Intensive early and sustained lowering of non-high-density lipoprotein cholesterol after myocardial infarction and prognosis: the SWEDEHEART registry.

BACKGROUND AND AIMS: Non-high-density lipoprotein cholesterol (HDL-C) provides an estimate of lipid-associated risk and is a secondary treatment target after myocardial infarction (MI). The aim was to study the relationship between non-HDL-C levels after MI and risk of adverse outcomes. METHODS: From the SWEDEHEART registry, 56,262 patients with MI were included. Outcomes were major adverse cardiovascular event (MACE: death, MI, ischaemic stroke), death, and non-fatal MI. Non-HDL-C was assessed at admission, 2 months, and 1 year. Target achievement (<2.2 mmol/L) of non-HDL-C, timing thereof, and outcomes were assessed. RESULTS: During median follow-up of 5.4 years, 9549 had MACE, 5427 died, and 3946 had MI. Long-term hazard ratio (HR) for MACE in the lowest versus the highest quartile of achieved non-HDL-C at 1 year was 0.76 (95% confidence interval 0.71-0.81). Short-term results were consistent also when assessing non-HDL-C levels at 2 months, including early events up to 1 year (HR 0.80, 95% CI 0.68-0.92). Similar results were observed for all outcomes. Patients achieving both early and sustained targets had lowest risk of outcomes (HR 0.80 95% CI 0.74-0.86) versus patients achieving target early or late (HR for both 0.86, 95% CI 0.79-0.93). CONCLUSIONS: The lowest achieved levels both at 2 months and at 1 year of non-HDL-C were associated with better outcome. The lowest risk was observed when target was achieved within 2 months of MI and sustained thereafter. These findings challenge the current stepwise approach for cholesterol lowering after MI which inevitably results in delaying goal attainment and possible harm.

Association of 28-day mortality with non-high-density lipoprotein cholesterol and the high-density lipoprotein cholesterol ratio (NHHR) in patients with sepsis: Results of MIMIC-IV database analysis.

BACKGROUND: The correlation between lipid profiles and sepsis has received increasing attention. The ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (NHHR) is one of the key lipid profiles. However, in-depth exploration of the correlation between NHHR and the mortality risk of patients with sepsis is limited. METHODS: Data from the MIMIC-IV (v2.2) database, we review the NHHR relevance and the sepsis severity index using Spearman's correlation analysis. Additionally, we research NHHR associated with sepsis patients' survival rate of 28 days using Cox regression analyses of continuous and categorical models. To further validate our findings, we conducted subgroup and sensitivity analyses. RESULTS: The study involved 3,142 patients diagnosed with sepsis, according to 28 days after in-hospital survival condition, divided into two groups. In this study, 2932 patients were in the survival group and 210 patients died within 28 days (mortality group). Of note, the mean NHHR of patients in the mortality group exceeded that of the survival group (3.5 vs. 2.9). Additionally, NHHR was positively correlated with the severity index. After adjusting for demographic and laboratory data, an increased NHHR was positively correlated with higher sepsis mortality risk (OR = 1.06; 95% CI: 1.02-1.11; P = 0.013). Subgroup analysis shown the same results. Contributors were be categorized into two groups based on NHHR levels, with a threshold of 2.61. Contrast the mortality risk between low-NHHR group and high-NHHR group, high-NHHR show greater mortality risk on 28-day, 60-day, 90-day, in ICU, and in hospital. CONCLUSION: Elevated NHHR is to be correlated with an increased risk of mortality in patients with sepsis. Further research on NHHR may contribute to advancements in sepsis prevention and treatment.

Linking elevated HbA1c with atherogenic lipid profile among high risk cardiovascular patients at Qassim, Saudi Arabia.

The relationship between glycated hemoglobin (HbA1c) and an atherogenic lipid profile which is associated with a higher risk of cardiovascular disease is of interest. A retrospective cross-sectional study was conducted on 83 participants aged between 14 and 77 years. Their venous blood was drawn to determine the HbA1c and fasting lipid profile including total cholesterol triglycerides and high-density lipoprotein cholesterol (HDL-C) low-density lipoprotein cholesterol (LDL-C) non-HDL cholesterol and the LDL/HDL ratio were also calculated. The correlations between HbA1c levels and these lipid profile parameters were analyzed. The study showed a significant correlation between HbA1c and LDL-C non-HDL-C and the LDL/HDL ratio. Although there was no significant difference in total cholesterol levels among all groups the levels of total cholesterol and HbA1c were positively correlated. HDL-C exhibited direct correlations with HbA1c there was no correlation between HbA1c and clinical characteristics except for age. Data shows that HbA1c can be used as a predictor of dyslipidemia in diabetic patients there is a significant correlation between HbA1c and an atherogenic lipid profile which highlights the importance of glycemic control in reducing the risk of cardiovascular disease.

