Atherosclerotic Cardiovascular Disease Risk In Patients Research Articles

ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses?

Hypertriglyceridemia (HTG) is an independent and casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with HTG. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are key regulators of triglyceride-rich lipoprotein (TRL) metabolism. We review recent clinical trials targeting ANGPTL3 and apoC-III with monoclonal antibody and nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. ANGPTL3 and apoC-III inhibitors are effective in lowering plasma triglycerides and TRLs, with possibly greater efficacy with the inhibition of apoC-III. By contrast to ANGPTL3 inhibition that has the advantage of greater lowering of plasma low-density lipoprotein (LDL)-cholesterol and apoB levels, apoC-III inhibition only has a modest or no effect in lowering plasma LDL-cholesterol and apoB concentrations. Therapeutic inhibition of ANGPTL3 and apoC-III can correct HTG possibly by reducing production and increasing catabolism of TRL particles, but this remains to be formally investigated in patients with HTG. Novel agents targeting ANGPTL3 and apoC-III can correct HTG and potentially lower risk of ASCVD in patients with HTG. The long-term safety and cost-effectiveness of these agents await confirmation in ongoing and future studies.

The effect of rosuvastatin alone or in combination with fenofibrate or omega-3 fatty acids on lipoprotein(a) levels in patients with mixed hyperlipidemia.

Lipoprotein(a) [Lp(a)] is a strong, genetically determined, pathogenetic factor of atherosclerotic cardiovascular disease (ASCVD). The aim of this post-hoc analysis was to compare the effect of hypolipidemic treatment on Lp(a) levels of patients with mixed hyperlipidemia. We previously randomized patients with mixed hyperlipidemia (low-density lipoprotein [LDL-C] > 160 mg/dl and triglycerides > 200 mg/dl) to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or omega-3 fatty acids 2 g/day (RΩ group, n = 30). In the present post-hoc analysis, we included only the patients whose Lp(a) levels were assessed (16, 16 and 15 in the R, RF and RΩ groups, respectively). Lipid profile and Lp(a) were measured at baseline and after 3 months of treatment. Significant reductions in total cholesterol, LDL-C, non-high-density lipoprotein-cholesterol (non-HDL-C) and triglyceride levels were observed in all groups. A significant increase in Lp(a) levels was noted in the R (p = 0.017) and RF (p = 0.029) groups, while no significant difference was seen in the RΩ group (p = NS). Regarding Lp(a) elevations, no differences were found between groups. In the R group, a strong negative correlation between the changes in Lp(a) and LDL-C (r = -0.500, p = 0.049) was observed, while a significant negative correlation between the changes in Lp(a) and triglycerides (r = -0.531, p = 0.034) was noted in the RF group. Rosuvastatin and/or fenofibrate treatment increases Lp(a) levels in patients with mixed hyperlipidemia. Novel therapies should target Lp(a) level reduction to decrease the residual ASCVD risk in patients with mixed hyperlipidemia.

Association Between Use of Sodium-Glucose Cotransporter-2 Inhibitors or Angiotensin Receptor-Neprilysin Inhibitor and the Risk of Atherosclerotic Cardiovascular Disease With Coexisting Diabetes and Heart Failure.

This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications. This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy. The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure. The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions.

Abstract 17120: ARO-ANG3, an Investigational RNAi Therapeutic, Silences the Expression of ANGPTL3 and Decreases Atherogenic Lipoproteins in Patients With Mixed Dyslipidemia: ARCHES-2 Study Results

Background: Angiopoietin-like protein 3 (ANGPTL3) regulates lipoprotein metabolism by inhibiting lipoprotein and endothelial lipases. ANGPTL3 loss-of-function carriers have decreased circulating triglycerides (TGs), LDL-C, and HDL-C, and a lower risk of atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an investigational RNAi therapeutic designed to inhibit hepatic ANGPTL3 expression and reduce atherogenic lipoproteins. Aim: We report end-of-study results (data cutoff 09 December 2022) from ARCHES-2, a Phase 2b double-blind, placebo (pbo)-controlled study (NCT04832971) to evaluate the safety and efficacy of ARO-ANG3 in adults with mixed dyslipidemia (MD). Methods: Patients with fasting TGs 150-499 mg/dL and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL were randomized to receive 50 mg, 100 mg or 200 mg ARO-ANG3 or pbo by subcutaneous injections on Day 1 and Week 12. Patients were on a stable diet and optimal lipid-lowering therapies. The primary endpoint was the percent change in TGs from baseline at Week 24. Liver fat was assessed at baseline and Week 24 in a subset of patients with hepatic steatosis. Mixed models repeated measures was used for statistical analyses. Results: At Week 24, ARO-ANG3 decreased ANGPTL3 (up to 77%), TGs (up to 56%), remnant cholesterol (up to 56%), and apolipoprotein B (apoB) (up to 20%). Other lipoproteins including LDL-C, non-HDL-C, lipoprotein(a) and HDL-C were also decreased. Liver fat decreased similarly in ARO-ANG3 and pbo groups. TEAEs were consistent with those expected in this patient population and with associated underlying comorbidities. Conclusions: ARCHES-2 data demonstrate ARO-ANG3 efficacy by significantly lowering ANGPTL3 and atherogenic triglyceride-rich lipoproteins (TRLs), LDL and total apoB in patients with MD. The favorable changes in serum lipids and lipoproteins and safety profile support the potential of ARO-ANG3 to treat residual ASCVD risk in patients with elevated TRLs not at LDL-C goal.

Impact of anthropometric parameters on outcomes in Asians with metabolic dysfunction-associated fatty liver disease.

We examined the incidence and predictors of clinical outcomes in metabolic dysfunction-associated fatty liver disease (MAFLD), focusing on anthropometric parameters. Adult patients with MAFLD were identified in nationwide databases and a hospital cohort. Primary endpoints were atherosclerotic cardiovascular disease (ASCVD) and advanced fibrosis. Logistic and Cox regression analyses were used to analyse the association between anthropometric parameters and endpoints. In total, 4407 of 15256 (28.9%) and 6274 of 25784 subjects (24.3%) had MAFLD in the nationwide database; of these, 403 (9.2%) and 437 (7.0%) subjects were of lean/normal weight, respectively. Compared to the overweight/obese group, the lean/normal weight group had a significantly lower muscle mass (15.0 vs. 18.9kg) and handgrip strength (31.9 vs. 35.1kg) and had a higher ASCVD risk (9.0% vs. 6.3% and 15.9% vs. 8.5%; Ps<0.001). Sarcopenia (odds ratio [OR], 6.66; 95% confidence interval [CI], 1.79-24.80) and handgrip strength (OR, 0.92; 95% CI, 0.86-0.97; Ps=0.005) were associated with the ASCVD risk in the lean/normal weight group. In a hospital cohort (n=1363), the ASCVD risk was significantly higher in the lean/normal weight group than in the overweight/obese group (median follow-up, 39.1months). Muscle mass was inversely correlated with the ASCVD risk (hazard ratio [HR], 0.72; 95% CI, 0.56-0.94), while visceral adiposity was associated with advanced fibrosis (HR, 1.36; 95% CI, 1.10-1.69; Ps<0.05). Muscle mass/strength was significantly associated with the ASCVD risk in patients with MAFLD. Visceral adiposity was an independent predictor of advanced fibrosis.

LDL Cholesterol Variability Impacts the Prognosis of Patients with Chronic Ischemic Heart Disease: A Real-World Italian Experience.

Epidemiologic, genetic, and clinical intervention studies have indisputably shown that low-density lipoprotein cholesterol (LDL-C) is causal in the development of atherosclerotic cardiovascular disease (ASCVD). However, LDL-C variability could be related to increased ASCVD risk in patients already treated with statins. The aim of the present retrospective real-life study was to assess the prognostic impact of LDL-C variability on all-cause mortality and cardiovascular hospitalizations in patients with stable cardiovascular artery disease. A total of 3398 patients were enrolled and followed up for a median of 56 months. Considering LDL-C < 70 mg/dL as the therapeutical target, during follow-up, the percentage of patients who achieved this goal raised from 20.7% to 31.9%. In total, 1988 events were recorded, of which 428 were all-cause deaths and 1560 were cardiovascular hospitalizations. At the last medical examination, each increase in LDL-C levels of 20 mg/dL corresponded to a 6% raise in the risk of any event (HR 1.06; 95%CI, 1.03 to 1.09). In conclusion, our real-world study supports the hypothesis that a continuous and progressive downward trend in LDL-C levels is needed to achieve and maintain a cardiovascular benefit, at least in secondary prevention.

Apolipoprotein B compared with low-density lipoprotein cholesterol in the atherosclerotic cardiovascular diseases risk assessment

The subendothelial retention of apolipoprotein B (apoB)-containing lipoproteins is a critical step in the initiation of pro-atherosclerotic processes. Recent genetic and clinical evidence strongly supports the concept that the lipid content of the particles is secondary to the number of circulating atherogenic particles that are trapped within the arterial lumen. Since each low-density lipoproteins (LDL) particle contains one apoB molecule, as do intermediate density lipoprotein (IDL) and very low-density lipoprotein (VLDL) particles, apoB level represents the total number of atherogenic lipoproteins, which is independent of particle density, and not affected by the heterogeneity of particle cholesterol content (clinically evaluated by LDL-cholesterol level). From this perspective, apoB is proposed as a better proxy to LDL-cholesterol for assessing atherosclerotic cardiovascular disease risk, especially in specific subgroups of patients, including subjects with diabetes mellitus, with multiple cardiometabolic risk factors (obesity, metabolic syndrome, insulin resistance, and hypertension) and with high triglyceride levels and very low LDL-cholesterol levels. Therefore, given the causal role of LDL-cholesterol in atherosclerotic cardiovascular disease (ASCVD) development, routine measurement of both LDL-cholesterol and apoB is of utmost importance to properly estimate global cardiovascular risk and to determine the 'residual' risk of ASCVD in patients receiving therapy, as well as to monitor therapeutic effectiveness.

Normal-weight visceral obesity promotes a higher 10-year atherosclerotic cardiovascular disease risk in patients with type 2 diabetes mellitus–a multicenter study in China

BackgroundVisceral obesity is associated with high cardiovascular events risk in type 2 diabetes mellitus (T2DM). Whether normal-weight visceral obesity will pose a higher atherosclerotic cardiovascular disease (ASCVD) risk than body mass index (BMI)-defined overweight or obese counterparts with or without visceral obesity remains unclear. We aimed to explore the relationship between general obesity and visceral obesity and 10-year ASCVD risk in patients with T2DM.MethodsPatients with T2DM (6997) who satisfied the requirements for inclusion were enrolled. Patients were considered to have normal weight when 18.5 kg/m2 ≤ BMI < 24 kg/m2; overweight when 24 kg/m2 ≤ BMI < 28 kg/m2; and obesity when BMI ≥ 28 kg/m2. Visceral obesity was defined as a visceral fat area (VFA) ≥ 100 cm2. Patients were separated into six groups based on BMI and VFA. The odd ratios (OR) for a high 10-year ASCVD risk for different combinations of BMI and VFA were analysed using stepwise logistic regression. Receiver operating characteristic (ROC) curves for diagnosing the high 10-year ASCVD risk were constructed, and areas under the ROC curves were estimated. Potential non-linear relationships between VFA levels and high 10-year ASCVD risk were examined using restricted cubic splines (knot = 4). Multilinear regression was used to identify factors affecting VFA in patients with T2DM.ResultsIn patients with T2DM, subjects with normal-weight visceral obesity had the highest 10-year ASCVD risk among the six groups, which had more than a 2-fold or 3-fold higher OR than those who were overweight or obese according to BMI but did not have visceral obesity (all P < 0.05). The VFA threshold for high 10-year ASCVD risk was 90 cm2. Multilinear regression showed significant differences in the effect of age, hypertension, drinking, fasting serum insulin, fasting plasma glucose, 2 h postprandial C-peptide, triglyceride, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol on VFA in patients with T2DM (all P < 0.05).ConclusionsT2DM patients with normal-weight visceral obesity had a higher 10-year ASCVD risk than BMI-defined overweight or obese counterparts with or without visceral obesity, which should initiate standardised management for ASCVD primary prevention.

