👤 Robert S Rosenson

Elevated lipoprotein(a) [Lp(a)] is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Although Lp(a) is a genetically determined risk factor, the plasma proteomic features associated with Lp(a) and whether they provide information about ASCVD risk beyond Lp(a) concentration are not well characterized. We sought to identify plasma proteomic features associated with Lp(a) concentration and to evaluate whether an Lp(a)-associated proteomic signature is associated with ASCVD phenotypes in young, healthy adults. In the Coronary Artery Risk Development in Young Adults (CARDIA) study, we measured Year 7 Lp(a) and 184 cardiovascular proteins using the Olink proximity extension assay in 3,920 participants without prior coronary heart disease. Lp(a)-associated proteomic signatures were derived using LASSO regression in a split-sample design and tested for association with coronary artery calcification (CAC), incident CHD, and hs-CRP over 27 years of follow-up. External replication was performed in the UK Biobank (n=37,996). Lp(a) was associated with CAC (OR 1.23 [1.13-1.34]; p<0.0001) and incident CHD (HR 1.23 [1.07-1.41]; p=0.004). Lp(a) correlated with proteomic features reflecting immune activation, coagulation, and vascular dysfunction. A quantitative Lp(a) proteomic score was independently associated with incident CAC (standardized beta = 0.40, p<0.0001) and hs-CRP (standardized beta = 0.11, p = 0.00015) after adjustment for Lp(a) concentration. In the UK Biobank, a recalibrated Lp(a)-associated proteomic score was associated with CRP, incident CHD, and all-cause mortality. In young adults, Lp(a) is associated with distinct proteomic features that independently predict ASCVD phenotypes beyond Lp(a) concentration, generating hypotheses regarding biological pathways linked to Lp(a)-related cardiovascular risk. Show less

Lipoprotein(a) [Lp(a)] is an inherited cardiovascular risk factor. However, its association with coronary plaque characteristics beyond traditional risk enhancers remains unclear. We aimed to evaluate the association between Lp(a) levels and coronary plaque characteristics in asymptomatic primary prevention patients, and to compare its predictive value against other risk enhancers, including LDL particle concentration (LDL-P), high-sensitivity C-reactive protein (hsCRP), and coronary artery calcium (CAC) score. We retrospectively analyzed 547 asymptomatic patients undergoing coronary computed tomography angiography (CCTA) between 2018-2024. Plaque characteristics were assessed using artificial intelligence-based quantitative CCTA. Associations between Lp(a), LDL-P, hsCRP, CAC score, and plaque features were evaluated using multivariable regression adjusted for age and sex. Median age was 56 years, 69.8% were male. Higher Lp(a) was associated with greater total plaque volume (β=23.1 mm³, p=0.006), calcified plaque (β=11.1 mm³, p=0.014), non-calcified plaque (β=12.0 mm³, p=0.027), and low-density non-calcified plaque (LDNCP; β=0.4 mm³, p<0.001) volumes, as well as increased area stenosis (β=1.9%, p=0.031) and remodeling index (β=0.02, p=0.017). In multivariable models, CAC score was the strongest predictor of overall plaque burden including calcified and non-calcified plaque (p<0.000) but was not associated with LDNCP. Lp(a) remained independently associated with LDNCP (β=0.45 mm³, p=0.013), while LDL-P and hsCRP showed no significant associations. In asymptomatic primary prevention patients, Lp(a) was independently associated with high-risk coronary plaque features, specifically LDNCP, beyond traditional risk enhancers. These findings highlight the unique role of Lp(a) in identifying coronary plaque vulnerability and suggest complementary roles for Lp(a) and CAC in refining cardiovascular risk stratification. Show less

