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OBJECTIVE The glucagon-like peptide-1 receptor agonist dulaglutide reduced MACE in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. This article expores the relationship of selected biomarkers to both dulaglutide and major adverse cardiovascular events (MACE). RESEARCH DESIGN AND METHODS In this post hoc analysis, stored fasting baseline and 2-year plasma samples from 824 REWIND participants with MACE during follow-up and 845 matched non-MACE participants were analyzed for 2-year changes in 19 protein biomarkers. Two-year changes in 135 metabolites were also analyzed in 600 participants with MACE during follow-up and in 601 matched non-MACE participants. Linear and logistic regression models were used to identify proteins that were associated with both dulaglutide treatment and MACE. Similar models were used to identify metabolites that were associated with both dulaglutide treatment and MACE. RESULTS Compared with placebo, dulaglutide was associated with a greater reduction or lesser 2-year rise from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), high-sensitivity C-reactive protein, and a greater 2-year rise in C-peptide. Compared with placebo, dulaglutide was also associated with a greater fall from baseline in 2-hydroxybutyric acid and a greater rise in threonine (P < 0.001). Increases from baseline in two of the proteins (but neither metabolite) were associated with MACE, including NT-proBNP (OR 1.267; 95% CI 1.119, 1.435; P < 0.001) and GDF-15 (OR 1.937; 95% CI 1.424, 2.634; P < 0.001). CONCLUSIONS Dulaglutide was associated with a reduced 2-year rise from baseline of NT-proBNP and GDF-15. Higher rises of these biomarkers were also associated with MACE.

Supplemental Digital Content is available in the text., Objective: Plasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and Results: We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (The Addition of Evacetrapib to Atorvastatin Compared to Placebo, High Intensity Atorvastatin, and Atorvastatin With Ezetimibe to Evaluate LDL-C Lowering in Patients With Primary Hyperlipidemia; 130 mg evacetrapib; n=126) and ILLUMINATE (Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation of the Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily [Qd], Compared With Atorvastatin Alone, on the Occurrence of Major Cardiovascular Events in Subjects With Coronary Heart Disease or Risk Equivalents; 60 mg torcetrapib; n=80). We measured the concentration of apoA1 in total plasma and 17 protein-based HDL subspecies at baseline and 3 months. Both CETP inhibitors increased apoA1 in HDL that contains apoC3 the most of all HDL subspecies (median placebo-adjusted percent increase: evacetrapib 99% and torcetrapib 50%). They also increased apoA1 in other HDL subspecies associated with higher coronary heart disease risk such as those involved in inflammation (α-2-macroglobulin and complement C3) or hemostasis (plasminogen), and in HDL that contains both apoE and apoC3, a complex subspecies associated with higher coronary heart disease risk. ApoA1 in HDL that contains apoC1, associated with lower risk, increased 71% and 40%, respectively. Only HDL that contains apoL1 showed no response to either drug. Conclusions: CETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition.

Context Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss. Objective Assess plasma metabolome changes mediated by tirzepatide. Design Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed. Setting Post hoc analysis. Participants 259 subjects with T2D. Intervention(s) Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo. Main Outcome Measure(s) Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction. Results At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species. Conclusions Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health.

In the REWIND trial, dulaglutide (DU) reduced the risk of CV outcomes compared with placebo (PL) (Major Adverse Cardiovascular Event [MACE]-3 hazard ratio 0.88) . This post hoc analysis studied circulating protein biomarkers associated with CV events to better understand how DU reduces CV risk. Patients ≥50 years of age with T2D, A1C ≤9.5%, BMI ≥23 kg/m2, and CV risk were treated DU (1.5 mg weekly) or PL. This case/control study matched 9 cases with MACE with 9 non-MACE controls. A total of protein biomarkers were measured by immunoassay in plasma and serum. Biomarkers associated with DU were first identified by fitting the natural log (ln) of biomarker changes from baseline to 2 years of treatment to an ANCOVA model; the p value cutoff was 0.0026 after Bonferroni correction. Then, the identified biomarkers were fit to a logistic regression model for MACE case/control to test possible impact on CV outcome. Four biomarkers were associated with DU: C-reactive protein (hsCRP) , N-terminal prohormone of brain natriuretic peptide (NT-proBNP) , and Growth/Differentiation Factor-15 (GDF-15) had attenuated increases over 2 years for DU vs. PL, and C-peptide had a greater increase over 2 years for DU vs. PL. Logistic regression analyses showed that patients with smaller increases in hsCRP, NT-proBNP, and GDF-15 were less likely to have MACE. C-peptide levels did not significantly impact MACE occurrence. Disclosure J.M.Wilson: Employee; Eli Lilly and Company. K.L.Duffin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company, Pfizer Inc. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. G.Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. S.Lee: None. H.M.Colhoun: Advisory Panel; Bayer AG, Eli Lilly and Company, Novo Nordisk, Consultant; AstraZeneca, Research Support; AstraZeneca, Stock/Shareholder; Bayer AG, Roche Pharmaceuticals. H.Qian: Employee; Eli Lilly and Company, Stock/Shareholder; Apple, Eli Lilly and Company. V.Pirro: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Hoover: Employee; Eli Lilly and Company. M.Lakshmanan: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. G.Ruotolo: None. Funding Eli Lilly and Company

Aim To better understand the marked decrease in serum triglycerides observed with tirzepatide in patients with type 2 diabetes, additional lipoprotein-related biomarkers were measured post hoc in available samples from the same study. Materials and Methods Patients were randomized to receive once-weekly subcutaneous tirzepatide (1, 5, 10 or 15 mg), dulaglutide (1.5 mg) or placebo. Serum lipoprotein profile, apolipoprotein (apo) A-I, B and C-III and preheparin lipoprotein lipase (LPL) were measured at baseline and at 4, 12 and 26 weeks. Lipoprotein particle profile by nuclear magnetic resonance was assessed at baseline and 26 weeks. The lipoprotein insulin resistance (LPIR) score was calculated. Results At 26 weeks, tirzepatide dose-dependently decreased apoB and apoC-III levels, and increased serum preheparin LPL compared with placebo. Tirzepatide 10 and 15 mg decreased large triglyceride-rich lipoprotein particles (TRLP), small low-density lipoprotein particles (LDLP) and LPIR score compared with both placebo and dulaglutide. Treatment with dulaglutide also reduced apoB and apoC-III levels but had no effect on either serum LPL or large TRLP, small LDLP and LPIR score. The number of total LDLP was also decreased with tirzepatide 10 and 15 mg compared with placebo. A greater reduction in apoC-III with tirzepatide was observed in patients with high compared with normal baseline triglycerides. At 26 weeks, change in apoC-III, but not body weight, was the best predictor of changes in triglycerides with tirzepatide, explaining up to 22.9% of their variability. Conclusions Tirzepatide treatment dose-dependently decreased levels of apoC-III and apoB and the number of large TRLP and small LDLP, suggesting a net improvement in atherogenic lipoprotein profile.

