glycemic control and cardiovascular risk. A meta-regression analysis that combined data from more than 95 000 persons without diagnosed diabetes found a graded relationship between fasting and postprandial blood glucose levels and subsequent risk for a cardiovascular event (15). An important clinical question is whether improving long-term glycemic control in persons with diabetes reduces the risk for cardiovascular disease events. Glycosylated hemoglobin reflects long-term glycemic control and is a more accurate and stable measure than fasting blood glucose levels (16). It tracks well over time in persons with diabetes and has less measurement error than fasting blood glucose (17-20). Glycosylated hemoglobin is at the center of the clinical management of hyperglycemia in persons with diabetes. However, clinical guidelines for glycosylated hemoglobin levels are based on cut-points relevant for the prevention of microvascular complications (21). The relationship between glycosylated hemoglobin and cardiovascular disease, the most deadly complication of diabetes mellitus, has not been adequately characterized. We performed a systematic review to characterize the risk relation between long-term glycemic control, as measured by glycosylated hemoglobin, and cardiovascular end points (peripheral arterial disease, coronary heart disease, and cerebrovascular disease) in persons with type 1 and type 2 diabetes mellitus. Methods Study Design We systematically reviewed prospective cohort studies of glycosylated hemoglobin and cardiovascular disease in persons with diabetes mellitus. This study was part of a larger project commissioned by the Agency for Healthcare Research and Quality, which was conducted by the Johns Hopkins Evidenced-based Practice Center (22). Study Selection We searched the MEDLINE database for articles published in English from 1966 to July 2003 by using Medical Subject Heading terms and text words related to cardiovascular disease (coronary heart disease, peripheral arterial disease, or cerebrovascular disease), diabetes mellitus, glycemic control, and glycosylated hemoglobin (the Appendix contains the full text of the search string). We reviewed all abstracts obtained from our search for relevance. We manually reviewed bibliographies and review articles for additional citations and obtained the full text of all potentially relevant articles. We also queried experts to identify any additional studies. Our prespecified inclusion criteria were as follows: 1) prospective cohort studies that examined the cardiovascular outcomes of interest (peripheral arterial disease, coronary heart disease, and stroke) and 2) studies that reported a measure of glycosylated hemoglobin and that were conducted in samples that included persons with type 1 or type 2 diabetes. Persons described as having insulin-dependent diabetes mellitus or younger- or juvenile-onset diabetes were classified as having type 1 diabetes. Individuals described as having noninsulin-dependent diabetes mellitus or older-onset diabetes were classified as having type 2 diabetes. We excluded studies if they 1) had no original data, 2) did not address persons with diabetes, 3) involved nonprospective studies (for example, cross-sectional and retrospective casecontrol studies), 4) had less than 1 year of follow-up, 5) assessed the effect of glycemic control on cardiovascular outcomes after admission to a hospital or after surgery, and 6) involved only patients receiving dialysis or transplants. We excluded 1 additional study (23) in which the outcome was self-reported and the authors did not use standard definitions for classifying cardiovascular outcomes. When several, sequentially published studies were performed in the same sample, the publication with the longest follow-up was selected for inclusion in our analysis. For multiple studies of the same sample with equivalent follow-up, the most recent publication was selected. Data Abstraction Two investigators independently reviewed each article that met the selection criteria and abstracted the data by using standardized data abstraction forms. Discrepancies were resolved by consensus. Data abstracted were age, percentage of male and female study participants, sample size, outcome or outcomes, duration of follow-up, method of measuring glycosylated hemoglobin, main results, statistical methods, number of study participants included in the final analysis, and variables included in the adjusted model or models. For each prospective cohort study that met our inclusion criteria, we abstracted adjusted effect estimates (odds ratios, relative risks, or relative hazards) for the association between cardiovascular risk (based on incident events during follow-up) and baseline or updated mean glycosylated hemoglobin values. Standard errors for the estimates were abstracted or derived by using data reported in the manuscript. The cardiovascular disease end points, defined a priori, were fatal and nonfatal coronary heart disease (myocardial infarction, angina, and ischemic heart disease); cerebrovascular disease (fatal and nonfatal stroke); peripheral arterial disease (lower-extremity peripheral arterial disease, amputation, and claudication); and a combined cardiovascular disease outcome that included studies of coronary heart disease and stroke (but not peripheral arterial disease). We conducted separate analyses for each cardiovascular end point and for samples of persons with type 1 and type 2 diabetes. Studies using a combined outcome that included both coronary heart disease and stroke (24-26) were excluded from the pooled effect estimates for stroke alone and coronary heart disease alone but were included in the combined coronary heart disease and stroke subgroup. Statistical Analysis We conducted separate meta-analyses of the prospective cohort studies for study samples of persons with type 1 and type 2 diabetes and for the different cardiovascular outcomes. Most studies reported glycosylated hemoglobin as percentage hemoglobin A1c or its equivalent, although some studies (27-32) measured hemoglobin A1 and 1 study (33) measured total glycosylated hemoglobin. Although the American Diabetes Association advises that all measurements of glycosylated hemoglobin be reported as percentage hemoglobin A1c or its equivalent (16), there are direct linear relationships between glycosylated hemoglobin subfractions (34); therefore, we did not consider the measured subfraction to be an important source of heterogeneity across studies. For 4 studies (27, 30-32) that reported relative risk estimates for participants in the highest tertile of glycosylated hemoglobin compared with participants in the 2 lowest tertiles, we assumed a normal distribution for glycosylated hemoglobin values and used the reported mean and SD to estimate the 33rd and 83rd percentiles of glycosylated hemoglobin (corresponding to the midpoints of the 2 lowest and the highest tertiles, respectively). Then, we divided the log relative risk by the difference of these 2 values to estimate the effect of a 1-unit change in glycosylated hemoglobin (35). For the study (36) that reported a dichotomous relative risk estimate (it compared glycosylated hemoglobin above and below the median), we used the same method to estimate the effect of a 1-unit change in glycosylated hemoglobin but calculated the 25th and 75th percentiles and divided the log relative risk by the difference of these 2 values. One study (29) did not report relative risks or odds ratios but reported the mean and SD of glycosylated hemoglobin in persons with and without cardiovascular disease events. In this case, we estimated the odds ratio and its 95% CI on the basis of a linear discriminant function model. This m

