Tina Thethi

Systematic review: glucose control and cardiovascular disease in type 2 diabetes.

Context The relative benefits and harms of intensive versus conventional glucose control for type 2 diabetes are controversial. Contribution This review of 5 large trials found that, compared with conventional control, intensive glucose control reduced the risk for cardiovascular disease (mostly nonfatal myocardial infarction) but not for cardiovascular death or all-cause mortality, and increased risk for severe hypoglycemia. Trial design, achieved control, and findings were heterogeneous: Early trials suggested possible decreased risk for death with intensive control, whereas some more recent trials suggested possible increased risk for death with more stringent control. Caution The investigators did not evaluate costs. They pooled summary findings from trials rather than individual data from patients. The Editors The prevalence of type 2 diabetes is increasing globally (13). Epidemiologic evidence indicates that diabetes is a major risk factor for cardiovascular disease (CVD), and recent data suggest that the CVD burden attributable to diabetes is on the rise (47). Clinical trials have shown that intensive glucose control reduces the risk for microvascular complications among patients with type 2 diabetes, but its effect on CVD, including coronary heart disease (CHD), stroke, and peripheral arterial disease, is uncertain (810). Early data from the UKPDS (United Kingdom Prospective Diabetes Study) 34 suggested a protective effect of improved glucose control on CVD, CVD deaths, and all-cause mortality (11). However, within the past year, 3 large randomized, controlled trials have reported conflicting results (1214). Although ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) and VADT (Veterans Affairs Diabetes Trial) found no effect of intensive glucose control on major cardiovascular events (13, 14), ACCORD (Action to Control Cardiovascular Disease in Diabetes) identified an increased risk for death from cardiovascular causes and total mortality associated with intensive glucose control (12). On the basis of these results, a recent article by Montori and colleagues suggested that additional research is needed to confirm or refute the importance of tight glucose control (15). Thus, recommendations for health care providers regarding optimal hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes remain unclear. Because of the early termination of ACCORD and fewer events than anticipated in ADVANCE and VADT, there is real concern that these studies were underpowered to capture the true effects of intensive glucose control on CVD risk (1214). Therefore, we conducted a meta-analysis of randomized, controlled trials to examine the effects of intensive glucose control on CVD among patients with type 2 diabetes. Furthermore, we examined the separate effects of intensive glucose control on all-cause mortality, CVD mortality, CHD, congestive heart failure (CHF), stroke, and peripheral artery disease. In an effort to explain incongruities among trial results, we conducted subgroup analyses and examined the occurrence of severe hypoglycemia. Methods Data Sources and Searches We developed and followed a standard protocol for all steps of the review. Investigators searched the MEDLINE database (January 1950 through April 2009) using the Medical Subject Headings cardiovascular diseases; coronary disease; stroke; peripheral vascular diseases; hypoglycemic agents; and diabetes mellitus, type 2, as well as the keywords coronary heart disease, glucose control, and glycemic control. We restricted the search to randomized, controlled trials conducted among human adults (age 19 years), with no language restrictions. We also manually searched references cited in the published original reports and contacted experts in the field. Study Selection Two investigators independently reviewed the contents of 341 abstracts or full-text manuscripts identified through the literature search to determine whether they met the eligibility criteria. Studies were eligible for inclusion if 1) the study was a randomized, controlled trial; 2) the study compared intensive glucose control with conventional treatment, with a priori specification of glycemic goals for the intensive and conventional glucose control groups; 3) clinical CVD was the primary end point; 4) the study sample size was 500 patients or more; and 5) the study participants had type 2 diabetes mellitus. Reviewers resolved disagreements about study inclusion or exclusion by consensus and by referring to the original reports. Data Extraction and Quality Assessment Study investigators independently abstracted data in duplicate using a standardized data collection form. Reviewers did not contact authors to request additional information. Reviewers abstracted characteristics of each trial and its participants. Reviewers critically appraised methodological characteristics of trials, such as randomization procedures, blinded assessment of outcomes, adjudication procedures for outcomes, and follow-up rates, but did not use a scoring system to formally rate study quality of the individual trials (Appendix Table 1). Appendix Table 1. Assessment of Methodological Characteristics Reviewers recorded the following as the main outcomes of interest: number of clinical CVD, CHD, stroke, and CHF events, along with cardiovascular deaths and all-cause mortality, for the intensive and conventional glucose control groups. Reviewers also recorded single end points, including nonfatal myocardial infarction, fatal myocardial infarction, nonfatal stroke, fatal stroke, and peripheral artery disease. In addition, reviewers recorded the number of severe hypoglycemic events for each trial group. Because definitions of certain composite outcomes varied between trials, each outcome is defined for each trial in Appendix Table 2. Appendix Table 2. Definitions of Composite Outcomes for Each Trial Data Synthesis and Analysis We examined the relationship between intensive glucose control and risk for all study outcomes using relative risk and risk difference measures. We calculated the relative risks in each trial on the basis of the number of events in the intensive glucose control and conventional treatment groups and used these estimates for pooling analyses. To estimate the risk difference, we first calculated the annual absolute risk for an event in participants in each trial group by dividing the number of events in each trial group by the corresponding number of person-years (estimated as median treatment time number of participants in the trial group). We then multiplied the annual absolute risk by 5 to estimate the 5-year risk among participants in each trial group. We calculated the risk difference for each trial by subtracting the 5-year risk in the conventional glucose control group from the 5-year risk in the intensive glucose control group. We logarithmically transformed the relative risks and risk differences and their corresponding standard errors to stabilize the variance and normalize their distribution. We pooled relative risks and risk differences using both fixed-effects and DerSimonian and Laird random-effects models (16). We used inverse variance weighting to calculate fixed- and random-effects summary estimates. We assessed heterogeneity formally by using the Dersimonian and Laird Q test, considering any P value less than 0.100 as evidence of heterogeneity, and by examining the I 2 quantity. Although fixed- and random-effects models yielded similar findings, we detected between-study heterogeneity for several study outcomes (severe hypoglycemia, cardiovascular deaths, all-cause mortality, and fatal myocardial infarction). Because of this heterogeneity and trial differences in median diabetes duration of participants, achieved HbA1c levels, and therapeutic regimens, we present results from the random-effects models. We conducted a prestated subgroup analysis to examine the effects of intensive glucose control on all study outcomes. We then compared the relative risks for CVD, CHD, CHF, stroke, cardiovascular deaths, all-cause mortality, and severe hypoglycemia, as well as fatal and nonfatal myocardial infarction, fatal and nonfatal stroke, and peripheral artery disease between the early UKPDS trials (8, 11) and the 3 more recent ACCORD, ADVANCE, and VADT trials (1214). We conducted all analyses by using Stata software, version 9.2 (Stata Corp, College Station, Texas). Role of the Funding Source This study was funded in part by a career development award from the National Heart, Lung, and Blood Institute and by an award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The funding sources played no role in the study design; collection, analysis, and interpretation of the data; writing of the report; or decision to submit the paper for publication. Results Figure 1 depicts the study selection process. We excluded 2 trials, the Kumamoto Study (n = 110) and the Veterans Affairs (VA) Diabetes Feasibility Trial (n = 153), because of small sample sizes (9, 17). The VA Diabetes Feasibility Trial was a pilot study that examined whether intensive glucose control could be effectively sustained in patients with type 2 diabetes and was a precursor to the subsequent VADT. The Kumamoto Study examined the effects of intensive glucose control on microvascular complications of diabetes. The current meta-analysis included a total of 5 trials conducted among 27 802 participants (8, 1114). Table 1 presents the characteristics of the 5 randomized, controlled trials and trial participants. The number of trial participants ranged from 753 to 11 140, while intervention duration ranged from 3.4 to 10.7 years. The UKPDS 33 and 34 recruited participants with newly diagnosed diabetes. Those inclusion criteria differed from those of ADVANCE, ACCORD and VADT, whose participants had an average duration of diabetes ranging

