Hyperlipidaemia in diabetes: are there particular considerations for next-generation therapies?

Dyslipidaemias are major cardiovascular risk factors, especially in people with diabetes. In this area, next-generation therapies targeting circulating lipoparticle metabolism (LDL, VLDL, chylomicrons, HDL) have recently been approved by the European and US medical agencies, including anti- proprotein convertase subtilisin/kexin 9 (PCSK9) antibodies; an siRNA targeting PCSK9; bempedoic acid, which targets ATP citrate lyase; an antisense oligonucleotide targeting apolipoprotein C-III; an anti-angiopoietin-like 3 antibody; and a purified omega-3 fatty acid, icosapent ethyl. Other therapies are in different phases of development. There are several important considerations concerning the link between these new lipid-lowering therapies and diabetes. First, since concerns were first raised in 2008 about an increased risk of new-onset diabetes mellitus (NODM) with intensive statin treatment, each new lipid-lowering therapy is being evaluated for its associated risk of NODM, particularly in individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Second, people with diabetes represent a large proportion of those at high or very high cardiovascular risk in whom these lipid-lowering drugs are currently, or will be, prescribed. Thus, the efficacy of these drugs in subgroups with diabetes should also be closely considered, as well as any potential effects on glycaemic control. In this review, we describe the efficacy of next-generation therapies targeting lipoprotein metabolism in subgroups of people with diabetes and their effects on glycaemic control in individuals with diabetes and prediabetes and in normoglycaemic individuals.

Relationship between LDL-cholesterol, small and dense LDL particles, and mRNA expression in a cohort of African Americans.

Understanding the characteristics and behavior of low-density lipoprotein (LDL) particles provides insights into the atherogenic risk of elevated LDL cholesterol in hypercholesterolemia, cardiovascular disease risks. Studying LDL particles helps identify specific LDL subtypes [e.g., small dense LDL particles (sdLDL)] that may be atherogenic and, consequently, potential targets for therapeutics. This study cohort consists of African Americans (AAs), a population disproportionately affected by cardiovascular diseases, thereby accentuating the importance of the investigation. Differential expression (DE) analysis was undertaken using a dataset comprising 17,947 protein-coding mRNAs from the whole blood transcriptomes of 416 samples to identify mRNAs associated with low-density lipoprotein cholesterol (LDL-C) and sdLDL plasma levels. Subsequently, mediation analyses were used to investigate the mediating role of sdLDL particles on the relationship between LDL-C levels and mRNA expression. Finally, pathway enrichment analysis was conducted to identify pathways involving mRNAs whose relationship with LDL-C is mediated by sdLDL. DE analysis revealed 1,048 and 284 mRNA transcripts differentially expressed by LDL-C and sdLDL levels, respectively. Mediation analysis revealed that the associations between LDL-C and 33 mRNAs were mediated by sdLDL. Of the 33 mRNAs mediated by sdLDL, 18 were mediated in both males and females. Nine mRNAs were mediated only in females, and six were mediated only in males. Pathway analysis showed that 33 mRNAs are involved in pathways associated with the immune system, inflammatory response, metabolism, and cardiovascular disease (CVD) risk. In conclusion, our study provides valuable insights into the complex interplay between LDL-C, sdLDL, and mRNA expression in a large sample of AAs. The results underscore the importance of incorporating sdLDL measurement alongside LDL-C levels to improve the accuracy of managing hypercholesterolemia and effectively stratify the risk of CVD. This is essential as differences in sdLDL modulate atherogenic properties at the transcriptome level.NEW & NOTEWORTHY The study investigated the interplay between LDL-C and mRNA expression, focusing on the role of small dense LDL (sdLDL) particles and sex differences. Differential expression analysis identified 1,048 and 284 mRNAs associated with LDL-C and sdLDL levels, respectively. Mediation analysis revealed that sdLDL mediates the relationship between LDL-C and 33 mRNAs involved in immune, inflammatory, and metabolic pathways. These findings highlight the significance of sdLDL in cardiovascular disease risk assessment and underscore sex-specific differences in lipid metabolism.

Metabolic effects and cardiovascular disease risks of antiviral treatments in patients with chronic hepatitis B.