In a phase 2 trial of once-weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo, the dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide dose-dependently reduced HbA1c and body weight in patients with type 2 diabetes. In this post hoc analysis, inflammation, endothelial dysfunction, and cellular stress biomarkers were measured at baseline, 4, 12, and 26 weeks to evaluate the additional effects of tirzepatide on cardiovascular risk factors. At 26 weeks, tirzepatide 10 and 15 mg decreased YKL-40 (also known as chitinase-3 like-protein-1), intercellular adhesion molecule 1 (ICAM-1), leptin, and growth differentiation factor 15 levels versus baseline, and YKL-40 and leptin levels versus placebo and dulaglutide. Tirzepatide 15 mg also decreased ICAM-1 levels versus placebo and dulaglutide, and high-sensitivity C-reactive protein (hsCRP) levels versus baseline and placebo, but not dulaglutide. GlycA, interleukin 6, vascular cell adhesion molecule 1, and N-terminal-pro hormone B-type natriuretic peptide levels were not significantly changed in any group. YKL-40, hsCRP, and ICAM-1 levels rapidly decreased within 4 weeks of treatment with tirzepatide 10 and 15 mg, whereas the decrease in leptin levels was more gradual and did not plateau by 26 weeks. In this hypothesis-generating exploratory analysis, tirzepatide decreased several biomarkers that have been associated with cardiovascular risk.

Despite optimal medical treatment, patients with diabetes and established atherosclerotic disease remain at high risk for recurrent cardiovascular events. Consequently, identification and modification of novel risk factors that mediate residual risk remain an important clinical priority. Lipoprotein (a) [Lp(a)] is an LDL-like particle in which apolipoprotein B is covalently bound by a single disulfide bond to apolipoprotein A, and it has both thrombotic and proinflammatory characteristics (1). There is also a growing body of evidence showing causality of atherosclerotic disease with elevated Lp(a) (1). However, little is known about the predictive role of Lp(a) in patients with diabetes and established cardiovascular disease receiving optimal medical treatment. Thus, given that Lp(a) is an established marker of cardiovascular disease with targeted therapies currently in clinical trials (NCT03070782, ClinicalTrials.gov), we sought to see the impact of elevated Lp(a) in a high-risk secondary prevention cohort of patients with diabetes on optimal medical treatment enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial to identify patients who could potentially benefit from Lp(a)-targeted treatment (2). In our post hoc analysis, participants who met eligibility to enroll in the trial were divided into patients with and without diabetes to assess the impact of Lp(a) tertiles in each group. Baseline Lp(a) levels (in nmol/L) were measured by a central laboratory, using the …

Background: Despite optimal treatment, type II diabetes mellitus remains associated with an increased risk for future cardiovascular events. We sought to determine the association between baseline fasting plasma insulin levels and major adverse cardiovascular outcomes in patients with type II diabetes mellitus and high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods: We included all patients with type II diabetes mellitus who had a central laboratory measured fasting plasma insulin level drawn at baseline as part of the study protocol. Hazard ratios were generated for the risk of major adverse cardiovascular outcomes (composite of cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization) with increasing quartile of baseline fasting plasma insulin level. We then performed a multivariable regression adjusting for significant baseline characteristics. Results: Among 12,092 patients in ACCELERATE, 2042 patients with type II diabetes mellitus had a baseline fasting plasma insulin level drawn. Median follow-up was 28 months. The study population had a mean age of 66.6 years, 79.2% male and 96.2% had established coronary artery disease. During follow-up, major adverse cardiovascular outcomes occurred in 238 patients (11.6%); of these events, 177 were coronary revascularization (8.7%). We observed a statistically significant relationship between rates of revascularization and rising quartile of baseline fasting plasma insulin level which was not noted for the other individual components of major adverse cardiovascular outcomes. Patients with type II diabetes mellitus who underwent revascularization were noted to have significantly higher baseline fasting plasma insulin levels (27.7 vs 21.4 mU/L, p-value = 0.009) although baseline haemoglobin A1c (6.63% vs 6.55%), body mass index (31.5 vs 31.1 kg/m2) and medical therapy were otherwise similar to the group not undergoing revascularization. Following multivariable regression adjusting for significant characteristics including exposure to evacetrapib, the log of baseline fasting plasma insulin level was found to be an independent predictor for major adverse cardiovascular outcomes (hazard ratio = 1.36, 95% confidence interval = 1.09–1.69, p-value = 0.007); this was driven by need for future revascularization (hazard ratio = 1.56, 95% confidence interval = 1.21–2.00, p-value = 0.001). Conclusion: In a contemporary population of patients with type II diabetes mellitus and high-risk vascular disease on optimum medical therapy, baseline hyperinsulinaemia was an independent predictor for major adverse cardiovascular outcomes and need of future coronary revascularization. These results suggest a pathophysiological link between hyperinsulinaemia and progression of atherosclerotic vascular disease among diabetics.

Introduction: The dual GIP/GLP-1 receptor agonist tirzepatide dose-dependently reduced HbA1c and body weight in patients with obesity and type 2 diabetes (T2D) in a Phase 2 trial. Hypothesis: In this post hoc analysis, additional biomarkers of inflammation, endothelial dysfunction, and cellular stress were measured to better understand possible additional effects of tirzepatide treatment on cardiovascular risk factors. Methods: Patients with T2D were randomly assigned to receive either once-weekly subcutaneous injection of tirzepatide (1, 5, 10, or 15 mg), GLP-1 receptor agonist dulaglutide (1.5 mg), or placebo for 26 weeks. Soluble ICAM-1 and VCAM-1, IL-6, NT-proBNP, hsCRP and GDF-15 were assessed by immunoassay at baseline and 26 weeks in stored serum or EDTA plasma samples. Results were analyzed in a modified intent-to-treat population using a mixed effect model for repeated measures. Results: At 26 weeks, tirzepatide dose-dependently decreased ICAM-1 levels compared to baseline (Table). ICAM-1 levels were also significantly lower with tirzepatide 15 mg than placebo or dulaglutide. Moreover, tirzepatide 15 mg significantly decreased hsCRP levels from baseline compared with placebo. GDF-15 levels were decreased from baseline with all tirzepatide doses and with dulaglutide; however, changes in GDF-15 levels with tirzepatide were not significantly different from those with placebo or dulaglutide. Levels of IL-6, VCAM-1 or NT-proBNP were unchanged in all groups. Conclusions: In a 26-week study in patients with obesity and T2D, treatment with tirzepatide dose-dependently decreased circulating levels of specific biomarkers of inflammation and endothelial dysfunction previously associated with cardiovascular events, thus suggesting a net improvement in the cardiovascular risk profile of these patients. Clinical relevance of these changes will be assessed in the planned cardiovascular outcome study SURPASS-CVOT (NCT04255433).