Depression and Type 2 Diabetes Over the Lifespan: A meta-analysis

OBJECTIVE—It has been argued that the relationship between depression and diabetes is bi-directional, but this hypothesis has not been explicitly tested. This systematic review examines the bi-directional prospective relationships between depression and type 2 diabetes. RESEARCH DESIGN AND METHODS—A search was conducted using Medline for publications from 1950 through 2007. Reviewers assessed the eligibility of each report by exposure/outcome measurement and study design. Only comparative prospective studies of depression and type 2 diabetes that excluded prevalent cases of depression (for diabetes predicting depression) or diabetes (for depression predicting diabetes) were included. Two sets of pooled risk estimates were calculated using random effects: depression predicting type 2 diabetes and type 2 diabetes predicting depression. RESULTS—Of 42 full-text publications reviewed, 13 met eligibility for depression predicting onset of diabetes, representing 6,916 incident cases. Seven met criteria for diabetes predicting onset of depression, representing 6,414 incident cases. The pooled relative risk (RR) for incident depression associated with baseline diabetes was 1.15 (95% CI 1.02–1.30). The RR for incident diabetes associated with baseline depression was 1.60 (1.37–1.88). CONCLUSIONS—Depression is associated with a 60% increased risk of type 2 diabetes. Type 2 diabetes is associated with only modest increased risk of depression. Future research should focus on identifying mechanisms linking these conditions.

