Benefits of olezarsen in severe hypertriglyceridemia

Final results from the CORE studies show that olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (APOC3) messenger RNA, reduced triglycerides and the incidence of acute pancreatitis compared with placebo. These findings point to a new therapy for these difficult to manage patients.

The CORE studies were two double-blind, randomized, placebo-controlled trials (CORE-TIMI 72a and CORE2-TIMI 72b) including patients with severe hypertriglyceridemia, defined as plasma triglycerides > 500 mg/dL on two occasions while on stable lipid-lowering therapy according to the local standard of care. Patients  were randomly allocated to treatment with olezarsen (50 mg or 80 mg), or placebo monthly for 12 months. The primary endpoint was the percent change from baseline in the triglyceride level at 6 months, compared for each olezarsen dose group and placebo. In addition,  acute pancreatitis events were assessed across both trials.

Overall, 1061 patients were included in the primary analysis (617 in the CORE-TIMI 72a trial and 444 in the CORE2-TIMI 72b trial). Overall, the median age of patients was 54 years, 23.6% were women, and 63.4% had diabetes. Almost all patients were receiving at least one lipid-lowering medication, with 63.5% receiving a fibrate. At baseline, the median triglyceride level was 793 mg/dL (8.96 mmol/L).

At 6 months, the CORE-TIMI 72a trial showed that olezarsen 50 mg reduced the triglyceride level from baseline by −62.9% (95% CI −72.2 to −53.6; p<0.001, placebo-adjusted) and in the 80 mg dose group by −72.2 % (95% −81.4 to −63.1; p<0.001, placebo-adjusted). In the CORE2-TIMI 72b trial, the corresponding placebo-adjusted reduction from baseline in plasma triglycerides was−49.2% in the olezarsen 50 mg group and −54.5% in the olezarsen 80 mg group (p<0.001 versus placebo). Treatment with olezarsen was associated with a lower incidence of acute pancreatitis compared with placebo (mean rate ratio, 0.15; 95% confidence interval, 0.05 to 0.40; p<0.001). The incidence of any adverse event was similar across the three groups in each trial. Elevations in liver-enzyme levels and thrombocytopenia (platelet count <100,000 per microliter) were, however, more common with olezarsen 80 mg, and a dose-dependent increase in the hepatic fat fraction was also reported.

While the trials have limitations, notably the low proportion of women and a short treatment duration (1 year), the findings indicate therapeutic potential for olezarzsen in this patient group. Ongoing follow-up beyond 1 year is the focus of an open-label extension study (ClinicalTrials.gov number, NCT05681351).

Marston NA, Bergmark BA, Alexander VJ, et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med 2025; DOI: 10.1056/NEJMoa2512761

Key words: Olezarsen; ApoC3; severe hypertriglyceridemia; triglycerides; pancreatitis

DR10624: novel agent for severe hypertriglyceridemia

DR10624, a first-in-class agent which simultaneously activates three different receptors linked to triglyceride metabolism, FGF21 (Fibroblast Growth Factor 21), glucagon and glucagon-like peptide-1 (GLP-1) receptors, may have potential for the management of severe hypertriglyceridemia. Patients with this lipid disorder are at increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD; formerly called non-alcoholic fatty liver disease or NAFLD). To date, there are no specific pharmacological treatments for MASLD.  Currently, fibrates, high-dose omega-3 fatty acids or statins are the mainstay of severe hypertriglyceridemia management, but these may be insufficient for lowering triglyceride levels or reducing hepatic fat.

This phase 2 double-blind study enrolled 79 Asian adults (mean age 46 years, 89% men, almost all Han Chinese) with triglyceride levels between 500 and 2000 mg/dL. Patients were randomized to receive either a weekly, subcutaneous injection of DR10624 (12.5 mg, 25 mg or 50 mg) or a placebo for 12 weeks. Approximately 30% of the study group received concomitant triglyceride-lowering pharmacotherapy during the study.

After 12 weeks, the DR10624 12.5 mg group showed a 74.5% reduction in triglyceride levels, with a slightly lower response in the two higher dose groups (66.2% reduction with the 25 mg dose and 68.9% reduction with the 50 mg dose), compared with 8.0% reduction in triglycerides in the placebo group.  Overall, 89.5% of patients who received DR10624 attained triglyceride levels <500 mg/dL, versus 25.0% of patients on placebo. Additionally, 78.5% of patients treated with DR10624 showed > 50% reduction in plasma triglycerides from baseline, versus 5% of those on placebo. In addition, treatment with DR10624 led to 63.5% reduction in liver fat, versus 8.4% reduction in the placebo group. The most common side effects were gastrointestinal symptoms, such as nausea, which were generally mild.

Several limitations should be borne in mind, including the short duration of the treatment (12 weeks), limited patient sample, and lack of patient diversity. Almost all patients were Han Chinese, and therefore the study findings may not be generalisable to other ethnic groups. Despite these caveats, the results suggest that DR10624 may offer therapeutic potential for the management of severe hypertriglyceridemia.

Li J et al. American Heart Association Scientific Sessions 2025, Abstract 4392939.

Key words: DR10624, severe hypertriglyceridemia; metabolic dysfunction-associated steatotic liver disease

Enlicitide: a novel oral PCSK9 inhibitor

The CORALreef Lipids trial showed that once daily treatment with the oral PCSK9 inhibitor enlicitide resulted in significant reduction in low-density lipoprotein cholesterol (LDL-C) at 24 weeks which was sustained for 52 weeks. The study treatment was also well tolerated compared to placebo.

Treatments that target PCSK9 (either monoclonal antibodies or the RNA therapeutic inclisiran) are already established in the armamentarium of therapies for lowering     LDL-C in high-risk patients. While highly effective, these treatments are administered via subcutaneous injection.  An oral PCSK9 inhibitor could offer practical advantages for patients and healthcare personnel.

Enlicitide is an oral small molecule macrocyclic peptide which inhibits the binding of PCSK9 to LDL receptors. This phase 3 placebo-controlled double-blind trial enrolled 2,912 adults (mean age 63 years, 39% women) with a previous myocardial infarction or stroke or with an intermediate or high 10-year risk of these events.  All patients had   LDL-C levels exceeding recommended targets despite stable lipid-lowering therapy (at least moderate or high-intensity statin) for at least 30 days. Patients were randomized 2:1 to receive either 20 mg enlicitide once daily (n=1,935) or placebo (n=969). Five patients did not receive the study medication, and three were excluded due to inclusion in other trials. The treatment groups were comparable, with overall mean age 62.8 years, 39% female, 54% white and 58% with a prior atherosclerotic cardiovascular disease event. Almost all (95%) patients were on moderate to high intensity statin treatment.

After 24 weeks, enlicitide treatment resulted in up to a 60% reduction in LDL-C, with sustained reductions at 52 weeks. In addition, there was at least 50% reduction in non-high-density lipoprotein cholesterol and apolipoprotein B, as well as 28% reduction in lipoprotein(a). Overall, 70.3% of patients in the enlicitide group had at least a 50% reduction in LDL-C and achieved an LDL-C level below 70 mg/dL, and 67.5% had a reduction in LDL-C by at least 50% and achieved levels below 55 mg/dL. The study is currently ongoing and full publication is awaited.

Navar AM, et al. Efficacy and safety of enlicitide, an oral PCSK9 inhibitor, for lowering LDL cholesterol in adults with or at-risk for ASCVD: the Phase 3 CORALreef Lipids Trial. American Heart Association Scientific Sessions 2025, Late-Breaking Science Abstract 4391578.

Key words: Enlicitide; oral PCSK9 inhibitor; CORALreef Lipids Trial

Genetic modelling supports cardiovascular risk reduction with APOC3 silencing

Using data from over 8,000 subjects in the UK Biobank, this genetic modelling study predicts that reducing triglyceride rich lipoproteins (TRL)/remnant cholesterol by 16–23 mg/dL with APOC3-silencing therapy could lower the risk of coronary heart disease (CHD) events by approximately 25% over 5 years, reinforcing the potential effectiveness of this targeted therapy.

While APOC3 gene-silencing agents have been shown to be effective in lowering TRL/remnant levels, the consequent effect on CHD risk is not yet known. This study used a polygenic score (PGS)-based model to investigate if the degree of TRL/remnant reduction evident in trials of APOC3-silencing agents would result in a meaningful reduction in CHD risk. CHD event rates for individuals with the highest PGS and genetically higher TRL/remnant levels (mimicking placebo) were compared with those with the lowest PGS and lower TRL/remnant levels (mimicking APOC3-silencing). Data from over 4,000 subjects were included in each group. 

Compared with the high PGS group, the low PGS group had 34% lower plasma triglycerides, 22.5% lower TRL/remnant cholesterol, as well as smaller reductions in non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and apolipoprotein B. These differences were comparable with those reported in trials of APOC3-silencing agents. The low PGS group also had a 28% lower lifetime CHD event rate. Extrapolating these data to a 5-year trial suggests that 16-23 mg/dL reduction in TRL/remnant cholesterol with an APOC3-silencing agent would be predicted to reduce CHD risk by approximately 25%. These results provide a rationale for testing these targeted therapies in cardiovascular outcomes studies.

