Latest Focus

Solbinsiran, siRNA targeting ANGPTL3, shows promise in mixed dyslipidemia

Ray KK, Oru E, Rosenson RS, et al. Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3): a double-blind, randomised, placebo-controlled, phase 2 trial.

In the PROLONG-ANG3 trial, solbinsiran, an N-acetylgalactosamine-conjugated small interfering RNA (siRNA) targeting hepatic angiopoietin-like protein 3 (ANGPTL3) expression, reduced apolipoprotein (apo)B  in adults with mixed dyslipidemia. There was no evidence of adverse effects on hepatic fat fraction. Further study is merited.

Potential for combination therapy targeting APOC3 and LDL-C

Wang W, Li R, Song Z, Huang N, et al. Joint associations of APOC3 and LDL-C–lowering variants with the risk of coronary heart disease.

Results from this genetic association study including over 400,000 UK Biobank subjects provide the first evidence that combined intervention against APOC3- and LDL-C-lowering targets could offer improved benefit for lipid profiles and reduction in coronary heart disease risk over monotherapy. These findings merit study in clinical trials.

2024                                             

Target remnant cholesterol to reduce residual risk of stroke

Han M, Huang K, Shen C, et al. Discordant high remnant cholesterol with LDL-C increases the risk of
stroke: A Chinese Prospective Cohort Study. Stroke 2024;55:2066-74.

In this prospective cohort study, high remnant cholesterol with controlled low-density lipoprotein cholesterol conferred higher risk of stroke, specifically ischemic stroke. These findings support targeting remnant cholesterol to reduce the high residual risk of ischemic stroke.

Olezarsen shows promise in hypertriglyceridemia

Bergmark BA, Marston NA, Prohaska TA, et al. Olezarsen for hypertriglyceridemia in patients at high cardiovascular risk. N Engl J Med 2024; DOI: 10.1056/NEJMoa2402309

In the Bridge–TIMI 73a trial, treatment with olezarsen, an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), significantly reduced triglycerides (TG) in patients with moderate hypertriglyceridemia and high cardiovascular risk.

Plozasiran: a novel APOC3 siRNA in mixed hyperlipidemia

Ballantyne CM, Vasas S, Azizad M, et al. Plozasiran, an RNA interference agent targeting APOC3, for
mixed hyperlipidemia. N Engl J Med 2024; doi: 10.1056/NEJMoa2404143

Plozasiran, a first-in-class hepatocyte-targeted APOC3 small interfering RNA therapeutic,
substantially reduced triglyceride levels in patients with mixed hyperlipidemia.

More insights into PROMINENT

Doi T, Langsted A, Nordestgaard BG. Remnant cholesterol, LDL cholesterol, and apoB absolute mass
changes explain results of the PROMINENT trial. Atherosclerosis 2024;393:117556

According to this analysis from the Copenhagen General Population Study Group, absolute mass
changes in remnant cholesterol, low-density lipoprotein cholesterol (LDL-C) and apolipoprotein
(apo)B explain the neutral results of the PROMINENT trial with pemafibrate.

Insights from CLEAR-Outcomes trial: Targeting LDL cholesterol alone is not enough

Ridker PM, Lei L, Louie MJ, et al. Inflammation and cholesterol as predictors of cardiovascular events among 13970 contemporary high-risk patients with statin intolerance. Circulation 2024;149:28–35.

According to this trial analysis, high-sensitivity C-reactive protein (hsCRP) predicts cardiovascular events more strongly than low-density lipoprotein cholesterol (LDL-C) in high-risk statin-intolerant patients.

Comorbid microvascular disease in patients with peripheral artery disease: an escalating issue

Grubman S, Algara M, Smolderen KG, et al. Examining outcomes in patients admitted with comorbid peripheral artery disease and microvascular disease. J Am Heart Assoc 2024;13:e030710.

Using data from over 33 million hospital admissions in the USA, over 25% of patients admitted with peripheral artery disease (PAD) had comorbid microvascular disease. This group was at higher risk of adverse limb and cardiovascular events.

Elevated lipoprotein(a) and coronary risk in acute coronary syndrome patients

Shiyovich A, Berman AN, Besser SA, et al. Cardiovascular outcomes in patients with coronary artery disease and elevated lipoprotein(a): implications for the OCEAN(a)-outcomes trial population. Eur Heart J Open 2023;3, 1–4.

This observational study in patients with coronary artery disease and elevated lipoprotein(a) [Lp(a)] levels, consistent with the population enrolled in the ongoing Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction [OCEAN(a)]-Outcomes trial, provides valuable insights.

2023                                             

Managing remnant cholesterol: consider both accumulation and visit variability

Wang J, Jin R, Jin X, et al. Separate and joint associations of remnant cholesterol accumulation and variability with carotid atherosclerosis: a prospective cohort study. J Am Heart Assoc 2023;12:e029352. DOI: 10.1161/. JAHA.122.029352

According to this study from China, the combination of higher cumulative remnant cholesterol and greater remnant cholesterol variability exacerbates the independent risk of carotid atherosclerosis in the general population.