Reference Interval for Non-HDL-Cholesterol, Remnant Cholesterol and Other Lipid Parameters in the Southern Iranian Population; Findings From Bandare Kong and Fasa Cohort Studies.

BACKGROUND: Growing evidence shows the undisputable role of non-HDL-C and remnant cholesterol (remnant-C) in cardiovascular disease (CVD) risk assessment and treatment. However, the reference interval (RI) for these lipid parameters is not readily available. The aim of the present investigation was to determine the age and sex-specific RIs for non-HDL-C and remnant-C as well as other lipid parameters among a healthy population in southern Iran. We also report the RI of lipid parameters in rural and urban residents, smokers and post-menopausal women. METHODS: Among 14063 participants of Bandare Kong and Fasa cohort studies, 792 healthy subjects (205 men and 578 women) aged 35-70 years were selected. Fasting blood samples were used for determination of total cholesterol (TC), triglycerides (TG) and HDL-C using colorimetric methods. Non-HDL-C and remnant-C were calculated using the valid formula. The 2.5th and 97.5th percentiles were calculated and considered as RI. RESULTS: In the total population (n=792, age 35-70), RIs for non-HDL-C and remnant-C was 74.0-206.8 and 8.0-52.7 mg/dL, respectively. Age (35-44 and≥45 years) and gender-specific RIs for serum non-HDL-C and remnant-C were determined. Remnant-C and non-HDL-C level were different between sex and age categories. The mean value of all lipid parameters except HDL-C was higher in men, urban residents, subject with age≥45 years and smokers. CONCLUSION: This is the first study in which the RIs for non-HDL-C and remnant-C in southern Iran are reported. This may help physicians to conveniently use these lipid parameters for patient care and better cardiovascular risk assessment.

Elevated remnant cholesterol and non-HDL cholesterol concentrations from real-world laboratory results: a cross-sectional study in Southeast Asians.

Introduction: Triglyceride-rich remnant lipoproteins (TRLs) are considered atherogenic due to the presence of remnant cholesterol, which is transported by apolipoprotein B. In clinical practice, the concentration of TRLs can be estimated by calculating remnant cholesterol or non-HDL cholesterol levels. Aim: This study aims to investigate the proportion of patients who have low LDL cholesterol (LDL-C) concentration but elevated remnant cholesterol concentration, stratified by the presence of hypertriglyceridaemia and ethnicity, using real-world hospital data. Our secondary aim is to investigate the proportion of patients with elevated non-HDL cholesterol levels using guideline-recommended goals. Methods: A 2-year retrospective study was conducted at a single centre, analyzing lipid blood tests of all patients, including directly measured LDL-C. Fasting for blood tests was not mandatory. Results: The study included a total of 21,605 consecutive patients with plasma lipid profiles analyzed in our hospital laboratory. The median age was 61 years. In patients with ASCVD (n = 14,704), 23.7% had an LDL-C level of <1.8 mmol/L, 11.3% had elevated remnant cholesterol concentrations at ≥0.65 mmol/L, and 48.8% were at the non-high-density lipoprotein cholesterol (non-HDL-C) goal (<2.6 mmol/L). Among patients diagnosed with atherosclerotic cardiovascular disease (ASCVD) with LDL-C levels of <1.8 mmol/L (n = 3,484), only 11.9% had high levels of remnant cholesterol, but 96% of the ASCVD patients also achieved the recommended non-HDL-C target of <2.6 mmol/L. When the LDL-C level was <1.8 mmol/L, the mean concentration of remnant cholesterol was 0.214 mmol/L when the triglyceride level was <1.7 mmol/L (n = 3,380), vs. 0.70 mmol/L when the triglyceride level was elevated (n = 724), p < 0.001. Among patients with a triglyceride level of ≥1.7 mmol/L and an LDL-C level of <.8 mmol/L, there were 254 patients with elevated remnant cholesterol concentration and 71 patients with suboptimal non-HDL levels. Malays had a higher mean remnant cholesterol concentration compared with both Chinese and Indians across all LDL-C levels, particularly in the presence of hypertriglyceridaemia. Conclusions: An elevated remnant cholesterol concentration of >0.65 mmol/L was present in 11% of all patients. The current guideline-recommended non-HDL-C goal, which uses a 0.8 mmol/L estimate of remnant cholesterol concentration, was achieved in >92% of patients, suggesting that it is unlikely to be clinically useful for the majority of our patient population except where there is concomitant hypertriglyceridaemia. Further studies are needed to establish the appropriate non-HDL-C goal or calculated remnant cholesterol concentration, paired with the LDL-C goal or otherwise, in a Southeast Asian population.