Patients with severe hypertriglyceridemia (sHTG) have variable lipoprotein lipase (LPL) activity levels that may influence therapeutic response. This exploratory analysis investigated post-heparin triglyceride lipase and phospholipase activities in three cohorts of patients with sHTG who received evinacumab (angiopoietin-like 3 inhibitor) for 12 or 24 weeks during a phase 2 trial: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function (LOF) LPL pathway mutations; cohort 2, multifactorial chylomicronemia syndrome (MCS) with heterozygous LOF LPL pathway mutations; and cohort 3, MCS without LPL pathway mutations. Post-heparin plasma samples were obtained at baseline and at week 24 (end of the treatment period). Triglyceride lipase activities (LPL and hepatic lipase [HL]) were measured using both a colorimetric and a scintillation assays. Phospholipase activities (HL and endothelial lipase [EL]) were measured using a colorimetric assay. Baseline post-heparin LPL triglyceride lipase activity was lowest in cohort 1; treatment with evinacumab for 12 or 24 weeks did not alter activity at week 24 versus baseline across cohorts using the colorimetric assay. Non-HL triglyceride lipase activity (mostly LPL) assessed using the scintillation assay showed a significant increase in cohort 1 at 24 weeks versus baseline (P = 0.04). Neither HL nor EL phospholipase activities differed among cohorts or changed with evinacumab treatment. High intra- and inter-patient variability in lipase activity was observed with all methods. Post-heparin LPL triglyceride lipase activity was lower in patients with sHTG with bi-allelic LPL pathway mutations and increased in that group with evinacumab. The high variability in lipase activities observed via differing methods supports the need for more robust assays. Show less

The development of tendinous xanthomas in childhood with a low-density lipoprotein (LDL) cholesterol level >400 mg/dL is characteristic of homozygous familial hypercholesterolemia (FH). We present the case of a patient with a severely elevated LDL cholesterol level and childhood-onset xanthomas who fulfilled clinical criteria for homozygous FH. However, genetic and absorption testing clarified his phenotype to be a unique digenic overlap of both heterozygous FH and heterozygous sitosterolemia with marked elevations in cholesterol absorption indices. Treatment with ezetimibe 10 mg daily resulted in a dramatic reduction in LDL cholesterol. Sitosterolemia, a rare autosomal recessive disorder of plant sterol hyperabsorption, can also result in xanthomatosis and thus can mimic FH. Although it is usually a homozygous disease, heterozygotes may exhibit intermediary phenotypes. Patients with severe hypercholesterolemia should undergo genetic and biochemical profiling for diagnostic confirmation and for ensuring that they receive optimal, personalized therapy. Show less

Despite the modern era of effective and safe high-intensity statins and non-statin agents, a significant portion of patients are still unable to achieve guideline-recommended lipid goals for the prevention of atherosclerotic cardiovascular disease (ASCVD) events. Accordingly, novel strategies are needed to further mitigate residual risk for patients on the background of maximally tolerated lipid-lowering therapies. The past decade has seen an explosion of new agents leveraging ribonucleic acid (RNA)-based technology which reduce plasma lipoprotein levels. In this state-of-the-art review, we examine the ongoing clinical development of lipid-lowering RNA therapeutics. We discuss the efficacy and safety profiles of antisense oligonucleotides and small interfering RNA agents targeting low-density lipoprotein, lipoprotein(a), and triglyceride-rich lipoproteins. We also present challenges future clinical trials must answer to prove RNA therapeutics as a viable strategy for ASCVD prevention among patients with refractory hyperlipidemia. Show less