Different antiviral treatments for chronic hepatitis B (CHB) have been known to have different metabolic effects. This study aimed to reveal whether tenofovir alafenamide (TAF)-induced dyslipidemia and its associated outcomes are significant. This study utilized 15-year historical cohort including patients with CHB in Korea and consisted of two parts: the single-antiviral and switch-antiviral cohorts. In the single-antiviral cohort, patients were divided into four groups (entecavir [ETV]-only, tenofovir disoproxil fumarate [TDF]-only, TAF-only, and non-antiviral). Propensity score matching (PSM) and linear regression model were sequentially applied to compare metabolic profiles and estimated atherosclerotic cardiovascular disease (ASCVD) risks longitudinally. In the switch-antiviral cohort, pairwise analyses were conducted in patients who switched NAs to TAF or from TAF. In the single-antiviral cohort, body weight and statin use showed significant differences between groups before PSM, but well-balanced after PSM. Changes in total cholesterol were significantly different between groups (-2.57 mg/dL/year in the TDF-only group and +2.88 mg/dL/year in the TAF-only group; p = 0.002 and p = 0.02, respectively). In the TDF-only group, HDL cholesterol decreased as well (-0.55 mg/dL/year; p < 0.001). The TAF-only group had the greatest increase in ASCVD risk, followed by the TDF-only group and the non-antiviral group. In the switch-antiviral cohort, patients who switched from TDF to TAF had a higher total cholesterol after switching (+9.4 mg/dL/year) than before switching (-1.0 mg/dL/year; p = 0.047). Sensitivity analysis on data with an observation period set to a maximum of 3 years for NA treatment showed consistent results on total cholesterol (-2.96 mg/dL/year in the TDF-only group and +3.09 mg/dL/year in the TAF-only group; p = 0.001 and p = 0.005, respectively). Another sensitivity analysis conducted on statin-treated patients revealed no significant change in cholesterol and ASCVD risk. TAF was associated with increased total cholesterol, whereas TDF was associated with decreased total and HDL cholesterol. Both TAF and TDF were associated with increased ASCVD risks, and statin use might mitigate these risks.

Short-term effects of gastric bypass versus sleeve gastrectomy on high LDL cholesterol: The BASALTO randomized clinical trial.

BACKGROUND: There has been a substantial increase in the use of laparoscopic sleeve gastrectomy (SG) to treat morbid obesity despite observational evidence demonstrating the superiority of Roux-en-Y gastric bypass (RYGB) for reducing low-density lipoprotein (LDL) cholesterol. The main aim was to ascertain whether high LDL cholesterol levels should be considered when selecting the most appropriate surgical procedure for each patient (RYGB or SG). METHODS: In this single-center, randomized clinical trial using intention-to-treat analysis, 38 patients with severe obesity and elevated levels of LDL cholesterol were randomly assigned to undergo RYGB or SG. The primary outcome was LDL cholesterol remission at 12 months, defined as LDL cholesterol < 3.36 nmol/l without lipid-lowering medications. Secondary outcomes included changes in weight, other comorbidities, qualitative lipoprotein traits, cholesterol esters, glycoproteins, cholesterol absorption and synthesis metabolites and complications. RESULTS: Intention-to-treat analysis revealed that LDL cholesterol remission occurred in 66.6% of RYGB patients compared to 27.8% of SG patients (p = 0.019). Among patients completing follow-up, RYGB demonstrated superior remission (80.0% vs. 29.4%, p = 0.005). Exclusive benefits of RYGB included a reduction in large, medium, and small LDL particles. Cholesterol absorption markers showed differential behavior after both techniques: campesterol (Δ -15.2 µg/mg, 95% CI -30.2 to -0.1) decreased after RYGB, and sitosterol (Δ 21.1 µg/mg, 95% CI 0.9 to 41.2), cholestanol (Δ 30.6 µg/mg, 95% CI 14.8 to 57.9) and campesterol (Δ 18.4 µg/mg, 95% CI 4.4 to 32.3) increased after SG. No differences in weight loss, cholesterol esters, glycoproteins, cholesterol synthesis metabolites or postoperative complications were observed between techniques. CONCLUSION: In conclusion, RYGB is superior to SG in terms of short-term of high LDL cholesterol remission. Furthermore, RYGB also led to a greater improvement in lipoprotein parameters that confer an atherogenic profile. Therefore, the presence of elevated levels of LDL cholesterol should be considered when determining the optimal bariatric surgery procedure for each patient. TRIAL REGISTRATION: Clinicaltrials.gov number, NCT03975478).

Familial hypercholesterolemia is related to cardiovascular disease, heart failure and atrial fibrillation. Results from a population-based study.