Management of triglycerides, non-high density lipoprotein cholesterol and high density lipoprotein cholesterol.

Dyslipidaemia characterised by elevated total cholesterol/LDL-C, triglyceride or both or decreased HDL-C is an important risk factor for the development of ASCVD. Atherogenic dyslipidaemia characterised by high TG, low HDL-C and elevated small dense LDL (sdLDL) is more prevalent in Asian Indians. Normal level of TG is generally considered as <150 mg/dl. Hypertriglyceridemia is closely associated with obesity, metabolic syndrome and diabetes mellitus. Goals of management of hypertriglyceridemia are to lower the risk of atherosclerotic cardiovascular events and reduce the risk of pancreatitis. Lifestyle modification is important. In severe hypertriglyceridemia, TG lowering pharmacotherapy is important to prevent pancreatitis. In mild to moderate hypertriglyceridemia, pharmacotherapy is employed only if associated with ASCVD or high risk factors and not controlled with lifestyle modifications and statins. Non-High Density Lipoprotein Cholesterol which estimates the cholesterol content of the atherogenic apoB containing lipoproteins, measured as total cholesterol minus HDL-C is equivalent to LDL-C in ASCVD risk assessment and superior to it in those with mild to moderate hypertriglyceridemia. Some international guidelines, have included measurement of non-HDL-C as primary therapeutic target for patients with ASCVD. Low HDL cholesterol is common in Indians. Despite evidence of inverse relationship between HDL-C and cardiovascular events, HDL-C as a causative factor for development of atherosclerosis is unproven. Therapeutic strategies directed at increasing HDL-C levels have not been shown to have cardiovascular benefits and hence HDL-C is currently not a target for drug-based treatment.

Effectiveness and Safety of Fenofibrate in Routine Treatment of Patients with Hypertriglyceridemia and Metabolic Syndrome.

Background: Multiple trials have demonstrated the efficacy of fenofibrate for the management of dyslipidemia. Real-world evidence may provide important insights into the effectiveness and safety of fenofibrate in patients with metabolic syndrome and elevated triglyceride (TG) levels, but such evidence is currently scarce. MATERIALS AND METHODS: A non-interventional study was conducted among routine healthcare providers. Patients with TG levels of >2.3 mmol/L on stable statin therapy starting fenofibrate treatment were enrolled. Data on medical history, fenofibrate treatment, change in lipid levels, and C-reactive protein (CRP) were collected from medical records every 3 months for 6 to 7 months of observation. RESULTS: Overall, 988 patients receiving fenofibrate were enrolled (median age [95% CI] 60 [26.0-86.0] years), and 46.4% of the participants were females. Most patients had concomitant cardiovascular disease. A baseline TG level of 3.6 ± 1.5 mmol/L was reduced by 50.1% to 1.7 ± 0.58 mmol/L at 6 months of treatment (p < 0.001). Baseline non-high-density lipoprotein cholesterol (non-HDL-C) levels decreased by 33.7% at 6 months. Total cholesterol and low-density lipoprotein levels by the end of follow-up were reduced by 24.7 and 25.5% (p < 0.001 for both). C-reactive protein level decreased more than 39% from baseline. CONCLUSIONS: Fenofibrate in a real-world setting significantly reduced TG, LDL-C, and non-HDL-C levels. In addition, a C-reactive protein level reduction of 39% was achieved.

MK-0616: an oral PCSK9 inhibitor for hypercholesterolemia treatment.

INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality worldwide. Lowering LDL-cholesterol, by lifestyle modification or therapeutically, reduces the risk of ASCVD. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein which binds to the LDL-receptor and induces degradation, is a clinically validated target to lower LDL-cholesterol. Injectable PCSK9 inhibitor therapies have demonstrated substantial reductions in LDL-cholesterol with associated decreased risk of ASCVD events. AREAS COVERED: MK-0616 is an orally bioavailable, renally excreted, macrocyclic peptide inhibitor of PCSK9. The article provides an understanding of the chemistry and development, pharmacokinetic and pharmacodynamic characteristics of MK-0616 and insight into its clinical efficacy and safety. In clinical trials, MK-0616 produced dose-dependent reductions in LDL-cholesterol, non-HDL-cholesterol, and apolipoprotein (apo) B levels. Furthermore, MK-0616 modestly lowered lipoprotein (a) [Lp(a)]. EXPERT OPINION: MK-0616 is a potent, oral macrocyclic peptide inhibitor of PCSK9 that is not only able to reduce LDL-cholesterol, non-HDL-cholesterol, and apoB, but can also lower Lp(a). Safety and tolerability studies reported to date are promising. MK-0616 may offer advantages over injectable anti-PCSK9 therapies in terms of ease of dosing, patient preference and cost. The results from phase III trials of MK-0616 on cardiovascular outcomes are awaited with interest.

Cumulative non-high-density lipoprotein cholesterol burden and risk of atherosclerotic cardiovascular disease: a prospective community-based study.

Background: The relationship between cumulative non-high-density lipoprotein cholesterol (non-HDL-C) burden and atherosclerotic cardiovascular disease (ASCVD) remains unclear. Objective: To prospectively examine the association between cumulative non-HDL-C burden and ASCVD risk in the Kailuan cohort of China. Methods: A total of 49,679 subjects who were free of ASCVD participated in three consecutive examinations in 2006, 2008 and 2010 were enrolled. Duration and concentration of cumulative exposure to non-HDL-C (cumNon-HDL-C) were respectively used to estimate the extent of cumulative non-HDL-C burden. The participants were divided into four groups according to durations of cumNon-HDL-C (0, 2, 4 and 6 years) and five groups according to the quintiles of cumNon-HDL-C concentration (<10.93, 10.93-12.68, 12.69-14.32, 14.33-16.72 and ≥16.73 mmol/L). Cox regression models were used to analyze the influence of cumulative non-HDL-C burden on ASCVD risk. Results: We identified 1,134 incident ASCVD cases during a mean of 4.89 years of follow-up. Multivariable adjusted analysis revealed that compared with no exposure, cumNon-HDL-C duration 2, 4 and 6 years increased ASCVD risk by 26% (HR: 1.26, 95% CI: 1.07-1.47), 56% (HR: 1.56, 95% CI: 1.31-1.86) and 91% (HR: 1.91, 95% CI: 1.59-2.31) respectively; The hazard ratios (HRs) for the fourth and fifth versus lowest quintile of cumNon-HDL-C concentration were 1.25 and 1.72 for ASCVD. Each standard deviation increment in cumNon-HDL-C concentration was associated with a 10% increased risk of ASCVD. Conclusion: Long-term and higher cumNon-HDL-C were all significantly associated with an increased risk of ASCVD independent of single non-HDL-C level.

Association Between Omega-3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose-Response Meta-Analysis of Randomized Controlled Trials.

Background Previous results provide supportive but not conclusive evidence for the use of omega-3 fatty acids to reduce blood lipids and prevent events of atherosclerotic cardiovascular disease, but the strength and shape of dose-response relationships remain elusive. Methods and Results This study included 90 randomized controlled trials, reported an overall sample size of 72 598 participants, and examined the association between omega-3 fatty acid (docosahexaenoic acid, eicosapentaenoic acid, or both) intake and blood lipid changes. Random-effects 1-stage cubic spline regression models were used to study the mean dose-response association between daily omega-3 fatty acid intake and changes in blood lipids. Nonlinear associations were found in general and in most subgroups, depicted as J-shaped dose-response curves for low-/high-density lipoprotein cholesterol. However, we found evidence of an approximately linear dose-response relationship for triglyceride and non-high-density lipoprotein cholesterol among the general population and more evidently in populations with hyperlipidemia and overweight/obesity who were given medium to high doses (>2 g/d). Conclusions This dose-response meta-analysis demonstrates that combined intake of omega-3 fatty acids near linearly lowers triglyceride and non-high-density lipoprotein cholesterol. Triglyceride-lowering effects might provide supportive evidence for omega-3 fatty acid intake to prevent cardiovascular events.

The cholesterol-lowering effect of statins is modified by LILRB5 intolerance genotype: Results from a recruit-by-genotype clinical trial.

