Comparison of nonfasting and fasting lipoprotein subfractions and size in 15,397 apparently healthy individuals: An analysis from the VITamin D and OmegA-3 TriaL.

BACKGROUND: Elevated postprandial triglycerides reflect a proatherogenic milieu, but underlying mechanisms are unclear. OBJECTIVE: We examined differences between fasting and nonfasting profiles of directly measured lipoprotein size and subfractions to assess if postprandial triglycerides reflected increases in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and remnants, or small dense lipid depleted LDL (sdLDL) particles. METHODS: We conducted a cross-sectional analysis of 15,397 participants (10,135 fasting; 5262 nonfasting [<8 hours since last meal]) from the VITamin D and OmegA-3 TriaL. Baseline cholesterol subfractions were measured by the vertical auto profile method and particle subfractions by ion mobility. We performed multivariable linear regression adjusting for cardiovascular and lipoprotein-modifying risk factors. RESULTS: Mean age (SD) was 68.0 years (±7.0), with 50.9% women. Adjusted mean triglyceride concentrations were higher nonfasting by 17.8 ± 1.3%, with higher nonfasting levels of directly measured VLDL cholesterol (by 3.5 ± 0.6%) and total VLDL particles (by 2.0 ± 0.7%), specifically large VLDL (by 12.3 ± 1.3%) and medium VLDL particles (by 5.3 ± 0.8%), all P < .001. By contrast, lower concentrations of low density lipoprotein (LDL) and IDL cholesterol and particles were noted for nonfasting participants. sdLDL cholesterol levels and particle concentrations showed no statistically significant difference by fasting status (-1.3 ± 2.1% and 0.07 ± 0.6%, respectively, P > .05). CONCLUSIONS: Directly measured particle and cholesterol concentrations of VLDL, not sdLDL, were higher nonfasting and may partly contribute to the proatherogenicity of postprandial hypertriglyceridemia. These differences, although statistically significant, were small and may not fully explain the increased risk of postprandial hypertriglyceridemia.

Serum 25-hydroxyvitamin D in the VITamin D and OmegA-3 TriaL (VITAL): Clinical and demographic characteristics associated with baseline and change with randomized vitamin D treatment.

BACKGROUND: The VITamin D and OmegA-3 TriaL (VITAL) is a completed randomized, placebo-controlled trial of vitamin D3 (2000 IU/day) and marine omega-3 (1 g/day) supplements in the primary prevention of cancer and cardiovascular disease. Here we examine baseline and change in 25-hydroxyvitamin D (25(OH)D) and related biomarkers with randomized treatment and by clinical factors. METHODS: Baseline 25(OH)D was measured in 15,804 participants (mean age 68 years.; 50.8% women; 15.7% African Americans) and in 1660 1-year follow-up samples using liquid chromatography-tandem mass spectrometry and chemiluminescence. Calcium and parathyroid hormone (iPTH) were measured by chemiluminescence and spectrophotometry respectively. RESULTS: Mean baseline total 25(OH)D (ng/mL ±â€¯SD) was 30.8 ±â€¯10.0 ng/mL, and correlated inversely with iPTH (r = -0.28), p < .001. After adjusting for clinical factors, 25(OH)D (ng/mL ±â€¯SE) was lower in men vs women (29.7 ±â€¯0.30 vs 31.4 ±â€¯0.30, p < .0001) and in African Americans vs whites (27.9 ±â€¯0.29 vs 32.5 ±â€¯0.22, p < .0001). It was also lower with increasing BMI, smoking, and latitude, and varied by season. Mean 1-year 25(OH)D increased by 11.9 ng/mL in the active group and decreased by 0.7 ng/mL in placebo. The largest increases were noted among individuals with low baseline and African Americans. Results were similar for chemiluminescent immunoassay. Mean calcium was unchanged, and iPTH decreased with treatment. CONCLUSION: In VITAL, baseline 25(OH)D varied by clinical subgroups, was lower in men and African Americans. Concentrations increased with vitamin D supplementation, with the greatest increases in those with lower baseline 25(OH)D. The seasonal trends in 25(OH)D, iPTH, and calcium may be relevant when interpreting 25(OH)D levels for clinical treatment decisions. CLINICAL TRIAL REGISTRATION: VITAL ClinicalTrials.gov number NCT01169259.

Class effects of SGLT2 inhibitors on cardiorenal outcomes.