The Link Between the Renin-Angiotensin-Aldosterone System and Renal Injury in Obesity and the Metabolic Syndrome

Obesity is a risk factor for type 2 diabetes mellitus (DM) and is associated with chronic kidney disease. Activation of the renin-angiotensin-aldosterone system (RAAS) is common in obesity. The RAAS is an important mediator of hypertension. Mechanisms involved in activation of the RAAS in obesity include sympathetic stimulation, synthesis of adipokines in the RAAS by visceral fat, and hemodynamic alterations. The RAAS is known for its role in regulating blood pressure and fluid and electrolyte homeostasis. The role of local/tissue RAAS in specific tissues has been a focus of research. Urinary angiotensinogen (UAGT) provides a specific index of the intrarenal RAAS. Investigators have demonstrated that sex steroids can modulate the expression and activity of the different components of the intrarenal RAAS and other tissues. Our data suggest that obese women without DM and hypertension have significantly higher levels of UAGT than their male counterparts. These differences existed without any background difference in the ratio of microalbumin to creatinine in the urine or the estimated glomerular filtration rate, raising a question about the importance of baseline gender differences in the endogenous RAAS in the clinical spectrum of cardiovascular diseases and the potential utility of UAGT as a marker of the intrarenal RAAS. Animal studies have demonstrated that modifying the amount of angiotensin, the biologically active component of the RAAS, directly influences body weight and adiposity. This article reviews the role of the RAAS in renal injury seen in obesity and the metabolic syndrome.