Background/Aims: Statin intolerance leads to poor adherence to statin therapy, resulting in a failure to achieve desired cholesterol reduction and adverse outcomes. The LILRB5 Asp247Gly genotype has been identified as being associated with statin intolerance and statin-induced myalgia. We conducted a randomized clinical trial to examine its role in immune response through T regulatory cell aggregation and in achieving cholesterol reduction targets. Methods: A double-blind, cross-over, recruit-by-genotype trial was undertaken. A total of 18 participants who had either the Asp247Asp (T/T) genotype or the Gly247Gly (C/C) genotype were recruited to the study. Participants were randomised to receive placebo or atorvastatin 80 mg daily for 28 days. Following a washout period of 3 weeks, they were then switched to the opposite treatment. Biochemical and immunological measurements as well as interviews were performed prior to and after both treatment periods. Within genotype group comparisons were performed using repeated measures Wilcoxon tests. Two-way repeated measures ANOVA with genotype and treatment as factors were used to compare changes in biochemical parameters between groups during placebo and atorvastatin periods. Results: Individuals with the Asp247Asp genotype had a greater increase in creatine kinase (CK) compared to those with Gly247Gly genotype in response to atorvastatin (p = 0.03). Those with Gly247Gly genotype had a mean non-HDL cholesterol reduction of 2.44 (95% CI:1.59 - 3.29) mmol/L while in Asp247Asp genotype group the mean reduction was 1.28 (95%CI: 0.48 - 2.07) mmol/L. The interaction between the genotype and atorvastatin treatment for total cholesterol (p = 0.007) and non-HDL cholesterol response was significant (p = 0.025). Immunological assessment showed no significant changes in aggregation of T regulatory cells by genotype. Conclusion: The Asp247Gly variant in LILRB5, previously associated with statin intolerance, was associated with differential increases in creatine kinase and total cholesterol and non-HDL cholesterol-lowering response to atorvastatin. Taken together, these results suggest that this variant could have utility in precision cardiovascular therapy.

Nomograms Based on Non-High-Density Lipoprotein to Predict Outcomes in Patients with Prior Coronary Artery Bypass Grafting with Acute Coronary Syndrome: A Single-Center Retrospective Study.

Introduction: Non-high-density-lipoprotein cholesterol (non-HDL-C) is a secondary therapeutic target in cardiovascular diseases and is used for residual risk assessment in patients with coronary artery syndrome (ACS). This study was designed to determine the association between non-HDL-C in patients with prior coronary artery bypass graft (CABG) with ACS and clinical outcomes. Methods: We retrospectively analyzed 468 patients with prior CABG with ACS and categorized them into two groups based on the median non-HDL-C level. The primary endpoints were major adverse cardiovascular events (MACEs), including cardiovascular death and recurrent myocardial infarction. Kaplan-Meier curves, Cox proportional-hazard regressions, and restricted cubic splines were used to determine the association between non-HDL-C and MACEs. The discrimination and reclassification of the nomogram based on non-HDL-C were assessed using time-dependent receiver operating characteristic (ROC) curves and net reclassification improvement (NRI). Results: During the average follow-up time of 744.5 days, non-HDL-C was independently associated with the occurrence of MACEs (hazard ratio [HR] = 5.01, 95% confidence interval [CI] = 1.65-15.24; p = 0.005) after adjusting for other lipid parameters. The spline curves indicated a linear relationship between non-HDL-C and MACEs (p-nonlinear: 0.863). The time-dependent areas under the ROC curves of prior-CABG-ACS nomograms containing non-HDL regarding MACEs in two consecutive years were 91.7 (95% CI: 85.5-97.9) and 91.5 (95% CI: 87.3-95.7), respectively. The NRI analysis indicated that the prior-CABG-ACS model improved the reclassification ability for 1- and 2-year MACEs (22.4% and 7%, p < 0.05, respectively). Discussion: Non-HDL is independently associated with the risk of MACEs in patients with prior CABG with ACS. The prior-CABG-ACS nomogram based on non-HDL-C and five convenient variables generates valid and stable predictions of MACE occurrence.

Strong Negative Association of non-HDL Cholesterol Goal Achievement With Incident CKD Among Adults With Diabetes.

Context: The relative importance of the control of different metabolic risk factors for the prevention of chronic kidney disease among patients with diabetes in real life conditions is insufficiently understood. Objective: We evaluated the effect of the achievement of glycated hemoglobin A1c (HbA1c), systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDLc) or non-high-density lipoprotein cholesterol (non-HDLc) goals (ABC goals) on the development of incident chronic kidney disease (iCKD) among patients with diabetes. Methods: In a nationwide registry of all individuals diagnosed with diabetes assisted by the health system in Colombia, we analyzed the association between baseline or sustained goal achievement and development of iCKD over a 4-year follow-up. iCKD was defined as a new occurrence of an estimated glomerular filtration rate less than 60 mL/min/1.73 m2, hemodialysis, peritoneal dialysis, or kidney transplant. Results: The study included 998 790 adults with diabetes (56% female, mean age 59). There were 125 626 cases of iCKD. After adjustment for multiple confounders, a baseline SBP less than 130 mm Hg (odds ratio [OR] 0.79 [0.78-0.80]) and a baseline HbA1c less than 7.0% (OR 0.86 [0.85-0.87]) were negatively associated with iCKD. Sustained achievement showed stronger negative associations with iCKD than just baseline achievement. Considering each goal separately, sustained non-HDLc less than 130 mg/dL had the strongest negative association with iCKD (OR 0.67 [0.65-0.69]). Patients who maintained the triple ABC goal over the entire follow-up had 32% (29-34) lower odds of developing CKD, 38% (34-42) if they additionally kept a normal body mass index (BMI). Sustained ABC control including a normal BMI was more strongly associated with a lower incidence of CKD in patients of Black race (OR 0.72 vs 0.89; P for interaction = .002). Conclusion: At the country level, sustained achievement of ABC goals and most especially non-HDLc were associated with substantial reductions in iCKD.

A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis.

Background & Aims: Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis. Methods: Patients with NASH and stage 4 fibrosis (n = 30) were randomized 2:1 to receive efruxifermin 50 mg (n = 20) or placebo (n = 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy. Results: Efruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n = 7, 23.3%) or grade 2 (n = 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB] -9 µg/L efruxifermin vs. -3.4 µg/L placebo; p = 0.0130) and ELF score (-0.4 efruxifermin vs. +0.4 placebo; p = 0.0036), with a trend towards reduced liver stiffness (LSMCFB -5.7 kPa efruxifermin vs. -1.1 kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients. Conclusions: Efruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies. Lay summary: Cirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH. Clinical Trial Number: NCT03976401.

Effect of evolocumab on fasting and post fat load lipids and lipoproteins in familial dysbetalipoproteinemia.

BACKGROUND: Familial dysbetalipoproteinemia (FD) is the second most common monogenic lipid disorder (prevalence 1 in 850-3500), characterized by postprandial remnant accumulation and associated with increased cardiovascular disease (CVD) risk. Many FD patients do not achieve non-HDL-C treatment goals, indicating the need for additional lipid-lowering treatment options. OBJECTIVES: To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in patients with FD. METHODS: A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. At the start and end of each treatment period patients received an oral fat load. The primary endpoint was the 8-hour post fat load non-HDL-C area under the curve (AUC). Secondary endpoints included fasting and post fat load lipids and lipoproteins. RESULTS: In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an Ɛ2Ɛ2 genotype. Evolocumab reduced the 8-hour post fat load non-HDL-C AUC with 49% (95%CI 42-55) and apolipoprotein B (apoB) AUC with 47% (95%CI 41-53). Other fasting and absolute post fat load lipids and lipoproteins including triglycerides and remnant-cholesterol were also significantly reduced by evolocumab. However, evolocumab did not have significant effects on the rise above fasting levels that occurred after consumption of the oral fat load. CONCLUSIONS: Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and absolute post fat load concentrations of non-HDL-C, apoB and other atherogenic lipids and lipoproteins in FD patients. The clinically significant decrease in lipids and lipoproteins can be expected to translate into a reduction in CVD risk in these high-risk patients.

Asociación del índice triglicérido-glucosa con colesterol-no-HDL aumentado como indicador de riesgo cardiometabólico en estudios poblacionales / Association of the triglyceride-glucose index with increased non-HDL-cholesterol as an indicator of cardiometabolic risk in population studies / Associação do índice triglicerídeo-glicose com colesterol-não-HDL aumentado como indicador de risco cardiometabólico em estudos populacionais / Reconocimiento a la trayectoria del Prof. Dr. Juan Miguel Castagnino†

Resumen Se propone la asociación de dos indicadores para la detección de personas con riesgo cardiometabólico (RCM) en estudios poblacionales: triglicéridoglucosa (TyG) >8,75 y colesterol-no-HDL (C-no-HDL) ≥160 mg/dL, que se denominará indicador de RCM. La enfermedad cardiovascular aterosclerótica (ECVA) y la diabetes tipo 2 (DT2) son muy frecuentes. TyG aumentado es un estimador de insulinorresistencia y síndrome metabólico (SM) y está relacionado con la detección precoz de riesgo para DT2. C-no-HDL ≥160 mg/ dL ha sido recomendado informarlo en los estudios de laboratorio vinculados con el riesgo para ECVA, sus aumentos están relacionados con todas las lipoproteínas aterogénicas y es de mucho interés en hipertrigliceridemias y SM, por la presencia de lipoproteínas remanentes. En un estudio poblacional sobre 540 personas del sur argentino se halló un aumento significativo de RCM luego de los 20 años y luego de los 40 años de edad un tercio de la población lo tenía presente. El RCM se halló asociado con el índice de masa corporal (IMC), luego de ajustar para edad y género. Después de los 30 años, el RCM estaba presente en un tercio de las personas con IMC ≥27 kg/m2. En otro estudio realizado en personas con riesgo para DT2 con RCM presente, 65,8% tenían HOMA-IR (homeostasis model assessment-insulin-resistance) >2,1 y 61,8% SM. Se concluye que la asociación de TyG >8,75 y C-no-HDL ≥160 mg/dL (RCM) podría ser de interés para la detección de grupos poblacionales con alto riesgo cardiometabólico, en la prevención de ECVA y DT2.

