Coronary Artery Calcium and Cognitive Decline in the Diabetes Prevention Program Outcomes Study.

Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.

Risk Factors for the Development of Retinopathy in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Experience.

OBJECTIVE: To determine glycemic and nonglycemic risk factors that contribute to the presence of diabetic retinopathy (DR) before and after the onset of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: During the Diabetes Prevention Program (DPP) and DPP Outcome Study (DPPOS), we performed fundus photography over time in adults at high risk for developing T2D, including after they developed diabetes. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system, with DR defined as typical lesions of DR (microaneurysms, exudates, hemorrhage, or worse) in either eye. RESULTS: By DPPOS year 16 (∼20 years after random assignment into DPP), 24% of 1,614 participants who had developed T2D and 14% of 885 who remained without diabetes had DR. In univariate analyses, using results from across the entire duration of follow-up, American Indian race was associated with less frequent DR compared with non-Hispanic White (NHW) race, and higher HbA1c, fasting and 2-h plasma glucose levels during an oral glucose tolerance test, weight, and history of hypertension, dyslipidemia, and smoking, but not treatment group assignment, were associated with more frequent DR. On multivariate analysis, American Indian race was associated with less DR compared with NHW (odds ratio [OR] 0.36, 95% CI 0.20-0.66), and average HbA1c was associated with more DR (OR 1.92, 95% CI 1.46-1.74 per SD [0.7%] increase in HbA1c). CONCLUSIONS: DR may occur in adults with prediabetes and early in the course of T2D. HbA1c was an important risk factor for the development of DR across the entire glycemic range from prediabetes to T2D.

Clinical Approach to Assessment and Amelioration of Atherosclerotic Vascular Disease in Diabetes.

Atherosclerotic cardiovascular disease is increased on average 2-3-fold in people with diabetes as compared to their non-diabetic counterparts and is the major cause of the increased morbidity and mortality in this disease. There is however heterogeneity in cardiovascular risk between individuals based on demographic, cardiometabolic and clinical risk factors in the setting of hyperglycemia, insulin resistance and obesity that needs to be taken into consideration in planning preventive interventions. Randomized clinical trials of agents or procedures used for amelioration of augmented CVD risk in diabetes have been pivotal in providing evidenced-based treatments. Improvement in hyperglycemia in both type 1 and type 2 diabetes is considered to be central in the prevention of microvascular and macrovascular complications although selected antihyperglycemic agents have demonstrated beneficial as well as possible deleterious off-target effects. Lowering low density lipoprotein cholesterol, treating hypertension and stopping smoking each play important roles in preventing cardiovascular disease in diabetes as they do in the general population and low dose aspirin is overall beneficial in high risk individuals. Hypertriglyceridemia may represent another important marker for augmented cardiovascular risk in diabetes and newer agents targeting dyslipidemia appear promising. The fall in cardiovascular events over the past two decades offers hope that modern intervention strategies as well as novel approaches such as those targeting inflammation may contribute to a continued reduction of cardiovascular disease in people with diabetes.

Non-traditional biomarkers and incident diabetes in the Diabetes Prevention Program: comparative effects of lifestyle and metformin interventions.

AIMS/HYPOTHESIS: We compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker-incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes. METHODS: The Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850 mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2 years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1 year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2 h glucose, HbA1c, systolic blood pressure, inverse of fasting insulin and insulinogenic index. Cox proportional hazard models were used to assess the effects of each biomarker on the development of diabetes assessed semi-annually and the effects of covariates on these. RESULTS: E-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]). CONCLUSIONS/INTERPRETATION: These findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.

Androgens, Irregular Menses, and Risk of Diabetes and Coronary Artery Calcification in the Diabetes Prevention Program.

Context: It is unclear whether relative elevations in androgens or irregular menses (IM) are associated with greater cardiometabolic risk among women who are already overweight and glucose intolerant. Research Design and Methods: We conducted a secondary analysis of the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). Participants included women with sex hormone measurements who did not use exogenous estrogen (n = 1422). We examined whether free androgen index (FAI) or IM was associated with diabetes risk during the DPP/DPPOS or with coronary artery calcification (CAC) at DPPOS year 10. Models were adjusted for menopausal status, age, race or ethnicity, randomization arm, body mass index (BMI), and hemoglobin A1c. Results: Women had an average age of 48.2 ± 9.9 years. Elevations in FAI and IM were associated with greater BMI, waist circumference, and blood pressure and lower adiponectin. FAI was not associated with diabetes risk during the DPP/DPPOS [hazard ratio (HR) 0.97; 95% confidence interval (CI), 0.93 to 1.02] or increased odds of CAC [odds ratio (OR) 1.06; 95% CI, 0.92 to 1.23]. IM was also not associated with diabetes risk during the DPP/DPPOS (HR 1.07; 95% CI, 0.87 to 1.31) or increased odds of CAC (OR 0.89; 95% CI, 0.53 to 1.49). Women who had both relative elevations in FAI and IM had similar diabetes risk and odds of CAC as women without these conditions. Differences by treatment arm and menopausal status were not observed. Conclusions: Among midlife women who were already glucose intolerant and overweight, androgen concentrations and IM did not additionally contribute to increased risk for diabetes or CAC.

