Increasing evidence has implicated lipoprotein(a) Lp(a) in the causality of atherosclerosis and calcific aortic stenosis. This has stimulated immense interest in developing novel approaches to ...integrating Lp(a) into the setting of cardiovascular prevention. Current guidelines advocate universal measurement of Lp(a) levels, with the potential to influence cardiovascular risk assessment and triage of higher-risk patients to use of more intensive preventive therapies. In parallel, considerable activity has been undertaken to develop novel therapeutics with the potential to achieve selective and substantial reductions in Lp(a) levels. Early studies of antisense oligonucleotides (e.g., mipomersen, pelacarsen), RNA interference (e.g., olpasiran, zerlasiran, lepodisiran) and small molecule inhibitors (e.g., muvalaplin) have demonstrated effective Lp(a) lowering and good tolerability. These agents are moving forward in clinical development, in order to determine whether Lp(a) lowering reduces cardiovascular risk. The results of these studies have the potential to transform our approach to the prevention of cardiovascular disease.
Abstract Background Statins can regress coronary atheroma and lower clinical events. Although pre-clinical studies suggest procalcific effects of statins in vitro, it remains unclear if statins can ...modulate coronary atheroma calcification in vivo. Objectives This study compared changes in coronary atheroma volume and calcium indices (CaI) in patients receiving high-intensity statin therapy (HIST), low-intensity statin therapy (LIST), and no-statin therapy. Methods In a post-hoc patient-level analysis of 8 prospective randomized trials using serial coronary intravascular ultrasound, serial changes in coronary percent atheroma volume (PAV) and CaI were measured across matched coronary segments in patients with coronary artery disease. Results Following propensity-weighted adjustment for differences in baseline and changes in clinical, laboratory, and ultrasonic characteristics, HIST (n = 1,545) associated with PAV regression from baseline (−0.6 ± 0.1%; p < 0.001), whereas both LIST (n = 1,726) and no-statin therapy (n = 224) associated with PAV progression (+0.8 ± 0.1% and +1.0 ± 0.1%; p < 0.001, respectively; p < 0.001 for both HIST vs. LIST and HIST vs. no-statin; p = 0.35 for LIST vs. no-statin). Significant increases in CaI from baseline were noted across all groups (median interquartile range HIST, +0.044 0.0–0.12; LIST, +0.038 0.0–0.11; no-statin, +0.020 0.0–0.10; p < 0.001 for all), which could relate to statin intensity (p = 0.03 for LIST vs. no-statin; p = 0.007 for HIST vs. no-statin; p = 0.18 for HIST vs. LIST). No correlations were found between changes in CaI and on-treatment levels of atherogenic and antiatherogenic lipoproteins, and C-reactive protein, in either of the HIST groups or the no-statin group. Conclusions Independent of their plaque-regressive effects, statins promote coronary atheroma calcification. These findings provide insight as to how statins may stabilize plaque beyond their effects on plaque regression.
ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ...ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear.
We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (
) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer.
A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The
and
scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval CI, 0.78 to 0.87; P = 4.0×10
) for the
score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9×10
) for the
score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer.
Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).
Inhibitors of cholesteryl ester transfer protein (CETP) were developed due to their ability to raise HDL‐C levels. Preclinical studies demonstrated favorable effects on atherosclerotic plaque with ...CETP inhibitory approaches in animal models. While these agents raise HDL‐C and lower LDL‐C, most have not proven to reduce cardiovascular event rates in large outcome trials. The state of opinion after all of these clinical trials is reviewed.
The purpose of this study was to determine the effect of evolocumab on optical coherence tomography (OCT) measures of plaque composition.
The proprotein convertase subtilisin kexin type-9 inhibitor ...evolocumab produced coronary atheroma regression in statin-treated patients.
Patients with a non–ST-segment elevation myocardial infarction were treated with monthly evolocumab 420 mg (n = 80) or placebo (n = 81) for 52 weeks. Patients underwent serial OCT and intravascular ultrasound imaging within a matched arterial segment of a nonculprit vessel. The primary analysis determined the change in the minimum fibrous cap thickness and maximum lipid arc throughout the imaged arterial segment. Additional analyses determined changes in OCT features in lipid-rich plaque regions and plaque burden. Safety and tolerability were evaluated.
