👤 Erin D Michos

Elevated atherogenic lipoproteins increase risk of atherosclerotic cardiovascular disease (ASCVD), though long-term risk for adults without ASCVD who have low-normal levels has not been well described. This study used pooled data from 16,384 individuals in 3 population-based prospective cohorts. At baseline all participants were without ASCVD and were not taking lipid-lowering therapy. We evaluated ASCVD events by baseline LDL-C, non-HDL-C and apoB, including low-normal values. ASCVD risk was assessed using multivariable Cox proportional hazards. The study cohort had a mean age of 52 (SD 18) years with 56.5% women, 64.7% of White race and 35.3% of Black race. Over a median follow-up of 18.8 years, unadjusted ASCVD event incidence was similar for adults with baseline LDL-C < 70 mg/dL and 70 to 99 mg/dL, and higher with LDL-C ≥ 100 mg/dL; trends were similar for non-HDL-C and apoB categories. Compared to having baseline LDL-C 70 to 99 mg/dL, LDL-C < 70 mg/dL was associated with similar ASCVD risk (adjusted HR 1.16 [95% Confidence Interval, 95% CI 0.90-1.50]) and LDL-C ≥ 130 mg/dL was associated with higher risk (adjusted HR 1.31 [95% CI 1.14-1.50]) after multivariable adjustment; adults with non-HDL-C ≥ 160 mg/dL or apoB ≥ 90 mg/dL also had higher risk after multivariable adjustment. Among adults without ASCVD not taking lipid-lowering therapy at baseline, ASCVD risk for adults with low-normal and high-normal LDL-C, non-HDL-C and apoB was similar, and their risk remained less than in adults with elevated lipoproteins. These findings emphasize the importance of achieving normal atherogenic lipoprotein levels for primary prevention of ASCVD from early adulthood through middle age. Show less

Insulin resistance (IR) and lipoprotein(a), Lp(a), are established contributors to cardiovascular disease (CVD) risk. Whether IR modifies the association between Lp(a) and CVD in primary prevention remains uncertain. This prospective cohort study included UK Biobank participants without baseline CVD. IR at enrollment was assessed using the triglyceride-glucose index (TyG). The primary outcome was first major adverse cardiovascular event, defined as peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, or cardiovascular death. Cox models estimated adjusted hazard ratios (aHRs) with 95% CIs for log-transformed Lp(a) and TyG, adjusting for each other. Lp(a) was categorized as <125 or ≥125 nmol/L; high IR was TyG ≥75th cohort percentile. Participants were stratified into 4 joint Lp(a)/IR groups using low Lp(a)/low IR as reference. Among 328 031 participants (mean age 56.4 years; 54.7% women), 26 865 CVD events occurred over 14.6 years median follow-up (interquartile range 13.7-15.4). Per 1-SD increase, aHRs were 1.08 (95% CI, 1.06-1.09) for log-Lp(a) and 1.06 (95% CI, 1.04-1.07) for TyG, each adjusted for the other. The Lp(a) and IR each independently contribute to cardiovascular risk, with a combination offering improved risk stratification. This suggests that accounting for IR may enhance the assessment of Lp(a)-associated risk in the context of primary CVD prevention setting. Show less

Obicetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor with promising lipid-lowering effects. While earlier CETP inhibitors have shown inconsistent cardiovascular outcomes and safety concerns, the efficacy and safety of obicetrapib remain under active investigation. We systematically searched PubMed, Embase, and Cochrane Central databases for randomized controlled trials (RCTs) comparing obicetrapib versus placebo in adults with dyslipidemia or at high cardiovascular risk. We pooled mean differences (MDs) with 95 % confidence intervals (CI) with a random effects model. We used R software version 4.4.2 for statistical analysis. We included 7 RCTs comprising 3381 participants, of whom 2151 (63 %) received obicetrapib. The mean age was 64.3 years, and 36 % were women. Compared with placebo, obicetrapib significantly reduced mean LDL-C (MD: -37.21 %; 95 % CI: -41.53 to -32.90; Among patients with dyslipidemia and/or high cardiovascular risk, obicetrapib significantly reduces LDL-C, lipoprotein(a), apolipoprotein B, and non-HDL-C. No significant differences were observed in adverse events, supporting the favorable safety profile of obicetrapib. Show less