Examining a Bidirectional Association Between Depressive Symptoms and Diabetes

CONTEXT Depressive symptoms are associated with development of type 2 diabetes, but it is unclear whether type 2 diabetes is a risk factor for elevated depressive symptoms. OBJECTIVE To examine the bidirectional association between depressive symptoms and type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Multi-Ethnic Study of Atherosclerosis, a longitudinal, ethnically diverse cohort study of US men and women aged 45 to 84 years enrolled in 2000-2002 and followed up until 2004-2005. MAIN OUTCOME MEASURES Elevated depressive symptoms defined by Center for Epidemiologic Studies Depression Scale (CES-D) score of 16 or higher, use of antidepressant medications, or both. The CES-D score was also modeled continuously. Participants were categorized as normal fasting glucose (< 100 mg/dL), impaired fasting glucose (100-125 mg/dL), or type 2 diabetes (> or = 126 mg/dL or receiving treatment). Analysis 1 included 5201 participants without type 2 diabetes at baseline and estimated the relative hazard of incident type 2 diabetes over 3.2 years for those with and without depressive symptoms. Analysis 2 included 4847 participants without depressive symptoms at baseline and calculated the relative odds of developing depressive symptoms over 3.1 years for those with and without type 2 diabetes. RESULTS In analysis 1, the incidence rate of type 2 diabetes was 22.0 and 16.6 per 1000 person-years for those with and without elevated depressive symptoms, respectively. The risk of incident type 2 diabetes was 1.10 times higher for each 5-unit increment in CES-D score (95% confidence interval [CI], 1.02-1.19) after adjustment for demographic factors and body mass index. This association persisted following adjustment for metabolic, inflammatory, socioeconomic, or lifestyle factors, although it was no longer statistically significant following adjustment for the latter (relative hazard, 1.08; 95% CI, 0.99-1.19). In analysis 2, the incidence rates of elevated depressive symptoms per 1000-person years were 36.8 for participants with normal fasting glucose; 27.9 for impaired fasting glucose; 31.2 for untreated type 2 diabetes, and 61.9 for treated type 2 diabetes. Compared with normal fasting glucose, the demographic-adjusted odds ratios of developing elevated depressive symptoms were 0.79 (95% CI, 0.63-0.99) for impaired fasting glucose, 0.75 (95% CI, 0.44-1.27) for untreated type 2 diabetes, and 1.54 (95% CI, 1.13-2.09) for treated type 2 diabetes. None of these associations with incident depressive symptoms were materially altered with adjustment for body mass index, socioeconomic and lifestyle factors, and comorbidities. Findings in both analyses were comparable across ethnic groups. CONCLUSIONS A modest association of baseline depressive symptoms with incident type 2 diabetes existed that was partially explained by lifestyle factors. Impaired fasting glucose and untreated type 2 diabetes were inversely associated with incident depressive symptoms, whereas treated type 2 diabetes showed a positive association with depressive symptoms. These associations were not substantively affected by adjustment for potential confounding or mediating factors.

The cardiovascular toll of stress

Psychological stress elicits measurable changes in sympathetic-parasympathetic balance and the tone of the hypothalamic-pituitary-adrenal axis, which might negatively affect the cardiovascular system both acutely-by precipitating myocardial infarction, left-ventricular dysfunction, or dysrhythmia; and chronically-by accelerating the atherosclerotic process. We provide an overview of the association between stress and cardiovascular morbidity, discuss the mechanisms for this association, and address possible therapeutic implications.

Prevalence and Incidence of Endocrine and Metabolic Disorders in the United States: A Comprehensive Review

CONTEXT There has not been a comprehensive compilation of data regarding the epidemiology of all endocrine and metabolic disorders in the United States. EVIDENCE ACQUISITION We included 54 disorders with clinical and public health significance. We identified population-based studies that provided U.S. prevalence and/or incidence data by searching PubMed in December 2007 for English-language reports, hand-searching reference lists of six textbooks of endocrinology, obtaining additional resources from identified experts in each subspecialty, and searching epidemiological databases and web sites of relevant organizations. When available, we selected articles with data from 1998 or later. Otherwise, we selected the article with the most recent data, broadest geographical coverage, and most stratifications by sex, ethnicity, and/or age. Ultimately, we abstracted data from 70 articles and 40 cohorts. EVIDENCE SYNTHESIS Endocrine disorders with U.S. prevalence estimates of at least 5% in adults included diabetes mellitus, impaired fasting glucose, impaired glucose tolerance, obesity, metabolic syndrome, osteoporosis, osteopenia, mild-moderate hypovitaminosis D, erectile dysfunction, dyslipidemia, and thyroiditis. Erectile dysfunction and osteopenia/osteoporosis had the highest incidence in males and females, respectively. The least prevalent conditions, affecting less than 1% of the U.S. population, were diabetes mellitus in children and pituitary adenoma. Conditions with the lowest incidence were adrenocortical carcinoma, pheochromocytoma, and pituitary adenomas. Certain disorders, such as hyperparathyroidism and thyroid disorders, were more common in females. As expected, the prevalence of diabetes mellitus was highest among ethnic minorities. Sparse data were available on pituitary, adrenal, and gonadal disorders. CONCLUSIONS The current review shows high prevalence and incidence of common endocrine and metabolic disorders. Defining the epidemiology of these conditions will provide clues to risk factors and identify areas to allocate public health and research resources.