Background/Introduction In a Phase 2 trial, tirzepatide (TZP) dose-dependently reduced HbA1c, body weight and serum triglycerides in moderately obese type 2 diabetes (T2D) patients. Purpose To understand changes in fasting serum lipids with TZP, lipidomics profiling of multiple lipid classes was conducted. Methods Patients (n=314) were randomized to receive weekly subcutaneous TZP, dulaglutide, or placebo for 26 weeks. Shotgun lipidomic analysis was performed in positive electrospray using a Sciex Triple TOF 5600 mass spectrometer operating in MS/MSALL mode and sphingomyelin (SPM) data were acquired in positive electrospray TOF mode. Data were assessed using MMRM. Results At 26 weeks, total cholesterol esters (CE), phosphatidylcholines (PC) and phosphatidylinositols (PI) increased with placebo; dulaglutide treatment did not affect any lipid class (Table). With TZP 10 and 15 mg, total triacylglycerides (TAG), diacylglycerides (DAG), phosphatidylethanolamines (PE), PC and PI dose-dependently decreased at 4, 12 and 26 weeks, whereas total CE and phosphatidylserines (PS) levels did not change at any timepoint. At 26 weeks, individual, but not total, SPM and ceramide (Cer) changes were observed with TZP 15 mg. Most saturated, long chain SPM (14:0, 20:0, 21:0, 22:0, 23:0, 24:0) and Cer (22:0, 23:0, 24:0) were reduced by 8–16% and 14–20%, respectively. Conversely, unsaturated SPM (24:1,24:2) increased by 6.5% and 11.4%, and unsaturated glycosylated Cer 16:0 lactosyl and 24:1 hexosyl increased by 22.4% and 19.3%, respectively. TZP 10 and 15 mg decreased total SPM by 4–6% at 4 weeks, and total Cer between 8% and 13% at 4 and 12 weeks. Conclusions Tirzepatide dose-dependently reduced levels of total TAG, DAG, PE, PC, and PI at all timepoints, whereas levels of saturated long chain SPM and Cer were reduced and those of some unsaturated SPM and glycosylated Cer increased at 26 weeks. Net improvements in lipidomics profiling with tirzepatide warrant further evaluation of potential benefits on cardiovascular events and NASH. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Eli Lilly and Company

Genome-wide polygenic scores (GPSs) integrate information from many common DNA variants into a single measure of inherited susceptibility, and can identify individuals who are at substantially elevated risk of developing important common diseases.(1,2) For coronary artery disease, about 8% of the population can be identified who are at triple the normal risk based on genetic variation alone.(1) Among these high polygenic score individuals, adherence to a healthy lifestyle or use of statins may offset increased inherited risk.(2,3)

Background The contemporary impact of glycemic control on patients with diabetes mellitus at high cardiovascular risk remains unclear. We evaluated the utility of hemoglobin A1c (HbA1c) as a marker of risk on the composite end point of cardiovascular death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization in an optimally treated population with diabetes mellitus and established coronary artery disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with established diabetes mellitus and measured HbA1c (N=8145) and estimated Kaplan‐Meier (KM) events rates, stratified by increasing baseline HbA1c levels censored at 30 months. We then performed a multivariable regression for the primary end point. Increasing baseline HbA1c was strongly associated with the occurrence of the primary end point (KM estimate, 12.6–18.2; P P =0.003) as well as the individual end points of nonfatal myocardial infarction (KM estimate, 3.1–7.0; P P =0.003), and revascularization (KM estimate, 7.3–11.1; P =0.001), although not stroke (KM estimate, 1.4–2.4; P =0.45). The rates of cardiovascular mortality (KM estimate, 2.6–4.3; P =0.21) and all‐cause mortality ( KM estimate, 4.8–5.9; P =0.21) were similar regardless of baseline HbA1c levels. When adjusting for relevant baseline characteristics, baseline HbA1c was an independent predictor for the primary end point (hazard ratio, 1.06; 95% CI , 1.02–1.11; P =0.003). Conclusions Glycemic control, as measured by HbA1c, remains strongly and independently associated with cardiovascular outcomes in high‐risk patients with diabetes mellitus on statin therapy. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 01687998.

The HDL (high-density lipoprotein) Workshop was established in 2009 as a forum for candid discussions among academic basic scientists, clinical investigators, and industry researchers about the role of HDL in cardiovascular disease. This ninth HDL Workshop was held on May 16 to 17, 2019 in Boston, MA, and included outstanding oral presentations from established and emerging investigators. The Workshop featured 5 sessions with topics that tackled the role of HDL in the vasculature, its structural complexity, its role in health and disease states, and its interaction with the intestinal microbiome. The highlight of the program was awarding the Jack Oram Award to the distinguished professor emeritus G.S. Getz from the University of Chicago. The tenth HDL Workshop will be held on May 2020 in Chicago and will continue the focus on intellectually stimulating presentations by established and emerging investigators on novel roles of HDL in cardiovascular and noncardiovascular health and disease states.