BACKGROUND: To summarize the four recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials: Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin CardioVascular Assessment Study (CANVAS) Program, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and explore the potential determinants for their cardiovascular, renal, and safety outcomes. RESULTS: The composite renal outcome event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 3.7, 7.0, 47%; 5.5, 9.0, 40%; 6.3, 11.5, 46%; 43.2, 61.2, 30% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively (event definitions varied across trials). The major adverse cardiovascular (CV) event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14%; 38.7, 48.7, 20% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events and CREDENCE the most. These differences were presumably due to varying inclusion criteria resulting in DECLARE-TIMI 58 having the best baseline renal filtration function and CREDENCE the worst (mean estimated glomerular filtration rate 85.2, 76.5, 74, 56.2 mL/min/1.73 m2 for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively). Additionally, CREDENCE had considerably higher rates of albuminuria (median urinary albumin-creatinine ratios (UACR) were 927, 12.3, and 13.1 mg/g for CREDENCE, CANVAS, and DECLARE-TIMI 58, respectively; EMPA-REG OUTCOME had 59.4% UACR < 30, 28.6% UACR > 30-300, 11.0% UACR > 300 mg/g). CONCLUSIONS: Dapagliflozin, empagliflozin, and canagliflozin have internally and externally consistent and biologically plausible class effects on cardiorenal outcomes. Baseline renal filtration function and degree of albuminuria are the most significant indicators of risk for both CV and renal events. Thus, these two factors also anticipate the greatest clinical benefit for SGLT2i.

Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review.

In this systematic review, we sought to summarize the 3 recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials (Dapagliflozin Effect on CardiovasculAR Events (DECLARE-TIMI 58), Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, and Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME)) and to explore the potential causes for their different results. We found that the major adverse cardiovascular event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14% for DECLARE-TIMI 58, CANVAS, and EMPA-REG OUTCOME, respectively. DECLARETIMI 58 had the fewest cardiorenal events (across treatment and control arms) and EMPA-REG OUTCOME the most. DECLARE-TIMI 58 used alternative inclusion criterion for baseline renal function (creatinine clearance ≧ 60 mL/min) compared to the other trials (estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 bodysurface area). Therefore, the DECLARE-TIMI 58 study cohort had higher eGFR (mean eGFR 85.2 mL/min/1.73 m2 compared to 76.5 and 74 in CANVAS and EMPAREG OUTCOME, respectively); this may have caused the difference in results. Additionally contributing to the high event rate in EMPA-REG OUTCOME was the requirement of prior confirmed cardiovascular disease (CVD), resulting in 99.2% of patients with CVD compared to only 65.6% and 40.6% in CANVAS and DECLARE-TIMI 58, respectively (which did not require CVD). In conclusion, there is a need for large-scale studies of SGLT2i with matching inclusion/exclusion criteria and appropriate endpoints to ensure a truly direct comparison of the drugs.

Impact of Subclinical Hypothyroidism on Cardiometabolic Biomarkers in Women.

CONTEXT: Whether subclinical hypothyroidism (SCH) is associated with cardiometabolic abnormalities is uncertain. OBJECTIVE: To examine diverse cardiometabolic biomarkers across euthyroid, SCH, and overt hypothyroidism (HT) in women free of cardiovascular disease (CVD). DESIGN: Cross-sectional adjusted associations for lipids, lipoprotein subclasses, lipoprotein insulin resistance score, inflammatory, coagulation, and glycemic biomarkers by ANCOVA for thyroid categories or TSH quintiles on a Women's Health Study subcohort. SETTING: Outpatient. PATIENTS OR OTHER PARTICIPANTS: Randomly sampled 3,914 middle-aged and older women for thyroid function analysis (thyroid-stimulating hormone [TSH], free T4), of whom 3,321 were not on lipid lowering therapy. INTERVENTION: None. MAIN OUTCOME MEASURE: Associations of SCH and HT with cardiometabolic markers. RESULTS: Going from euthyroid to HT, the lipoprotein subclasse profiles were indicative of insulin resistance [respective values and p for trend]: larger VLDL size (nm)[51.5 (95%CI51.2, 51.8) to 52.9 (51.8, 54.1) p=0.001]; higher LDL particles concentration (nmol/L)[1283 (95%CI1267, 1299) to 1358 (1298, 1418) p=0.004] and smaller LDL size. There was worsening lipoprotein insulin resistance score from euthyroid 49.2 (95%CI 48.3, 50.2) to SCH 52.1 (95%CI 50.1, 54.0), and HT 52.1 (95%CI 48.6, 55.6), p for trend 0.008. Of the other biomarkers, SCH and HT were associated with higher hs-CRP and HbA1c. For increasing TSH quintiles results were overall similar. CONCLUSIONS: In apparently healthy women, SCH cardiometabolic profiles indicated worsening insulin resistance and higher CVD risk markers compared with euthyroid individuals, despite similar LDL and total cholesterol. These findings suggest that cardiometabolic risk may increase early in the progression towards SCH and OH.