Björnson E, Packard C, Adiels M, et al. Genetic modelling of triglyceride-rich lipoprotein/remnant lowering mimics APOC3-silencing and predicts clinically relevant coronary heart disease event reductions. Eur J Prev Cardiol 2025 Oct 14:zwaf657.  doi: 10.1093/eurjpc/zwaf657. 

Keywords: APOC3; Cardiovascular risk; Gene silencing; Genetic modelling; Triglyceride-rich lipoproteins; UK Biobank.

Higher remnant cholesterol tracks higher myocardial risk after stenting

Remnant cholesterol, the cholesterol content of remnant lipoproteins, is known to be associated with cardiovascular risk.  However, studies evaluating the impact of remnant cholesterol level in patients with stable coronary heart disease undergoing percutaneous coronary intervention (PCI) for reasons other than for myocardial infarction (MI) are limited. This study addressed this question and showed that a higher level of remnant cholesterol was a marker for incident ischemic endpoints in this patient group.

The study included data from 19,289 patients who underwent PCI between 2012 to 2023. Patients were categorized according to calculated remnant cholesterol percentiles (<50^th [reference], 50^th to <75^th, 75^th to <90^th, ≥90^th). The primary endpoint was a composite of all-cause mortality, spontaneous MI and stroke one year after PCI. Patients with remnant cholesterol in the ≥90^th percentile group had a 54% increased risk of incident MI versus those in the <50% percentile group (p-value=0.010). There was, however, no difference between the groups for the primary endpoint. Despite this, the study supports higher remnant cholesterol as a marker for increased risk of MI within one year of coronary artery stenting.

Pitaro N, Bay B, Sartori S, et al. Impact of remnant cholesterol on cardiovascular outcomes in non-myocardial infarction patients undergoing percutaneous coronary intervention. Eur J Prevent Cardiol 2025; doi.org/10.1093/eurjpc/zwaf683

Key words: remnant cholesterol; PCI; major adverse cardiovascular outcomes; ischemic events

Who benefits from anti-inflammatory therapy?

Defining factors associated with elevated high-sensitivity C-reactive protein (hs-CRP), may help to identify patients most likely to benefit from anti-inflammatory therapy.  This cross-sectional study investigated this issue using real-world data for individuals with atherosclerotic cardiovascular disease from the UK Biobank (2006-2010, n = 23,045) and the US National Health and Nutrition Examination Survey (NHANES; 1999-2010 and 2015-2018, n = 3,415).

Overall, six factors (all p<0.05) were associated with elevated hsCRP in both cohorts, with obesity the most important factor (odds ratio [95% confidence interval]: 3.48 [3.18-3.80] for the UK cohort and 4.11 [2.66-6.34]) for the USA cohort). Other factors associated with elevated hs-CRP were being overweight (1.56 [1.44-1.70] and 2.26 [1.51-3.38]), respectively, or a smoker (2.47 [2.27-2.69] and 1.96 [1.23-3.10]), or being female (1.69 [1.59-1.80] and 1.69 [1.24-2.31]). Among lipid factors, both increased low-density lipoprotein cholesterol and increased triglycerides were associated with higher hs-CRP levels.

An increasing number of these factors was associated with higher hs-CRP levels, with median hs-CRP among individuals with all seven factors ranging between 5.39 mg/L in the UK Biobank cohort and 6.99 mg/L in the NHANES cohort.

Taken together, these findings may aid clinical decisions regarding who to test for hs-CRP levels to identify those patients who might benefit most from anti-inflammatory therapy.

Ray KK, Reuter SB,  Dalbeler A et al. Factors associated with elevated high-sensitivity C-Reactive Protein levels in individuals with atherosclerotic cardiovascular disease in the US and the UK. Eur J Prev Cardiol 2025 Oct:zwaf609.  doi: 10.1093/eurjpc/zwaf609.

Keywords: ASCVD; NHANES; UK Biobank; hsCRP; real-world evidence; systemic inflammation.

More insights from REDUCE-IT

In this latest analysis from REDUCE-IT, the benefit from treatment with icosapent ethyl in high cardiovascular risk patients with moderately elevated triglycerides on statin therapy extended to most subtypes of myocardial infarction (MI). There was also no increase in bleeding risk with this treatment.
REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trial previously reported that treatment with icosapent ethyl (4 g/day) significantly reduced the primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization, compared with placebo. Treatment with icosapent ethyl also reduced the incidence of §MI by 31%. This analysis investigated whether this effect was consistent for the individual endpoints of fatal MI and nonfatal MI (prespecified), as well as across different MI subtypes, including ST-segment elevation MI (STEMI), non-STEMI (NSTEMI), and according to infarct size (post hoc analysis).
Fatal MI and nonfatal MI were each reduced by treatment with icosapent ethyl (by 45%, p=0.05 and 30%, p<0.0001, respectively). The significant benefit of icosapent ethyl versus placebo was observed for STEMI (hazard ratio 0.60, 95% CI 0.44-0.81, p=0.0008), NSTEMI (hazard ratio 0.73, 95% CI 0.60-0.89, p=0.001), as well as most sizes of MI, especially large MI (reduction by up to 65%, p<0.00001). Treatment with icosapent ethyl was also associated with fewer related complications, including reduction in resuscitated MI.
The post hoc design of this analysis (other than for fatal and nonfatal MI) confers limitations, as the comparisons are observational rather than based on randomized group assignment. Bearing this in mind, however, the findings add to evidence that the benefit of high-dose icosapent ethyl is consistent across the range of cardiovascular outcomes, including the type and size of MI, and further support guideline recommendations in high cardiovascular risk patients with elevated triglycerides.

Gurevitz C, Bhatt DL, Giugliano RP et al. Benefit of icosapent ethyl across types and sizes of myocardial infarction in REDUCE-IT. Eur J Prev Cardiol 2025. doi: 10.1093/eurjpc/zwaf602.

Key words: icosapent ethyl; REDUCE-IT; myocardial infarction subtypes

State of the art review: Triglyceride-rich lipoproteins, remnants and atherosclerotic cardiovascular disease: what do clinicians need to know?

This timely review addresses two key questions: What is known and What is still to be discerned about triglyceride-rich lipoproteins (TRL) and remnants and their association with atherosclerotic cardiovascular disease (ASCVD). The review aims to tease out the reasons for the apparent conundrum that while there is evidence of a strong association between plasma TRL levels and ASCVD, intervention trials of different triglyceride-lowering therapies have produced inconsistent results, even with evidence of a sufficiently large decrease in plasma triglycerides.
The review emphasises that circulating TRL particles vary considerably in size and composition. Thus, measurement of plasma triglycerides or TRL/remnant cholesterol provides a crude index of the total numbers of these particles in the circulation and does not provide any insights into the complexity of these particles. There is limited information available relating to the relevance of bioactive lipids within TRL and remnants to their physiological roles.
These and other questions discussed in the review are relevant to the impact of triglyceride lowering on ASCVD prevention. Key questions in this context include:
• Should targeting plasma apolipoprotein B be the primary goal in individuals with combined hyperlipidaemia?
• What is the relevance of changes in high-density lipoprotein (HDL) and its subfraction distribution (as it is difficult to disentangle triglyceride and HDL effects)?
• Are changes in minor lipids present in TRL important in the mechanism of benefit of icosapent ethyl observed in REDUCE-IT?
While the ‘one-size fits all’ paradigm is appropriate for LDL, the complexity of TRL and remnants means it is not appropriate. The development of specific gene-silencing agents that act at individual targets key to TRL regulation offers the possibility to address the many questions arising from the Pandora’s box of these complex lipoproteins.

Chapman MJ, Packard CJ, Björnson E, et al. Triglyceride-rich lipoproteins, remnants and atherosclerotic cardiovascular disease: What we know and what we need to know. Atherosclerosis 2025; https://doi.org/10.1016/j.atherosclerosis.2025.120529

Key words: Triglyceride-rich lipoproteins; remnants; atherosclerosis; outcomes trials; mechanisms; review

Residual inflammatory risk in type 1 diabetes: REC1TE trial

Chronic low-grade inflammation is present in individuals with type 2 diabetes and is associated with risk for macrovascular complications. Inflammation also plays an important role in the development of type 1 diabetes. Evidence of increased circulating inflammatory protein concentrations, more pronounced than in type 2 diabetes, suggests that residual inflammatory risk may contribute to cardiovascular risk in type 1 diabetes. The anti-inflammatory agent colchicine may offer therapeutic potential in type 1 diabetes by reducing inflammation, although this needs to be weighed against possible effects on insulin sensitivity and acute complications such as hypoglycaemia and ketoacidosis.  The Repurposing Colchicine for Reduction of Residual Inflammatory Risk in Type 1 Diabetes (REC1TE, ClinicalTrials.gov ID NCT05949281) aims to assess the efficacy of low-dose colchicine on residual inflammatory risk in individuals with type 1 diabetes.