Androgens and Diabetes in Men: Results from the Third National Health and Nutrition Examination Survey (NHANES III)

OBJECTIVE—Low levels of androgens in men may play a role in the development of diabetes; however, few studies have examined the association between androgen concentration and diabetes in men in the general population. The objective of this study is to test the hypothesis that low normal levels of total, free, and bioavailable testosterone are associated with prevalent diabetes in men. RESEARCH DESIGN AND METHODS—The study sample included 1,413 adult men aged ≥20 years who participated in the morning session of the first phase of the Third National Health and Nutrition Examination Survey, a cross-sectional survey of the civilian, noninstitutionalized population of the U.S. Bioavailable and free testosterone levels were calculated from serum total testosterone, sex hormone–binding globulin, and albumin concentrations. RESULTS—In multivariable models adjusted for age, race/ethnicity, and adiposity, men in the first tertile (lowest) of free testosterone level were four times more likely to have prevalent diabetes compared with men in the third tertile (odds ratio 4.12 [95% CI 1.25–13.55]). Similarly, men in the first tertile of bioavailable testosterone also were approximately four times as likely to have prevalent diabetes compared wth men in the third tertile (3.93 [1.39–11.13]). These associations persisted even after excluding men with clinically abnormal testosterone concentrations defined as total testosterone <3.25 ng/ml or free testosterone <0.07 ng/ml. No clear association was observed for total testosterone after multivariable adjustment (P for trend across tertiles = 0.27). CONCLUSIONS—Low free and bioavailable testosterone concentrations in the normal range were associated with diabetes, independent of adiposity. These data suggest that low androgen levels may be a risk factor for diabetes in men.

Comparative Effectiveness and Safety of Methods of Insulin Delivery and Glucose Monitoring for Diabetes Mellitus: A Systematic Review and Meta-analysis

BACKGROUND Patients with diabetes mellitus need information about the effectiveness of innovations in insulin delivery and glucose monitoring. PURPOSE To review how intensive insulin therapy (multiple daily injections [MDI] vs. rapid-acting analogue-based continuous subcutaneous insulin infusion [CSII]) or method of monitoring (self-monitoring of blood glucose [SMBG] vs. real-time continuous glucose monitoring [rt-CGM]) affects outcomes in types 1 and 2 diabetes mellitus. DATA SOURCES MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through February 2012 without language restrictions. STUDY SELECTION 33 randomized, controlled trials in children or adults that compared CSII with MDI (n=19), rt-CGM with SMBG (n=10), or sensor-augmented insulin pump use with MDI and SMBG (n=4). DATA EXTRACTION 2 reviewers independently evaluated studies for eligibility and quality and serially abstracted data. DATA SYNTHESIS In randomized, controlled trials, MDI and CSII showed similar effects on hemoglobin A1c (HbA1c) levels and severe hypoglycemia in children or adults with type 1 diabetes mellitus and adults with type 2 diabetes mellitus. In adults with type 1 diabetes mellitus, HbA1c levels decreased more with CSII than with MDI, but 1 study heavily influenced these results. Compared with SMBG, rt-CGM achieved a lower HbA1c level (between-group difference of change, 0.26% [95% CI, 0.33% to 0.19%]) without any difference in severe hypoglycemia. Sensor-augmented insulin pump use decreased HbA1c levels more than MDI and SMBG did in persons with type 1 diabetes mellitus (between-group difference of change, 0.68% [CI, 0.81% to 0.54%]). Little evidence was available on other outcomes. LIMITATION Many studies were small, of short duration, and limited to white persons with type 1 diabetes mellitus. CONCLUSION Continuous subcutaneous insulin infusion and MDI have similar effects on glycemic control and hypoglycemia, except CSII has a favorable effect on glycemic control in adults with type 1 diabetes mellitus. For glycemic control, rt-CGM is superior to SMBG and sensor-augmented insulin pumps are superior to MDI and SMBG without increasing the risk for hypoglycemia. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: A scientific statement from the American Heart Association and the American Diabetes Association

Cardiovascular disease risk factor control as primary prevention in patients with type 2 diabetes mellitus has changed substantially in the past few years. The purpose of this scientific statement is to review the current literature and key clinical trials pertaining to blood pressure and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification. We present a synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus.