Consequences of delayed pump infusion line change in patients with type 1 diabetes mellitus treated with continuous subcutaneous insulin infusion

OBJECTIVE To systematically investigate the effect of lack of adherence to the recommended change in insulin pump infusion line use beyond 48 h and determine whether the type of insulin made a difference. RESEARCH DESIGN AND METHODS This was a double-blind, randomized, crossover trial with 20 patients with diabetes mellitus I using insulins aspart and lispro without a line change for up to 100 h. Using retrospective continuous glucose monitoring, we analyzed the average glucose over the day. Changes in serum 1,5-anhydroglucitol, carboxymethyllysine, and free 15-F(2t) isoprostane were also studied. RESULTS From Day 2 to Day 5 of the pump line use, the daily average glucose level increased from 122.7 to 163.9 mg/dl (P<.05), fasting glucose from 120.3 to 154.5 mg/dl (P<.05), postprandial glucose from 114.6 to 172.1 mg/dl (P<.05), and the daily maximum glucose from 207.7 to 242.8 dl (P<.05 for the trend). Time period that the glucose was >180 mg/dl increased from 14.5% to 38.3% (P<.05). Loss of control occurred despite increase in total daily insulin dose from 48.5+/-11.8 to 55.3+/-17.9 U (P=.05). There was no difference in loss of control between insulin types, and biomarkers measured did not change significantly. CONCLUSIONS The insulin pump infusion should be changed every 48 h in patients using continuous subcutaneous insulin infusion (CSII), to avoid loss of glycemic control. In the short-term, this loss of glycemic control has no impact on oxidative stress and glycation.

Effect of paricalcitol on endothelial function and inflammation in type 2 diabetes and chronic kidney disease

AIMS Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) have impaired endothelial function. Vitamin D and its analogs may play a role in regulation of endothelial function and inflammation. We studied effects of paricalcitol compared to placebo on endothelial function and markers of inflammation and oxidative stress in patients with T2DM and CKD. METHODS A double blind, randomized, placebo-controlled trial was conducted in 60 patients with T2DM and stage 3 or 4 CKD. Paricalcitol 1 mcg or placebo was administered orally once daily for three months. Brachial artery flow mediated dilatation (FMD), nitroglycerine mediated dilation (NMD), and plasma concentrations of inflammatory cytokines, tumor necrosis factor -α and interleukin-6, highly-sensitive C-reactive protein; endothelial surface proteins, intercellular adhesion molecule -1 and monocyte chemo attractant protein-1, and plasma glucose, insulin, free fatty acids, and urinary isoprostane were measured at baseline and end of three months. RESULTS 27 patients in the paricalcitol group and 28 patients in the control group completed the study, though analysis of FMD at both time points was possible in 23 patients in each group. There was no significant difference in the change in FMD, NMD or the biomarkers examined after paricalcitol or placebo treatment. CONCLUSIONS Treatment with paricalcitol at this dose and duration did not affect brachial artery FMD or biomarkers of inflammation and oxidative stress. The lack of significance may be due to the fact that the study patients had advanced CKD and that effects of paricalcitol are not additive to the effects of glycemic, lipid and anti-hypertensive therapies.