Mixed dyslipidaemia, characterised by elevated concentrations of circulating triglycerides and LDL cholesterol (LDL-C), is associated with an increased risk of atherosclerotic cardiovascular disease. Solbinsiran, a GalNAc-conjugated small interfering RNA targeting hepatic angiopoietin-like protein 3 (ANGPTL3), reduced triglycerides and LDL-C concentrations in a phase 1 study. This study aimed to assess the durability and efficacy of solbinsiran in reducing concentrations of atherogenic lipoproteins in adults with mixed dyslipidaemia. This double-blind, parallel-arm, randomised, placebo-controlled, phase 2 trial enrolled adults (aged ≥18 years) with mixed dyslipidaemia at 41 clinical research units across seven countries. Patients receiving moderate-intensity or high-intensity statins, and with concentrations of fasting triglycerides between 1·69 mmol/L and 5·64 mmol/L, LDL-C of at least 1·81 mmol/L, and non-HDL cholesterol of at least 3·36 mmol/L were included. Using an interactive web-response system, patients were randomly assigned (1:2:2:2) to receive either solbinsiran 100 mg, solbinsiran 400 mg, solbinsiran 800 mg, or placebo, by subcutaneous injection on days 0 and 90. Patients were followed up for at least 270 days. The primary outcome was percent change in apolipoprotein B (apoB) concentration from baseline to day 180 with solbinsiran compared with placebo, analysed under an efficacy estimand (in patients who received at least one dose of the study drug). This trial is completed and registered with ClinicalTrials.gov, NCT05256654. Of 585 patients screened, 205 patients were enrolled in the study between July 20, 2022, and March 4, 2024. Patients (111 [54%] female and 94 [46%] male; median age 57 years [IQR 49-65]) were randomly assigned to receive solbinsiran 100 mg (n=30), solbinsiran 400 mg (n=58), solbinsiran 800 mg (n=59), or placebo (n=58). At baseline, median concentrations were 111 mg/dL (IQR 96-130) for apoB, 2·64 mmol/L (2·06-3·29) for triglycerides, and 3·16 mmol/L (2·57-3·82) for LDL-C. The placebo-adjusted percent change in apoB concentration from baseline at day 180 was -2·8% (95% CI -15·5 to 11·9; p=0·69) for solbinsiran 100 mg; -14·3% (-23·6 to -3·9; p=0·0085) for solbinsiran 400 mg; and -8·3% (-18·3 to 2·9; p=0·14) for solbinsiran 800 mg. Solbinsiran administration was well tolerated, with a low incidence of adverse events. The number of patients with treatment-emergent adverse events was 18 [60%] of 30 patients in the solbinsiran 100 mg group, 30 [52%] of 58 patients in the solbinsiran 400 mg group, 26 [44%] of 59 patients in the solbinsiran 800 mg group, and 37 [65%] of 57 patients in the placebo group. Solbinsiran 400 mg reduced apoB in patients with mixed dyslipidaemia and was generally well tolerated. The impact of solbinsiran on cardiovascular outcomes remains to be investigated. Eli Lilly and Company. Show less

Plozasiran, an investigational siRNA targeting hepatic apoC-III, reduces triglyceride-rich lipoproteins (TRLs). The impact of plozasiran on lipoprotein particle numbers and sizes is unknown. However, reductions in the number of TRL particles (TRL-P) and a shift to possibly less atherogenic large low-density lipoprotein particles (LDL-P) are expected. This study aimed to determine the impact of plozasiran on lipoprotein particle concentration and subclass distribution using nuclear magnetic resonance (NMR) in 2 phase 2 studies. Patients (N = 403) from SHASTA-2 (severe hypertriglyceridemia) and MUIR (mixed hyperlipidemia) were administered 2 total subcutaneous doses of plozasiran (10, 25, or 50 mg) or placebo at baseline and week 12. Comprehensive lipoprotein profiling was conducted with NMR. In SHASTA-2, there was a dose-dependent reduction in TRL-P, with placebo-adjusted total TRL-P reductions of -46% and reductions across all TRL subclasses with plozasiran. While total LDL-P was unchanged, large LDL-P concentration increased by +53% and medium by +56%; small LDL-P trended lower (-13%). Total HDL-P increased by +8%, primarily driven by a +36% increase in large high-density lipoprotein particles (HDL-Ps). Similarly, in MUIR, there were dose-dependent reductions in TRL-P, with total TRL-P significantly reduced by -48% (pooled plozasiran) and reductions across all TRL subclasses with plozasiran. While total LDL-P was unchanged, large and medium LDL-P levels increased by +88% and +46%, respectively; small LDL-P levels decreased by -28%. Total HDL-P increased by +12%, driven by a +83% increase in large HDL-P. Plozasiran induced reductions in apoC-III and showed potentially favorable quantitative and qualitative changes in lipoproteins as assessed by NMR in patients with hypertriglyceridemia and mixed hyperlipidemia. Plozasiran reduced TRL-P by ∼50%, shifted LDL to larger particles, and modestly increased HDL-P concentration. While high-potency TRL-lowering therapies can lead to an overall LDL-C increase, plozasiran did not increase LDL-P or apoB but shifted LDL particle size distribution from small dense LDL toward larger sizes. The ∼50% reduction in TRL-P with no increase in apoB and possibly beneficial qualitative changes in LDL suggests the potential of plozasiran to lower cardiovascular risk, which may be evaluated in a prospective outcomes trial. Show less