Background The failure of cholesteryl ester transfer protein inhibitor torcetrapib was associated with an off‐target increase in plasma aldosterone. We sought to evaluate the impact of evacetrapib on plasma aldosterone level and determine the association between plasma aldosterone level and major adverse cardiovascular events among patients with stable high‐risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with a plasma aldosterone level (N=1624) and determined the impact of evacetrapib exposure compared with placebo on plasma aldosterone levels after 12 months of treatment. Using baseline and postexposure aldosterone levels, hazard ratios for major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, cerebrovascular accident, hospitalization for unstable angina, and revascularization) with increasing quartile of baseline and percentage change in plasma aldosterone level at follow‐up were calculated. The average age was 65.2 years, 75.7% were men, 93.7% were hypertensive, 73.3% were diabetic, and 57.6% had a prior myocardial infarction. Baseline plasma aldosterone level (85.2 [43, 150] versus 86.8 [43, 155] pmol/L; P =0.81) and follow‐up percentage change (13.6% [−29, 88] versus 17.9% [−24, 87]; P =0.23) were similar between those who received evacetrapib and placebo. During median follow‐up of 28 months, major adverse cardiovascular events occurred in 263 patients (16.2%). The hazard ratios for increasing quartile of baseline or percentage change in plasma aldosterone level at follow‐up were not significant for major adverse cardiovascular events. These findings remained consistent when adjusting for significant characteristics. Conclusions Exposure to evacetrapib did not result in significant change in plasma aldosterone levels compared with placebo. Among patients with stable high‐risk vascular disease, plasma aldosterone levels were not a predictor for future cardiovascular events. Clinical Trial Registration URL : http://www.ClinicalTrials.gov . Unique identifier: NCT 01687998.

BackgroundHigh-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition with evacetrapib results in a marked increase in HDL and reduction in low-density lipoprotein (LDL) levels. We evaluated the impact of treatment with evacetrapib versus placebo in the subset of 8236 patients with diabetes mellitus (DM) enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes trial.Methods and resultsTime to first occurrence of any component of the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, revascularization, and hospitalization for unstable angina was compared among patients with DM randomized to treatment with evacetrapib (n=4127) or placebo (n=4109) over a median of 26 months of follow-up. The mean baseline LDL at initiation was 80 mg/dL with a mean baseline HDL of 44 mg/dL. In patients with DM, evacetrapib resulted in a 131% mean increase in HDL levels and a 32% mean decrease in LDL at 3 months that was sustained during the course of the trial. At 6 months, hemoglobin A1c (HbA1c) levels were lower with evacetrapib than placebo (7.08% vs 7.15%, p=0.023). Composite event rates were higher in patients with DM than without DM (Kaplan-Meier estimates: 15.2% vs 10.6%, HR 1.46, 95% CI 1.30 to 1.64, pConclusionDespite a favorable increase in HDL, and decreases in LDL and HbA1c levels in patients with DM, we observed no benefits of treatment with evacetrapib on prespecified clinical outcomes in this high-risk population.

IMPORTANCE: Although lipoprotein(a) (Lp[a]) is a causal genetic risk factor for atherosclerotic cardiovascular disease, it remains unclear which patients with established atherosclerotic cardiovascular disease stand to benefit the most from Lp(a) lowering. Whether inflammation can modulate Lp(a)-associated cardiovascular (CV) risk during secondary prevention is unknown. OBJECTIVE: To examine whether Lp(a)-associated CV risk is modulated by systemic inflammation in optimally treated patients at high risk of CV disease. DESIGN, SETTING, AND PARTICIPANTS: A prespecified secondary post hoc analysis of the double-blind, multicenter randomized clinical Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial was conducted between October 1, 2012, and December 31, 2013; the study was terminated October 12, 2015. The study was conducted at 543 academic and community hospitals in 36 countries among 12 092 patients at high risk of CV disease (acute coronary syndrome, stroke, peripheral arterial disease, or type 2 diabetes with coronary artery disease) with measurable Lp(a) and high-sensitivity C-reactive protein (hsCRP) levels during treatment. Statistical analysis for this post hoc analysis was performed from September 26, 2018, to March 28, 2020. INTERVENTIONS: Participants received evacetrapib, 130 mg/d, or matching placebo. MAIN OUTCOMES AND MEASURES: The ACCELERATE trial found no significant benefit or harm of evacetrapib on 30-month major adverse cardiovascular events (CV death, myocardial infarction [MI], stroke, coronary revascularization, or hospitalization for unstable angina). This secondary analysis evaluated rates of CV death, MI, and stroke across levels of Lp(a). RESULTS: High-sensitivity C-reactive protein and Lp(a) levels were measured in 10 503 patients (8135 men; 8561 white; 10 134 received concurrent statins; mean [SD] age, 64.6 [9.4] years). In fully adjusted analyses, in patients with hsCRP of 2 mg/L or more but not less than 2 mg/L, increasing quintiles of Lp(a) were significantly associated with greater rates of death, MI, and stroke (P = .006 for interaction). Each unit increase in log Lp(a) levels was associated with a 13% increased risk of CV death, nonfatal MI, or stroke only in those with hsCRP levels of 2 mg/L or more (P = .008 for interaction). There was also a significant stepwise relationship between increasing Lp(a) quintiles and time to first CV death, MI, or stroke (log-rank P

ObjectivesLipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs.MethodsLipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study.ResultsTreatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated.ConclusionsBaricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications.Trial registration numberNCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.

Background Potent cholesteryl ester transfer protein (CETP) inhibitors have been shown to substantially increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I levels as monotherapy and combined with statins. However, data on the effects of this class of drugs on macrophage cholesterol efflux capacity (CEC), a functional assay that characterizes a key step in the process of reverse cholesterol transport, are limited. Objectives This study assessed the impact of evacetrapib, statins, or combination therapy on CEC. Methods We analyzed samples from 377 subjects with elevated low-density lipoprotein cholesterol (LDL-C) or low HDL-C levels who were enrolled in a phase 2 trial of evacetrapib. Percent changes from baseline in CEC (total, non–ABCA1-, and ABCA1-specific) and HDL subpopulations were evaluated after 12 weeks of treatment with placebo, statin monotherapy, evacetrapib monotherapy, or evacetrapib combined with statins. Pre–beta-1 HDL levels were quantified by immunofixation and nondenaturing 2-dimensional gel electrophoresis (2DGE). Results Relative to placebo, evacetrapib monotherapy increased dose-dependent total and non–ABCA1-specific CEC up to 34% and 47%, respectively. Evacetrapib monotherapy also increased ABCA1-specific CEC up to 26%. Relative to statin monotherapy, evacetrapib with statins also increased total, non–ABCA1-, and ABCA1-specific CEC by 21%, 27%, and 15%, respectively. In contrast, rosuvastatin and simvastatin significantly reduced total and ABCA1-specific CEC, whereas atorvastatin had no significant effect. Consistent with ABCA1-specific CEC, evacetrapib monotherapy and evacetrapib combined with statins significantly increased pre–beta-1 HDL levels as measured by either method. Conclusions Evacetrapib, as monotherapy and combined with statins, not only increased total CEC, but also increased ABCA1-specific CEC and pre–beta-1 HDL. The mechanisms by which potent CETP inhibition increases ABCA1-specific CEC and pre–beta-1 HDL require further study. (A Study of LY2484595 in Patients With High LDL-C or Low HDL-C; NCT01105975 )