Examining the Bethesda criteria risk stratification of thyroid nodules

BACKGROUND The Bethesda criteria are proposed for appropriate stratification of malignancy risk in thyroid nodules, but controversy exists regarding their accuracy and reliability in decision making. Additionally, previous studies have suggested higher rates of both malignancy and false negative fine needle aspiration biopsy (FNA) associated with increasing nodule size. This study aims to determine the accuracy of ultrasound (US)-guided FNA using the current Bethesda criteria in surgical practice. We also aimed to investigate the relationship between nodule size and malignancy. METHODS A retrospective analysis of US-guided FNAs by a single surgeon during a 4.5 year period. FNA results using Bethesda criteria were compared to final surgical pathology. RESULTS 611 patients with thyroid nodules underwent US-guided FNA. FNA results in 375 subsequently excised thyroid nodules were recorded according to the Bethesda criteria: 192 (51%) benign, 65 (17%) atypia of unknown significance/follicular lesion of undetermined significance (AUS/FLUS), 42 (11%), suspicious for follicular neoplasm (SFN), 17 (5%) suspicious for malignancy (SM), 28 (8%) malignancy, and 31 (8%) non-diagnostic. Malignancy was confirmed by surgical pathology in 15%, 34%, 50%, 88%, 100%, and 39% of the above groups respectively. Sensitivity, specificity, and false-negative rate were 61%, 99%, and 15% respectively. No correlation existed between the size of nodules with indeterminate FNA results and malignancy rate (p=0.89), or size of nodules with non-diagnostic FNA and malignancy rate (p=0.50). CONCLUSION The current Bethesda risk stratification system underestimated malignancy rates in benign, indeterminate and non-diagnostic cytopathologic categories in our experience. There was no positive linear correlation between nodule size and malignancy rate in these cytopathologic categories.

Evaluation of a Remote Monitoring System for Diabetes Control

PURPOSE The use of technology to implement cost-effective health care management on a large scale may be an alternative for diabetes management but needs to be evaluated in controlled trials. This study assessed the utility and cost-effectiveness of an automated Diabetes Remote Monitoring and Management System (DRMS) in glycemic control versus usual care. METHODS In this randomized, controlled study, patients with uncontrolled diabetes on insulin were randomized to use of the DRMS or usual care. Participants in both groups were followed up for 6 months and had 3 clinic visits at 0, 3, and 6 months. The DRMS used text messages or phone calls to remind patients to test their blood glucose and to report results via an automated system, with no human interaction unless a patient had severely high or low blood glucose. The DRMS made adjustments to insulin dose(s) based on validated algorithms. Participants reported medication adherence through the Morisky Medication Adherence Scale-8, and diabetes-specific quality of life through the diabetes Daily Quality of Life questionnaire. A cost-effectiveness analysis was conducted based on the estimated overall costs of DRMS and usual care. FINDINGS A total of 98 patients were enrolled (59 [60%] female; mean age, 59 years); 87 participants (89%) completed follow-up. HbA1c was similar between the DRMS and control groups at 3 months (7.60% vs 8.10%) and at 6 months (8.10% vs 7.90%). Changes from baseline to 6 months were not statistically significant for self-reported medication adherence and diabetes-specific quality of life, with the exception of the Daily Quality of Life-Social/Vocational Concerns subscale score (P = 0.04). IMPLICATIONS An automated system like the DRMS may improve glycemic control to the same degree as usual clinic care and may significantly improve the social/vocational aspects of quality of life. Cost-effectiveness analysis found DRMS to be cost-effective when compared to usual care and suggests DRMS has a good scale of economy for program scale up. Further research is needed to determine how to sustain the benefits seen with the automated system over longer periods.

Association of Malignancy Prevalence With Test Properties and Performance of the Gene Expression Classifier in Indeterminate Thyroid Nodules

Importance It is crucial for clinicians to know the malignancy prevalence within each indeterminate cytologic category to estimate the performance of the gene expression classifier (GEC). Objective To examine the variability in the performance of the GEC. Design, Setting, and Participants This retrospective cohort study of patients with Bethesda category III and IV thyroid nodules used single-institution data from January 1, 2013, through February 29, 2016. Expected negative predictive value (NPV) was calculated by adopting published sensitivity and specificity. Observed NPV was calculated based on the true-negative rate. Outcomes were compared with pooled data from 11 studies published January 1, 2010, to January 31, 2016. Results A total of 145 patients with 154 thyroid nodules were included in the study (mean [SD] age, 56.0 [16.2] years; 106 females [73.1%]). Malignancy prevalence was 45%. On the basis of this prevalence, the expected NPV is 85% and the observed NPV is 69%. If the prevalence is assumed to be 25%, the expected NPV would be 94%, whereas the observed NPV would be 85%. Pooled data analysis of 11 studies comprising 1303 participants revealed a malignancy prevalence of 31% (95% CI, 29%-34%) and a pooled NPV of 92% (95% CI, 87%-96%). Conclusions and Relevance In this study, variability in the performance of the GEC was not solely a function of malignancy prevalence and may have been attributable to intrinsic variability of the test sensitivity and specificity. The utility of the GEC in practice is elusive because of this variability. A better definition of the GEC’s intrinsic properties is needed.