BACKGROUND: Familial hypercholesterolemia (FH) is associated with atherosclerotic cardiovascular disease (ASCVD). However, the prevalence of FH among a general population remains unknown, and it is unclear if FH is associated with other cardiovascular complications, including heart failure (HF) and atrial fibrillation (AF). METHODS: Analyses were conducted on individuals without a prior history of cardiovascular disease using a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2022 (n = 4,126,642; median age, 44 years; 57.5% men). We defined FH as either LDL cholesterol ≥250 mg/dL or LDL cholesterol ≥175 mg/dL under the lipid-lowering medications under the assumption that lipid-lowering medications reduced LDL cholesterol by 30%. We assessed the associations between FH and composite outcomes, including, ASCVD (myocardial infarction, angina pectoris, and stroke), HF, and AF using Cox proportional hazard model. RESULTS: We identified 11,983 (.29%) FH patients. In total, 181,150 events were recorded during the mean follow-up period of 3.5 years. The status FH was significantly associated with composite outcomes after adjustments (hazard ratio [HR]; 1.38, 95% confidence interval [CI]: 1.30-1.47, p < .001). Interestingly, the status FH was significantly associated with HF (HR: 1.48, 95% CI: 1.36-1.61, p < .001) and AF (HR: 1.33, 95% CI: 1.08-1.64, p < .001) in addition to angina pectoris (HR: 1.45, 95% CI: 1.33-1.58, p < .001) and stroke (HR: 1.19, 95% CI: 1.04-1.36, p < .001). CONCLUSION: We found that the prevalence of FH was .29% in a general population. FH was significantly associated with a higher risk of developing cardiovascular disease, HF and AF. LAY SUMMARY: We sought to identify the prevalence of FH among a general population, and to clarify whether FH increases the risk of not only ASCVD but also HF and AF.

A comparison of dry bean and pea consumption on serum cholesterol: A randomized controlled trial in adults with mild hypercholesterolemia.

BACKGROUND: Diets including pulses are associated with better cardiovascular profiles, including lipid, glycemia and hemodynamics, however, evidence is lacking regarding the contributions of individual pulse varieties. OBJECTIVE: This randomized, controlled trial examined the effects of beans or peas individually, relative to rice, on LDL-cholesterol levels (primary outcome) and other indices of cardiovascular disease risk (secondary outcomes) at 6 weeks in adults with mild hypercholesterolemia. METHODS: This randomized, controlled, single-blind, three-arm parallel-group study was conducted in two Canadian cities (Edmonton, Alberta; Winnipeg, Manitoba). Participants (n=60/group) were randomly assigned to 6 weeks of regular consumption of foods containing either 120g (∼¾ cups) of beans (mixture of black, great northern, navy, pinto,) or 120 g (∼¾ cups) peas (mixture of yellow, green) or identical foods containing white, parboiled rice (control foods). LDL-cholesterol (primary outcome) and indices of lipid metabolism, glycemia and hemodynamics (secondary outcomes) were assessed. RESULTS: LDL-cholesterol was lower (mean, (95%CI)) in the bean (-0.21,-0.39 - -0.03) but not the pea (-0.11, -0.29 - 0.07) group, relative to rice after 6 weeks. Non-HDL-cholesterol (-0.20, -0.40 - -0.002) and total cholesterol (-0.28, -0.49- -0.06) were also lower in bean vs. rice groups. No changes were noted in triglycerides (-0.07, -0.28-0.14), glucose (0.02, -0.17-0.14), insulin (4.94, -5.51-11.38), or blood pressure (systolic: -1.39, -5.18-2.40; diastolic: -1.89, -4.65-0.88). Dietary fiber intake (g/day or g/1000 kcal) was not correlated with the LDL-cholesterol (g/d: r2=0.209, p=0.142; g/1000 kcal: r2=0.126, p=0.379) in the bean group. Gastrointestinal effects were transient and most often not related to the study foods. CONCLUSIONS: Beans, but not peas, lowered LDL-cholesterol, relative to rice, in adults with mild hypercholesterolemia. Fibre may not be responsible for the effect of beans, suggesting other phytochemicals may be the active component(s). Strategies incorporating 120g of pulses in a meal are feasible for managing some cardiometabolic risk factors. CLINICAL TRIAL REGISTRY: Clinical Trials.Gov NCT01661543.

PCSK9 Monoclonal Antibodies Have Come a Long Way.

