Discordance of Low-Density Lipoprotein and High-Density Lipoprotein Cholesterol Particle Versus Cholesterol Concentration for the Prediction of Cardiovascular Disease in Patients With Metabolic Syndrome and Diabetes Mellitus (from the Multi-Ethnic Study of Atherosclerosis [MESA]).

A stronger association for low-density lipoprotein particle (LDL-P) and high-density lipoprotein particle (HDL-P) versus cholesterol concentrations (LDL-C and HDL-C) in predicting coronary heart disease (CHD) has been noted. We evaluate the role of these factors and extent of particle-cholesterol discordance in those with diabetes mellitus (DM) and metabolic syndrome (MetS) for event prediction. In the Multi-Ethnic Study of Atherosclerosis, we examined discordance of LDL and HDL (defined as a subject's difference between baseline particle and cholesterol percentiles), LDL-C, LDL-P, HDL-C, and HDL-P in relation to incident CHD and cardiovascular disease (CVD) events in subjects with DM, MetS (without DM), or neither condition using Cox regression. Of the 6,417 subjects with 10-year follow-up, those with MetS (n = 1,596) and DM (n = 838) had significantly greater LDL and HDL discordance compared with those without these conditions. In discordance models, only LDL discordance (per SD) within the MetS group was positively associated with CHD events (adjusted hazard ratio [HR] = 1.22, 95% confidence interval [CI] 1.01 to 1.48, p <0.05). In models with individual particle/cholesterol variables (per SD), within the DM group, HDL-P was inversely (HR 0.71, 95% CI 0.52 to 0.96, p <0.05) and LDL-C positively (HR 1.47, 95% CI 1.07 to 2.03, p <0.05) associated with CHD. In those with MetS, only LDL-P was positively associated with CHD (HR 1.34, 95% CI 1.00 to 1.78, p <0.05). Similar findings were also seen for CVD. LDL discordance and higher LDL-P in MetS, and higher LDL-C and lower HDL-P in DM, predict CHD and CVD, supporting a potential role for examining lipoprotein particles and discordances in those with MetS and DM

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE

The development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. The Executive Summary of this document contains 87 recommendations of which 45 are Grade A (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%), and 9 (10.3%) are Grade D. These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world medical care. The evidence base presented in the subsequent Appendix provides relevant supporting information for Executive Summary Recommendations. This update contains 695 citations of which 203 (29.2 %) are EL 1 (strong), 137 (19.7%) are EL 2 (intermediate), 119 (17.1%) are EL 3 (weak), and 236 (34.0%) are EL 4 (no clinical evidence). This CPG is a practical tool that endocrinologists, other health care professionals, health-related organizations, and regulatory bodies can use to reduce the risks and consequences of dyslipidemia. It provides guidance on screening, risk assessment, and treatment recommendations for a range of individuals with various lipid disorders. The recommendations emphasize the importance of treating low-density lipoprotein cholesterol (LDL-C) in some individuals to lower goals than previously endorsed and support the measurement of coronary artery calcium scores and inflammatory markers to help stratify risk. Special consideration is given to individuals with diabetes, familial hypercholesterolemia, women, and youth with dyslipidemia. Both clinical and cost-effectiveness data are provided to support treatment decisions. 4S = Scandinavian Simvastatin Survival Study A1C = glycated hemoglobin AACE = American Association of Clinical Endocrinologists AAP = American Academy of Pediatrics ACC = American College of Cardiology ACE = American College of Endocrinology ACS = acute coronary syndrome ADMIT = Arterial Disease Multiple Intervention Trial ADVENT = Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study AHA = American Heart Association AHRQ = Agency for Healthcare Research and Quality AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides trial ASCVD = atherosclerotic cardiovascular disease ATP = Adult Treatment Panel apo = apolipoprotein BEL = best evidence level BIP = Bezafibrate Infarction Prevention trial BMI = body mass index CABG = coronary artery bypass graft CAC = coronary artery calcification CARDS = Collaborative Atorvastatin Diabetes Study CDP = Coronary Drug Project trial CI = confidence interval CIMT = carotid intimal media thickness CKD = chronic kidney disease CPG(s) = clinical practice guideline(s) CRP = C-reactive protein CTT = Cholesterol Treatment Trialists CV = cerebrovascular CVA = cerebrovascular accident EL = evidence level FH = familial hypercholesterolemia FIELD = Secondary Endpoints from the Fenofibrate Intervention and Event Lowering in Diabetes trial FOURIER = Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial HATS = HDL-Atherosclerosis Treatment Study HDL-C = high-density lipoprotein cholesterol HeFH = heterozygous familial hypercholesterolemia HHS = Helsinki Heart Study HIV = human immunodeficiency virus HoFH = homozygous familial hypercholesterolemia HPS = Heart Protection Study HPS2-THRIVE = Treatment of HDL to Reduce the Incidence of Vascular Events trial HR = hazard ratio HRT = hormone replacement therapy hsCRP = high-sensitivity CRP IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial IRAS = Insulin Resistance Atherosclerosis Study JUPITER = Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin LDL-C = low-density lipoprotein cholesterol Lp-PLA2 = lipoprotein-associated phospholipase A2 MACE = major cardiovascular events MESA = Multi-Ethnic Study of Atherosclerosis MetS = metabolic syndrome MI = myocardial infarction MRFIT = Multiple Risk Factor Intervention Trial NCEP = National Cholesterol Education Program NHLBI = National Heart, Lung, and Blood Institute PCOS = polycystic ovary syndrome PCSK9 = proprotein convertase subtilisin/kexin type 9 Post CABG = Post Coronary Artery Bypass Graft trial PROSPER = Prospective Study of Pravastatin in the Elderly at Risk trial QALY = quality-adjusted life-year ROC = receiver-operator characteristic SOC = standard of care SHARP = Study of Heart and Renal Protection T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus TG = triglycerides TNT = Treating to New Targets trial VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial VLDL-C = very low-density lipoprotein cholesterol WHI = Women's Health Initiative

Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial

Importance: Muscle-related statin intolerance is reported by 5%to 20%of patients. Objective: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions: Phase A: atorvastatin (20mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420mg monthly) or oral ezetimibe (10mg daily). Main Outcome and Measures: Coprimary end pointswere the mean percent change in LDL-C level from baseline to the mean ofweeks 22 and 24 levels and from baseline toweek 24 levels. Results: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9]mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72]mg/dL). For the mean ofweeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7%(95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5%(95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptomswere reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drugwas stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety

Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2015 Executive Summary

This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician