Physicians' Academy for Cardiovascular Education

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

Literature -

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

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

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