Lipid control in high-risk patients: women still lag behind men

Dong W, Yang Z. Trends in lipid profile and lipid control among survivors of stroke or myocardial infarction among US adults, 2001–2018. Front Endocrinol 2023;14:1128878

While data from the US National Health and Nutrition Survey (NHANES) 2001-2018 showed a trend for improved lipid control among survivors of a stroke or myocardial infarction (MI), women still have poorer lipid control than men.

Elevated triglycerides, a prevalent identifier of high cardiovascular risk

Leatherman S, Ferguson R, Hau C, et al. Increased residual cardiovascular risk in U.S. veterans with moderately elevated baseline triglycerides and well-controlled LDL-C levels on statins. Front Cardiovasc Med 2022; 9:982815. doi: 10.3389/fcvm.2022.982815

In a large cohort study including nearly 400,000 US veterans, elevated triglycerides (TG) helped to identify individuals with established cardiovascular disease or with diabetes alone at high residual cardiovascular risk.

2022                                             

RESPECT-EPA– Randomized Trial for Evaluating Secondary Prevention Efficacy of Combination Therapy – Statin and Eicosapentaenoic Acid

Daida H, et al. RESPECT-EPA – Randomized Trial for Evaluating Secondary Prevention Efficacy of Combination Therapy – Statin and Eicosapentaenoic Acid. Presented at the American Heart Association Scientific Sessions 2022.

The RESPECT-EPA trial showed a marginally significant effect of highly purified eicosapentaenoic acid (EPA) on the primary outcome (a composite of cardiovascular death, nonfatal myocardial infarction [MI], nonfatal ischemic stroke, unstable angina pectoris, or coronary revascularization). The study did, however, have large dropout and protocol violation rates.

News from TRANSLATE-TIMI 70 with vupanorsen, ANGPLT3 antisense oligonucleotide

Bergmark BA, Marston NA, Bramson CR, et al. Effect of vupanorsen on non-high-density lipoprotein cholesterol levels in statin-treated patients with elevated cholesterol: TRANSLATE-TIMI 70. Circulation 2022;145:1377-1386.

In TRANSLATE-TIMI 70 (ClinicalTrials.gov Identifier: NCT04516291) treatment with vupanorsen, an antisense oligonucleotide that inhibits hepatic angiopoietin-like 3 (ANGPTL3) protein synthesis, reduced non-high-density lipoprotein cholesterol (non-HDL-C) in statin-treated patients. Triglycerides were also reduced in a dose-dependent manner.

Elevated lipoprotein(a) promotes progression of vulnerable plaque

Kaiser Y, Daghem M, Tzolos E, et al. Association of lipoprotein(a) with atherosclerotic plaque progression. J Am Coll Cardiol 2022;79:223–233.

Among patients with advanced coronary artery disease, elevated serum levels of lipoprotein(a) [Lp(a)] were associated with accelerated progression of the low-attenuation necrotic core of atherosclerotic plaques, as assessed by coronary computed tomography angiography.

Triglycerides and mortality risk in diabetes

Wadström BN, Wang Y. Higher fasting triglyceride predicts higher risks of diabetes mortality in US adults. Lipids in Health and Disease 2021;20:181.

This report from the National Health and Nutrition Examination Surveys (NHANES) showed that a higher fasting triglyceride level was associated with a higher risk of diabetes-related death.

2021                                             

New study makes the case for identifying remnant cholesterol-related residual risk in primary prevention

Quispe R, Martin S, Michos ED et al. Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study. Eur Heart J 2021 doi: 10.1093/eurheartj/ehab432. Online ahead of print.

Analysis of pooled data from individuals free of atherosclerotic cardiovascular disease (ASCVD) showed that levels of remnant cholesterol were associated with ASCVD independent of traditional cardiovascular risk factors, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C) or apolipoprotein B levels

PESA study: elevated triglycerides associate with subclinical atherosclerosis

Raposeiras-Roubin S, Rosselló X, Oliva B et al. Triglycerides and residual atherosclerotic risk. J Am Coll Cardiol 2021;22: 3031 – 41.

In this report from the PESA (Progression of Early Subclinical Atherosclerosis) study, triglyceride (TG) levels ≥150 mg/dL (≥1.7 mmol/L) were associated with subclinical atherosclerosis, even if low-density lipoprotein cholesterol (LDL-C) levels were normal.

Direct or calculated remnant cholesterol: does it matter?

Varbo A, Nordestgaard BG. Directly measured vs. calculated remnant cholesterol identifies additional overlooked individuals in the general population at higher risk of myocardial infarction. Eur Heart J 2021 ; doi: 10.1093/eurheartj/ehab293. Online ahead of print.

In this report from the Copenhagen General Population Study, direct measurement of remnant cholesterol identifies an additional 5% of individuals in the general population with cholesterol-rich, triglyceride (TG)-poor remnants who are at increased risk of myocardial infarction.

Identifying residual cardiovascular risk: which are the best lipid biomarkers?

Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG. Apolipoprotein B and non-HDL cholesterol better reflect residual risk than LDL cholesterol in statin-treated patients. J Am Coll Cardiol 2021;77:1439-50.