Prospective investigation of autonomic nervous system function and the development of type 2 diabetes: The atherosclerosis risk in communities study, 1987-1998

Background—Autonomic nervous system (ANS) dysfunction has been correlated with fasting insulin and glucose, independent of clinically diagnosed diabetes. We tested whether men and women (aged 45 to 64 years) from the Atherosclerosis Risk In Communities study (n=8185) with ANS dysfunction, estimated by high heart rate (HR) and low HR variability (HRV), were at increased risk for developing type 2 diabetes. Methods and Results—Supine HR and HRV indices were measured for 2 minutes at baseline; indices were divided into quartiles for analyses. From 1987 to 1998 (mean follow-up 8.3 years), there were 1063 cases of incident diabetes. The relative risk (RR) of developing diabetes for participants with low-frequency (LF) power (0.04 to 0.15 Hz) HRV in the lowest quartile (<7.7 ms2) compared with the highest quartile (≥38.9 ms2) was 1.2 (95% CI 1.0–1.4) after adjustment for age, race, sex, study center, education, alcohol drinking, current smoking, prevalent coronary heart disease, physical activity, and body mass index. Participants in the uppermost (>72.7 bpm) versus the lowest (≤60.1 bpm) quartile of HR had a 60% increased risk (95% CI 33%–92%) of developing diabetes. Results were similar when the sample was restricted to participants with normal fasting glucose (glucose <6.1 mmol/L) at baseline (n=7192) or when adjusted for baseline glucose (HR quartile 4 versus quartile 1, RR=1.4, 95% CI 1.2–1.7). Conclusions—These findings suggest that ANS dysfunction may be associated with the development of diabetes in healthy adults.

Health Disparities in Endocrine Disorders: Biological, Clinical, and Nonclinical Factors—An Endocrine Society Scientific Statement

OBJECTIVE The aim was to provide a scholarly review of the published literature on biological, clinical, and nonclinical contributors to race/ethnic and sex disparities in endocrine disorders and to identify current gaps in knowledge as a focus for future research needs. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The Endocrine Societys Scientific Statement Task Force (SSTF) selected the leader of the statement development group (S.H.G.). She selected an eight-member writing group with expertise in endocrinology and health disparities, which was approved by the Society. All discussions regarding the scientific statement content occurred via teleconference or written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. EVIDENCE The primary sources of data on global disease prevalence are from the World Health Organization. A comprehensive literature search of PubMed identified U.S. population-based studies. Search strategies combining Medical Subject Headings terms and keyword terms and phrases defined two concepts: 1) racial, ethnic, and sex differences including specific populations; and 2) the specific endocrine disorder or condition. The search identified systematic reviews, meta-analyses, large cohort and population-based studies, and original studies focusing on the prevalence and determinants of disparities in endocrine disorders. consensus process: The writing group focused on population differences in the highly prevalent endocrine diseases of type 2 diabetes mellitus and related conditions (prediabetes and diabetic complications), gestational diabetes, metabolic syndrome with a focus on obesity and dyslipidemia, thyroid disorders, osteoporosis, and vitamin D deficiency. Authors reviewed and synthesized evidence in their areas of expertise. The final statement incorporated responses to several levels of review: 1) comments of the SSTF and the Advocacy and Public Outreach Core Committee; and 2) suggestions offered by the Council and members of The Endocrine Society. CONCLUSIONS Several themes emerged in the statement, including a need for basic science, population-based, translational and health services studies to explore underlying mechanisms contributing to endocrine health disparities. Compared to non-Hispanic whites, non-Hispanic blacks have worse outcomes and higher mortality from certain disorders despite having a lower (e.g. macrovascular complications of diabetes mellitus and osteoporotic fractures) or similar (e.g. thyroid cancer) incidence of these disorders. Obesity is an important contributor to diabetes risk in minority populations and to sex disparities in thyroid cancer, suggesting that population interventions targeting weight loss may favorably impact a number of endocrine disorders. There are important implications regarding the definition of obesity in different race/ethnic groups, including potential underestimation of disease risk in Asian-Americans and overestimation in non-Hispanic black women. Ethnic-specific cut-points for central obesity should be determined so that clinicians can adequately assess metabolic risk. There is little evidence that genetic differences contribute significantly to race/ethnic disparities in the endocrine disorders examined. Multilevel interventions have reduced disparities in diabetes care, and these successes can be modeled to design similar interventions for other endocrine diseases.