Background and aims: The optimal approaches to management of patients treated with moderate statin doses on lipid parameters are unknown. The ACCENTUATE study aimed to compare the effects of adding the cholesteryl ester transfer protein inhibitor (CETP) evacetrapib, ezetimibe or increasing statin dose in atorvastatin-treated high-vascular risk patients on lipid parameters. Methods: 366 patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes were treated with atorvastatin 40 mg/day for 28 days prior to randomization to atorvastatin 40 mg plus evacetrapib 130 mg, atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe 10 mg or atorvastatin 40 mg plus placebo, daily for 90 days at 64 centers in the United States. Lipid parameters, safety and tolerability were measured. Results: Addition of evacetrapib significantly reduced LDL-C (−33%) compared with ezetimibe (−27%, p=0.045), increasing statin dose (−6%) and statin alone (0%, p

Objectives We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib. Methods Healthy volunteers received multiple daily doses of evacetrapib (10–600 mg) administered for up to 15 days in a placebo-controlled study. Key findings Mean peak plasma concentrations of evacetrapib occurred at 4–6 h and terminal half-life ranged 24–44 h. Steady state was achieved at approximately 10 days; all subjects had undetectable levels of evacetrapib 3 weeks after their last dose. The trough inhibition of cholesteryl ester transfer protein (CETP) activity was 65 and 84% at 100 and 300 mg, respectively. At the highest dose (600 mg), evacetrapib significantly inhibited CETP activity (91%), increased HDL-C (87%) and apo AI (42%), and decreased LDL-C (29%) and apo B (26%) relative to placebo. For the highest dose tested, levels of evacetrapib, CETP activity, CETP mass, HDL-C and LDL-C returned to levels at or near baseline after a 2-week washout period. Evacetrapib at the highest dose tested did not produce any significant effect on 24-h ambulatory systolic or diastolic blood pressure. Conclusions Multiple doses of evacetrapib potently inhibited CETP activity, leading to substantial elevations in HDL-C and lowering of LDL-C. Evacetrapib was devoid of clinically relevant effects on blood pressure and mineralocorticoid levels.

The cholesteryl ester transfer protein (CETP) inhibitor evacetrapib has been previously shown to increase high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels, as monotherapy or in combination with statins. In this study, 165 Japanese patients with elevated LDL-C or low HDL-C levels were randomly assigned to receive placebo, evacetrapib monotherapy 30 mg, 100 mg, or 500 mg, atorvastatin 10 mg, or evacetrapib 100 mg in combination with atorvastatin 10 mg. After 12 weeks, evacetrapib monotherapy increased HDL-C levels by 74%, 115%, and 136% and decreased LDL-C levels by 15%, 23%, and 22% and CETP activity by 50%, 83%, and 95% (for the 30-mg, 100-mg, and 500-mg dose groups, respectively) versus placebo. In combination with atorvastatin 10 mg, evacetrapib 100 mg increased HDL-C levels by 103% and decreased LDL-C levels by 15% and CETP activity by 68% versus atorvastatin alone. After a 4- to 6-week washout, HDL-C, LDL-C, and CETP mass and activity returned to baseline levels in the evacetrapib-treated groups, and most patients had evacetrapib concentrations below the quantitation limit. Evacetrapib monotherapy or in combination with atorvastatin was not likely to be associated with any significant change in blood pressure and did not have any adverse effects on mineralocorticoid or glucocorticoid measures. Notably, plasma evacetrapib concentrations were mostly undetectable, and all pharmacodynamic biomarkers (HDL-C and LDL-C levels and CETP mass and activity) returned to baseline after a 4- to 6-week washout. In conclusion, evacetrapib as monotherapy or in combination with atorvastatin effectively decreased CETP activity and LDL-C levels and increased HDL-C levels after 12 weeks in Japanese patients with dyslipidemia.

Aims Fibrate medications weakly stimulate the nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α) and are currently employed clinically in patients with dyslipidaemia. The potent and selective agonist of PPAR-α LY518674 is known to substantially increase apolipoprotein A-I (apoA-I) turnover without major impact on steady-state levels of apoA-I or high-density lipoprotein-cholesterol (HDL-C). We sought to determine whether therapy with a PPAR-α agonist impacts cholesterol efflux capacity, a marker of HDL function. Methods and results Cholesterol efflux capacity was measured at baseline and after 8 weeks of therapy in a randomized, placebo-controlled trial involving participants with metabolic syndrome treated with either LY518674 100 μg daily ( n = 13) or placebo ( n = 15). Efflux capacity assessment was quantified using a previously validated ex vivo assay that measures the ability of apolipoprotein-B depleted plasma to mobilize cholesterol from macrophages. LY518674 led to a 15.7% increase from baseline (95% CI 3.3–28.1%; P = 0.02, P vs. placebo = 0.01) in efflux capacity. The change in apoA-I production rate in the active treatment arm was strongly linked to change in cholesterol efflux capacity ( r = 0.67, P = 0.01). Conclusions Potent stimulation of PPAR-α leads to accelerated turnover of apoA-I and an increase in cholesterol efflux capacity in metabolic syndrome patients despite no change in HDL-C or apoA-I levels. This finding reinforces the notion that changes in HDL-C levels may poorly predict impact on functionality and thus has implications for ongoing pharmacologic efforts to enhance apoA-I metabolism.

Objective To assess the effects of baricitinib on lipid profiles in patients with moderate-to-severe rheumatoid arthritis. Methods Treatment with once-daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4-mg and 8-mg baricitinib groups. Results Treatment with baricitinib resulted in dose-dependent increases in serum lipid levels from baseline to week 12 (low-density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high-density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group-wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A-I, apolipoprotein B, and apolipoprotein CIII were observed with 4-mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8-mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL-associated apolipoprotein CIII (–4.5% with 4-mg baricitinib; –9.0% with 8-mg baricitinib). Baricitinib reduced HDL-associated serum amyloid A when administered at 4 mg (−36.0%) and 8 mg (−32.0%); a significant reduction in lipoprotein (a) was observed only with 8-mg doses (−16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship. Conclusion Baricitinib-associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.