PURPOSE OF THE REVIEW: This review examines the pivotal role of monoclonal antibodies against PCSK9 in lipid-lowering therapy, emphasizing their biological and clinical impact. RECENT FINDINGS: Randomized controlled trials have validated that PCSK9 monoclonal antibodies (Mabs) effectively reduce LDL-c levels by approximately 50%, even when added to maximal statin therapy. They moreover produce a notable 15-20% relative decrease in major cardiovascular events, with a greater reduction among high-risk patients and no evidence for serious adverse effects, assuaging previous concerns. This review highlights the benefits of PCSK9 Mabs in high cardiovascular risk patients. Despite their efficacy and safety, these therapies are hindered by limited access, and require broader integration into clinical practice to optimize therapeutic outcomes.

A register-based study describing time trends in risk factor control and serious hypoglycaemia together with the effects of starting continuous glucose monitoring in people with type 1 diabetes in Norway.

AIMS: To describe trends in risk factor control and serious hypoglycaemia in people with type 1 diabetes and to assess the effect of starting continuous glucose monitoring (CGM) in the real-world setting. METHODS: Two cross-sectional surveys including 5746 individuals in 2012 and 18,984 individuals in 2020 based on data recorded in the Norwegian Diabetes Register for Adults (NDR-A) and an analysis of a longitudinal cohort of 2057 individuals where data on CGM and HbA1c were available in the NDR-A in 2012 and 2020. RESULTS: In the cross-sectional surveys mean HbA1c decreased from 66 mmol/mol (99% CI 65, 66) (8.2%) in 2012 to 61 mmol/mol (99% CI 61, 61) (7.7%) in 2020 (p < 0.0001). The proportion reporting serious hypoglycaemia decreased from 16.9 to 6.2% in 2020 (p < 0.0001). Mean LDL-cholesterol decreased from 2.80 (99% CI 2.78, 2.83) to 2.63 (99% CI 2.61, 2.65) mmol/l in 2020 (p < 0.0001). Mean blood pressure increased slightly. In the CGM cohort, we found a 3 mmol/mol (0.3%) greater improvement in mean HbA1c and a greater reduction in serious hypoglycaemia (-12.3% vs. -6.2%) among individuals that had started using CGM between 2013 and 2020 when compared with individuals that had not started using CGM. CONCLUSIONS: Between 2012 and 2020, we found marked improvements in glycaemic control and a considerable decrease in the proportion of individuals reporting serious hypoglycaemia. The proportion of individuals using CGM increased substantially and individuals that had started using CGM by 2020 showed greater improvement in glycaemic control and less serious hypoglycaemia.

Assessment of three equations to calculate plasma LDL cholesterol concentration in fasting and non-fasting hypertriglyceridemic patients.

OBJECTIVES: Low-density lipoprotein cholesterol (LDL-C) concentration was calculated for many years using the Friedewald equation, but those from Sampson and extended-Martin-Hopkins perform differently. Their accuracy in fasting hypertriglyceridemia and non-fasting state were compared and the clinical impact of implementing these equations on risk classification and on the setting of lipid treatment goals was assessed. METHODS: Seven thousand six standard lipid profiles and LDL-C concentrations measured after ultracentrifugation (uLDL-C) were retrospectively included. uLDL-C were compared to calculated LDL-C in terms of correlation, root mean square error, residual error, mean absolute deviations and cardiovascular stratification. RESULTS: In fasting state (n=5,826), Sampson equation was the most accurate, exhibited the highest percentage of residual error lower than 0.13 mmol/L (67 vs. 57 % and 63 % using Friedewald, or extended-Martin-Hopkins equations respectively) and the lowest misclassification rate. However, the superiority of this equation was less pronounced when triglyceride concentration (TG) <4.5 mmol/L were considered. In post-prandial state (n=1,180), extended-Martin-Hopkins was the most accurate equation, exhibited the highest percentage of residual error lower than 0.13 mmol/L (73 vs. 39 % and 57 % using Friedewald and Sampson equation respectively). Overall, the negative bias with Sampson equation may lead to undertreatment. Conversely, a positive bias was observed with extended Martin-Hopkins. CONCLUSIONS: None of the equations tested are accurate when TG>4.52 mmol/L. When TG<4.52 mmol/L both Sampson and Martin-Hopkins equations performed better than Friedewald. The switch to one or the other should take in account their limitations, their ease of implementation into the lab software and the proportion of non-fasting patients.

Multi-biobank Mendelian randomization analyses identify opposing pathways in plasma low-density lipoprotein-cholesterol lowering and gallstone disease.