REC1TE is a randomized, double-blind, placebo-controlled phase 2 trial evaluating low-dose colchicine (0.5 mg/day) in individuals with type 1 diabetes, with or at high risk of atherosclerotic cardiovascular disease and with residual inflammatory risk (defined as two consecutive measurements of high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L). Eligible patients are randomly assigned to treatment with colchicine or placebo (1:1) for up to 52 weeks in addition to standard of care. The primary endpoint is the difference in hsCRP between the two groups at week 26. To date, 102 patients have been enrolled, and the last patient visit is anticipated early in 2026.

Mathiesen DS, Hansen JV, Høck A, et al. Repurposing colchicine for reduction of residual inflammatory risk in type 1 diabetes: Design and rationale of the REC1TE trial. Diabetes Obes Metab 2025 Oct 6.  doi: 10.1111/dom.70139. 

Keywords: cardiovascular; colchicine; residual inflammatory risk; type 1 diabetes

Remnant cholesterol contributes to cardiovascular risk reduction with LDL-C lowering therapies

According to a meta-regression analysis of randomized controlled trials, remnant cholesterol is a contributor to the cardiovascular risk reduction observed with treatment with a statin, ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

Low-density lipoprotein cholesterol (LDL-C) is undoubtedly causal for atherosclerotic cardiovascular disease and therefore the priority for preventive lipid lowering therapy. However, it is also recognised that non-LDL lipids are associated with cardiovascular risk. This study tested whether reduction in remnant cholesterol contributes to the cardiovascular risk reduction observed in statin, ezetimibe, and PCSK9 inhibitor trials.

The analysis included data from 327,264 patients in 43 trials who experienced 42,016 major adverse cardiovascular events (MACE).  Overall, remnant cholesterol was reduced 0.19 mmol/L per 1 mmol/L reduction in LDL-C with an 11% reduction per 20% reduction in LDL-C. Fixed/random effects risk ratios per 1 mmol/L reduction were 0.88 (95% confidence interval 0.85-0.91)/0.82 (0.74-0.91) for LDL-C adjusted for the reduction in remnant cholesterol and 0.74 (0.60-0.92)/0.92 (0.45-1.187) for remnant cholesterol adjusted for the reduction in LDL-C. These findings indicate that remnant cholesterol lowering accounts for part of the cardiovascular risk reduction observed in statin, ezetimibe, and PCSK9 inhibitor trials, and underline the need for lipid lowering therapy that targets both LDL-C and remnant cholesterol to reduce residual cardiovascular risk.

Tybjærg Nordestgaard A, Nordestgaard BG. Remnant cholesterol lowering in cardiovascular disease risk reduction in statin, ezetimibe, and PCSK9 inhibitor trials: meta-regression analyses. Eur J Prev Cardiol 2025:  doi: 10.1093/eurjpc/zwaf337. 

NHANES shows trend for decreasing prevalence of high remnant cholesterol

The National Health and Nutrition Examination Survey (NHANES) is a programme designed to assess the health and nutritional status of adults and children in the USA.  The current study used data from 24,658 adults surveyed over the period 1999-2020 and with data for fasting total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglycerides. The primary aim was to investigate long-term trends in the prevalence of high remnant cholesterol in the USA. Remnant cholesterol was calculated as TC– HDL-C – LDL-C, with high remnant cholesterol defined as ≥0.78 mmol/L.

Overall, the data showed a trend for a decrease in the prevalence of high remnant cholesterol from 26.6% (1999–2002) to 13.7% (2015–2020) with a 5.4% reduction per year (p for linear trend<0.001). There was a more pronounced decline in individuals aged ≥60 years and non-Hispanic black individuals.  This overall decrease in the prevalence of high remnant cholesterol coincided with increased uptake of lipid lowering therapy over the same period (from 8.3% to 19.9%). Other studies have also reported trends for improved lipid control in the USA over a similar period which support these findings.

However, the presence of obesity and pre-diabetes/diabetes significantly increased the risk of high remnant cholesterol, with a 27% increase in prevalence of high remnant cholesterol per 5 kg/m² increase in body mass index. With increasing obesity and diabetes, a substantial proportion of the adult population remains at risk of high remnant cholesterol. Addressing these key modifiable risk factors for high remnant cholesterol is an urgent priority with public health interventions targeting diet, lifestyle and weight.

Xun Y, Hu G. Trends in high remnant cholesterol level and its risk factors among US adults using NHANES data from 1999 to 2020: a serial cross-sectional study. BMJ Open 2025; 15:e095079.

Low-grade inflammation and elevated remnant cholesterol in impaired renal function

Chronic kidney disease (CKD) confers an increased risk of atherosclerotic cardiovascular disease (ASCVD). Both inflammation, a key factor in the development and progression of CKD, and remnant cholesterol have been associated with increased risk of ASCVD in CKD.  In this report from the Copenhagen General Population Study, individuals with impaired renal function with both low-grade inflammation and elevated remnant cholesterol were at highest risk of myocardial infarction, ASCVD, and all-cause mortality.

The study included data from 102,906 individuals from the Copenhagen General Population Study, of whom 9,935 had impaired renal function (estimated glomerular filtration rate <60 mL/min/1.73 m²). Remnant cholesterol was calculated from a standard lipid profile, and low grade-inflammation was defined as C-reactive protein ≥1.3 mg/L & <10 mg/L. The primary outcome was ASCVD, defined as myocardial infarction, coronary heart disease death, ischemic stroke, or coronary revascularization.

Over a median follow-up of 9 years, among individuals with impaired renal function, myocardial infarction was diagnosed in 566, ASCVD in 1,122, ischemic stroke in 583, and 3,139 died from any cause.  Compared with individuals with low C-reactive protein (<1.3 mg/L) and remnant cholesterol, those with both high C-reactive protein and remnant cholesterol were at the highest risk of myocardial infarction (Hazard ratio 1.39, 95% confidence interval [CI] 1.10–1.76), ASCVD (1.33, 95%CI 1.13–1.57), and all-cause mortality (1.20, 95%CI 1.09–1.33). While the sample size and long duration of follow-up strengthen the robustness of these findings, the authors do acknowledge several limitations, including the observational design, one-time assessment of estimated glomerular filtration rate, and the predominantly White ethnicity of the sample. Despite these limitations, the study findings may help to guide the design of trials for the prevention of ASCVD in this high-risk population.

Elías-Lopez D, Kobyleckia CJ, Vedel-Krogh S, et al. Association of low-grade inflammation and elevated remnant cholesterol with risk of ASCVD and mortality in impaired renal function. Atherosclerosis 2025; doi.org/10.1016/j.atherosclerosis.2025.119241.

Triglyceride glucose-waist circumference index predicts obstructive sleep apnoea risk.

Obstructive sleep apnoea (OSA), a sleep disorder associated with recurrent upper airway obstruction and airflow reduction, together with intermittent hypoxia and sleep fragmentation, is common among individuals with cardiovascular disease but is often underrecognized and undertreated. Previous studies have indicated a positive link between OSA prevalence and the triglyceride-glucose index, a marker for insulin resistance. There is also evidence to suggest that modified versions that incorporate body composition measures may enhance the predictive ability of this index. However, large scale investigation to support the association between these modified triglyceride-glucose indices and OSA have been lacking. This gap in evidence was addressed by this study using data from 7,789 individuals from four NHANES cycles (2005–2008 and 2015–2018), of whom 3,959 were identified with OSA based on self-reported symptoms.

Multivariable logistic regression analysis showed that a modified triglyceride-glucose index incorporating body mass index (odds ratio 1.55; 95% confidence interval [CI] 1.20–2.00; p < 0.05) or waist circumference (odds ratio 1.13; 95% CI 1.04–1.23; p < 0.05) were independently linked with OSA. Area-under-the-curve receiver operating characteristic (ROC) analysis indicated that the index incorporating waist circumference offered the greatest predictive capacity for OSA, with a significant rise in risk at levels exceeding 773.86. The study also showed a non-linear relationship between the triglyceride-glucose-waist circumference index and mortality among individuals with OSA. Taken together, these findings suggest that this modified index incorporating waist circumference may offer a useful tool for detecting individuals at increased risk for OSA.

Zhang Y, Li T, Yu H. The triglyceride glucose-waist circumference index is a predictor of obstructive sleep apnea risk and all-cause and cardiovascular mortality. Sci Rep 2025; doi: 10.1038/s41598-025-11246-w.