Abstract The association of two indicators was proposed for the detection of people with cardiometabolic risk (CMR) in population studies: triglyceride-glucose (TyG) >8.75 and non-HDL-cholesterol (Non-HDL-C) ≥160 mg/dL, which will be called CMR indicator. Atherosclerotic cardiovascular disease (ACVD) and type 2 diabetes (T2D) are very common. Increased TyG is an estimator of insulin resistance and metabolic syndrome (MS) and is related to the early detection of risk for T2D. Non-HDL-C≥160 mg/dL has been recommended to be reported in laboratory studies related to the risk for CVA and its increases are related to all atherogenic lipoproteins and it is of great interest in hypertriglyceridemia and MS, due to the presence of lipoproteins remnants. In a population study of 540 people from Southern Argentina, a significant increase in CMR was found after 20 years of age, and after 40 years of age; a third of the population had it. CMR was found to be associated with body mass index (BMI), after adjusting for age and gender. After age 30 years, CMR was present in a third of the people with a BMI ≥27 kg/m2. In another study conducted in people at risk for T2D with CMR present, 65.8% had HOMA-IR (homeostasis model assessment-insulin-resistance) >2.1 and 61.8% MS. It is concluded that the association of TyG <8.75 and non-HDL-C ≥160 mg/dL (CMR) could be of interest for the detection of population groups with high cardiometabolic risk, in the prevention of ACVD and T2D.

Resumo A associação de dois índices é proposta para a detecção de pessoas com risco cardiometabólico (RCM) em estudos populacionais: triglicerídeo-glicose (TyG) >8,75 e colesterol-não-HDL (C-não-HDL) ≥160 mg/ dL, que será denominado indicador de RCM. A doença cardiovascular aterosclerótica (DCVA) e o diabetes tipo 2 (DT2) são muito comuns. TyG aumentado é um estimador de resistência à insulina e síndrome metabólica (SM) e está relacionado com a detecção precoce de risco para DT2. C-não-HDL ≥160 mg/dL tem sido recomendado para relatá-lo em estudos laboratoriais vinculados com o risco de DCVA e seus aumentos estão relacionados com todas as lipoproteínas aterogênicas e é de grande interesse na hipertrigliceridemia e SM devido à presença de restos de lipoproteínas. Em um estudo populacional de 540 pessoas do sul da Argentina, foi encontrado um aumento significativo de RCM após os 20 anos de idade e, depois dos 40 anos, um terço da população o apresentava. A RCM foi associada ao índice de massa corporal (IMC), após ajustar para idade e gênero. Após os 30 anos, a RCM estava presente em um terço das pessoas com IMC ≥27 kg/m2. Em outro estudo realizado em pessoas com risco para DT2 com RCM presente, 65,8% tinham HOMA-IR (homeostasis model assessment-insulin-resistance) >2,1 e 61,8% SM. Conclui-se que a associação de TyG >8,75 e C-não-HDL ≥160 mg/dL (RCM) poderia ser de interesse para a detecção de grupos populacionais com alto risco cardiometabolico, na prevenção de DCVA e DT2.

Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles: a Mendelian randomization analysis.

BACKGROUND AND AIMS: The causal contribution of apolipoprotein B (apoB) particles to coronary artery disease (CAD) is established. We examined whether this atherogenic contribution is better reflected by non-high-density lipoprotein cholesterol (non-HDL-C) or apoB particle concentration. METHOD AND RESULTS: We performed Mendelian randomization (MR) analysis using 235 variants as genetic instruments; testing the relationship between their effects on the exposures, non-HDL-C and apoB, and on the outcome CAD using weighted regression. Variant effect estimates on the exposures came from the UK Biobank (N = 376 336) and on the outcome from a meta-analysis of five CAD datasets (187 451 cases and 793 315 controls). Subsequently, we carried out sensitivity and replication analyses.In univariate MR analysis, both exposures associated with CAD (ßnon-HDL-C = 0.40, P = 2.8 × 10-48 and ßapoB = 0.38, P = 1.3 × 10-44). Adding effects on non-HDL-C into a model that already included those on apoB significantly improved the genetically predicted CAD effects (P = 3.9 × 10-5), while adding apoB into the model including non-HDL-C did not (P = 0.69). Thirty-five per cent (82/235) of the variants used as genetic instruments had discordant effects on the exposures, associating with non-HDL-C/apoB ratio at P < 2.1 × 10-4 (0.05/235). Fifty-one variants associated at genome-wide significance. CONCLUSION: Many sequence variants have discordant effects on non-HDL-C and apoB. These variants allowed us to show that the causal mechanism underlying the relationship between apolipoprotein B particles and CAD is more associated with non-HDL-C than apoB particle concentration.