Plasma low-density lipoprotein (LDL)-cholesterol is positively associated with coronary artery disease risk while biliary cholesterol promotes gallstone formation. Different plasma LDL-cholesterol lowering pathways may have distinct effects on biliary cholesterol and thereby gallstone disease risk. We conducted a Mendelian randomization (MR) study using data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls). We first performed drug-target MR analyses substantiated by colocalization to investigate the effects of plasma LDL-cholesterol lowering therapies on gallstone disease risk. We then performed clustered MR analyses and pathway analyses to identify distinct mechanisms underlying the association of plasma LDL-cholesterol with gallstone disease risk. For a 1-standard deviation reduction in plasma LDL-cholesterol, genetic mimics of statins were associated with lower gallstone disease risk (odds ratio 0.72 [95% confidence interval 0.62, 0.83]), but genetic mimics of PCSK9 inhibitors and targeting apolipoprotein B were associated with higher risk (1.11 [1.03, 1.19] and 1.23 [1.13, 1.35]). The association for statins was supported by colocalization (posterior probability 98.7%). Clustered MR analyses identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease risk, with some evidence for ancestry-and sex-specific associations. Among variants lowering plasma LDL-cholesterol, those associated with lower gallstone disease risk were mapped to glycosphingolipid biosynthesis pathway, while those associated with higher risk were mapped to pathways relating to plasma lipoprotein assembly, remodelling, and clearance and ATP-binding cassette transporters. This MR study provides genetic evidence that different plasma LDL-cholesterol lowering pathways have opposing effects on gallstone disease risk.

Statin therapy and cardiovascular protection in type 2 diabetes: The role of baseline LDL-Cholesterol levels. A systematic review and meta-analysis of observational studies.

AIM: The guidelines recommend statins to prevent cardiovascular events in patients with type 2 diabetes (T2D) however, the importance of baseline LDL-Cholesterol (LDL-C) levels remains controversial. This study aimed to determine the association of statin use in T2D patients with major adverse cardiovascular events (MACE) and all-cause mortality and whether this association differs by baseline LDL-C levels. DATA SYNTHESIS: Medline, Embase, and Web of Science were systematically searched from inception until January 2022. Observational studies in patients with T2D comparing statin users vs non-users, with reports of the baseline LDL-C levels, were included. Random-effects meta-analysis and meta-regression were performed to estimate the overall effect on the risk of all-cause mortality and MACE (a composite of myocardial infarction, heart failure, stroke, and revascularization events) and the modification in the association by baseline LDL-C levels. We categorized studies according to their baseline LDL-C levels into 1) <100 mg/dl (2.59 mmol/l), 2) 100-130 mg/dl (2.59-3.37 mmol/l) and 3) >130 mg/dl (3.37 mmol/l) categories. A total of 9 cohort studies (n = 403,411 individuals) fulfilled our criteria. The follow-up duration ranged from 1.7 to 8 years. The overall combined estimate showed that statin therapy was associated with a significantly lower risk of MACE (Hazard Ratio (HR): 0.70 [95% CI 0.59 to 0.83], Absolute risk reduction percentage (ARR%): 3.19% [95%CI 0.88 to 5.50%) and all-cause mortality (HR: 0.60 [95% CI 0.46 to 0.79], ARR%: 5.23% [95% CI 2.18 to 8.28%), but varied, albeit not statistically significant, by baseline LDL-C levels. Studies with baseline LDL-C levels higher than 130 mg/dl had the greatest reduction of MACE (HR: 0.58 [95% CI 0.37 to 0.90]) and all-cause mortality risk (HR: 0.51 [95% CI [ 0.29 to 0.90]). The HRs of MACE in studies with LDL-C levels of 100-130 mg/dl and <100 mg/dl categories were respectively (0.70 [95% CI 0.59 to 0.83]) and (0.83 [95% CI [0.68 to 1.00]); and that of all-cause mortality were respectively (0.62 [95% CI 0.38 to 1.01]) and (0.67 [95% CI [0.44 to 1.02]). Statin use changes the HRs of MACE (0.99 [95%CI, 0.98 to 0.99]; P = 0.04) and all-cause mortality (0.99 [95% CI 0.98 to 1.01]; P = 0.8) per each mg/dl increase in baseline LDL-C level in meta-regression analyses. CONCLUSION: Statin therapy in patients with T2D was associated with reduced risk of MACE and all-cause mortality. Significant differences across studies with different baseline LDL-C levels were not observed.

Airborne particles and cardiovascular morbidity in severe inherited hypercholesterolemia: Vulnerable endothelium under multiple attacks.