Reducing LDL cholesterol prevents atherosclerotic cardiovascular disease (ASCVD) events. The aim of this study was to evaluate the LDL cholesterol-lowering efficacy of a fixed-dose combination (FDC) of obicetrapib, a CETP inhibitor, and ezetimibe. This randomised, double-blind trial across 48 US sites including hospitals, private and group practices, and independent research centres included participants at least 18 years old with pre-existing or high risk for ASVCD or heterozygous familial hypercholesterolaemia with LDL cholesterol concentrations of 1·8 mmol/L (70 mg/dL) or greater despite maximally tolerated lipid-lowering therapy excluding ezetimibe, or having statin intolerance. Participants were randomly assigned (1:1:1:1) to obicetrapib 10 mg plus ezetimibe 10 mg FDC, obicetrapib 10 mg monotherapy, ezetimibe 10 mg monotherapy, or placebo administered daily for 84 days. The co-primary endpoints in the intention-to-treat population were the percent LDL cholesterol changes in the FDC group compared with placebo, ezetimibe monotherapy, and obicetrapib monotherapy, and the placebo-adjusted change in the obicetrapib monotherapy group. The trial was prospectively registered (NCT06005597) and is completed. Between March 4 and July 3, 2024, 407 participants were randomly assigned. The median age was 68·0 years (IQR 62·0-73·0) and 177 (43%) were female. Mean baseline LDL cholesterol was 2·4 mmol/L, 2·5 mmol/L, 2·6 mmol/L, and 2·5 mmol/L in the placebo (n=102), ezetimibe monotherapy (n=101), obicetrapib monotherapy (n=102), and FDC groups (n=102), respectively. At day 84, percent differences in LDL cholesterol reduction with the FDC were -48·6% (95% CI -58·3 to -38·9) versus placebo, -27·9% (-37·5 to -18·4) versus ezetimibe, and -16·8% (-26·4 to -7·1) versus obicetrapib. Obicetrapib monotherapy decreased LDL cholesterol by 31·9% (22·1 to 41·6) versus placebo. Adverse event rates were similar in the FDC (52 [51%] of 102), obicetrapib (55 [54%] of 102), and ezetimibe (54 [53%] of 101) groups and lowest with placebo (38 [37%] of 102). Serious adverse event rates were generally similar across FDC (three [3%] of 102), obicetrapib (six [6%] of 102), ezetimibe (seven [7%] of 101), and placebo (four [4%] of 102) groups. Deaths occurred in one [1%] of 102 participants with FDC, one [1%] of 102 with obicetrapib, one [1%] of 101 with ezetimibe, and none with placebo. Combination therapy of obicetrapib and ezetimibe significantly reduced LDL cholesterol. This oral, single-pill therapy could improve LDL cholesterol management in patients with pre-existing or high risk for ASCVD. NewAmsterdam Pharma. Show less

Extreme hypertriglyceridemia, defined as triglyceride (TG) levels ≥1000 mg/dL, is almost always indicative of chylomicronemia. The current diagnostic approach categorizes individuals with chylomicronemia into familial chylomicronemia syndrome (FCS; prevalence 1-10 per million), caused by the biallelic combination of pathogenic variants that impair the lipolytic action of lipoprotein lipase (LPL), or multifactorial chylomicronemia syndrome (MCS, 1 in 500). A pragmatic framework should emphasize the severity of the phenotype and the risk of complications. Therefore, we endorse the term "persistent chylomicronemia (PC)" defined as TG ≥1000 mg/dL in more than half of the measurements to encompass patients with the highest risk for pancreatitis, regardless of their genetic predisposition. We suggest classification of PC into 4 subtypes: (1) genetic FCS, (2) clinical FCS, (3) PC with "alarm" features, and (4) PC without alarm features. Although patients with FCS most likely have PC, the vast majority with PC do not have genetic FCS. Proposed alarm features are: (a) history of recurrent TG-induced acute pancreatitis, (b) recurrent hospitalizations for severe abdominal pain without another identified cause, (c) childhood pancreatitis, (d) family history of TG-induced pancreatitis, and/or (e) postheparin LPL activity <20% of normal value. Alarm features constitute the strongest risk factors for future acute pancreatitis risk. Patients with PC and alarm features have very high risk of pancreatitis, comparable to that in patients with FCS. Effective, innovative treatments for PC, like apolipoprotein C-III inhibitors, have been developed. Combined with lifestyle modifications, these agents markedly lower TG levels and risk of pancreatitis in the very-high-risk groups, irrespective of the monogenic etiology. Pragmatic definitions, education, and focus on patients with PC, specifically those with alarm features, could help mitigate the risk of acute pancreatitis and other complications. Show less

