Novel Therapies for Lipoprotein(a): Update in Cardiovascular Risk Estimation and Treatment.

PURPOSE OF REVIEW: Lipoprotein(a) is an important causal risk factor for cardiovascular disease but currently no available medication effectively reduces lipoprotein(a). This review discusses recent findings regarding lipoprotein(a) as a causal risk factor and therapeutic target in cardiovascular disease, it reviews current clinical recommendations, and summarizes new lipoprotein(a) lowering drugs. RECENT FINDINGS: Epidemiological and genetic studies have established lipoprotein(a) as a causal risk factor for cardiovascular disease and mortality. Guidelines worldwide now recommend lipoprotein(a) to be measured once in a lifetime, to offer patients with high lipoprotein(a) lifestyle advise and initiate other cardiovascular medications. Clinical trials including antisense oligonucleotides, small interfering RNAs, and an oral lipoprotein(a) inhibitor have shown great effect on lowering lipoprotein(a) with reductions up to 106%, without any major adverse effects. Recent clinical phase 1 and 2 trials show encouraging results and ongoing phase 3 trials will hopefully result in the introduction of specific lipoprotein(a) lowering drugs to lower the risk of cardiovascular disease.

Lipids and lipoproteins.

Lipids are essential in human physiology, triglycerides for energy and cholesterol as a structural component in cells and as a precurser for hormones and vitamins. However, high blood levels of cholesterol cause atherosclerosis, leading to cardiovascular disease, which is the number one cause of death globally. Genetic evidence suggests that lipoprotein(a) and remnant cholesterol, cholesterol in very low-density and intermediate-density lipoproteins, are causally involved in the development of cardiovascular disease together with low-density lipoproteins and this has spurred the development of drugs potently lowering these.

Elevated remnant cholesterol increases the risk of peripheral artery disease, myocardial infarction, and ischaemic stroke: a cohort-based study.

AIMS: The atherogenic potential of cholesterol in triglyceride-rich lipoproteins, also called remnant cholesterol, is being increasingly acknowledged. Elevated remnant cholesterol is associated with increased risk of myocardial infarction and ischaemic stroke. We tested the hypothesis that elevated remnant cholesterol is also associated with increased risk of peripheral artery disease (PAD). METHODS AND RESULTS: We studied 106 937 individuals from the Copenhagen General Population Study recruited in 2003-15. During up to 15 years of follow-up, 1586 were diagnosed with PAD, 2570 with myocardial infarction, and 2762 with ischaemic stroke. We also studied 13 974 individuals from the Copenhagen City Heart Study recruited in 1976-78. During up to 43 years of follow-up, 1033 were diagnosed with PAD, 2236 with myocardial infarction, and 1976 with ischaemic stroke. Remnant cholesterol was calculated from a standard lipid profile. Diagnoses were from Danish nationwide health registries. In the Copenhagen General Population Study, elevated remnant cholesterol levels were associated with higher risk of PAD, up to a multivariable adjusted hazard ratio (HR) of 4.8 (95% confidence interval 3.1-7.5) for individuals with levels ≥1.5 mmol/L (58 mg/dL) vs. <0.5 mmol/L (19 mg/dL). Corresponding results were 4.2 (2.9-6.1) for myocardial infarction and 1.8 (1.4-2.5) for ischaemic stroke. In the Copenhagen City Heart Study, corresponding HRs were 4.9 (2.9-8.5) for PAD, 2.6 (1.8-3.8) for myocardial infarction, and 2.1 (1.5-3.1) for ischaemic stroke. CONCLUSION: Elevated remnant cholesterol is associated with a five-fold increased risk of PAD in the general population, higher than for myocardial infarction and ischaemic stroke.

Spectrophotometry of cerebrospinal fluid for xanthochromia is a sensitive and specific test for subarachnoid bleeding but adds little to computed tomography.

Subarachnoid hemorrhage (SAH) is a serious neurological event associated with high morbidity and mortality. Computed tomography of the cerebrum (CTC) is the diagnostic method of choice, but in case of negative CTC but strong suspicion of SAH, lumbar puncture with spectrophotometric analysis of cerebrospinal fluid (CSF) for xanthochromia is performed. We wanted to examine the diagnostic properties of CSF spectrophotometry for xanthochromia testing. We performed a retrospective study of the diagnostic properties of CSF analysis for xanthochromia using spectrophotometry in the diagnosis of SAH. A total of 489 CSF samples were analyzed for xanthochromia, according to international guidelines, from 2009 until 2014 and for 411 of these the patient files were retrieved and examined for final clinical diagnosis and result of CTC. One patient with SAH did not have a positive spectrophotometry report and another patient with SAH had an equivocal report. In four patients did initial CTC not correctly identify SAH. For patients with a negative CTC within six hours of symptom onset spectrophotometry for xanthochromia in the CSF had a diagnostic sensitivity of 100% and a diagnostic specificity of 98.5%. The positive predictive value was 16.7% and the negative predictive value 100%. We conclude that spectrophotometry of CSF for xanthochromia is a sensitive and specific test for diagnosing SAH. However, it seems that an initial CTC identifies almost all patients with SAH. This suggests that in our and similar diagnostic settings, lumbar puncture and testing for xanthochromia might only be relevant in very few cases, if not obsolete.

Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes.

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.

Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.

BACKGROUND: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS: In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).