Among treated patients, (age 60.5 ± 9.6 years; 28.6% women; low-density lipoprotein cholesterol LDL-C, 141.3 ± 33.1 mg/dL), 135 had evaluable imaging at follow-up. The evolocumab group achieved lower LDL-C levels (28.1 vs 87.2 mg/dL; P < 0.001). The evolocumab group demonstrated a greater increase in minimum fibrous cap thickness (+42.7 vs +21.5 μm; P = 0.015) and decrease in maximum lipid arc (−57.5o vs. −31.4o; P = 0.04) and macrophage index (−3.17 vs −1.45 mm; P = 0.04) throughout the arterial segment. Similar benefits of evolocumab were observed in lipid-rich plaque regions. Greater regression of percent atheroma volume was observed with evolocumab compared with placebo (−2.29% ± 0.47% vs −0.61% ± 0.46%; P = 0.009). The groups did not differ regarding changes in microchannels or calcium.
The combination of statin and evolocumab after a non–ST-segment elevation myocardial infarction produces favorable changes in coronary atherosclerosis consistent with stabilization and regression. This demonstrates a potential mechanism for the improved clinical outcomes observed achieving very low LDL-C levels following an acute coronary syndrome. (Imaging of Coronary Plaques in Participants Treated With Evolocumab; NCT03570697)
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Atherosclerosis and its clinical manifestation as ischaemic heart disease remains a considerable health burden. Given that many factors contribute to ischaemic heart disease, a multifactorial ...approach to prevention is recommended, starting with lifestyle advice, smoking cessation, and control of known cardiovascular risk factors, such as blood pressure and lipids. Within the lipid profile, the principal target is lowering LDL cholesterol, firstly with lifestyle interventions and subsequently with pharmacological therapy. Statins are the recommended first-line pharmacological treatment. Some individuals might require further lowering of LDL cholesterol or be unable to tolerate statins. Additional therapies targeting different pathways in cholesterol metabolism are now available, ranging from small molecules taken orally, to injectable therapies. Examples include ezetimibe, which targets Niemann-Pick C1-like protein, and monoclonal antibodies that target PCSK9. Phase 3 trials have also been completed for bempedoic acid (targeting ATP-citrate lyase) and inclisiran (an interference RNA-based therapeutic targeting hepatic PCSK9 synthesis). In addition to LDL cholesterol, mendelian randomisation studies support a causal role for lipoprotein(a) and triglycerides in ischaemic heart disease. In this Series paper, we appraise currently available and emerging therapies for lowering LDL cholesterol, lipoprotein(a), and triglycerides for prevention of ischaemic heart disease.
Summary Background Several clinical trials have reported inconsistent findings for the effect of fibrates on cardiovascular risk. We undertook a systematic review and meta-analysis to investigate the ...effects of fibrates on major clinical outcomes. Methods We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and March, 2010. We included prospective randomised controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo. Summary estimates of relative risk (RR) reductions were calculated with a random effects model. Outcomes analysed were major cardiovascular events, coronary events, stroke, heart failure, coronary revascularisation, all-cause mortality, cardiovascular death, non-vascular death, sudden death, new onset albuminuria, and drug-related adverse events. Findings We identified 18 trials providing data for 45 058 participants, including 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths. Fibrate therapy produced a 10% RR reduction (95% CI 0–18) for major cardiovascular events (p=0·048) and a 13% RR reduction (7–19) for coronary events (p<0·0001), but had no benefit on stroke (−3%, −16 to 9; p=0·69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, −8 to 7; p=0·92), cardiovascular mortality (3%, −7 to 12; p=0·59), sudden death (11%, −6 to 26; p=0·19), or non-vascular mortality (−10%, −21 to 0·5; p=0·063). Fibrates reduced the risk of albuminuria progression by 14% (2–25; p=0·028). Serious drug-related adverse events were not significantly increased by fibrates (17 413 participants, 225 events; RR 1·21, 0·91–1·61; p=0·19), although increases in serum creatinine concentrations were common (1·99, 1·46–2·70; p<0·0001). Interpretation Fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia. Funding National Health and Medical Research Council of Australia.
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