"Several lines of evidence suggest the involvement of infectious agents in the pathogenesis of atherosclerosis. Furthermore, a correlation between infection-driven inflammatory burden and acute manifestation of coronary artery disease has been hypothesized. The aim of this work was to assess whether human herpesvirus (HHV)-6 and HHV-8, two DNA viruses with a distinct tropism for endothelium and lymphocytes, may be associated with coronary instability. An age- and gender-matched cross-sectional study was undertaken in 70 patients with testing of plasma HHV-6 and HHV-8 DNA load in different cardiovascular clinical settings: 29 patients with acute myocardial infarction, 21 patients with stable coronary artery disease, and 20 patients without coronary and carotid artery atherosclerosis subjected to cardiac valve replacement. In all patients, HHV-6 and HHV-8 plasma DNA was tested by using highly sensitive, calibrated quantitative real-time PCR assays which employ a synthetic DNA calibrator to adjust for DNA extraction and amplification efficiency. HHV-8 viremia was undetectable in all three groups. HHV-6 viremia was detected in a substantial fraction of the samples examined (18.6%) without significant differences among the three groups (ST segment elevation myocardial infarction: 17.2%; stable coronary artery disease: 14.3%; patients without coronary and carotid artery atherosclerosis: 25%). Furthermore, no significant differences in plasma HHV-6 load were observed amongst the three groups of patients. These findings indicate that coronary instability is not associated specifically with active HHV-6 or HHV-8 infection. However, an unusually high rate of active HHV-6 infection was documented among patients without atherosclerosis admitted to hospital with cardiac disease. "

Type 2 diabetes is associated with risk of cancer. Hyperinsulinemia and insulin resistance may be the link with cancer, but whether this is independent of the diabetes status, obesity/visceral obesity and metabolic syndrome is uncertain and the present study wanted to address this issue. Fifteen-year all-cause, CVD and cancer mortality data were obtained through the Regional Health Registry in 2,011 out of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes mellitus in Italy in which anthropometric and metabolic characteristics were collected. During the 15-year observation period, 495 deaths were registered: 221 CVD related and 180 cancer related. Age and sex were independently associated with all-cause, cancer and CVD mortality rates. Age- and sex-adjusted analysis showed that HOMA-IR, cigarette smoking and diabetes were independently associated with all-cause mortality; HOMA-IR, systolic blood pressure and fibrinogen were independently associated with CVD mortality; HOMA-IR and smoking habit were independently associated with cancer mortality. Individuals in the highest quintile of serum insulin had a 62% higher risk of cancer mortality (HR = 1.62 95% CI: 1.19-2.20; P

A fatty liver, which is a common feature in insulin-resistant states, can lead to chronic liver disease. It has been hypothesized that a fatty liver can also increase the rates of non-hepatic-related morbidity and mortality. Therefore, we wanted to determine whether the fatty liver index (FLI), a surrogate marker and a validated algorithm derived from the serum triglyceride level, body mass index, waist circumference, and γ-glutamyltransferase level, was associated with the prognosis in a population study. The 15-year all-cause, hepatic-related, cardiovascular disease (CVD), and cancer mortality rates were obtained through the Regional Health Registry in 2011 for 2074 Caucasian middle-aged individuals in the Cremona study, a population study examining the prevalence of diabetes mellitus in Italy. During the 15-year observation period, 495 deaths were registered: 34 were hepatic-related, 221 were CVD-related, 180 were cancer-related, and 60 were attributed to other causes. FLI was independently associated with the hepatic-related deaths (hazard ratio = 1.04, 95% confidence interval = 1.02-1.05, P < 0.0001). Age, sex, FLI, cigarette smoking, and diabetes were independently associated with all-cause mortality. Age, sex, FLI, systolic blood pressure, and fibrinogen were independently associated with CVD mortality; meanwhile, age, sex, FLI, and smoking were independently associated with cancer mortality. FLI correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), a surrogate marker of insulin resistance (Spearman's ρ = 0.57, P < 0.0001), and when HOMA-IR was included in the multivariate analyses, FLI retained its association with hepatic-related mortality but not with all-cause, CVD, and cancer-related mortality. Conclusion: FLI is independently associated with hepatic-related mortality. It is also associated with all-cause, CVD, and cancer mortality rates, but these associations appear to be tightly interconnected with the risk conferred by the correlated insulin-resistant state. © 2011 American Association for the Study of Liver Diseases

ApoE is a polymorphic protein involved in the metabolism of plasma lipoproteins; the e4 allele was shown to be associated with coronary and aortic atherosclerosis in age-dependent fashion mediated by unknown mechanisms. This study was undertaken to assess whether the apoE isoforms in humans were associated with normal glucose tolerance and with metabolic and inflammatory risk factors of CVD. ApoE genotype was assessed in 365 individuals. Of those, 309 were studied in the postabsorptive conditions and 142 of them also underwent a 3h-OGTT; 56 additional subjects were studied by means of the insulin clamp in combination with [6,6-2H2] glucose infusion. ApoE genotype frequencies were similar to those previously reported and were not influenced by age and BMI. Fasting plasma glucose, insulin, FFA, the lipid profile, surrogate markers (HOMA-IR, OGTT-derived index) as well as the clamp-derived parameters or insulin sensitivity and insulin secretion were not different by apoE genotypes. Serum adipokines concentrations (leptin, adiponectin, resistin) and markers of inflammation (serum fasting hsCRP and MCP1/CCL2) were also not different by apoE genotypes. In the subgroup of young e4 carriers which underwent the clamp procedure, a higher fasting endogenous glucose production was detected. ApoE genotype was not associated with insulin resistance or altered insulin secretion, and no abnormalities in the typical circulating endocrine, metabolic, and inflammatory features of the insulin resistance syndrome were detected. © Springer-Verlag 2011

OBJECTIVE Some obese individuals have normal insulin sensitivity. It is controversial whether this phenotype is associated with increased all-cause mortality risk. RESEARCH DESIGN AND METHODS Fifteen-year all-cause mortality data were obtained through the Regional Health Registry for 2,011 of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes in Italy. Individuals were divided in four categories according to BMI (nonobese: RESULTS Obese insulin-sensitive subjects represented 11% (95% CI 8.1–14.5) of the obese population. This phenotype had similar BMI but lower waist circumference, blood pressure, fasting glucose, triglycerides, and fibrinogen and higher HDL cholesterol than obese insulin-resistant subjects. In the 15-year follow-up, 495 deaths (cardiovascular disease [CVD]: n = 221; cancer: n = 180) occurred. All-cause mortality adjusted for age and sex was higher in the obese insulin-resistant subjects (hazard ratio 1.40 [95% CI 1.08–1.81], P = 0.01) but not in the obese insulin-sensitive subjects (0.99 [0.46–2.11], P = 0.97) when compared with nonobese insulin-sensitive subjects. Also, mortality for CVD and cancer was higher in the obese insulin-resistant subjects but not in the obese insulin-sensitive subjects when compared with nonobese insulin-sensitive subjects. CONCLUSIONS In contrast to obese insulin-resistant subjects, metabolically healthy obese individuals are less common than previously thought and do not show increased all-cause, cancer, and CVD mortality risks in a 15-year follow-up study.

