This phase 3 trial evaluated the safety and efficacy of inclisiran, a small interfering RNA that inhibits hepatic PCSK9 synthesis, in 482 adults with heterozygous familial hypercholesterolemia, who ...received subcutaneous injections of inclisiran or placebo on days 1, 90, 270, and 450. Changes in cholesterol were assessed up to day 540.
Inclisiran, a small interfering RNA therapeutic, reduces hepatic synthesis of PCSK9. In two separate randomized trials, subcutaneous injections of inclisiran on day 1, day 90, and then every 6 months ...reduced LDL cholesterol levels by approximately 50% at month 17, with a modest excess of injection-site adverse events.
In a post hoc analysis of the Treating to New Targets study, high-density lipoprotein cholesterol levels in patients receiving statin therapy were shown to be predictive of subsequent major ...cardiovascular events, even when low-density lipoprotein (LDL) cholesterol levels were taken into account and even among patients with very low levels of LDL cholesterol (<70 mg per deciliter).
High-density lipoprotein cholesterol levels in patients receiving statin therapy were shown to be predictive of subsequent major cardiovascular events, even among patients with very low levels of LDL cholesterol.
Population studies have consistently shown that high-density lipoprotein (HDL) cholesterol levels are a strong, independent inverse predictor of cardiovascular disease.
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In the Framingham Heart Study, HDL cholesterol level was more potent as a risk factor for coronary heart disease than was the level of low-density lipoprotein (LDL) cholesterol.
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An analysis of data from four large studies concluded that each increase of 1 mg per deciliter (0.03 mmol per liter) in HDL cholesterol is associated with a decrease of 2 to 3% in the risk of future coronary heart disease.
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Intervention trials using statins to lower LDL cholesterol have consistently . . .
IMPORTANCE: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. OBJECTIVE: To determine the effects on ...cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. INTERVENTIONS: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins. MAIN OUTCOMES AND MEASURES: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. RESULTS: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean SD age, 62.5 9.0 years; 35% women; 70% with diabetes; median low-density lipoprotein LDL cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 95% CI, 0.90-1.09; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil–treated patients (14.7%). CONCLUSIONS AND RELEVANCE: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02104817
In a randomized trial, alirocumab (a monoclonal antibody that inhibits PCSK9), as compared with placebo, reduced LDL cholesterol levels by an additional 62 percentage points. In a post hoc analysis, ...the incidence of cardiovascular events was reduced with alirocumab.
Monoclonal antibodies to proprotein convertase subtilisin–kexin type 9 (PCSK9) have been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are being treated with statins. In phase 2 studies lasting 8 to 12 weeks, the PCSK9 inhibitor alirocumab lowered LDL cholesterol levels by 40 to 70% when added to background statin therapy.
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However, this new treatment needs to be evaluated in larger populations for longer periods of follow-up to establish its safety and efficacy.
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We conducted a 78-week trial comparing alirocumab (150 mg every 2 weeks) with placebo in 2341 patients at high risk for cardiovascular . . .
Torcetrapib, a cholesteryl ester transfer protein inhibitor, markedly raises levels of high-density lipoprotein cholesterol. Unexpectedly, in the ILLUMINATE trial, torcetrapib therapy in combination ...with atorvastatin, as compared with atorvastatin alone, increased the risk of death from both cardiovascular and noncardiovascular causes. The drug also raised blood pressure.
Torcetrapib therapy in combination with atorvastatin, as compared with atorvastatin alone, increased the risk of death from both cardiovascular and noncardiovascular causes.
Evidence supporting the proposition that high-density lipoprotein (HDL) cholesterol should be considered as a therapeutic target includes experimental models of atherosclerosis,
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an inverse relationship to the risk of cardiovascular disease in humans,
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clinical trials of drugs for which raising HDL cholesterol levels is a primary pharmacologic effect,
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and the residual risk of cardiovascular disease associated with a low HDL cholesterol level after effective statin therapy.
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Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from HDL to other lipoproteins; the inhibition of this protein raises HDL cholesterol levels and decreases low-density lipoprotein (LDL) cholesterol levels. There is evidence . . .
Familial hypercholesterolemia is marked by very elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease. This 20-year follow-up study showed that statin initiation ...during childhood in affected persons slowed the progression of carotid intima–media thickness and reduced the risk of cardiovascular disease in adulthood.
In six trials comparing the anti–PCSK9 antibody bococizumab with placebo, the reduction in LDL cholesterol at 12 weeks was 55.2 percentage points lower with bococizumab. However, antidrug antibodies ...that developed in many patients reduced the magnitude of the reduction.
Reducing levels of low-density lipoprotein (LDL) cholesterol with statin therapy is a highly effective method for reducing cardiovascular risk.
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Trial data, observational studies, and genetic analyses indicate that further reductions in LDL cholesterol levels are likely to confer greater cardiovascular benefits.
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Yet, recent studies have shown wide variability in the individual response of patients to statin therapy in terms of the percent reduction in LDL cholesterol levels.
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Inhibitors of proprotein convertase subtilisin–kexin type 9 (PCSK9) reduce plasma LDL cholesterol levels by slowing PCSK9-mediated degradation of the LDL receptor.
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Fully human monoclonal antibodies such as alirocumab and evolocumab that . . .
The effects on lipid profiles of pharmacologic inhibition of ATP citrate lyase, an enzyme in the cholesterol–biosynthesis pathway upstream of HMGCR (the target of statins), are similar to those of ...statins. This inhibition may lower the risk of cardiovascular disease.
Inclisiran, a small interfering RNA that targets
PCSK9
mRNA, was given as a single injection at baseline or in two doses at baseline and 90 days. At 180 days, LDL cholesterol was significantly ...lowered among persons at high cardiovascular risk who had elevated levels at baseline.
Low-density lipoprotein (LDL) cholesterol is a causal factor in atherosclerotic cardiovascular disease. Statins have been shown to reduce LDL cholesterol levels and cardiovascular events in large outcome trials, findings that have made them the therapeutic cornerstone of clinical practice.
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Despite the proven efficacy of statins, there is considerable variability in individual responses to these drugs.
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Furthermore, some observational data suggest that as many as half of persons who begin statin therapy discontinue it within a year.
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Moreover, among patients receiving statin therapy who are at high risk for cardiovascular disease and who have persistent elevation of LDL cholesterol levels, the . . .
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