From the European Atherosclerosis Society Congress, 4-7th May 2025, Glasgow, UK

Favourable results with obicetrapib

Results from the BROADWAY study (Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies, ClinicalTrials.gov/NCT05142722) show that obicetrapib, a highly selective cholesteryl ester transfer protein inhibitor, reduced low-density lipoprotein cholesterol (LDL-C) by one-third (placebo-corrected) in high-cardiovascular risk patients on maximally tolerated lipid lowering therapy. The study results were presented as a late breaker at the Congress and simultaneously published in the New England Journal of Medicine.
The BROADWAY study randomized 2,530 patients (mean age 65 years, 34% female) with heterozygous familial hypercholesterolemia or a history of atherosclerotic cardiovascular disease and with LDL-C and non-high-density lipoprotein cholesterol above risk-based guideline targets to treatment with either obicetrapib 10 mg (n= 1686) or matching placebo (n=844) for 365 days. At day 84, (the primary endpoint), obicetrapib resulted in a 29.9% reduction in LDL-C versus 2.7% increase in the placebo group (between-group difference -32.6%, 95% confidence interval, -35.8 to -29.5; p<0.001).
Furthermore, in an additional safety analysis, obicetrapib treatment was associated with a 21% relative reduction (Hazard ratio 0.79, 95% confidence interval 0.54-1.15) in the exploratory endpoint of major adverse cardiovascular events, defined as a composite of coronary heart disease death, non-fatal myocardial infarction, non-fatal stroke, and coronary revascularization.
In conclusion, the results of the BROADWAY study extend the evidence base for obicetrapib, demonstrating efficacy in this difficult-to-treat patient group for whom existing therapies are either not sufficiently effective or well-tolerated.

Nicholls  SJ, Nelson AJ,  Ditmarsch M et al. Safety and efficacy of obicetrapib in patients at high cardiovascular risk. N Engl J Med 2025 doi: 10.1056/NEJMoa2415820.

Another late breaker presentation reported results from the TANDEM study (Study of Obicetrapib & Ezetimibe Fixed Dose Combination on Top of Maximum Tolerated Lipid-Modifying Therapies, NCT06005597) with the fixed-dose combination (FDC) of obicetrapib 10 mg and ezetimibe 10 mg. TANDEM randomized 407 high-cardiovascular risk patients with LDL-C levels of 1.8 mmol/lL (70 mg/dL) or higher despite maximally tolerated lipid lowering therapy to treatment with the FDC of obicetrapib plus ezetimibe, obicetrapib 10 mg monotherapy, ezetimibe 10 mg monotherapy, or placebo. 

At day 84, the FDC reduced LDL-C by 48. 6% versus placebo (p<0.001); obicetrapib monotherapy decreased LDL-C by 31.9% versus placebo. Importantly, more than 70% of patients achieved LDL-C levels less than 1.4 mmol/L (<55 mg/dL). Based on these findings, this oral, single-pill FDC treatment could improve LDL-C management in patients with, or at high risk of cardiovascular disease.

Sarraju A, Brennan D, Hayden K, et al. Fixed-dose combination of obicetrapib and ezetimibe for LDL cholesterol reduction (TANDEM): a phase 3, randomised, double-blind, placebo-controlled trial. The Lancet 2025; DOI: 10.1016/S0140-6736(25)00721-4.

First in-human data for novel ANGPTL4 inhibitor

Another exciting late breaker presented first clinical results with MAR001, a first-in-class monoclonal antibody that targets ANGPTL4 (angiopoietin-like protein 4). 

ANGPTL4, a protein highly expressed in adipose tissue and the liver, plays a key role in regulating lipid metabolism, mainly by inhibiting lipoprotein lipase, resulting in higher levels of triglycerides and remnant cholesterol. Population studies have shown that a high remnant cholesterol level is associated with higher risk of coronary artery disease and stroke. To date, however, there is a lack of treatments that specifically lower remnant cholesterol to reduce residual cardiovascular risk that persists in high-risk patients despite best evidence-based treatment.  Evidence from human genetics provides a rationale for therapeutic targeting of ANGPTL4 to lower remnant cholesterol. 

Multiple dosing with MAR001, a monoclonal antibody targeting ANGPTL4, was evaluated in 55 subjects with fasting triglycerides ≥1.7 and ≤5.6 mmol/lL. Individuals were randomly assigned to receive MAR001 or placebo every 2 weeks. Among this cohort, 10 were randomized to 150 mg MAR001, 9 to 300 mg MAR001, 17 to 450 mg MAR001, and 19 to placebo. At 12 weeks, the highest dose of MAR001 reduced remnant cholesterol by 52.5% and triglycerides by 52.7%; these decreases were greater in subjects with baseline triglycerides ≥200 mg/dL (66.0% and 64.0%, respectively). Importantly, MAR001 was well-tolerated, with no clinically significant findings, including no evidence of systemic inflammation, mediastinal lymph node enlargement, or local inflammatory changes.

Based on these favourable results, MAR001 will progress to Phase 2b clinical development. 

Cummings B, et al. A novel ANGPTL4 inhibitory antibody safely lowers plasma triglycerides and remnant cholesterol in humans.  Abstract 1320. Published online 17 May 2025: Cummings BB, Joing MP,  Bouchard PR, et al. Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies. Lancet 2025; doi: 10.1016/S0140-6736(25)00825-6

Remnant cholesterol and arterial stiffness: an early marker for cardiovascular risk?

Increased arterial stiffness, a surrogate marker of atherosclerotic cardiovascular disease (ASCVD), associates with higher remnant cholesterol levels, according to this analysis from  the National Health and Nutrition Examination Survey (NHANES). 

This study evaluated data from 12,505 individuals aged at least 20 years who were enrolled in NHANES from 1999 to 2018. Arterial stiffness was assessed using estimated pulse wave velocity (ePWV), a simpler, non-invasive, and more accessible measure than carotid-femoral pulse wave velocity, the gold standard index of arterial wall elasticity.

Higher remnant cholesterol levels were consistently associated with increased ePWV; when analysed by remnant cholesterol quintiles, those in the highest quintile exhibited substantially elevated ePWV compared to those in the lowest quintile. This association was more pronounced in individuals aged <40 years, females, non-Hispanic whites, and non-impoverished individuals. There was evidence of a potential saturation effect in this association at very high remnant cholesterol concentrations, suggesting that remnant cholesterol may have a non-linear impact on arterial stiffness. 

 Based on these findings, the authors concluded that remnant cholesterol may have utility as a clinical marker for identifying populations at high risk for ASCVD, which merits further study.

Lai T, Liang Y, Guan F, et al. Association between remnant cholesterol and arterial stiffness: Evidence from NHANES 1999–2018. Nutrition, Metabolism and Cardiovascular Diseases 2025; doi.org/10.1016/j.numecd.2025.104013

Lowering remnant cholesterol and ASCVD reduction

According to this modelling analysis based on the Copenhagen General Population Study,   aggressive lowering of remnant cholesterol has the potential for substantial reduction in cardiovascular events. Moreover, the estimated absolute reduction in cardiovascular risk was larger in people on statin treatment compared with statin-naïve subjects, which may in part reflect their higher risk. 

There is accumulating evidence to support remnant cholesterol as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) events. To date, however, there is no clinical trial evidence that lowering remnant cholesterol levels reduces cardiovascular events. This cohort modelling analysis aimed to investigate this question. 

The analysis included data from 56,422 women and 43,952 men without a history of ASCVD in the Copenhagen General Population Study. Over a median follow-up of 12 years, 4,946 women and 6,043 men developed ASCVD. In women at very-high cardiovascular risk, a 1 mmol/L (39 mg/dL) reduction in remnant cholesterol concentration was associated with decreases in absolute 10-year risk of ASCVD by 10% in statin users and 7% in those not on a statin; in men, the reduction in 10-year ASCVD risk was 11% and 9%, respectively. In individuals with high remnant cholesterol levels, a decrease by 2 mmol/lL (77 mg/dL) almost doubled the reduction in absolute risk. Taken together, these modelling data provide a rationale for studies to investigate the impact of aggressive lowering of remnant cholesterol on risk for cardiovascular events, especially among high-risk individuals.

Hvid K, Balling M, Afzal S, Nordestgaard BG.  Remnant cholesterol reduction for ASCVD prevention: modelling in the Copenhagen General Population Study. Eur J Prev Cardiol 2025; doi: 10.1093/eurjpc/zwaf203.

Remnant cholesterol and cardiovascular-kidney-metabolic syndrome

Extensive evidence supports remnant cholesterol as a risk factor for metabolic and cardiovascular disorders. This report from the China Health and Retirement Longitudinal Study investigated the association between remnant cholesterol and progression of cardiovascular-kidney-metabolic (CKM) syndrome. 

The China Health and Retirement Longitudinal Study (CHARLS) aims to collect health data from Chinese residents aged at least 45 years from 150 districts and 450 villages or urban communities across 28 provinces. In total, 89,031 individuals completed the surveys from 2011-2020, of whom 46,619 were eligible for inclusion. 