Chronic Pancreatitis and Risk of Atherosclerotic Cardiovascular Disease: A US Cohort Propensity-Matched Study.

Worldwide prevalence of chronic pancreatitis (CP) has risen in recent years, with data suggesting an increased risk of atherosclerotic cardiovascular disease (ASCVD) in these patients. We assessed the incidence and risk of ASCVD in patients with CP. We compared the risk of ischemic heart disease, cerebrovascular accident, and peripheral arterial disease between CP and non-CP cohorts after propensity matching of known risk factors of ASCVD using TriNetX, a multi-institutional database. We also evaluated the risk of outcomes of ischemic heart disease including acute coronary syndrome, heart failure, cardiac arrest, and all-cause mortality between CP and non-CP cohorts. Chronic pancreatitis cohort was also found to have an increased risk of ischemic heart disease (adjusted odds ratio [aOR], 1.08; 95% confidence interval [CI], 1.03-1.12), cerebrovascular accident (aOR, 1.12; 95% CI, 1.05-1.20), and peripheral arterial disease (aOR, 1.17; 95% CI, 1.1-1.24). Chronic pancreatitis patients with ischemic heart disease were also found to have an increased risk of acute coronary syndrome (aOR, 1.16; 95% CI, 1.04-1.30), cardiac arrest (aOR, 1.24; 95% CI, 1.01-1.53), and mortality (aOR, 1.60; 95% CI, 1.45-1.77). Chronic pancreatitis patients are at a higher risk of ASCVD when compared with the general population, matched for confounding etiological, pharmacological, and comorbid variables.

Relation of coronary calcium scoring with cardiovascular events in patients with diabetes: The CLARIFY Registry

IntroductionCoronary artery calcium (CAC) scoring is not routinely performed in patients with diabetes based on an existing class I indication for statin therapy in these patients. However, CAC scoring may improve risk classification and prediction of atherosclerotic cardiovascular disease (ASCVD) events beyond risk scores in asymptomatic individuals with prediabetes and diabetes, warranting CAC assessment in this population. The routine availability through provision of no-charge CAC as an alternative to routine probabilistic risk scores may improve utilization of preventive therapies especially in traditionally underserved populations. MethodsProspective observational study in a large health system offering no-charge CAC scoring for primary prevention risk prediction with available glycosylated hemoglobin (HbA1c) measurements between June 2015 and March 2019 were divided according to no diabetes (HbA1c <5.7 %), prediabetes (HbA1c 5.7 %–6.4 %), or diabetes (HbA1c ≥ 6.5 % or charted history) and followed for major adverse cardiovascular events [myocardial infarction, stroke, death (MACE) or coronary revascularization]. Patient characteristics, health history, laboratory data, and statin prescription rates were measured at baseline and at one year after CAC scoring. ResultsA total of 12,194 subjects with available HbA1c underwent CAC scoring during the study period (6462 diabetes, 2062 prediabetes, and 3670 without diabetes). At a median follow-up of 1.2 years, there were 458 MACE events (71 patients without diabetes, 66 patients with prediabetes, and 321 patients with diabetes). Among patients with diabetes or prediabetes, increased CAC was associated with MACE (HR 1.38 [1.26–1.51], p < 0.001) and MACE or revascularization (HR 1.70 [1.57–1.85], p < 0.001). In patients with diabetes, CAC category was associated with greater statin initiation (89.6 % for CAC≥400 vs 60.1 % for CAC = 0, p < 0.001) and high intensity statin initiation (42.2 % for CAC≥400 vs 16.8 % for CAC = 0, p < 0.001) at one year post CAC scoring. Patients with diabetes had greater reductions in systolic blood pressure, LDL-C, total cholesterol, and triglycerides from baseline with a CAC ≥400 compared to a lower CAC category (p = 0.007). ConclusionsCAC burden is associated with ASCVD risk in patients with diabetes. CAC scoring increases statin prescriptions and reduces ASCVD risk in patients with diabetes, potentially warranting routine CAC assessment in this population.