Despite recent advances in the research related to air pollution and associated adverse cardiovascular events, the combined effects of air pollution, climate change, and SARS-CoV-2 infection on cardiovascular health need to be researched further. This Commentary addresses their impacts on cardiovascular health in the approximately 25 million people with a severe form of inherited hypercholesterolemia, called familial hypercholesterolemia (FH). The arterial endothelium in these individuals is potentially under multiple attacks caused by particles of both endogenous and exogenous origin. Thus, they have a lifelong highly elevated level of circulating low density lipoprotein (LDL) cholesterol which drives premature atherosclerosis. The high levels of LDL particles, often associated with an elevated level of circulating lipoprotein(a) particles, are both capable of inducing and maintaining endothelial dysfunction. Such pre-existing endothelial dysfunction can be exacerbated by exposure to SARS-CoV-2 viral particles, by exposure to fine particulate matter generated by climate change-associated wildfires, and by dehydration during deadly heatwaves linked to the globally rising temperatures. The external factors can severely worsen the pre-existing endothelial dysfunction, and thereby significantly increase the risk of a cardiovascular event in the exposed FH patients.

Tick bite induced α-gal syndrome highlights anticancer effect of allergy.

Tick bite induced α-gal syndrome (AGS) following consumption of mammalian meat is a recently described intriguing disease occurring worldwide. Here we argue that AGS and delayed allergy in general is an adaptive defence method against cancer. Our hypothesis synthesizes two lines of supporting evidence. First, allergy has been shown to have direct anti-cancer effects with unknown mechanism. Second, eating processed meat was shown to be linked to developing cancer. Humans lost their genes encoding molecules α-gal 30 MYA and Neu5Gc 2 MYA, the latter co-occurring with the start of using fire. These molecules are acquired from external sources, as tick bite for α-gal and mammalian meat for Neu5Gc, the latter accumulating in tumors. The resulting specific delayed allergic response is a molecular adaptation to fight cancer. By further testing and applying our hypothesis, new avenues in cancer research and therapy will open that might save lives and decrease human suffering.

PCSK9 inhibitors on the management of primary and secondary cardiovascular prevention.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have represented an important change in the management of hypercholesterolemia, although, until now, they have barely been used. Without PCSK9i, many patients with atherosclerotic cardiovascular disease (CVD) or those at very high risk do not reach their therapeutic LDLc objectives. OBJECTIVE: The analysis aimed to examine the clinical and biochemical characteristics of subjects receiving PCSK9i treatment in the Dyslipidemia Registry of the Spanish Atherosclerosis Society. METHODS: All consecutive subjects aged ≥ 18 years from different Lipid Units included in the Dyslipidemia Registry of the SEA were analyzed. Inclusion criteria consisted of unrelated patients aged ≥ 18 at the time of inclusion with hypercholesterolemia (LDL-C ≥ 130 mg/dL or non-HDL-C ≥ 160 mg/dL after the exclusion of secondary causes) who were studied for at least two years after inclusion. Participants' baseline and final visit clinical and biochemical characteristics were analyzed based on whether they were on primary or secondary prevention and whether they were taking PCSK9i at the end of follow-up. RESULTS: Eight hundred twenty-nine patients were analyzed, 7014 patients in primary prevention and 1281 in secondary prevention at baseline. 4127 subjects completed the required follow-up for the final analysis. The median follow-up duration was 7 years (IQR 3.0-10.0). Five hundred patients (12.1%) were taking PCSK9i at the end of the follow-up. The percentage of PCSK9i use reached 35.6% (n = 201) and 8.7% (n = 318) in subjects with and without CVD, respectively. Subjects on PCSK9i and oral lipid-lowering agents with and without CVD achieved LDLc reductions of 80.3% and 75.1%, respectively, concerning concentrations without lipid-lowering drugs. Factors associated with PCSK9i use included increasing age, LDLc without lipid-lowering drugs and the Dutch Lipid Clinic Network (DLCN) score. However, hypertension, diabetes, smoking, and LDLc after oral lipid-lowering drugs were not independent factors associated with PCSK9i prescription. In subjects with CVD, the use of PCSK9i was higher in men than in women (an odds ratio of 1.613, P = 0.048). CONCLUSIONS: Approximately one-third of CVD patients received PCSK9i at the end of follow-up. The use of PCSK9i was more focused on baseline LDLc concentrations rather than on CVD risk. Women received less PCSK9i in secondary prevention compared to men.

Real-world evidence evaluation of LDL-C in hospitalized patients: a population-based observational study in the timeframe 2021-2022.