A Shift in ApoM/S1P Between HDL-Particles in Women With Type 1 Diabetes Mellitus Is Associated With Impaired Anti-Inflammatory Effects of the ApoM/S1P Complex.

OBJECTIVE: Type 1 diabetes mellitus (T1D) patients have an increased risk of cardiovascular disease despite high levels of high-density lipoproteins (HDL). Apolipoprotein M (apoM) and its ligand sphingosine 1-phospate (S1P) exert many of the anti-inflammatory effects of HDL. We investigated whether apoM and S1P are altered in T1D and whether apoM and S1P are important for HDL functionality in T1D. APPROACH AND RESULTS: ApoM and S1P were quantified in plasma from 42 healthy controls and 89 T1D patients. HDL was isolated from plasma and separated into dense, medium-dense, and light HDL by ultracentrifugation. Primary human aortic endothelial cells were challenged with tumor necrosis factor-α in the presence or absence of isolated HDL. Proinflammatory adhesion molecules E-selectin and vascular cellular adhesion molecule-1 were quantified by flow cytometry. Activation of the S1P1- receptor was evaluated by analyzing downstream signaling targets and receptor internalization. There were no differences in plasma levels of apoM and S1P between controls and T1D patients, but the apoM/S1P complexes were shifted from dense to light HDL particles in T1D. ApoM/S1P in light HDL particles from women were less efficient in inhibiting expression of vascular cellular adhesion molecule-1 than apoM/S1P in denser particles. The light HDL particles were unable to activate Akt, whereas all HDL subfractions were equally efficient in activating Erk and receptor internalization. CONCLUSIONS: ApoM/S1P in light HDL particles were inefficient in inhibiting tumor necrosis factor-α-induced vascular cellular adhesion molecule-1 expression in contrast to apoM/S1P in denser HDL particles. T1D patients have a higher proportion of light particles and hence more dysfunctional HDL, which could contribute to the increased cardiovascular disease risk associated with T1D.

New JAG1 Mutation Causing Alagille Syndrome Presenting With Severe Hypercholesterolemia: Case Report With Emphasis on Genetics and Lipid Abnormalities.

Context: Alagille syndrome is a rare autosomal-dominant genetic disorder caused by defects in the Notch signaling pathway, which involves multiple organ systems. Bile duct paucity is the main characteristic feature of the disease, which often leads to cholestatic hypercholesterolemia. Case Description: We report the case of a male infant who had developed failure to thrive, jaundice, intermittent pruritus, and multiple diffuse symmetrical skin xanthomas at 1 year of age. He was diagnosed with pulmonary stenosis, butterfly vertebrae of T4, T6, and T8; horseshoe kidney, and embryotoxon in the left eye. Laboratory workup revealed severe hypercholesterolemia. Alagille syndrome was suspected and confirmed by genetic testing, which identified a previously undescribed frameshift pathogenic heterozygous variant in the JAG1 gene, p.Arg486Lysfs*5. Conclusions: Here, we report a unique case of a patient diagnosed with Alagille syndrome who was found to have a previously undescribed frameshift pathogenic mutation in the JAG1 gene and who presented with xanthomatosis and levels of hypercholesterolemia more than 2 times higher than those previously reported in the literature. We also provide a review of the different pathophysiologic mechanisms associated with the increase in serum cholesterol and low-density lipoprotein cholesterol concentrations seen in cholestatic liver disease in general and in Alagille syndrome in particular.

Change in adiponectin explains most of the change in HDL particles induced by lifestyle intervention but not metformin treatment in the Diabetes Prevention Program.