GLP-1 Receptor Agonists in the Treatment of Patients with Type 2 Diabetes and Chronic Kidney Disease

Diabetic kidney disease (DKD) represents an important diabetes (DM) complication associated with significant impacts on morbidity, mortality, and quality of life. Recent evidence from cardiovascular and kidney outcome trials has dramatically impacted the standard of care for patients with DKD. While agents from the glucagon-like peptide-1 (GLP-1) receptor agonist class are known for their atherosclerotic cardiovascular disease (ASCVD) benefits, growing mechanistic and clinical evidence supports the benefit of GLP-1 receptor agonist therapy on progression of DKD. GLP-1 receptor activation is associated with anti-inflammatory and antifibrotic effects in the kidney, providing a plausible mechanism for kidney protection. Based on currently available clinical trial evidence, guidelines recommend the use of GLP-1 receptor agonists to mitigate ASCVD risk in patients with type 2 diabetes (T2D). Furthermore, based on secondary outcome data for kidney disease, GLP-1 receptor agonists are recommended as an option to mitigate kidney and ASCVD risk in patients with T2D and DKD who require intensification of glycemic control or for those who cannot take a sodium-glucose cotransporter-2 (SGLT2) inhibitor due to side effects or advanced stage DKD. Ongoing dedicated kidney disease outcome trials will further inform the role of GLP-1 receptor agonists in DKD management. This review discusses current considerations for GLP-1 receptor agonist use in patients with T2D and DKD.

Evaluation of coronary stenosis versus plaque burden for atherosclerotic cardiovascular disease risk assessment and management.

To provide a summary of recent literature on the relative impact of luminal stenosis versus atherosclerotic plaque burden in atherosclerotic cardiovascular disease (ASCVD) risk stratification and management. Recent results from both randomized controlled clinical trials as well as observational cohort studies have demonstrated that ASCVD risk is mediated mainly by the extent of atherosclerotic disease burden rather than by the presence of coronary stenosis or inducible ischemia. Although patients with obstructive CAD are generally at higher risk for ASCVD events than patients with nonobstructive CAD, this is driven by a higher plaque burden in those with obstructive CAD. Accordingly, the ASCVD risk for a given plaque burden is similar in patients with and without obstructive CAD. Accompanying these observations are randomized controlled trial data, which show that optimization of medical therapy instead of early revascularization is most important for improving prognosis in patients with stable obstructive CAD. Emerging evidence shows that atherosclerotic plaque burden, and not stenosis per se, is the main driver of ASCVD risk in patients with CAD. This information challenges the current paradigm of selecting patients for intensive secondary prevention measures based primarily on the presence of obstructive CAD.

Umbrella Review on Non-Statin Lipid-Lowering Therapy.