Extreme hypertriglyceridemia, defined as triglyceride (TG) levels ≥1000 mg/dL, is almost always indicative of chylomicronemia. The current diagnostic approach categorizes individuals with chylomicronemia into familial chylomicronemia syndrome (FCS; prevalence 1-10 per million), caused by the biallelic combination of pathogenic variants that impair the lipolytic action of lipoprotein lipase (LPL), or multifactorial chylomicronemia syndrome (MCS, 1 in 500). A pragmatic framework should emphasize the severity of the phenotype and the risk of complications. Therefore, we endorse the term "persistent chylomicronemia" defined as TG ≥1000 mg/dL in more than half of the measurements to encompass patients with the highest risk for pancreatitis, regardless of their genetic predisposition. We suggest classification of PC into four subtypes: 1) genetic FCS, 2) clinical FCS, 3) PC with "alarm" features, and 4) PC without alarm features. Although patients with FCS most likely have PC, the vast majority with PC do not have genetic FCS. Proposed alarm features are: (a) history of recurrent TG-induced acute pancreatitis, (b) recurrent hospitalizations for severe abdominal pain without another identified cause, (c) childhood pancreatitis, (d) family history of TG-induced pancreatitis, and/or (e) post-heparin LPL activity <20 % of normal value. Alarm features constitute the strongest risk factors for future acute pancreatitis risk. Patients with PC and alarm features have very high risk of pancreatitis, comparable to that in patients with FCS. Effective, innovative treatments for PC, like apoC-III inhibitors, have been developed. Combined with lifestyle modifications, these agents markedly lower TG levels and risk of pancreatitis in the very-high-risk groups, irrespective of the monogenic etiology. Pragmatic definitions, education, and focus on patients with PC specifically those with alarm features could help mitigate the risk of acute pancreatitis and other complications. Show less

Mounting evidence continues to support the causal role of triglyceride-rich lipoproteins (TRL) in the development of atherosclerotic cardiovascular disease (ASCVD). Substantial residual ASCVD risk remains among high-risk patients who have elevated triglycerides despite reduction in low-density lipoprotein cholesterol (LDL-C) with statin therapy. Ongoing research efforts have focused on evaluating triglyceride-lowering therapies among patients with hypertriglyceridemia. The REDUCE-IT trial showed that the addition of icosapent ethyl, a highly purified form of eicosapentaenoic acid (EPA), can reduce vascular events among statin-treated individuals with elevated triglycerides who have either clinical ASCVD or diabetes plus another risk factor. Although additional evidence for EPA has emerged from other trials, conflicting results have been reported by subsequent trials that tested different omega-3 fatty acid formulations. Randomized clinical trials have not demonstrated incremental ASCVD benefit of fibrates on background of statin therapy, but fibrates are used to help prevent pancreatitis in patients with severe hypertriglyceridemia. Selective inhibitors of apolipoprotein C-III (apoC3) and angiopoietin-like protein 3 (ANGPTL3), proteins that are involved in metabolism of TRLs by regulating lipoprotein lipase, have been tested in selected patient populations and showed significant reduction in triglyceride and LDL-C levels. Statin therapy continues to be the cornerstone of pharmacologic reduction of cardiovascular risk. High-dose EPA in the form of icosapent ethyl has been demonstrated to have cardiovascular benefit on top of statins in persons with elevated triglycerides at high ASCVD risk. Ongoing clinical trials are evaluating novel selective therapies such as apoC3 and ANGPTL3 inhibitors. Show less