Hypertriglyceridemia: the importance of identifying patients at risk.

This review aims to explain risk factors, consequences, and management strategies recommended for patients with hypertriglyceridemia. A search of PubMed was performed: 'Hypertriglyceridemia'[Majr], limited to English-language and published in the 5 years up to April 2016. Abstracts of the 680 results were screened for inclusion. Reference lists of publications included were also screened for inclusion. Approximately 25% of the United States population has elevated (≥150 mg/dL) triglycerides (TG) putting them at an increased risk of cardiovascular disease, non-alcoholic fatty liver disease, and pancreatitis. Risk factors for hypertriglyceridemia include genetics, lifestyle and diet, renal disease, endocrine disorders, and certain medications. Guidelines recommend that all patients with hypertriglyceridemia are advised on lifestyle modification to reduce TG to <150 mg/dL; a reduction in body weight of 5-10% can reduce TG by approximately 20%. For patients with TG <400 mg/dL, the primary goal is to reduce low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol, with most guidelines recommending statin therapy. When TG is ≥500 mg/dL the primary goal is to reduce TG levels to lower the risk of pancreatitis. Statin therapy (if LDL-C is elevated) in combination with a fibrate, or long-chain omega-3 fatty acid may be required. The Food and Drug Administration withdrew approval for niacin and some fibrates in combination with statins in April 2016 citing unfavorable benefit-risk profiles. With the increasing incidence of associated conditions (e.g. obesity, metabolic syndrome, and type 2 diabetes mellitus), it is likely that primary care physicians will encounter more patients with hypertriglyceridemia.

Coronary heart disease in women.

Coronary heart disease results in a worse prognosis following a primary event in women than in men, thus demonstrating the critical importance of primary prevention in at-risk individuals beginning early in adulthood. A medical history, physical examination, laboratory determination of lipid and HbA1c levels, as well as assessment of psychosocial factors, including tobacco use, provide a good initial estimate of cardiovascular risk in women. Women with coronary ischemia often present atypically, without dramatic chest pain, but with more subtle symptoms. Assessing traditional risk factors, as well as long-term risk screening, may help identify the higher-risk patients for evaluation and treatment. Statin therapy is generally used to lower LDL-C, whereas antihypertensive therapy is selected based on patient comorbidities and drug side effects. Addressing lifestyle and psychosocial factors is an important part of a comprehensive plan for cardiovascular risk reduction in women.

Treatment with exenatide once weekly or twice daily for 30 weeks is associated with changes in several cardiovascular risk markers.

BACKGROUND: Cyslipidemia and type 2 diabetes are two of the most significant risk factors for the development of cardiovascular disease. Measurement of lipoprotein subclasses provides important information about derangements in lipid metabolism and helps refine cardiovascular risk assessment. Exenatide, a glucagon-like peptide 1 receptor agonist, improved glycemic control, obesity, hypertension, and dyslipidemia in patients with type 2 diabetes in clinical trials. METHODS: In the DURATION-1 trial, patients with type 2 diabetes were treated with exenatide once weekly or twice daily for 30 weeks. This post hoc analysis evaluated the impact of exenatide on lipoprotein subclasses in 211 DURATION-1 patients using vertical auto profile methodology and the Statistical Package for the Social Sciences general linear model adjusted for glycosylated hemoglobin (HbA(1c)) and weight. RESULTS: Baseline lipids and high sensitivity C-reactive protein were normal overall based on the standard lipid panel. Once-weekly exenatide reduced apolipoprotein B and the apolipoprotein B to apolipoprotein A1 ratio (P < 0.05), independent of glycemic improvement and weight loss. A significant shift in lipoprotein pattern away from small, dense low-density lipoprotein-4 cholesterol was also observed (P < 0.05). Exenatide once weekly increased high-density lipoprotein-2 cholesterol, even after adjustment for changes in HbA(1c) and weight (P < 0.05). Triglycerides, very low-density lipoprotein cholesterol, and high sensitivity C-reactive protein were reduced with both the once-weekly and twice-daily exenatide regimens (P < 0.05). CONCLUSION: In this post hoc analysis, exenatide significantly improved a number of cardiovascular risk markers. Continuous exenatide exposure with exenatide once weekly elicited a greater response than did immediate-release exenatide twice daily, generally independent of glycemic improvement and weight loss. Thus, in addition to improving glycemic control, exenatide induced favorable changes in lipid and lipoprotein metabolism and decreased systemic inflammation.