The main aim of this review was to summarize current evidence on approved and emerging non-statin lipid-lowering therapies. Recent literature on U.S. FDA approved non-statin lipid-lowering therapies and evolving lipid-lowering drugs currently under development was reviewed. In the past 20 years, the emergence of non-statin cholesterol-lowering drugs has changed the landscape of dyslipidemia management. Food and Drug Administration approval of non-statin lipid-lowering therapies such as ezetimibe, proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab), bempedoic acid and combination of bempedoic acid and ezetimibe, evinacumab and other triglyceride-lowering agents (eg, icosapent ethyl) has emerged. The European Commission has also recently approved inclisiran for treatment of hypercholesterolemia and mixed hypercholesterolemia even though FDA has put the approval of this drug on hold. Recent guidelines have incorporated PCSK9 inhibitors to treat patients with primary hyperlipidemia and patients with very high-risk ASCVD, who could not achieve adequate lipid-lowering with combination therapy of maximally tolerated statin and ezetimibe. Icosapent ethyl use as an adjunct therapy to statins is also recommended to reduce the risk of ASCVD in patients with hypertriglyceridemia. Despite cost limitations, the uptake of PCSK9 inhibitors is increasing. Approval of bempedoic acid alone or in combination with ezetimibe has provided additional oral lipid-lowering drug alternatives to ezetimibe. Various lipid-lowering drug targets are under investigation.

Hypertriglyceridemia: new approaches in management and treatment.

Hypertriglyceridemia (HTG), a form of dyslipidemia characterized by elevated plasma of triglycerides (TG), is associated with an increased risk for acute pancreatitis. Moreover, HTG has recently been shown to be linked to the development of atherosclerotic cardiovascular disease (ASCVD); therefore, there is a great interest in better understanding the pathophysiology of HTG and improving its clinical management. In this review, we briefly describe TG metabolism, recent guidelines for the clinical management of HTG and provide an overview of the current and potential new therapies for HTG. Screening patients for HTG is valuable for not only identifying patients with extreme TG elevations, who are at risk for pancreatitis, but also for managing ASCVD risk in patients with more moderate forms of HTG. Therefore, the most recent USA guidelines for cardiovascular diseases recommend using TG as a risk enhancer test, leading to a more aggressive treatment of patients with intermediate risk. Currently, there are several available approaches for reducing plasma TG, which include lifestyle changes, fibrates and omega-3 fatty acid treatment. The addition of eicosapentaenoic acid (EPA) on top of statins has recently been shown to significantly reduce ASCVD events. Nevertheless, there is an unmet need for more effective treatment options. Several new therapies based on newly identified targets in TG metabolism, such as apolipoprotein C-III and angiopoietin-like 3 protein, are currently under development. The clinical management of HTG is important in the prevention and treatment of acute pancreatitis and also impacts on how ASCVD risk is managed. More work needs to be done to establish the mechanism for the ability of how EPA lowers ASCVD and how to best integrate it with other lipid-lowering therapies. The efficacy and safety of the novel therapies for HTG should be established soon in the ongoing late-stage clinical trials.

Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in Apoe\u2212/\u2212 Mice

ObjectiveIncreased myelopoiesis has been linked to risk of atherosclerotic cardiovascular disease (ACD). Excessive myelopoiesis can be driven by dyslipidemia and cholesterol accumulation in hematopoietic stem and progenitor cells (HSPC) and may involve increased signaling via Janus kinase 2 (JAK2). Constitutively activating JAK2 mutants drive biased myelopoiesis and promote development of myeloproliferative neoplasms (MPN) or clonal hematopoiesis, conditions associated with increased risk of ACD. JAK2 inhibitors have been developed as a therapy for MPNs. The potential for JAK2 inhibitors to protect against atherosclerosis has not been tested. We therefore assessed the impact of JAK2 inhibition on atherogenesis.MethodsA selective JAK2 inhibitor TG101348 (fedratinib) or vehicle was given to high-fat high-cholesterol Western diet (WD)–fed wild-type (WT) or Apoe−/− mice. Hematopoietic cell profiles, cell proliferation, and atherosclerosis in WT or Apoe−/− mice were assessed.ResultsTG101348 selectively reversed neutrophilia, monocytosis, HSPC, and granulocyte-macrophage progenitor (GMP) expansion in Apoe−/− mice with decreased cellular phosphorylated STAT5 and ERK1/2 and reduced cell cycling and BrdU incorporation in HSPCs, indicating inhibition of JAK/STAT signaling and cell proliferation. Ten-week WD feeding allowed the development of marked aortic atherosclerosis in Apoe−/− mice which was substantially reduced by TG101348.ConclusionsSelective JAK2 inhibition reduces atherogenesis by suppressing excessive myelopoiesis in hypercholesterolemic Apoe−/− mice. These findings suggest selective JAK2 inhibition as a potential therapeutic approach to decrease ACD risk in patients with increased myelopoiesis and leukocytosis.