Using Cox regression analysis, researchers showed that individuals with higher remnant cholesterol levels at baseline were at increased risk of advanced CKM stages compared to those in the lowest remnant cholesterol quartile (P for trend < 0.001). Over the median follow-up of 9.0 years, 1,498 (21.8%) individuals across CKM stages 0-3 developed cardiovascular disease. Higher remnant cholesterol was associated with a greater risk of cardiovascular disease; among individuals in quartile 3 or 4 for remnant cholesterol concentration, the risk was increased by nearly 20%  (quartile 3: hazard ratio 1.181, 95% confidence interval [CI] 1.02-1.36; and quartile 4: hazard ratio 1.195, 95% CI 1.03-1.38) compared to those in the lowest quartile. The authors concluded that early detection and management of remnant cholesterol may provide clinical benefits in preventing CKM progression.

Ding X, Tian J, Chang X, Liu J, Wang G. Association between remnant cholesterol and the risk of cardiovascular-kidney-metabolic syndrome progression: insights from the China Health and Retirement Longitudinal Study. Eur J Prev Cardiol 2025; doi: 10.1093/eurjpc/zwaf248. 

New review: Genetics of remnant cholesterol

Identifying the genetic determinants of remnant cholesterol and relating these to risk of cardiovascular disease has been a key driver in the search for new therapeutic options for managing elevated remnant cholesterol.  In this timely new publication, the authors review the human genetic epidemiology for variants in genes involved in lipoprotein metabolism that affect remnant cholesterol concentration. This includes the APOC3, ANGPTL3 and ANGPTL4 genes, which play a role in regulating the activity of lipoprotein lipase and thus impact remnant cholesterol levels. New RNA therapeutics offer the possibility for specific targeting of these genes and their associated proteins.

Wulff AB, Nordestgaard BG. Genetics of remnant cholesterol. Curr Opin Lipidol 2025; doi: 10.1097/MOL.0000000000000991. 

Remnant cholesterol, inflammation and cardiovascular risk: insights from the EPIC-Norfolk study

In this prospective analysis from the EPIC-Norfolk study, systemic inflammation had only a minor influence on the effect of remnant cholesterol on cardiovascular disease risk. These findings underline the need for therapeutic intervention targeting remnant cholesterol and inflammation to manage cardiovascular health. Elevated remnant cholesterol, recognized as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), is consistently associated with systemic inflammation. Conversely, while low-density lipoprotein cholesterol (LDL-C) is also established as causal for ASCVD, it is not associated with inflammation. Using data from the EPIC-Norfolk study, researchers investigated the extent to which inflammation mediates the effect of remnant cholesterol and LDL-C on nonfatal major adverse cardiovascular events (MACE), a composite of coronary artery disease and ischemic stroke. The cohort included 16,445 subjects without prior ASCVD (mean age 58.8 years, 56.9% women). Higher remnant cholesterol, but not higher LDL-C levels, were associated with increased systemic inflammation, as assessed by high-sensitivity C-reactive protein (hs-CRP). Notably, each 1 mmol/L increase in remnant cholesterol was associated with 29.5% (95% confidence interval [CI] 22.1-37.4%) higher hs-CRP levels. Furthermore each 1 mmol/L higher remnant cholesterol was associated with increased risk for MACE (Hazard ratio 1.31 95% CI 1.14 -1.50, p&lt;0.001), which was greater than that reported for each 1 mmol/l increase in LDL-C (Hazard ratio 1.21 95% CI 1.13-1.31, p&lt;0.001). Using mediation analysis, the researchers showed that hs-CRP contributed 5.9% (95% CI 1.2-10.6%, p&lt;0.001) of the effect of remnant cholesterol on MACE. The authors concluded that as inflammation was only a minor contributor to the effect of remnant cholesterol on ASCVD risk, both parameters need to be independently managed for cardiovascular health.

Kraaijenhof JM, Kerkvliet MJ, Nurmohamed NS, et al. The role of systemic inflammation in
remnant cholesterol associated cardiovascular risk: insights from the EPIC-Norfolk study. Eur J Prev Cardiol 2025; doi: 10.1093/eurjpc/zwaf037.

Elevated remnant cholesterol contributes to cardiovascular events in diabetes

Among individuals with diabetes, one in five atherosclerotic cardiovascular events can be attributed to elevated remnant cholesterol, based on findings from the Copenhagen General Population Study. High remnant cholesterol is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and increases ASCVD risk in people with diabetes. This analysis from the Copenhagen General Population study aimed to quantitate the contribution of elevated remnant cholesterol
to ASCVD in this patient group. The Copenhagen General Population Study is a large population study, initially designed to investigate risk factors for cardiovascular disease, with its scope subsequently broadened to include a wider range of other health conditions, and genetic and psychosocial factors. The current analysis was derived from a cohort of 107,243 individuals, of whom 3,806 were identified with diabetes. Elevated remnant cholesterol was defined as levels higher than those
observed in individuals with non-high-density lipoprotein (non-HDL) cholesterol &lt; 2.6 mmol/L (100 mg/dL), according to the European guideline goal. Over 15 years of follow-up, 498 patients experienced ASCVD events, 172 with peripheral artery disease, 185 with myocardial infarction and 195 with ischemic stroke. Median remnant cholesterol was 0.5 mmol/L (20 mg/dL) in individuals with non-HDL cholesterol &lt; 2.6 mmol/L, and 0.8 mmol/L (31 mg/dL) in those with diabetes. Using multivariable adjusted Poisson regression analysis, the researchers showed that elevated remnant cholesterol contributed to 19% (95% confidence interval 10-28%) of ASCVD events. This value was consistent with results from the UK Biobank, in which elevated remnant cholesterol contributed to 16% (9%-22%) of ASCVD events. Taken together, these findings support the importance of elevated remnant cholesterol as a risk factor for ASCVD in diabetes patients and provide a rationale for further study to investigate whether targeting this risk factor could prevent ASCVD in this high-risk patient group.

Wadström BN, Pedersen KM, Wulff AB, Nordestgaard BG. One in five atherosclerotic cardiovascular disease events in individuals with diabetes attributed to elevated remnant cholesterol. Diabetes Metab Res Rev 2024;40(8): e70005.

Remnant cholesterol in the elderly

Elevated remnant cholesterol is recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD). However, most of the evidence-base is derived from younger adults, with little information in the elderly (>70 years), of relevance given aging populations. This analysis from the Copenhagen General Population study showed that elevated remnant cholesterol was at least as important as a cardiovascular risk factor in the elderly (aged 70-100 years) as in younger adults. 

In total, the study included data from 90,875 women and men aged 20-100 years and without ASCVD, diabetes, or lipid-lowering therapy at baseline. During a median follow-up of 12.8 years, 7,352 individuals were diagnosed with ASCVD. Individuals aged 70-100 years with a remnant cholesterol level >1.0 mmol/L (>39 mg/dL) had the highest incidence rate of ASCVD (23 per 1000 person-years; 95% confidence interval [CI] 21-25). In the 70–100-year age group, each 1.0 mmol/L (39 mg/dL) increase in remnant cholesterol was associated with 31% higher cardiovascular risk (Hazard ratio 1.31, 95% CI: 1.20-1.44), similar to that observed in younger age groups. The attributable fraction for ASCVD of high remnant cholesterol was 12% at age 70 and 9% at age 100.  

In conclusion,  higher remnant cholesterol was associated with a higher incidence of ASCVD in older age groups. These findings underline the importance of intervention targeting elevated remnant cholesterol across the age ranges.

Riis J, Nordestgaard BG, Afzal S. High remnant cholesterol and atherosclerotic cardiovascular disease in healthy women and men ages 70-100. Eur J Prev Cardiol 2025; doi: 10.1093/eurjpc/zwaf092.

Latest news from the OCEAN(a)-DOSE trial with olpasiran

This latest analysis from the Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study (OCEAN(a)-DOSE) in patients with atherosclerotic cardiovascular disease (ASCVD) showed that olpasiran lowered lipoprotein(a) [L(a)] by more than 95% and also lowered levels of oxidized phospholipids, implicated in promotion of atherogenesis. 

OCEAN(a)-DOSE is a multicentre, randomized, double-blind, placebo-controlled dose-finding study in 281 patients with established ASCVD and Lp(a) > 150 nmol/L. The current pre-specified analysis included data from 272 patients (median age 62 years, 31.6% female). Patients were randomized to receive one of four active subcutaneous doses of olpasiran vs placebo: 10 mg, 75 mg, or 225 mg every 12 weeks; or 225 mg every 24 weeks. Oxidized phospholipoids on apolipoprotein B (Ox-PL-apoB), high-sensitivity C-reactive protein (hs-CRP), and high-sensitivity interleukin-6 (hs-IL-6) were measured at baseline, week 36, and week 48. The primary outcome was the placebo-adjusted change in Ox-PL-apoB from baseline to week 36.