OBJECTIVE: In addition to slowing diabetes development among participants in the Diabetes Prevention Program (DPP), intensive lifestyle change and metformin raised HDL-cholesterol (HDL-C) compared to placebo treatment. We investigated the lifestyle and metabolic determinants as well as effects of biomarkers of inflammation, endothelial dysfunction and coagulation and their changes resulting from lifestyle and metformin interventions on the increase in HDL-C in the DPP. METHODS: The effects of a 1year period of intensive lifestyle change aimed at achieving 7% weight loss or metformin 850mg twice daily versus placebo on HDL-C were assessed in 3070 participants with impaired glucose tolerance, and on HDL particle concentration (HDL-P) and size in a subgroup of 1645 individuals. Treatment-associated changes in lifestyle and metabolic factors as well as in novel biomarkers were investigated for their associations with change in HDL-C using multiple regression analysis. RESULTS: After adjusting for BMI, insulin resistance, glycemia, dietary saturated fat, alcohol intake, physical activity and nine different biomarkers, only adiponectin accounted for the effect of intensive lifestyle change on HDL-C via an increase in large HDL-P. By contrast baseline and change in BMI and tissue plasminogen activator levels attenuated the effect of metformin on HDL-C, with adiponectin having no specific effect. CONCLUSION: While both lifestyle and metformin interventions used to prevent diabetes increase HDL-C, the mechanisms involved differ between the two treatments and may have consequences for future risk of cardiovascular disease.

Impact of lifestyle intervention and metformin on health-related quality of life: the diabetes prevention program randomized trial.

BACKGROUND: Adults at high risk for diabetes may have reduced health-related quality of life (HRQoL). OBJECTIVE: To assess changes in HRQoL after interventions aimed at diabetes risk reduction. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial, the Diabetes Prevention Program, was conducted in 27 centers in the United States, in 3,234 non-diabetic persons with elevated fasting and post-load plasma glucose, mean age 51 years, mean BMI 34 Kg/m(2); 68 % women, and 45 % members of minority groups. INTERVENTIONS: Intensive lifestyle (ILS) program with the goals of at least 7 % weight loss and 150 min of physical activity per week, metformin (MET) 850 mg twice daily, or placebo (PLB). MEASUREMENTS: HRQoL using the 36-Item Short-Form (SF-36) health survey to evaluate health utility index (SF-6D), physical component summaries (PCS) and mental component summaries (MCS). A minimally important difference (MID) was met when the mean of HRQoL scores between groups differed by at least 3 %. RESULTS: After a mean follow-up of 3.2 years, there were significant improvements in the SF-6D (+0.008, p=0.04) and PCS (+1.57, p<0.0001) scores in ILS but not in MET participants (+0.002 and +0.15, respectively, p=0.6) compared to the PLB group. ILS participants showed improvements in general health (+3.2, p<0.001), physical function (+3.6, p<0.001), bodily pain (+1.9, p=0.01), and vitality (+2.1, p=0.01) domain scores. Treatment effects remained significant after adjusting sequentially for baseline demographic factors, and for medical and psychological comorbidities. Increased physical activity and weight reduction mediated these ILS treatment effects. Participants who experienced weight gain had significant worsening on the same HRQoL specific domains when compared to those that had treatment-related (ILS or MET) weight loss. No benefits with ILS or MET were observed in the MCS score. CONCLUSION: Overweight/obese adults at high risk for diabetes show small improvement in most physical HRQoL and vitality scores through the weight loss and increased physical activity achieved with an ILS intervention.

Fish oil in the treatment of dyslipidemia.

PURPOSE OF REVIEW: The recent availability of a concentrated prescription omega-3 fatty acid preparation provides physicians with an additional anti-dyslipidemic agent at a time when limitations of statin therapy in dyslipidemic high-risk patients are recognized. This review examines the evidence supporting the use of omega-3 fatty acid treatment in dyslipidemic states. RECENT FINDINGS: There is now considerable evidence that omega-3 fatty acid treatment at the prescription strength of 4 g/day effectively and safely lowers triglyceride levels and increases low-density lipoprotein size, as well as affecting high-density lipoprotein metabolism. Similar effects have been noted in patients treated with statins, and add-on prescription omega-3 fatty acid therapy significantly increases the proportion of statin-treated dyslipidemic patients reaching their non-high-density lipoprotein cholesterol goals. In addition to past studies showing a cardioprotective effect of low-dose omega-3 fatty acid treatment against sudden death, a recent controlled clinical trial showed that 1.8 g of omega-3 fatty acid in statin-treated patients reduced major coronary events by 19% compared with statin plus placebo treatment. SUMMARY: Omega-3 fatty acid treatment should be considered in patients with severe hypertriglyceridemia as well as in high-risk patients with an atherogenic lipoprotein phenotype.

Severe acquired (secondary) high-density lipoprotein deficiency.