Steven E. Nissen, Sreekumar G. Pillai, Stephen J. Nicholls, KathyWolski, Jeffrey S. Riesmeyer, Govinda J.Weerakkody, WendraM. Foster, Ellen McErlean, Lin Li, Pallav Bhatnagar, Giacomo Ruotolo, A. Michael Lincoff

It remains unknown whether the factors associated with major adverse cardiovascular events (MACE) in the contemporary setting of statin therapy for high vascular risk patients differ, according to gender. The ACCELERATE trial compared the effects of evacetrapib and placebo on MACE (cardiovascular

Increasing insights have supported the role of inflammation in progression of atherosclerotic cardiovascular disease. Numerous reports have suggested that levels of the neutrophil to lymphocyte ratio (NLR), a simple and inexpensive measure, may associate with major adverse cardiovascular outcomes

The purpose of this study was to test the hypothesis that specific epicardial adipose tissue (EAT) proinflammatory adipokines might be implicated in acute coronary syndrome (ACS). We compared expression and protein secretion of several EAT adipokines of male ACS with those of matched stable coronary artery disease (CAD) patients and controls with angiographically normal coronary arteries. The effect of supernatant of cultured EAT on endothelial cell permeability in vitro was also evaluated in the three study groups. EAT of ACS patients showed significantly higher gene expression and protein secretion of resistin than patients with stable CAD. Interleukin-6, plasminogen activator inhibitor-1, and monocyte chemoattractant protein-1 genes were also significantly overexpressed in ACS compared with the control group but not when compared with stable CAD. Immunofluorescence of EAT sections revealed a significantly greater number of CD68+cells in ACS patients than stable CAD and control groups. The permeability of endothelial cells in vitro was significantly increased after exposure to supernatant of cultured EAT from ACS, but not control or stable CAD groups, and this effect was normalized by anti-resistin antiserum. We found that EAT of patients with ACS is characterized by increased expression and secretion of resistin and associated with increased in vitro endothelial cell permeability.

AIMS/HYPOTHESIS: We aimed to investigate the risk of cancer mortality in relation to the glucose tolerance status classified according to the 2 h OGTT. METHODS: Data from 17 European population-based or occupational cohorts involved in the DECODE study comprising 26,460 men and 18,195 women aged 25-90 years were collaboratively analysed. The cohorts were recruited between 1966 and 2004 and followed for 5.9 to 36.8 years. Cox proportional hazards analysis with adjustment for cohort, age, BMI, total cholesterol, blood pressure and smoking status was used to estimate HRs for cancer mortality. RESULTS: Compared with people in the normal glucose category, multivariable adjusted HRs (95% CI) for cancer mortality were 1.13 (1.00, 1.28), 1.27 (1.02, 1.57) and 1.71 (1.35, 2.17) in men with prediabetes, previously undiagnosed diabetes and known diabetes, respectively; in women they were 1.11 (0.94, 1.30), 1.31 (1.00, 1.70) and 1.43 (1.01, 2.02), respectively. Significant increases in deaths from cancer of the stomach, colon-rectum and liver in men with prediabetes and diabetes, and deaths from cancers of the liver and pancreas in women with diabetes were also observed. In individuals without known diabetes, the HR (95% CI) for cancer mortality corresponding to a one standard deviation increase in fasting plasma glucose was 1.06 (1.02, 1.09) and in 2 h plasma glucose was 1.07 (1.03, 1.11). CONCLUSIONS/INTERPRETATION: Diabetes and prediabetes were associated with an increased risk of cancer death, particularly death from liver cancer. Mortality from all cancers rose linearly with increasing glucose concentrations.

Neuroendocrine/inflammatory and endothelial functions have been indicated as crucial for heart failure (HF) patients. We evaluated relation in HF patients among cytokines and asymmetric dimethylarginine (ADMA) and left ventricular ejection fraction (LVEF) at baseline and after long-term administration of carvedilol. Interleukin 10 (IL-10), interleukin 18 (IL-18), and ADMA were measured in 22 NYHA class II to IV HF patients at baseline and after 40 +/- 14 months of carvedilol treatment. Patients were divided into 2 groups according to whether, after treatment with carvedilol, LVEF had increased at least 5% (responders) or less than 5% (non-responders). In responders (11 of 22 patients), LVEF increased from 38 +/- 6% to 50 +/- 7%, (P < 0.001); in non-responders, it decreased from 36 +/- 9% to 31 +/- 6%, (P = 0.02); NYHA class significantly decreased in both groups. IL-18 decreased in responders (from 586.4 +/- 128 to 183.13 +/- 64.4 pg/mL; P < 0.001) and in non-responders (from 529.3 +/- 116.25 to 142.4 +/- 58.9 pg/mL; P < 0.001). IL-10 increased in responders (from 0.49 +/- 0.25 to 2.01 +/- 1.01 pg/mL; P < 0.001) and in non-responders (from 0.64 +/- 0.31 to 1.33 +/- 0.59 pg/mL; P < 0.001). Conversely, ADMA levels decreased only in responders (from 0.67 +/- 0.16 to 0.44 +/- 0.15 micromol/L; P < 0.001), and an inverse correlation was observed between basal ADMA levels and changes in LVEF after treatment. In HF patients, carvedilol appears to reduce symptoms and the expression of inflammation, regardless of the LV functional response. In those patients showing improvement of LVEF, the reduction of inflammation is paralleled by a reduction of ADMA. We surmise that carvedilol could be effective at various independent levels as a result of possible pleiotropic effects of this agent.