At baseline median (interquartile range [IQR]) Lp(a) concentration was 260.3 nmol/L (198.1-352.4) and median (IQR) Ox-PL-apoB concentration was 26.5 nmol/L (19.7-33.9). At 36 weeks, patients who received olpasiran 75 mg or higher every 12 weeks had at least 95% reduction in Lp(a) compared to the placebo group. Additionally, the placebo-adjusted mean percentage change in Ox-PL-apoB from baseline to week 36 ranged from 51.6% for the 10 mg 12-weekly dose to 93.7% for the 225 mg every 24 weeks dose. The effects of olpasiran were sustained at 48 weeks. Olpasiran did not, however, significantly impact hs-CRP or hs-IL-6 compared with placebo at either weeks 36 or 48.

These findings suggest that reduction in Lp(a) and Ox-PL-apoB may be the main drivers of potential clinical benefit with olpasiran.

Rosenson RS, López JAG, Gaudet D, et al. Olpasiran, oxidized phospholipids, and systemic inflammatory biomarkers: Results from the OCEAN(a)-DOSE Trial. JAMA Cardiol 2025:e245433. doi: 10.1001/jamacardio.2024.5433.

Obstructive sleep apnoea, acute coronary syndrome and remnant cholesterol

Obstructive sleep apnoea (OSA) is prevalent in patients with acute coronary syndrome (ACS), affecting up to two-thirds of this group. Studies show that the presence of OSA increases the risk of cardiovascular events in ACS patients. OSA and coronary artery disease also share risk factors and pathophysiological conditions that make this association relevant. Research indicates that OSA is associated with higher remnant cholesterol levels. The mechanisms are not fully understood, but may involve intermittent hypoxia, sleep fragmentation, and increased sympathetic activity. 

The OSA-ACS study is a large, prospective, observational study designed to investigate the association between OSA and long-term cardiovascular outcomes in patients with ACS. The current analysis investigated the association of OSA with cardiovascular outcomes in 1,833 ACS patients with both elevated remnant cholesterol and low-grade inflammation as indicated by high-sensitivity C-reactive protein (hs-CRP). The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or heart failure, and ischemia-driven revascularization.

Over a median follow-up of 35.1 months, the presence of OSA significantly increased the risk of MACCE (adjusted hazard ratio [HR] 1.58, 95% confidence interval [CI] 1.01-2.47; p = 0.045) and stroke (adjusted HR 5.23, 95% CI 1.19-22.99; p = 0.027) in patients with elevated remnant cholesterol and low-grade inflammation. These findings highlight the need for routine screening of both variables and comprehensive management to reduce cardiovascular risk in ACS patients with OSA.

Xu D, Zhang Y, Zhen L, et al. Association of obstructive sleep apnoea with cardiovascular events in acute coronary syndrome patients with dual risk of remnant cholesterol and low-grade inflammation: a post-hoc analysis of the OSA-ACS study. Sleep Breath 2025;29(1):119.

Is remnant cholesterol a non-invasive marker of end-stage diabetic kidney disease in type 2 diabetes?

Results from this cohort study showed that higher remnant cholesterol concentration was associated with a higher risk of end-stage kidney disease (ESKD) in patients with type 2 diabetes mellitus and diabetic nephropathy. These findings suggest that remnant cholesterol may represent a new non-invasive predictor of diabetic ESKD. 

This study evaluated the longitudinal relationship between baseline remnant cholesterol and kidney outcomes using data from 334 patients (mean age 51.1 years, 70% men) with type 2 diabetes mellitus and biopsy-confirmed diabetic nephropathy (T2DM-DN) from the 2010-2019 West China Hospital cohort. Remnant cholesterol was calculated using the Martin-Hopkins equation. The primary outcome was ESKD, which was defined as the need for chronic kidney replacement therapy or estimated glomerular filtration rate <15 mL/min/1.73 m2.  

Compared with patients in the lowest quartile for remnant cholesterol concentration, those in the highest quartile had lower cumulative renal survival and shorter median renal survival time (median [interquartile range] 34.0 [26.4-41.6] vs. 55.0 [29.8-80.2] months). The high remnant cholesterol group was also associated with a high risk of progression to ESKD, which was nearly 3-fold higher compared with the lowest quartile (Hazard ratio 2.857, 95% confidence interval 1.305-6.257, p = 0.009). A one standard deviation increase in remnant cholesterol was associated with 42% higher risk of progression to ESKD, after adjusted for confounding factors.  These findings merit further study and suggest that remnant cholesterol may be a new non-invasive predictor of ESKD in patients with type 2 diabetes.

Zhao Y, Liu K, Zou Y, et al. Remnant cholesterol and the risk of diabetic nephropathy progression to end-stage kidney disease in patients with type 2 diabetes mellitus: a longitudinal cohort study. Endocrine  2024;doi: 10.1007/s12020-024-03948-4

Study links high remnant cholesterol with dementia risk

An elevated remnant cholesterol level was independently associated with increased risks of all-cause dementia, Alzheimer’s disease, and vascular dementia, according to this nationwide, population-based cohort study in South Korea. 

Dyslipidemia has consistently demonstrated a robust association with increased susceptibility to various forms of dementia, including vascular dementia and Alzheimer’s disease. This cohort study aimed to investigate the relationship between remnant cholesterol and the risk of developing 

dementia, using data from South Korea’s National Health Insurance Service, a mandatory health insurance system for the majority (about 98%) of the population in South Korea. This analysis included data from subjects aged at least 40 years who underwent the national health examination in 2009. People with a triglyceride concentration of 400 mg/dL or higher were excluded due to concerns regarding the accuracy of calculated LDL-C concentration, as were those with a prior diagnosis of dementia.  

Overall, the analysis included data for 2,621,596 individuals aged at least 40 years. Over the median follow-up of 10.3 years, 5.6% developed all-cause dementia, 4.5% developed Alzheimer’s disease, and 0.6% developed vascular dementia. The risk of dementia increased progressively with higher remnant cholesterol concentration. When compared with individuals in the lowest quartile for remnant cholesterol concentration, those in the highest quartile had an 11% increase in risk for all-cause dementia, 11% increase in risk for Alzheimer’s disease, and 15% increase in risk for vascular dementia. The risk of dementia associated with high remnant cholesterol was more pronounced in individuals with diabetes, and in these individuals increased markedly with a longer duration of diabetes.  

While these findings highlight the need for further research to determine the causal relationship between remnant cholesterol and dementia, they also suggest that monitoring and managing remnant cholesterol concentrations, particularly in individuals with type 2 diabetes, may potentially mitigate dementia risk.

Heo JH, Jung HN, Roh E, et al. Association of remnant cholesterol with risk of dementia: a nationwide population-based cohort study in South Korea. Lancet Healthy Longev 2024; 5: 524–33.

Diabetes-related macrovascular complications increase risk of microvascular complications: UK Biobank study

In individuals with diabetes, the presence of macrovascular complications confers a higher risk of developing diabetes-related microvascular complications, and this risk was even higher in those individuals with 2 or more macrovascular morbidities. These were the key findings from this analysis from the UK Biobank. 

Recent advances in the management of diabetes-related complications have mainly focused on preventing macrovascular complications. However, about 50% of patients with diabetes will develop diabetes-related microvascular complications, including diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy, which adversely impact patient quality of life. Despite improved risk management, there has been little change in the frequency and costs of diabetes-related microvascular complications over recent decades, highlighting an unmet clinical need. 

This study investigated the impact of macrovascular complications on the risk of microvascular complications using data from 1,518 subjects with type 1 diabetes (T1D) and 20,802 subjects with type 2 diabetes from the UK Biobank, a prospective cohort study. The median (interquartile range [IQR]) follow-up was 12.3 (10.6–13.3) years. The primary study outcome was incident microvascular complications, which was a composite of diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy. 

Over the follow-up period, 596 (39.3%) subjects with type 1 diabetes and 4,113 (19.8%) with type 2 diabetes developed a diabetes-related microvascular complication. The prevalence of diabetes-related coronary heart disease (CHD), peripheral artery disease (PAD), stroke, and at least two of these macrovascular complications conferred an increased risk of both the primary outcome of diabetes-related microvascular outcomes, and the individual component outcomes, with the exception of associations between stroke and CHD and incident diabetic retinopathy in subjects with type 1 diabetes, and PAD and incident diabetic retinopathy in subjects with type 2 diabetes. For subjects with type 2 diabetes, the presence of CHD increased the risk of diabetes-related complications by 25% (hazard ratio [95% confidence interval] 1.25 [0.98−1.60]), stroke by 71% (1.71 [1.08−2.72]), and PAD increased the risk 3-fold (3.00 [1.86−4.84]). The presence of 2 or more macrovascular complications enhanced this risk (2.57 [1.66−3.99]) for subjects with type 2 diabetes. Intensive glycemic and blood pressure control, especially in patients with multiple macrovascular complications reduced the risk of incident microvascular events by 78% in subjects with type 1 diabetes and 60% in type 2 diabetes. In conclusion, these findings imply not only the need for greater efforts to prevent and control macrovascular complications in individuals with diabetes, but also the need for intensive screening and preventive strategies to reduce the associated high risk of diabetes-related microvascular complications.