Urinary Catalytic Iron in Obesity

INTRODUCTION Obesity precedes the development of many cardiovascular disease risk factors, including type 2 diabetes mellitus (DM), hypertension, and chronic kidney disease. Catalytic iron, which has been associated with these chronic diseases, may be one of the links between obesity and these multifactorial diverse disorders. OBJECTIVE We investigated whether urinary catalytic iron is increased in obese individuals without DM and overt kidney disease. STUDY DESIGN We measured urinary catalytic iron using established methods in 200 randomly selected individuals without DM [100 who were obese (body mass index ≥30 kg/m(2)) and 100 who were nonobese (body mass index ≤27)]. Participants were selected from an outpatient clinic and community setting and were part of an ongoing cross-sectional study of obesity in individuals between the ages of 18 and 70 years. RESULTS There was a significant difference in mean (95% CI) urinary catalytic iron excretion between the obese participants and the nonobese participants, 463 (343-582) nmol/mg [52.3 (38.8-65.8) nmol/μmol] vs 197 (141-253) nmol/mg [22.3 (15.9-28.6) nmol/μmol]; P < 0.001. The significant predictors of increased urinary catalytic iron were obesity (P = 0.001) and waist-to-hip ratio (P = 0.03). CONCLUSIONS Our study results demonstrate that obesity and waist-to-hip ratio are associated with increased urinary catalytic iron, which may be a useful marker of oxidative stress. Additional studies are needed to determine the role of catalytic iron in increased cardiovascular disease and chronic kidney disease associated with obesity.

Time to Recovery in Diabetes and Comorbidities Following Hurricane Katrina

BACKGROUND The impact of a natural disaster on self-care and health care delivery has been well documented. The objective of the study was to document the recovery pattern from the impact of a natural disaster such as Hurricane Katrina on clinical and biochemical measures of diabetes and its comorbidities. METHODS Patients were selected from Tulane University Hospital and Clinic, Southeast Louisiana Veterans Health Care System, and the Medical Center of Louisiana at New Orleans. Adults with diabetes and A(1c) measurement 6 months before (pre-K) Hurricane Katrina (February 28, 2005-August 27, 2005) and 6 to 16 months after (post-K) Katrina (March 1, 2006-December 31, 2006) were identified within the 3 facilities. Follow-up data (January 1, 2007-December 31, 2007) were 1 year after the first post-K visit. The outcome measures were hemoglobin A(1c) (HbA(1c)), systolic and diastolic blood pressure (BP), and lipids (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL], triglycerides). RESULTS Averaged across the 3 facilities, the parameters significantly different in the follow-up period compared with pre- and post-K were HbA(1c) (P = .04), HDL, and systolic and diastolic BP (P < .0001). Parameters with significantly different patterns of change in the 3 facilities over time were HbA(1c), HDL, systolic and diastolic BP (P < .0001), and low-density lipoprotein (P < .01). CONCLUSIONS Our results suggest that a variety of clinical and biochemical parameters related to diabetes and its comorbidities affected by natural disaster have varied the rate of recovery to predisaster levels.

Black Thyroid Associated with Thyroid Carcinoma

Objective. Black thyroid is a rare pigmented change seen almost exclusively in patients upon minocycline ingestion, and the process has previously been thought to be generally benign. There have been 61 reported cases of black thyroid. We are aware of 13 cases previously reported in association with thyroid carcinoma. This paper reports six patients with black thyroid pigmentation in association with thyroid carcinoma. Design. The medical records of six patients who were diagnosed with black thyroid syndrome, all of whom underwent thyroid surgery, were reviewed. Data on age, gender, race, preoperative fine needle aspiration biopsy (FNA), thyroid function levels, and pathology reports were collected. Main Outcome. The mean age was 60 years. There were 5 females, 4 of whom were African American. All patients were clinically and biochemically euthyroid. Black pigmentation was not diagnosed in preoperative FNA, and only one patient had a preoperative diagnosis of papillary thyroid carcinoma. The other patients underwent surgery and were found to have black pigmentation of the thyroid associated with carcinoma. Conclusions. FNA does not diagnose black thyroid, which is associated with thyroid carcinoma. Thyroid glands with black pigmentation deserve thorough pathologic examination, including several sections of each specimen.