AIMS: European registries and retrospective cohort studies have highlighted the failure to achieve low-density lipoprotein-cholesterol (LDL-C) targets in many very high-risk patients. Hospitalized patients are often frail, and frailty is associated with all-cause and cardiovascular mortality. The aim of this study is to evaluate LDL-C levels in a real-world inpatient setting, identifying cardiovascular risk categories and highlighting treatment gaps in the implementation of LDL-C management. METHODS: This retrospective, observational study included all adult patients admitted to an Italian hospital between 2021 and 2022 with available LDL-C values during hospitalization. Disease-related real-world data were collected from Hospital Information System using automated data extraction strategies and through the implementation of a patient-centered data repository (the Dyslipidemia Data Mart). We performed assessment of cardiovascular risk profiles, LDL-C target achievement according to the 2019 ESC/EAS guidelines, and use of lipid-lowering therapies (LLT). RESULTS: 13,834 patients were included: 17.15%, 13.72%, 16.82% and 49.76% were low (L), moderate (M), high (H) and very high-risk (VH) patients, respectively. The percentage of on-target patients was progressively lower towards the worst categories (78.79% in L, 58.38% in M, 33.3% in H and 21.37% in VH). Among LLT treated patients, 28.48% were on-target in VH category, 47.60% in H, 69.12% in M and 68.47% in L. We also analyzed the impact of monotherapies and combination therapies on target achievement. CONCLUSIONS: We found relevant gaps in LDL-C management in the population of inpatients, especially in the VH category. Future efforts should be aimed at reducing cardiovascular risk in these subjects.

Eliminate LDL cholesterol after heart attack but only for a while.

There is a clear demonstration of the inverse linear correlation between LDL cholesterol levels and clinical benefit. However, the timing of the action of lipid-lowering drugs is not clear. According to animal studies with recombinant lipoprotein A-1, the composition of atherosclerosis changes within 40 h (with variations in lipid and inflammatory contents). Progression-regression studies of atherosclerosis in humans confirm the data, highlighting a rapid change in the plaque over 5 weeks. The data are also in line with what emerges from the survival curves of the old study comparing atorvastatin 80 mg vs. placebo (Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering). The spacing of the curves occurs after only 4 weeks, indicating the precociousness of the favourable effects of powerful statins. Finally, a recent Odyssey post hoc analysis compared the risk of cardiac death and coronary revascularization between a group in which alirocumab lowered LDL cholesterol to below 15 mg (Group 1 and in which the drug was therefore stopped) against the subjects in the placebo group (Group 2), applying a propensity score matching. The primary endpoint occurred in a lower percentage of patients in Group 1 (6.4 vs. 8.4%). Furthermore, patients in Group 1 had a significantly lower hazard ratio (HR) for major adverse cardiovascular events [0.72; 95% confidence interval (CI) 0.51-0.997; P = 0.047] compared with the entire alirocumab group vs. placebo (HR 0.85; 95% CI 0.78-0.93; P < 0.001). According to these preliminary observations, aggressive and early treatment of hypercholesterolaemia in subjects with acute coronary syndrome translates into improved clinical results compared with a strategy that provides for more gradual control. These data will need to be confirmed through further prospective clinical studies and ideally with early conducted atherosclerosis regression studies.

There are those who would like zero LDL cholesterol.

The overwhelming evidence that the reduction of LDL cholesterol (LDLc) levels is associated with a parallel reduction in cardiovascular (CV) risk has led the scientific community to progressively and constantly reduce the optimal therapeutic targets of LDLc, both in patients with known CV disease and in patients undergoing primary prevention. The recent introduction of proprotein convertase subtilisin/kexin type 9 inhibitors has allowed clinicians to observe reductions in LDLc levels that go well beyond the limits set by the main international guidelines; following the 'the lower the better' paradigm, it is natural to ask how low LDLc can be reduced, whether this intervention is associated with a further reduction in CV risk and, above all, whether there are no issues related to safety in the use of polypharmacotherapies that determine an extreme reduction in LDLc levels. The purpose of this article is to summarize the main scientific evidence on the topic, trying to provide an answer to all clinicians who 'would like their LDLc to be-almost-zero'.

Triglyceride-rich lipoprotein remnants, low-density lipoproteins, and risk of coronary heart disease: a UK Biobank study.