Cardiovascular Consequences of Autoimmune Rheumatic Diseases

The increased risk of cardiovascular disease (CVD) among patients with autoimmune rheumatic diseases such as rheumatoid arthritis, spondyloarthritis and systemic lupus erythematosus has been extensively documented. Sub-clinical atherosclerosis can be assessed using various non-invasive imaging techniques. However, the mechanisms underlying the higher risk of atherosclerotic CVD in patients with autoimmune rheumatic diseases are not fully known, although they seem to include chronic low-grade systemic inflammation leading to prolonged endothelial activation, accompanied by a pro-thrombotic/pro-coagulant and autoantibody state. Furthermore, sub-clinical atherosclerosis is also influenced by other traditional risk factors for CVD. Including the individual components of the metabolic syndrome (MetS: obesity, impaired glucose metabolism, dyslipidemia and high blood pressure), the degree of which is higher in these patients than in controls. The aim of this narrative review is to discuss the CV manifestations and risk factors involved in the increased risk of CVD among patients with autoimmune rheumatic diseases.

Optimal Dietary Strategies for Prevention of Atherosclerotic Cardiovascular Disease in Diabetes: Evidence and Recommendations.

This review presents the current available evidence of the effects of several dietary patterns on atherosclerotic cardiovascular disease (ASCVD) risk in patients with type 2 diabetes (T2D). Evidence demonstrates improvements in cardiovascular risk factors with some dietary patterns in the general population. However, evidence is limited for glycemic control and cardiovascular benefit in patients with T2D for Dietary Approaches to Stop Hypertension and plant-based dietary patterns. Evidence suggests that carbohydrate-restricted dietary patterns improve glycemic control and decrease the use of anti-hyperglycemic medications. The Mediterranean dietary pattern has the most evidence for glycemic control and decreased ASCVD risk in patients with T2D. There is no evidence on ASCVD outcomes in patients with T2D for any other dietary pattern. The Mediterranean dietary pattern has the most evidence for cardiovascular benefit in patients with T2D. Future research should examine the effect of dietary patterns on ASCVD outcomes.

Dyslipidemia Management in Adults With Diabetes.

Lipid abnormalities beyond elevated low-density lipoprotein (LDL) cholesterol contribute to increased risk of atherosclerotic cardiovascular disease (ASCVD) in type 2 diabetes. We searched for English language randomized controlled trials of lipid-lowering therapies primarily since 2012 that included patients with diabetes. Diet and lifestyle advice are always a starting point for ASCVD prevention in diabetes. After almost 30years of widespread clinical use in diabetes, statin treatment to reduce LDL cholesterol remains the cornerstone of drug therapy to prevent ASCVD. Ezetimibe appears to be particularly beneficial for high-risk statin-treated patients with diabetes. Similarly, currently available proprotein convertase subtilisin kexin type 9 inhibitors-alirocumab and evolocumab-both reduce ASCVD risk in statin-treated patients with diabetes. High-dose icosapent ethyl is another worthwhile add-on treatment, especially in statin-treated patients with diabetes in whom triglyceride levels remain elevated. Fibrates might reduce ASCVD risk in patients with diabetes with high triglyceride and low high-density lipoprotein cholesterol; however, fibrates are more strongly recommended for prophylaxis of pancreatitis in patients with severe hypertriglyceridemia and may also slow progression of diabetic retinopathy. Several existing and newer drug treatments reduce ASCVD risk through LDL cholesterol and/or triglyceride reduction in patients with diabetes. Novel approaches using antisense oligonucleotides and monoclonal antibodies may provide potential future therapies for diabetic dyslipidemia.