Decreased high-density lipoprotein cholesterol (HDL-C) levels have been designated a major risk factor for cardiovascular disease, and there is considerable interest in identifying individuals with these abnormalities for appropriate management. Although low HDL-C may result from genetic factors, it is estimated that approximately 50% of cases may be secondary to other abnormal or disease states or to their treatment. Very low HDL-C levels, arbitrarily defined as <20 mg/dL, are uncommon, and are best known to result from major genetic mutations of key steps in HDL metabolism. Less well-described are secondary forms of severe HDL-C deficiency, which need to be distinguished from the primary causes. In this review, causes of severe acquired HDL-C deficiency are identified from the literature and are reviewed extensively. These include moderate to severe hypertriglyceridemia, critical illness, androgenic anabolic steroids, and acquired lecithin cholesteryl acyl transferase deficiency and liver disease. A relatively new entity referred to as the "disappearing HDL syndrome" was coined to describe the fairly rapid development of severe HDL-C deficiency in ambulant subjects with previously normal HDL-C and triglyceride levels. This may occur with peroxisome proliferation-activated receptor agonist treatment or in patients with benign or malignant paraproteinemias. Case discussions from our clinical experience are provided to illustrate to the practitioner the clinical context in which these severe acquired deficiencies of HDL occur.

Management of dyslipidemia in diabetes.

Diabetes is associated with a high risk of cardiovascular disease. The management of dyslipidemia, a well-recognized and modifiable risk factor among patients with type 2 diabetes, is an important element in the multifactorial approach to prevent coronary heart disease. Diabetic dyslipidemia typically consists of elevated triglyceride, low high-density lipoprotein cholesterol (HDL-C), and the predominance of small dense low-density lipoprotein (LDL) particles. LDL cholesterol (LDL-C) levels in patients with diabetes are similar to those found in the rest of the population. During the past few years, clinical trials have provided evidence that lipid-lowering therapy has a similar beneficial effect on cardiovascular outcomes in diabetic and nondiabetic individuals. According to current guidelines, the primary lipid target is an LDL-C <100 mg/dL (<70 mg/dL in very high-risk patients) and, to this end, statins are the agents of choice. The appropriate management of dyslipidemia in patients with diabetes, particularly in individuals with low LDL-C, remains controversial. To achieve lipid targets, attention should be directed first toward nonpharmacologic therapeutic interventions to control dyslipidemia, such as diet, exercise, smoking cessation, weight loss, and glycemic control. Statin therapy is recommended for most subjects but, frequently, a combination of lipid-lowering agents is required. A number of combinations are possible, and several factors should be considered to improve the safety of this strategy.

Management of diabetic dyslipidemia.

Identification and management of dyslipidemia is an important element in the multi-factorial approach to prevent coronary heart disease. Diabetic dyslipidemia typically consists of elevated triglyceride, low high-density lipoprotein cholesterol, predominance of small, dense low-density lipoprotein (LDL) particles, and average LDL cholesterol (LDL-C). Lipid-lowering therapy has a beneficial effect on cardiovascular outcomes. Statin treatment is beneficial in patients who are older than 40 years of age, irrespective of the LDL-C value. To achieve lipid targets, attention should be directed first toward nonpharmacologic therapeutic interventions, such as diet, exercise, smoking cessation, weight loss, and improving glycemic control. Although statin therapy is recommended for most subjects, judicious use of combination therapy should be considered in the highest risk subjects.

Sensory function and albumin excretion according to diagnostic criteria for diabetes.

OBJECTIVE: The purpose of this study was to examine sensory function and albumin excretion according to categories of glucose tolerance in individuals undergoing screening for diabetes. RESEARCH DESIGN AND METHODS: Sensory function and albumin excretion measurements were obtained in 636 individuals at the time of screening for diabetes according to American Diabetes Association glucose tolerance criteria. Sensory thresholds were measured by forced-choice techniques. Albumin-to-creatinine ratios were calculated from spot urine samples. RESULTS: Of 90 individuals whose glucose levels were in the range for diabetes, 65 had fasting glucose values >or=126 mg/dl, whereas 25 had 2-h glucose values >or=200 mg/dl, with fasting glucose values <126 mg/dl. In covariance analyses, those with fasting glucose levels >or=126 mg/dl had higher vibration (P < 0.01) and thermal (P < 0.05 for cool and warm) thresholds than those with normal glucose tolerance. This pattern was also evident for albumin-to-creatinine ratios (P < 0.001). In contrast, those with 2-h glucose values >or=200 mg/dl and fasting glucose values <126 mg/dl had sensory threshold and albumin-to-creatinine ratio values similar to those of the normal group. Individuals with fasting glucose levels >or=126 mg/dl had higher vibration threshold and albumin-to-creatinine ratio values (<0.05 and <0.01, respectively) than those with levels <126 mg/dl. CONCLUSIONS: Sensory threshold and albumin excretion values already tend to be greater than normal at screening in individuals with fasting glucose levels >or=126 mg/dl, but not in those with levels <126 mg/dl. A reliance on fasting glucose levels >or=126 mg/dl for screening might not be sufficient for early intervention and the optimal prevention of diabetes complications.