Coronary heart disease in men.

Elimination of key risk factors such as dyslipidemia and hypertension is important for reducing cardiovascular events later in life. A medical history, physical examination, and laboratory determination of lipid and glycosylated hemoglobin levels provide a good assessment of cardiovascular risk. A statin is first-line therapy for reducing LDL-C, which is the primary lipid target in most patients. High-dose statin therapy may be required to reach desired target levels. The choice of initial antihypertensive therapy is based on patient comorbidities and drug side effects; however, most patients require combination antihypertensive therapy to reach goal. The combination of this multifactorial risk approach along with smoking cessation and modification of other risk factors should complement current and future cardiovascular care for men.

Differentiating among incretin-based therapies in the management of patients with type 2 diabetes mellitus.

The glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have become important options for the management of patients with type 2 diabetes mellitus. While the GLP-1R agonists and DPP-4 inhibitors act on the incretin system to regulate glucose homeostasis, there are important clinical differences among the five agents currently available in the U.S. For example, the GLP-1R agonists require subcutaneous administration, produce pharmacological levels of GLP-1 activity, promote weight loss, have a more robust glucose-lowering effect, and have a higher incidence of adverse gastrointestinal effects. In contrast, the DPP-4 inhibitors are taken orally, increase the half-life of endogenous GLP-1, are weight neutral, and are more commonly associated with nasopharyngitis. Differences in efficacy, safety, tolerability, and cost among the incretin-based therapies are important to consider in the primary care management of patients with type 2 diabetes mellitus.

Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data.

Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular (CV) disease; however, conclusive evidence that glycemic control leads to improved cardiovascular outcomes is lacking. Saxagliptin is a potent, selective dipeptidyl peptidase-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Saxagliptin was evaluated in a series of phase III trials as monotherapy; add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione; and as initial therapy in combination with metformin. Saxagliptin consistently improved glycemic control (as reflected by significant decreases in glycated hemoglobin, fasting plasma glucose, and postprandial glucose compared with controls) and was generally well tolerated. In these analyses, saxagliptin had clinically neutral effects on body weight, blood pressure, lipid levels, and other markers of CV risk compared with controls. A retrospective meta-analysis of 8 phase II and phase III trials found no evidence that saxagliptin increases CV risk in patients with T2DM (Cox proportional hazard ratio, 0.43; 95% CI, 0.23-0.80 for major adverse cardiovascular events retrospectively adjudicated). Instead, it raised the hypothesis that saxagliptin may reduce the risk of major adverse CV events. A long-term CV outcome trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-THrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) is currently ongoing to determine whether saxagliptin reduces CV risk in T2DM.

Lipoprotein associated phospholipase A(2): role in atherosclerosis and utility as a biomarker for cardiovascular risk.

Atherosclerosis and its clinical manifestations are widely prevalent throughout the world. Atherogenesis is highly complex and modulated by numerous genetic and environmental risk factors. A large body of basic scientific and clinical research supports the conclusion that inflammation plays a significant role in atherogenesis along the entire continuum of its progression. Inflammation adversely impacts intravascular lipid handling and metabolism, resulting in the development of macrophage foam cell, fatty streak, and atheromatous plaque formation. Given the enormous human and economic cost of myocardial infarction, ischemic stroke, peripheral arterial disease and amputation, and premature death and disability, considerable effort is being committed to refining our ability to correctly identify patients at heightened risk for atherosclerotic vascular disease and acute cardiovascular events so that they can be treated earlier and more aggressively. Serum markers of inflammation have emerged as an important component of risk factor burden. Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) potentiates intravascular inflammation and atherosclerosis. A variety of epidemiologic studies support the utility of Lp-PLA(2) measurements for estimating and further refining cardiovascular disease risk. Drug therapies to inhibit Lp-PLA(2) are in development and show considerable promise, including darapladib, a specific molecular inhibitor of the enzyme. In addition to substantially inhibiting Lp-PLA(2) activity, darapladib reduces progression of the necrotic core volume of human coronary artery atheromatous plaque. The growing body of evidence points to an important role and utility for Lp-PLA(2) testing in preventive and personalized clinical medicine.