Low statin use in nondialysis-dependent chronic kidney disease in the absence of clinical atherosclerotic cardiovascular disease or diabetes.

Both reduced glomerular filtration rate and increased urine albumin excretion, markers of chronic kidney disease (CKD), are associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). However, CKD is not recognized as an ASCVD risk equivalent by most lipid guidelines. Statin medications, especially when combined with ezetimibe, significantly reduce ASCVD risk in patients with nondialysis-dependent CKD. Unless physicians recognize the heightened ASCVD risk in this population, statins may not be prescribed in the absence of clinical cardiovascular disease or diabetes, a recognized ASCVD risk equivalent. We examined statin use in adults with nondialysis-dependent CKD and examined whether the use differed in the presence of clinical ASCVD and diabetes. This study ascertained statin use from pharmacy dispensing records during fiscal years 2012 and 2013 from the US Department of Veterans Affairs Healthcare System. The study included 581344 veterans aged ≥50 years with nondialysis-dependent CKD Stages 3-5 with no history of kidney transplantation or dialysis. The 10-year predicted ASCVD risk was calculated with the pooled risk equation. Of veterans with CKD, 62.1% used statins in 2012 and 55.4% used statins continuously over 2 years (2012-13). Statin use in 2012 was 76.2 and 75.5% among veterans with CKD and ASCVD or diabetes, respectively, but in the absence of ASCVD, diabetes or a diagnosis of hyperlipidemia, statin use was 21.8% (P < 0.001). The 10-year predicted ASCVD risk was ≥7.5% in 95.1% of veterans with CKD, regardless of diabetes status. Statin use is low in veterans with nondialysis-dependent CKD in the absence of ASCVD or diabetes despite high-predicted ASCVD risk. Future studies should examine other populations.

Evaluation of the HbA1c Reduction Cut Point for a Nonglycemic Effect on Cardiovascular Benefit of Hypoglycemic Agents in Patients with Type 2 Diabetes Based on Endpoint Events.

Background Atherosclerotic cardiovascular disease (ASCVD) is a major cause of death among patients with diabetes but can be improved by certain hypoglycemic agents. However, adjudicating criteria on whether improvements are a glycemic or nonglycemic effect of these agents remain unclear. Methods Hypoglycemic agents that produce a cardiovascular benefit in nondiabetic patients are considered to do so via a nonglycemic effect. We performed a subgroup analysis for primary and secondary prevention or very high risk of ASCVD in patients with type 2 diabetes (T2DM). Where glycosylated hemoglobin (HbA1c) was reduced to the same extent in a head-to-head comparison, cardiovascular benefits were judged as a nonglycemic effect. Furthermore, by analyzing the endpoints of four important randomized controlled intensive glucose control studies, UKPDS33, ADVANCE, ACCORD, and VADT, we calculated the cut point of HbA1c reduction for a nonglycemic effect on cardiovascular benefit by hypoglycemic agents in ASCVD groups of different severities. Results For the ASCVD primary prevention group of T2DM, UKPDS33 indicated a reduction in HbA1c < 0.9%, and a cardiovascular benefit within 10 years was considered a nonglycemic effect. For ASCVD secondary prevention or in the very high-risk group, pioglitazone exerted a nonglycemic effect on cardiovascular benefit in nondiabetic patients with insulin resistance; metformin may exert a similar effect in T2DM patients in a head-to-head study. Analysis of T2DM intensive glucose control studies showed a reduction in HbA1c of <1.0%, and a cardiovascular benefit after approximately 5 years was deemed a nonglycemic effect. Conclusions For ASCVD primary prevention in T2DM, a reduction in HbA1c < 0.9% and a cardiovascular benefit within 10 years were considered a nonglycemic effect. For ASCVD secondary prevention or in a very high-risk population, a reduction in HbA1c < 1.0% and a cardiovascular benefit within about 5 years were also considered a nonglycemic effect.