In this report from the Copenhagen General Population Study, apolipoprotein B or non-high-density lipoprotein cholesterol (non-HDL-C) were preferred to low-density lipoprotein cholesterol (LDL-C) to better identify residual cardiovascular risk in statin-treated patients.

PREDIMED shows association between remnant cholesterol and incident cardiovascular disease

Castañer O, Pintó X, Subirana I et al. Remnant cholesterol, not LDL cholesterol, is associated with incident cardiovascular disease. J Am Coll Cardiol 2020;76: 2712-24.

Among overweight or obese high-risk primary prevention patients, levels of triglycerides (TG) and remnant cholesterol – but not low-density lipoprotein cholesterol (LDL-C) – associate with cardiovascular outcomes.

Empagliflozin reduced the total burden of cardiovascular complications in type 2 diabetes patients with cardiovascular disease

McGuire DK, Zinman B, Inzucchi SE, et al. Effects of empagliflozin on first and recurrent clinical events in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a secondary analysis of the EMPA-REG OUTCOME trial. Lancet Diabetes Endocrinol 2020;8:949-59.

This latest report from the EMPA-REG OUTCOME trial showed continued aggregation of benefit beyond first cardiovascular events with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin on top of the current standard of care.

2020                                             

Vupanorsen, an N-acetyl galactosamine-conjugated ANGPTL3 antisense drug, shows promise

Gaudet D, Karwatowska-Prokopczuk E, Baum SJ et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur Heart J 2020 ; doi:10.1093/eurheartj/ehaa689

Targeting hepatic angiopoietin-like 3 (ANGPTL3) protein synthesis with vupanorsen (AKCEA-ANGPTL3-L Rx) reduced fasting triglycerides and apolipoprotein B-containing atherogenic lipoproteins in patients with type 2 diabetes, hepatic steatosis, and elevated triglycerides.

Lipoprotein(a): a marker of residual cardiovascular risk

Lipoprotein(a) may offer prognostic value when assessing the risk of recurrent cardiovascular events, according to this real-world analysis of secondary prevention patients.

Liu HH, Cao YX, Jin JL et al. Association of lipoprotein(a) levels with recurrent events in patients with coronary artery disease. Heart 2020; doi:10.1136/heartjnl-2020-316586.

Insights from the Women’s Health Study: Cholesterol in triglyceride-rich lipoproteins strongly associates with incident cardiovascular disease

Results from a prospective case-cohort study within the Women’s Health Study show that the cholesterol content of triglyceride-rich lipoproteins (TRLs) influences atherogenesis independently of low-density lipoprotein cholesterol.

Duran EK, Aday AW, Cook NR et al. Triglyceride-rich lipoprotein cholesterol, small dense LDL cholesterol, and incident cardiovascular disease. J Am Coll Cardiol 2020; 75:2122–35.

Meta-analysis: Association between triglyceride lowering and reduction of cardiovascular risk

In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for low-density lipoprotein cholesterol (LDL-C) lowering.

Marston NA, Giugliano RP, Im KA, et al. Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering therapeutic classes. A systematic review and meta-regression analysis of randomized controlled trials. Circulation 2019;140:1308–17.

Real world data: Hypertriglyceridemia is common among patients with cardiovascular disease and confers higher cardiovascular risk

One in four patients with cardiovascular disease and controlled low-density lipoprotein cholesterol have elevated triglyceride levels (135–499 mg/dL or 1.52–5.63 mmol/L). The risk of cardiovascular events in this group increases as triglyceride levels increase.

Lawler PR, Kotrri G, Koh M et al. Real-world risk of cardiovascular outcomes associated with hypertriglyceridaemia among individuals with atherosclerotic cardiovascular disease and potential eligibility for emerging therapies. Eur Heart J 2019; doi:10.1093/eurheartj/ehz767

2019                                             

ANGPTL3 monoclonal antibody in hypertriglyceridemia

Evinacumab, a monoclonal antibody to ANGPTL3 (angiopoietin-like protein 3), produced substantial and sustained reduction in triglycerides in Phase I trials in patients with mild to moderate hypertriglyceridaemia.

Ahmad Z, Banerjee P, Hamon S et al. Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia. Circulation 2019; DOI: 10.1161/CIRCULATIONAHA.118.039107

Remnant cholesterol and risk of ischaemic stroke

High remnant cholesterol levels were associated with a higher risk of ischaemic stroke according to this report from the Copenhagen General Population Study.

Varbo A, Nordestgaard BG. Remnant cholesterol and risk of ischemic stroke in 112,512 individuals from the general population. Ann Neurol 2019;85:550-9.

2018                                             

More evidence linking remnants with cardiovascular disease

Findings from the ARIC (Atherosclerosis Risk in Communities) study show that both remnant lipoprotein cholesterol (RLP-C) and low-density lipoprotein triglycerides (LDL-TG) levels were predictive of cardiovascular disease and associated with APOE variants.

Saeed A, Feofanova EV, Yu B et al. Remnant-like particle cholesterol, low-density lipoprotein triglycerides, and incident cardiovascular disease. J Am Coll Cardiol 2018;72:156–69.