Distinguishing among incretin-based therapies. Glucose-lowering effects of incretin-based therapies.

Extensive experience from randomized clinical trials demonstrates the efficacy of GLP-1 agonists and DPP-4 inhibitors as monotherapy and in combination with metformin and other agents, although reductions in FPG and PPG, and consequently A1C, are greater with GLP-1 agonists than with DPP-4 inhibitors. This difference may result from the pharmacologic levels of GLP-1 activity that are achieved with the GLP-1 agonists and their direct action on the GLP-1 receptor. The GLP-1 agonists have attributes that would make either of them an appropriate choice in the management of all 3 patients in our case studies, while either DPP-4 inhibitor would be an appropriate choice for Case 1. Differences in dosing, administration, safety, and tolerability should be considered.

Distinguishing among incretin-based therapies. Patient education and self-management.

Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.

Distinguishing among incretin-based therapies. Safety, tolerability, and nonglycemic effects of incretin-based therapies.

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

Distinguishing among incretin-based therapies. Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies.

The multifactorial nature of the pathogenesis of T2DM provides an opportunity to combine treatments that act upon different mechanisms. In addition to improving insulin resistance and pancreatic ß-cell dysfunction, the GLP-1 agonists and DPP-4 inhibitors improve the impaired incretin response, as well as increase insulin secretion and reduce glucagon secretion, both in a glucose-dependent manner. As a result of these multiple actions, the GLP-1 agonists and DPP-4 inhibitors lower both fasting and postprandial glucose levels. The effects of GLP-1 agonists tend to be greater, probably because they produce pharmacologic levels of GLP-1 compared to physiologic levels with the DPP-4 inhibitors. Another difference is that unlike the DPP-4 inhibitors, the GLP-1 agonists also slow gastric emptying and promote satiety.

Distinguishing among incretin-based therapies. Introduction.

The "treat to target" approach is to quickly achieve the target glycosylated hemoglobin (AIC) goal of <7% in most people, and then intensify or change therapy as needed to maintain glycemic control. Results of an online survey demonstrate uncertainty regarding the clinical differences between glucagon-like peptide (GLP-1) agonists and dipeptidyl peptidase (DPP)-4 inhibitors. The increasingly important roles of the GLP-1 agonists and DPP-4 inhibitors stem from their overall good efficacy and safety profiles compared with other treatment options.

Carotid intima-media thickness: knowledge and application to everyday practice.

Heart disease is the primary cause of death in the United States. Fortunately, intervention measures can reduce the risk of cardiovascular disease (CVD) after a patient has been accurately assessed. Atherosclerotic disease, one of the driving forces behind CVD, is not always detected by traditional risk assessment. Carotid intima-media thickness (CIMT), as measured by B-mode ultrasound, is a surrogate marker for atherosclerosis and can be used to detect an accelerated disease process and subclinical disease. Advantages of CIMT are that it is noninvasive, relatively inexpensive, and can be repeatedly performed with no adverse effects on the patient. Carotid intima-media thickness is associated with CVD and is an independent predictor of stroke and myocardial infarction. Therefore, CIMT is valuable for clarifying CVD risk, particularly for patients with intermediate risk by conventional risk assessment. Screening for subclinical disease even in low-risk patients may have benefit, especially for those with a family history of premature CVD or those with any of the National Cholesterol Education Program risk factors. The detection of subclinical atherosclerosis allows the physician to implement prevention efforts prior to a devastating CVD event and to investigate possible reasons for increased arterial thickening, such as an occult underlying insulin-resistant condition or residual lipid risk markers. Treatment with several types of drugs has been demonstrated to halt the progression or even reduce CIMT. Carotid intima-media thickness is currently limited by the lack of standardized protocols that may affect reproducibility from measure to measure. Efforts to draft a standardized protocol are underway by the Society of Atherosclerosis Imaging and Prevention that will address this issue. Carotid intima-media thickness provides a valuable tool for physicians to clarify the CVD risk of their patients. Practical implications of CIMT for everyday clinical practice are addressed.