Lipoprotein(a) (Lp[a]) is thought to be the major carrier of oxidized phospholipids (OxPL). OxPL are believed to be a potent driver of inflammation and atherosclerosis. Olpasiran, a small interfering RNA, blocks Lp(a) production by inducing degradation of apolipoprotein(a) messenger RNA. Olpasiran's effects on OxPL and systemic markers of inflammation are not well described. To assess the effects of olpasiran on OxPL, high-sensitivity interleukin 6 (hs-IL-6), and hs-C-reactive protein (hs-CRP) in the OCEAN(a)-DOSE randomized clinical trial. OCEAN(a)-DOSE was an international, multicenter, placebo-controlled, phase 2, dose-finding randomized clinical trial conducted between July 2020 and November 2022. A total of 281 patients with atherosclerotic cardiovascular disease and Lp(a) levels greater than 150 nmol/L were included. Participants were randomized to receive 1 of 4 active subcutaneous doses of olpasiran vs placebo: (1) 10 mg, administered every 12 weeks (Q12W); (2) 75 mg, Q12W; (3) 225 mg, Q12W; or (4) 225 mg, administered every 24 weeks (Q24W). OxPL on apolipoprotein B (OxPL-apoB), hs-CRP, and hs-IL-6 were assessed at baseline, week 36, and week 48 in 272 patients. The primary outcome was placebo-adjusted change in OxPL-apoB from baseline to week 36. Among 272 participants, median (IQR) age was 62 years (56-69), and 86 participants (31.6%) were female. Baseline median (IQR) Lp(a) concentration was 260.3 nmol/L (198.1-352.4) and median (IQR) OxPL-apoB concentration was 26.5 nmol/L (19.7-33.9). The placebo-adjusted mean percentage change in OxPL-apoB from baseline to week 36 was -51.6% (95% CI, -64.9% to -38.2%) for the 10-mg Q12W dose, -89.7% (95% CI, -103.0% to -76.4%) for the 75-mg Q12W dose, -92.3% (95% CI, -105.6% to -78.9%) for the 225-mg Q12W dose, and -93.7% (95% CI, -107.1% to -80.3%) for the Q24W dose (P < .001 for all). These effects were maintained to week 48 (-50.8%, -100.2%, -104.7%, and -85.8%, respectively; P < .001 for all). There was a strong correlation between percentage reduction in Lp(a) and OxPL-apoB for patients treated with olpasiran (r = 0.79; P < .001). Olpasiran did not significantly impact hs-CRP or hs-IL-6 compared with placebo to weeks 36 or 48 (P > .05). In the OCEAN(a)-DOSE multicenter randomized clinical trial, olpasiran led to a significant and sustained reduction in OxPL-apoB but no significant effects on hs-CRP or hs-IL-6. Show less

Multiple agents are being developed that inhibit apolipoprotein (apo) C-III. This state-of-the-art review examines their potential for atherosclerotic cardiovascular disease (ASCVD) risk reduction. Apo C-III, an apolipoprotein on the surface of triglyceride-rich lipoproteins (TRLs), impairs clearance of TRLs through both lipoprotein lipase dependent and independent pathways, thereby resulting in increased concentrations of triglycerides. Apo C-III has also been shown to have pro-atherogenic effects when bound to high-density lipoprotein (HDL) particles. Classical and genetic epidemiology studies provide support for the concept that apo C-III is associated with an increased risk of ASCVD events. Drug efficacy of agents that silence APOC3 mRNA has been studied in populations with varying hypertriglyceridemia severity, including those with familial chylomicronemia syndrome, multifactorial chylomicronemia syndrome/severe hypertriglyceridemia, and mixed hyperlipidemia. Randomized controlled trials have reported significant reductions in TG and non-HDL cholesterol levels among these patients treated with APOC3 inhibitors. Upcoming clinical outcomes trials seek to establish a role for APOC3 inhibitors to reduce risk of ASCVD. Show less