Zhang X, Zhao S, Huang Y, et al. Diabetes-related macrovascular complications are associated with an increased risk of diabetic microvascular complications: a prospective study of 1518 patients with type 1 diabetes and 20 802 patients with type 2 diabetes in the UK Biobank. J Am Heart Assoc 2024;13(11):e032626.

Women still receive suboptimal lipid lowering therapy post-MI

Women are still at a disadvantage regarding prescription of high-intensity lipid lowering therapy after acute myocardial infarction (AMI), which is likely to adversely impact their survival and risk of cardiovascular events. These were the findings from an analysis of the FAST-MI program, a French nationwide registry. 

The FAST-MI program registry includes patients admitted for AMI ≤48 hours from onset over a one-month period in 2005, 2010 and 2015, with long-term follow-up. This analysis focused on the use of high-intensity lipid lowering therapy (atorvastatin≥40 mg or equivalent, or any combination of statin and ezetimibe) in women and men. Overall, women accounted for 28% of the 12,659 patients. At discharge, women were less likely to be prescribed high-intensity lipid lowering therapy (54% vs. 68% in men, p<0.001), and this trend that did not improve over the follow-up period. In contrast, there was no apparent sex bias for the use of other recommended treatments at discharge including beta-blockers or renin-angiotensin blockers.  These findings highlight the need for action to improve implementation of high-intensity lipid lowering treatment in women at discharge following AMI.

Weizman O, Hauguel-Moreau M, Tea V, et al. Prognostic impact of high-intensity lipid-lowering therapy under-prescription after Acute Myocardial Infarction in women. Eur J Prevent Cardiol 2024; doi.org/10.1093/eurjpc/zwae255

PALISADE demonstrates efficacy of plozasiran in familial chylomicronemia syndrome

opline results from the pivotal Phase 3 PALISADE study showed that plozasiran, a first-in-class hepatocyte-targeted APOC3 small interfering RNA (siRNA) therapeutic, successfully met the primary endpoint of triglyceride (TG)-lowering in patients with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome (FCS). 

FCS is a severe and ultra-rare genetic disease leading to extremely high TG levels, typically over 880 mg/dL. While several genetic causes have been associated with FCS, lipoprotein lipase is implicated in about 80% of people with FCS. Acute pancreatitis is the most serious complication of FCS and can occur repeatedly, leading to long-term pancreatic dysfunction and may be fatal if untreated. Thus, one of the main goals of treatment is to reduce this risk as much as possible.  

The PALISADE study was conducted in 39 trial sites in 18 countries. Overall, 75 patients were randomized to treatment with either 25 mg or 50 mg plozasiran, or matching placebo once every 3 months. Patients who completed the randomized period were eligible to enter a two-part extension period in which all participants received plozasiran. The primary endpoint was the placebo-adjusted median change in TG levels at month 10. 

Overall, mean TG reductions from baseline to month 10 were 80% with 25 mg plozasiran and 78% with 50 mg plozasiran (versus 17% with placebo, p<0.001), and the maximum reduction was 98%. At 12 months, patients treated with 25 mg and 50 mg plozasiran achieved median TG reductions of 78% and 73% (versus 7% with placebo), respectively, and the maximum reduction was 99%.  APOC3 reduction at month 10 was 88% with 25 mg and 94% with 50 mg plozasiran. 

All key secondary endpoints were met with plozasiran treatment with statistical significance compared with placebo. Multiplicity-controlled secondary endpoints included the percent change from baseline at months 10 and 12 in fasting TGs, the percent change from baseline at month 10 in fasting APOC3, the percent change from baseline at month 12 in fasting APOC3, and the incidence of positively adjudicated events of acute pancreatitis during the randomized period. Treatment with plozasiran was associated with a favourable safety profile. Full publication of this trial is awaited. On the basis of these results, plozasiran has been granted Orphan Drug Designation and Fast Track Designation by the US Food and Drug Administration and Orphan Drug Designation by the European Medicines Agency.

Arrowhead Pharmaceuticals reports successful topline results for plozasiran from the pivotal phase 3 Palisade study in patients with familial chylomicronemia syndrome. Arrowhead Pharmaceuticals Inc. June 3, 2024. Accessed June 3, 2024. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-reports-successful-topline-results.
Arrowhead receives FDA Fast Track designation for aro-APOC3. Arrowhead Pharmaceuticals Inc. March 20, 2023. Accessed May 28, 2024. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-receives-fda-fast-track-designation-aro-apoc3.

ANGPTL3 siRNA Zodasiran in mixed hyperlipidemia

Despite efficacious low-density lipoprotein cholesterol (LDL-C) therapy, patients with elevated triglyceride (TG) levels remain at high residual cardiovascular risk. Novel approaches have investigated the potential of targeting other regulators of TG-rich lipoprotein metabolism. One such target is angiopoietin-like 3 (ANGPTL3), which inhibits lipoprotein and endothelial lipases and hepatic uptake of TG-rich lipoprotein remnants. Genetic studies have shown that individuals with ANGPTL3 loss-of-function variants have lower levels of TGs and LDL-C and are at lower risk of atherosclerotic cardiovascular disease than noncarriers. These data provide support for investigating the potential of targeting ANGPTL3 expression in mixed hyperlipidemia patients.

This double-blind, placebo-controlled, dose-ranging phase 2b trial randomized 204 patients with mixed hyperlipidemia (i.e. fasting TGs 150 to 499 mg/dL and either LDL-C ≥70 mg/dL or non-high-density lipoprotein cholesterol [HDLC-] ≥100 mg/dL). Patients were randomly allocated in a 3:1 ratio to treatment with subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed to week 36. The primary endpoint was the percent change in the TG level from baseline to week 24.

At week 24, zodasiran treatment was associated with substantial and significant decreases from baseline in ANGPTL3 and TG levels. Compared with placebo, mean decreases from baseline in TG levels of 51% with 50 mg, 57% with 100 mg and 63% with 200 mg zodasiran were observed (p<0.001 for all comparisons). Commensurate with this, there were also decreases in levels of LDL-C (14-20%), non-HDL-C (29-36%) and apolipoprotein B (15-22%). The findings from this study support further investigation of this therapeutic approach.  

Rosenson RS, Gaudet D, Hegele RA, et al. Zodasiran, an RNAi therapeutic targeting ANGPTL3, for mixed hyperlipidemia. N Engl J Med 2024; doi: 10.1056/NEJMoa2404147

Pemafibrate in Metabolic dysfunction-associated steatotic liver disease

There is an unmet clinical need for treatments for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Results from the PORTRAIT Study favour pemafibrate over omega-3-acid ethyl ester for lipid management in patients with elevated triglyceride (TG) levels complicated by MASLD. 

The PORTRAIT study compared the effects of treatment with pemafibrate or omega-3-acid ethyl ester for 24 weeks on hepatic function in 80 patients with hypertriglyceridemia complicated by MASLD. The primary endpoint was the change in alanine aminotransferase (ALT) from baseline to week 24. Secondary endpoints included other hepatic enzymes, lipid profiles, and hepatic fibrosis biomarkers. 

The adjusted mean change in ALT from baseline to week 24 was significantly greater in the pemafibrate group (-19.7±5.9 U/L) than in the omega-3-acid ethyl ester group (6.8±5.5 U/L) (intergroup difference, 26.5 U/L; 95% confidence interval, -42.3 to -10.7 U/L; p=0.001). Pemafibrate also significantly improved levels of other hepatic enzymes (aspartate aminotransferase and gamma-glutamyl transpeptidase), as well as TG levels, total and non-high-density lipoprotein cholesterol, and hepatic fibrosis biomarkers.  Taken together, these results indicate that pemafibrate may have a potential role in treatment strategies for patients with MASLD/MASH.

Sumida Y, Toyoda H, Yasuda S, et al. Comparison of efficacy between pemafibrate and omega-3-acid ethyl ester in the liver: the PORTRAIT Study. J Atheroscler Thromb 2024; doi: 10.5551/jat.64896.

Inflammatory risk in polyvascular disease

Individuals with polyvascular disease are known to be at high risk of cardiovascular events. Studies have demonstrated that some individuals may exhibit concomitant higher levels of atherogenic lipoproteins and inflammatory markers, exacerbating this risk. Given that inflammation affects residual risk following percutaneous coronary intervention (PCI), this study aimed to investigate residual inflammatory risk in individuals with polyvascular disease undergoing PCI. 