To evaluate whether the metabolic syndrome (MetS) defined by the International Diabetes Federation (IDF) criteria, which has abdominal adiposity as a mandatory element, predicts cardiovascular disease (CVD) mortality better than the cluster of other IDF-defined abnormalities not including abdominal adiposity.Data from nine European population-based studies, including 7782 men and 7739 women (aged 30-89 years), with a median follow-up of 8.55 years, were jointly analyzed. Hazard ratios for CVD mortality were calculated with Cox regression models.In total, 41% of the men and 38% of the women had the IDF MetS. Individuals with the IDF MetS were by definition more obese and had a higher prevalence of diabetes than non-obese subjects withor = 2 IDF abnormalities; whereas non-obese men withor = 3 factors had more atherogenic lipid profiles. Multivariate adjusted hazard ratio for CVD death in men and women with the IDF MetS was 2.44 (1.69-2.98) and 2.32 (1.27-4.23); in non-obese men with 2 andor = 3 factors the hazard ratio was 1.60 (1.12-2.30) and 2.44 (1.62-3.66), respectively, and in non-obese women with 2 factors the hazard ratio was 2.41 (1.09-5.33).The cluster of the CVD risk factors predicted CVD mortality regardless of the presence or absence of the abdominal adiposity. Inclusion of abdominal adiposity as a prerequisite will miss those non-obese individuals who have increased CVD mortality.

Background: Although more frequent in diabetic patients, restenosis after percutaneous coronary intervention (PCI) is less common in those with good glycemic control. High circulating insulin levels may also be associated with more frequent restenosis. Methods: Fasting blood samples were obtained from 162 diabetic patients immediately prior to the PCI and analyzed for glucose, hemoglobin A1C, and insulin. Nine-month follow-up information was obtained in 145 (89.5%) patients. Target vessel revascularization (TVR) was the surrogate for restenosis. Results: Patients were divided into quartiles with regard to their blood levels. Insulin, calculated insulin resistance, and hemoglobin A1C were not associated with increased TVR rates. Glucose level was significantly associated (P=.02). Patients in the two lower quartiles (glucose V128 mg/dl) had a 9-month TVR rate of 12.7% while those in the two higher quartiles (N128 mg/dl) had a rate of 33.8% (P=.005). Level of glucose was independent of hemoglobin A1C. In patients whose A1C level was V7%, the TVR rate was greater in those with a glucose level N128 mg/dl (39.1% vs. 10.6%, P=.009). Similarly, in patients with a hemoglobin A1C level N7%, the TVR rate was lower in patients with a glucose level V128 mg/dl, but this difference did not reach statistical significance (16.6% vs. 31.3%, P=.3). Conclusions: Hemoglobin A1C, insulin, and insulin resistance at the time of the PCI are not associated with restenosis. Periprocedural hyperglycemia may promote restenosis in diabetics.

Background Potent CETP inhibitors reduce plasma concentrations of atherogenic lipoprotein biomarkers of cardiovascular risk. Objectives To evaluate the effects of the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, as monotherapy or with statins, on atherogenic apolipoprotein B (apoB)–containing lipoproteins in mildly hypercholesterolemic patients. Methods VLDL and LDL particle concentrations and sizes (using nuclear magnetic resonance spectroscopy) and lipoprotein(a) concentration (using nephelometry) were measured at baseline and week 12 in a placebo-controlled trial of 393 patients treated with evacetrapib as monotherapy (30 mg/d, 100 mg/d, or 500 mg/d) or in combination with statins (100 mg plus simvastatin 40 mg/d, atorvastatin 20 mg/d, or rosuvastatin 10 mg/d; Clinicaltrials.gov Identifier: NCT01105975). Results Evacetrapib monotherapy resulted in significant placebo-adjusted dose-dependent decreases from baseline in Lp(a) (up to −40% with evacetrapib 500 mg), total LDL particle (LDL-P) (up to −54%), and small LDL particle (sLDL) (up to −95%) concentrations. Compared to statin alone, coadministration of evacetrapib and statins also resulted in significant reduction from baseline in Lp(a) (−31%), LDL-P (−22%), and sLDL (−60%) concentrations. The percentage of patients with concentrations above optimal concentrations for LDL-P (>1000 nmol/L) and sLDL (>600 nmol/L) decreased from 88% and 55% at baseline, respectively, to 20% and 12% at week 12, for patients treated with evacetrapib plus statins. Evacetrapib, alone or with statins, significantly increased LDL-P size. Conclusions Evacetrapib, as monotherapy or with statins, significantly reduces the concentrations of atherogenic apoB-containing lipoproteins, including Lp(a), LDL-P, and sLDL.

Dietary factors influence the development of cardiovascular disease (CVD). The diet of Alaskan Eskimos differs from that of other populations. We surveyed Eskimo adults in Northwest Alaska to document their usual dietary intakes, differences based on gender and age, and sources of selected nutrients, and to generate appropriate dietary advice to reduce CVD. Interviewers surveyed 850 men and women 17-92 y old, using a quantitative food-frequency instrument. We observed many significant (chi(2) analysis P < 0.05) differences in nutrient intakes among 3 age-groups. Energy intake from carbohydrate was negatively related to participant age-group (P < or = 0.01). Energy intake from all fats (P < 0.001) and polyunsaturated fat (P < or = 0.01) was positively related to age-group among both men and women in contrast to other studies in which age differences were either not observed or decreased with age. Native foods were major sources of monounsaturated and polyunsaturated fats, including 56% of (n-3) fatty acids primarily from seal oil and salmon. However, Native foods contributed significantly less to the diets of young adults than to those of elders, especially among women. Store-bought foods were the main sources of energy, carbohydrate, fat, saturated fat, and fiber for all adults. Based on their nutrient density and potential to inhibit CVD, continued consumption of traditional foods is recommended. Variations in intake by age may portend changing eating patterns that will influence CVD as participants age. These data will contribute to understanding dietary risk factors for cardiovascular disease in this population.

The primary dyslipidemia related to obesity is characterized by increased triglycerides, decreased HDL levels, and abnormal LDL composition. Much work has been done to elucidate the pathogenesis of the dyslipidemia of obesity, which seems to be closely related to insulin resistance in obese individuals; however, more studies in humans are needed to further understand the metabolic mechanisms underlying the changes, and to distinguish between the roles of insulin resistance and body fat in the lipoprotein changes. The dyslipidemia associated with obesity no doubt plays a major role in the development of atherosclerosis and CVD in obese individuals. All of the components of the dyslipidemia, including higher triglycerides, decreased HDL levels, and increased small, dense LDL particles, have been shown to be atherogenic. Weight loss and exercise, even if they do not result in normalization of body weight, can improve this dyslipidemia and thus reduce CVD risk. In addition, obese individuals should be targeted for intense lipid-lowering therapy, when necessary.