Physicians' Academy for Cardiovascular Education

Preclinical and clinical studies strengthen the promise of ANGPTL3 as a therapeutic target

Dewey et al., NEJM May 24, 2017 | Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease

Graham et al., NEJM May 24, 2017 | Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides

Background

Genome-wide association studies and exome sequencing have identified associations between genetic variants of angiopoietin-like proteins (ANGPTLs) and lipoprotein and triglyceride levels. ANGPTLs are important regulators of lipoprotein metabolism.

ANGPTL3 is an endogenous inhibitor of lipoprotein lipase (LPL). Loss-of-function (LOF) variants in LPL have been shown to increase the risk of coronary artery disease (CAD), whereas gain-of-function variants decrease this risk [1-3]. Rare LOF variants of ANGPTL3 have been reported to be associated with lower triglyceride (TG) levels and lower LDL-c and HDL-c levels in humans. In ApoE-deficient mice, deletion of Angptl3 reduced development of atherosclerosis [4]. LOF variants in ANGPTL3 have also been associated with beneficial metabolic effects, such as higher LPL and endothelial lipase activity, higher insulin sensitivity and lower levels of free fatty acid in the serum [5].

Dewey et al examined the relationship between ANGPTL3 LOF variants and CAD in a sample from the large DiscovEHR US health care system, with follow-up studies in four population cohorts. In addition, effects of pharmacologic antagonism of ANGPTL3 with the monoclonal antibody evinacumab (REGN1500) on lipid metabolism and atherosclerosis were evaluated in a mouse model of atherosclerosis, and on lipid levels in human volunteers.

Graham et al evaluated the effect of antisense oligonucleotide (ASOs) directed against Angptl3 mRNA on plasma lipid levels, TG clearance, liver TG content, insulin sensitivity and atherosclerosis in mice, and they conducted a randomized trial with subcutaneous injections of placebo or ASO targeting ANGPTL3 mRNA in 44 humans.

Main results

Dewey et al.

Graham et al.

Conclusion

Dewey and colleagues reported that in over 400 carriers of heterozygous LOF variants in ANGPTL3, a lower risk of CAD was observed as compared with non-carriers. This observation is in line with the lower lipid levels and slower atherosclerosis progression seen in dyslipidemic mice treated with evinacumab. Moreover, the dose-dependent effects of treatment with evinacumab in humans appear to recapitulate the lipid phenotype of carriers of an ANGPTL3 LOF variant. These findings suggest that the hypolipidemic profile induced by genetic or therapeutic antagonism of ANGPTL3 consisting of reduced levels of HDL-c, LDL-c and TG, is anti-atherogenic.

The study by Graham and colleagues demonstrated that inhibition of ANGPTL3 mRNA resulted in favorable cardiometabolic effects in various mouse models and in healthy humans. The preclinical studies showed that hepatic suppression Angptl3 protein production in mice resulted in lower levels of TG, LDL-c, non-HDL-c and VLDL-c. A lower liver TG content was seen, higher insulin sensitivity and a reduction of atherosclerosis progression. Similar effects were seen in the phase I trial in humans.

These studies provide a rationale for continued development of an ANGPTL3-targeted therapy for persons with elevated levels of TG-rich lipoproteins, in order to lower residual CV risk in patients already taking recommended medical and preventive therapies. Both the antibody-based and the ASO-approach deserve further study.

References

Show references

Read the article of Dewey et al at NEJM Read the article of Graham et al at NEJM