Premature coronary artery disease, risk factors, clinical presentation, angiography and interventions: Hospital based registry.

BACKGROUND & AIMS: Premature coronary artery disease (CAD) is endemic in India. We performed a study to identify risk factors, clinical presentation, angiographic findings and interventions in premature CAD. METHODS: Successive patients who underwent percutaneous intervention (PCI) were enrolled from January 2018 to June 2021. Premature CAD was defined as women 45-59 y and men 40-54 y and very premature as women <45 y and men <40 y. Descriptive statistics are presented. Univariate odds ratio (OR) and 95% confidence intervals (95%CI) were calculated to identify differences in various groups. RESULTS: 4672 patients (women 936, men 3736) were enrolled. Premature CAD was in 1238 (26.5%; women 31.9%; men 25.1%) and very premature in 212 (4.5%; women 6.5%, men 4.0%). In premature and very premature vs non-premature CAD, OR (95%CI) for high cholesterol ≥200 mg/dl [women 1.52(1.03-2.25) and 1.59(0.79-3.20); men 1.73(1.38-2.17) and 1.92(1.22-3.03)], non-HDL cholesterol ≥130 mg/dl [women 1.84(1.35-2.52) and 1.32(0.72-2.42); men 1.69(1.43-1.90) and 1.67(1.17-2.34)], LDL cholesterol [men 1.10(0.95-1.25) and 1.04(0.77-1.41)], and tobacco [women 1.40(0.84-2.35) and 2.14(0.95-4.82); men 1.63(1.34-1.98) and 1.27(0.81-1.97)] were higher while hypertension, diabetes and chronic kidney disease were more in non-premature(p < 0.05). Presentation as STEMI was marginally more in women with premature [1.13(0.85-1.51)] and very premature [1.29(0.75-2.22)] CAD and was significantly higher in men [1.35(1.16-1.56) and 1.79(1.29-2.49)]. Location and extent of CAD were not different. CONCLUSIONS: In India, a third of CAD patients presenting for coronary intervention have premature disease. Important risk factors are high total and non-HDL cholesterol and tobacco (men) with greater presentation as STEMI. Extent and type of CAD are similar to non-premature CAD indicating severe disease.

Lipoprotein Assessment in the twenty-first Century.

Based on decades of both basic science and epidemiologic research, there is overwhelming evidence for the causal relationship between high levels of cholesterol, especially low-density lipoprotein cholesterol and cardiovascular disease. Risk evaluation and monitoring the response to lipid-lowering therapies are heavily dependent on the accurate assessment of plasma lipoproteins in the clinical laboratory. This article provides an update of lipoprotein metabolism as it relates to atherosclerosis and how diagnostic measures of lipids and lipoproteins can serve as markers of cardiovascular risk, with a focus on recent advances in cardiovascular risk marker testing.

Effects of semaglutide on cardiovascular risk factors and eating behaviors in type 2 diabetes.

AIMS: Aim of the present study was to evaluate the impact of once-weekly semaglutide on different end-points indicative of metabolic control, cardiovascular risk, dietary behavior, and treatment satisfaction in T2DM. METHODS: This was a retrospective observational study conducted in a diabetes clinic. Changes in HbA1c, fasting blood glucose (FBG), weight, blood pressure, lipid profile, and number of antihypertensive drugs at 32 weeks (T1) after the first prescription of semaglutide (T0) were analyzed. Furthermore, at T1 patients were asked to fill-in the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the Control of Eating Questionnaire (COEQ). RESULTS: Overall, 104 patients were identified (mean age 63.6 ± 10.4 years, 58.7% men, diabetes duration 12.7 ± 8.7 years). After 32 weeks of treatment with semaglutide, HbA1c levels were reduced by 1.38%, FBG by - 56.53 mg/dl, weight by 6.03 kg. Systolic and diastolic blood pressure, total, HDL-, LDL-, and non -HDL cholesterol, and triglycerides significantly improved. The number of glucose-lowering and antihypertensive drugs also decreased. At T1, DTSQ score was 32.23 ± 1.44, whereas COEQ indicated low levels of hunger and good control of eating. CONCLUSIONS: The study documented benefits of semaglutide on metabolic control and multiple CV risk factors, simplification of therapeutic schemes and high satisfaction with diabetes treatment, and eating behaviors indicative of healthy diet and reduced food intake.