Overall, 10,359 patients undergoing PCI for chronic coronary disease were included, of whom 1801 (17.4%) had polyvascular disease. These patients had higher levels of high-sensitivity Creactive protein (hsCRP) than those without polyvascular disease; 33.6% had hsCRP levels >3 mg/L compared with 24.7% of patients without polyvascular disease. There was an independent association between elevated hsCRP and risk for major adverse cardiovascular events (MACE) in patients with polyvascular disease,  but not in patients without polyvascular disease. Patients with both polyvascular disease and elevated hsCRP levels had significantly higher rates of MACE than all other subgroups at 1-year follow-up. 

Taken together, these findings could help identifying patients at elevated residual inflammatory risk for tailored treatment to improve clinical outcome following PCI.

Bay B, Vogel B, Sharma R, et al. Inflammatory risk and clinical outcomes according to polyvascular atherosclerotic disease status in patients undergoing PCI. Clin Res Cardiol 2024; doi: 10.1007/s00392-024-02471-w

Semaglutide in patients with type 2 diabetes and chronic kidney disease

Results from this major trial show that semaglutide reduced the risk of kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease (CKD). This trial randomized 3533 patients with type 2 diabetes and CKD (defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 ml/min/1.73 m² of body-surface area and a urinary albumin-to-creatinine ratio of >300 and <5000 or an eGFR of 25 to <50 ml/min/1.73 m² and a urinary albumin-to-creatinine ratio of >100 and <5000) to treatment with subcutaneous semaglutide 1.0 mg weekly or placebo. The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml/min/1.73 m²), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes.

At a median follow-up of 3.4 years, early trial cessation was recommended at a prespecified interim analysis. Semaglutide was associated with a 24% lower risk of a primary-outcome event (hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; p=0.0003), 21% lower risk of kidney-specific components of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94) and 29% lower risk for cardiovascular death (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results for all confirmatory secondary outcomes favoured semaglutide, including the risk of major cardiovascular events, which was 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; p=0.029), and the risk of death from any cause, which was 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, p=0.01). Taken together, the results show that semaglutide has important clinical benefit in this patient population at high risk for kidney failure, cardiovascular events, and death.

Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med 2024; DOI: 10.1056/NEJMoa2403347

Residual inflammatory risk in ischaemic stroke

Acute ischaemic stroke is one of the major causes of economic burden in China. Inflammation is an important driver of atherogenesis and plaque rupture, and a high residual inflammatory risk increases the risk of recurrent ischaemic stroke. Therefore, this study evaluated the association between high residual inflammatory risk and vulnerable plaques in the carotid artery in Chinese patients with acute ischaemic stroke.
The study enrolled 468 patients (mean age 64 years, 65% male) with ischaemic stroke, 157 (33.5%) who were shown to have vulnerable plaques. Overall, 28.6% had residual inflammatory risk only (low-density lipoprotein cholesterol [LDL-C] &lt;2.6 mmol/L and high-sensitivity C-reactive protein [hsCRP] ≥2 mg/L), 18.8% had residual cholesterol risk only (LDL-C ≥2.6 mmol/L and hsCRP &lt;2 mg/L), 19.7% had both risk or residual cholesterol and inflammatory risk (LDL-C ≥2.6 mmol/L and hsCRP ≥2 mg/L), and 32.9% had neither risk (LDL-C &lt;2.6 mmol/L and hsCRP &lt;2 mg/L). Residual inflammatory risk was associated with vulnerable plaques after adjustment for major confounding factors (odds ratio 1.98, 95% confidence interval 1.13–3.45, p =0.016), especially in the large artery atherosclerosis subtype (odds ratio 2.71, 95% confidence interval 1.08–6.77, p = 0.034).
The significant positive association between residual inflammatory risk and vulnerable plaques in the carotid artery in patients with ischaemic stroke, especially in the large atherosclerotic subtype, suggest that these patients may benefit further from anti-inflammatory therapy in addition to lipid-lowering therapy. Prospective trials are indicated to investigate anti-inflammatory interventions in these high-risk patients.

Gong X, Yu C, Lu Z, et al. Residual inflammatory risk and vulnerable plaque in the carotid artery in patients with ischemic stroke. Front Neurol 2024; DOI 10.3389/fneur.2024.1325960

Inclisiran in people with diabetes or obesity

Pooled analyses of the ORION-9, ORION-10 and ORION-11 trials showed that inclisiran was associated with substantial and durable lowering of low-density lipoprotein (LDL) cholesterol across glycaemic/body mass index (BMI) levels. In these trials, patients were randomized 1:1 to receive 300 mg inclisiran or placebo twice yearly, after initial and 3-month doses up to 18 months, together with background oral lipid-lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (&lt;25, ≥25 to &lt;30, ≥30 to &lt;35, and ≥35 kg/m 2 ). The primary endpoints were percentage and time-adjusted percentage change in LDL cholesterol from baseline.
The percent LDL cholesterol change (placebo-corrected) with inclisiran from baseline to Day 510 ranged from -47.6% to -51.9% across glycaemic levels and from -48.8% to -54.4% across BMI strata. Time-adjusted percentage changes after Day 90 and up to Day 540 ranged from -46.8% to -52.0% and from 48.6% to -53.3% across glycaemic/BMI strata, respectively. Inclisiran treatment was also associated with significant reductions in other atherogenic lipids and lipoproteins versus placebo. Importantly, attainment of LDL cholesterol thresholds of &lt;1.8 mmol/L and &lt;1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata.
Taken together, these findings support the value of inclisiran in lowering LDL cholesterol in patients with normal and elevated glycaemic/BMI levels.

Leiter LA, Raal FJ, Schwartz GG, et al. Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION-9, ORION-10 and ORION-11 Phase 3 randomized trials. Diabetes Obes Metab 2024; doi: 10.1111/dom.15650.

High remnant cholesterol prevalent in Mexicans

According to this report, almost 10 million Mexicans have a high-risk remnant cholesterol blood concentration (&gt;38 mg/dL), predisposing to elevated cardiovascular risk. This study analysed data from 9,591 adults from the National Survey of Health and Nutrition (ENSANUT) 2018 to evaluate the association between chronic diseases and blood remnant cholesterol concentration. Data from NHANES (2005-2014) was used as a population reference. Across all percentiles, levels of remnant cholesterol were higher in Mexicans than in other ethnicities. Remnants were independently associated with cardiovascular risk, diabetes, hypertension, obesity, and metabolic syndrome. For all outcomes, the blood remnant cholesterol concentration was a stronger predictor of risk than low-density lipoprotein cholesterol.

These findings highlight elevated remnant cholesterol level as a strong independent factor for cardiovascular disease and other chronic diseases in the Mexican population, underlining the need for tailored intervention.

Cruz-Bautista I, Escamilla -Núñez, Yuscely F, et al. Distribution of triglyceride-rich lipoproteins and their remnants and their contribution to cardiovascular risk in the Mexican population. J Clin Lipidol 2024; DOI:https://doi.org/10.1016/j.jacl.2024.05.002.

Stagnating risk factor control in US

This recent report from the National Health and Nutrition Examination Survey (NHANES) shows that previous improvements in the management of blood pressure and non–high-density lipoprotein cholesterol (non-HDL-C) control has stagnated. Risk factor control over the period 1999 to 2018 was evaluated in 55,021 adults (mean age 47 years, 48.0% men), including 5717 with atherosclerotic cardiovascular disease (ASCVD). Risk factor control was defined as hemoglobin A1c <7%, blood pressure <140/90mmHg, and non–HDL-C <100mg/dL.
 
While ASCVD prevalence was stable over this period (between 7.3% and 8.9%), among these patients the prevalence of diabetes almost doubled (from 21.4% to 38.0%). Additionally, the rate of improvement in risk factor control stalled; notably the prevalence of non-HDL-C control more than doubled between 1999 and 2006 (from 7.1% to 15.7%) but subsequently levelled off, with 22.5% in 2007-2010, 27.3% in 2011-2014, and 30.9% in 2015-2018 achieving non-HDL-C <100 mg/dL. Similar trends were observed for blood pressure and glycaemic control. This decline in risk factor control was exacerbated by increases in obesity and heavy alcohol consumption. Moreover, the study identified disparities in risk factor control between men and women, different ethnicities, and different socioeconomic groups. In particular, women with ASCVD were less likely to receive statin therapy and less likely to have all risk factors controlled. Taken together, the findings from this latest NHANES survey highlight the need for tailored interventions to improve cardiovascular health across all demographic groups.

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Remnant cholesterol linked with chronic kidney disease severity

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Novel ANGPTL3 inhibitor

ORION-8: largest trial to date with inclisiran, targeting PCSK9

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New ESC guidelines

Escalating cost of cardiovascular disease in Europe

Higher remnant cholesterol linked with bioprosthetic valve degeneration

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News from the SUSTAIN 6 and PIONEER 6 trials with semaglutide

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Triglyceride-rich lipoproteins associate with early in-stent neointimal atherosclerosis formation

Higher remnant cholesterol increases mortality risk

Remnant cholesterol and cardiovascular disease

Nonalcoholic fatty liver disease in Chile

Do patients in lipid-lowering trials represent those seen in routine practice?