Low-density lipoprotein cholesterol (LDL-C) is used to guide lipid-lowering therapy after a myocardial infarction (MI). Lack of LDL-C testing represents a missed opportunity for optimizing therapy and reducing cardiovascular risk. The purpose of this study was to estimate the proportion of Medicare beneficiaries who had their LDL-C measured within 90 days following MI hospital discharge. We conducted a retrospective cohort study of Medicare beneficiaries ≥66 years of age with an MI hospitalization between 2016 and 2020. The primary analysis used data from all beneficiaries with fee-for-service coverage and pharmacy benefits (532,767 MI hospitalizations). In secondary analyses, we used data from a 5% random sample of beneficiaries with fee-for-service coverage without pharmacy benefits (10,394 MI hospitalizations), and from beneficiaries with Medicare Advantage (176,268 MI hospitalizations). The proportion of beneficiaries who had their LDL-C measured following MI hospital discharge was estimated accounting for the competing risk of death. In the primary analysis (mean age 76.9 years, 84.4% non-Hispanic White), 29.9% of beneficiaries had their LDL-C measured within 90 days following MI hospital discharge. Among Hispanic, Asian, non-Hispanic White, and non-Hispanic Black beneficiaries, the 90-day postdischarge LDL-C testing was 33.8%, 32.5%, 30.0%, and 26.0%, respectively. Postdischarge LDL-C testing within 90 days was highest in the Middle Atlantic (36.4%) and lowest in the West North Central (23.4%) U.S. regions. In secondary analyses, the 90-day postdischarge LDL-C testing was 26.9% among beneficiaries with fee-for-service coverage without pharmacy benefits, and 28.6% among beneficiaries with Medicare Advantage coverage. LDL-C testing following MI hospital discharge among Medicare beneficiaries was low. Show less

Persons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non-high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)-mediated inhibition of lipoprotein lipase. We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24. A total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of -49.8 percentage points (95% confidence interval [CI], -59.0 to -40.6) with the 10-mg-quarterly dose, -56.0 percentage points (95% CI, -65.1 to -46.8) with the 25-mg-quarterly dose, -62.4 percentage points (95% CI, -71.5 to -53.2) with the 50-mg-quarterly dose, and -44.2 percentage points (95% CI, -53.4 to -35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose. In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted. (Funded by Arrowhead Pharmaceuticals; MUIR ClinicalTrials.gov number NCT04998201.). Show less