AIMS: The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to be resolved. METHODS AND RESULTS: Single-nucleotide polymorphisms (SNPs) associated with TRL/remnant cholesterol (TRL/remnant-C) and LDL cholesterol (LDL-C) were identified in the UK Biobank population. In a multivariable Mendelian randomization analysis, TRL/remnant-C was strongly and independently associated with CHD in a model adjusted for apolipoprotein B (apoB). Likewise, in a multivariable model, TRL/remnant-C and LDL-C also exhibited independent associations with CHD with odds ratios per 1 mmol/L higher cholesterol of 2.59 [95% confidence interval (CI): 1.99-3.36] and 1.37 [95% CI: 1.27-1.48], respectively. To examine the per-particle atherogenicity of TRL/remnants and LDL, SNPs were categorized into two clusters with differing effects on TRL/remnant-C and LDL-C. Cluster 1 contained SNPs in genes related to receptor-mediated lipoprotein removal that affected LDL-C more than TRL/remnant-C, whereas cluster 2 contained SNPs in genes related to lipolysis that had a much greater effect on TRL/remnant-C. The CHD odds ratio per standard deviation (Sd) higher apoB for cluster 2 (with the higher TRL/remnant to LDL ratio) was 1.76 (95% CI: 1.58-1.96), which was significantly greater than the CHD odds ratio per Sd higher apoB in cluster 1 [1.33 (95% CI: 1.26-1.40)]. A concordant result was obtained by using polygenic scores for each cluster to relate apoB to CHD risk. CONCLUSION: Distinct SNP clusters appear to impact differentially on remnant particles and LDL. Our findings are consistent with TRL/remnants having a substantially greater atherogenicity per particle than LDL.

An 8-SNP LDL Cholesterol Polygenic Score: Associations with Cardiovascular Risk Traits, Familial Hypercholesterolemia Phenotype, and Premature Coronary Heart Disease in Central Romania.

Familial hypercholesterolemia (FH) is the most significant inherited risk factor for coronary heart disease (CHD). Current guidelines focus on monogenic FH, but the polygenic form is more common and less understood. This study aimed to assess the clinical utility of an 8-SNP LDLC polygenic score in a central Romanian cohort. The cohort included 97 healthy controls and 125 patients with premature (P)CHD. The weighted LDLC polygenic risk score (wPRS) was analyzed for associations with relevant phenotypic traits, PCHD risk, and clinical FH diagnosis. The wPRS positively correlated with LDLC and DLCN scores, and LDLC concentrations could be predicted by wPRS. A trend of increasing LDLC and DLCN scores with wPRS deciles was observed. A +1 SD increase in wPRS was associated with a 36% higher likelihood of having LDLC > 190 mg/dL and increases in LDLC (+0.20 SD), DLCN score (+0.16 SD), and BMI (+0.15 SD), as well as a decrease in HDLC (-0.14 SD). Although wPRS did not predict PCHD across the entire spectrum of values, individuals above the 90th percentile were three times more likely to have PCHD compared to those within the 10th or 20th percentiles. Additionally, wPRS > 45th percentile identified "definite" clinical FH (DLCN score > 8) with 100% sensitivity and 45% specificity. The LDLC polygenic score correlates with key phenotypic traits, and individuals with high scores are more likely to have PCHD. Implementing this genetic tool may enhance risk prediction and patient stratification. These findings, the first of their kind in Romania, are consistent with the existing literature.

Impact of CYP2C19 Gene Variants on Long-Term Treatment with Atorvastatin in Patients with Acute Coronary Syndromes.

The effectiveness of lipid-lowering therapies may be insufficient in high-risk cardiovascular patients and depends on the genetic variability of drug-metabolizing enzymes. Customizing statin therapy, including treatment with atorvastatin, may improve clinical outcomes. Currently, there is a lack of guidelines allowing the prediction of the therapeutic efficacy of lipid-lowering statin therapy. This study aimed to determine the effects of clinically significant gene variants of CYP2C19 on atorvastatin therapy in patients with acute coronary syndromes. In total, 92 patients with a confirmed diagnosis of ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI) were sequenced for target regions within the CYP2C19 gene on the Illumina Miniseq system. The CYP2C19 poor metabolizer phenotype (carriers of CYP2C19*2, CYP2C19*4, and CYP2C19*8 alleles) was detected in 29% of patients. These patients had significantly lower responses to treatment with atorvastatin than patients with the normal metabolizer phenotype. CYP2C19-metabolizing phenotype, patient age, and smoking increased the odds of undertreatment in patients (∆LDL-C (mmol/L) < 1). These results revealed that the CYP2C19 phenotype may significantly impact atorvastatin therapy personalization in patients requiring LDL lipid-lowering therapy.