Severe hypertriglyceridemia (sHTG) confers increased risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic steatohepatitis, and acute pancreatitis. Despite available treatments, persistent ASCVD and acute pancreatitis-associated morbidity from sHTG remains. To determine the tolerability, efficacy, and dose of plozasiran, an APOC3-targeted small interfering-RNA (siRNA) drug, for lowering triglyceride and apolipoprotein C3 (APOC3, regulator of triglyceride metabolism) levels and evaluate its effects on other lipid parameters in patients with sHTG. The Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia (SHASTA-2) was a placebo-controlled, double-blind, dose-ranging, phase 2b randomized clinical trial enrolling adults with sHTG at 74 centers across the US, Europe, New Zealand, Australia, and Canada from May 31, 2021, to August 31, 2023. Eligible patients had fasting triglyceride levels in the range of 500 to 4000 mg/dL (to convert to millimoles per liter, multiply by 0.0113) while receiving stable lipid-lowering treatment. Participants received 2 subcutaneous doses of plozasiran (10, 25, or 50 mg) or matched placebo on day 1 and at week 12 and were followed up through week 48. The primary end point evaluated the placebo-subtracted difference in means of percentage triglyceride change at week 24. Mixed-model repeated measures were used for statistical modeling. Of 229 patients, 226 (mean [SD] age, 55 [11] years; 176 male [78%]) were included in the primary analysis. Baseline mean (SD) triglyceride level was 897 (625) mg/dL and plasma APOC3 level was 32 (16) mg/dL. Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)-mean reductions in triglyceride levels (primary end point) of -57% (95% CI, -71.9% to -42.1%; P < .001), driven by placebo-adjusted reductions in APOC3 of -77% (95% CI, -89.1% to -65.8%; P < .001) at week 24 with the highest dose. Among plozasiran-treated patients, 144 of 159 (90.6%) achieved a triglyceride level of less than 500 mg/dL. Plozasiran was associated with dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) level, which was significant in patients receiving the highest dose (placebo-adjusted LS-mean increase 60% (95% CI, 31%-89%; P < .001). However, apolipoprotein B (ApoB) levels did not increase, and non-high-density lipoprotein cholesterol (HDL-C) levels decreased significantly at all doses, with a placebo-adjusted change of -20% at the highest dose. There were also significant durable reductions in remnant cholesterol and ApoB48 as well as increases in HDL-C level through week 48. Adverse event rates were similar in plozasiran-treated patients vs placebo. Serious adverse events were mild to moderate, not considered treatment related, and none led to discontinuation or death. In this randomized clinical trial of patients with sHTG, plozasiran decreased triglyceride levels, which fell below the 500 mg/dL threshold of acute pancreatitis risk in most participants. Other triglyceride-related lipoprotein parameters improved. An increase in LDL-C level was observed but with no change in ApoB level and a decrease in non-HDL-C level. The safety profile was generally favorable at all doses. Additional studies will be required to determine whether plozasiran favorably modulates the risk of sHTG-associated complications. ClinicalTrials.gov Identifier: NCT04720534. Show less

Severe hypertriglyceridemia (sHTG), defined as a triglyceride (TG) concentration ≥ 500 mg/dL (≥ 5.7 mmol/L) is an important risk factor for acute pancreatitis. Although lifestyle, some medications, and certain conditions such as diabetes may lead to HTG, sHTG results from a combination of major and minor genetic defects in proteins that regulate TG lipolysis. Familial chylomicronemia syndrome (FCS) is a rare disorder caused by complete loss of function in lipoprotein lipase (LPL) or LPL activating proteins due to two homozygous recessive traits or compound heterozygous traits. Multifactorial chylomicronemia syndrome (MCS) and sHTG are due to the accumulation of rare heterozygous variants and polygenic defects that predispose individuals to sHTG phenotypes. Until recently, treatment of sHTG focused on lifestyle interventions, control of secondary factors, and nonselective pharmacotherapies that had modest TG-lowering efficacy and no corresponding reductions in atherosclerotic cardiovascular disease events. Genetic discoveries have allowed for the development of novel pathway-specific therapeutics targeting LPL modulating proteins. New targets directed towards inhibition of apolipoprotein C-III (apoC-III), angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), and fibroblast growth factor-21 (FGF21) offer far more efficacy in treating the various phenotypes of sHTG and opportunities to reduce the risk of acute pancreatitis and atherosclerotic cardiovascular disease events. Show less

Triglyceride-rich lipoproteins (TRLs) are a source of residual risk in patients with atherosclerotic cardiovascular disease, and are indirectly correlated with triglyceride (TG) levels. Previous clinical trials studying TG-lowering therapies have either failed to reduce major adverse cardiovascular events or shown no linkage of TG reduction with event reduction, particularly when these agents were tested on a background of statin therapy. Limitations in trial design may explain this lack of efficacy. With the advent of new RNA-silencing therapies in the TG metabolism pathway, there is renewed focus on reducing TRLs for major adverse cardiovascular event reduction. In this context, the pathophysiology of TRLs, pharmacological effects of TRL-lowering therapies, and optimal design of cardiovascular outcomes trials are major considerations. Show less