ANGPTL3 antagonism may further decrease lipid levels, risk for CVD
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Therapeutic and genetic antagonism of angiopoietin-like 3 decreased lipid levels and the risk for atherosclerotic CVD, according to a study in The New England Journal of Medicine.
“In the clinic, I treat many patients with very high triglycerides, but our current medications aren’t lowering triglycerides enough in many cases,” investigator Richard L. Dunbar, MD, assistant professor of cardiovascular medicine and a member of the division of translational medicine and human genetics at the University of Pennsylvania, said in a press release. “I’m delighted at the prospect of a new treatment that’s a lot more potent, all the more because it lowers LDL at the same time. It’s very reassuring to see that people with this genetic defect actually seem to be protected from heart disease. I think that really bodes well for a therapeutic that’s targeting the ANGPTL3 pathway.”
Genetic analysis
Researchers conducted human genetics studies on DNA samples from 58,335 participants of European ancestry, in which 13 loss-of-function variants were found in ANGPTL3. Those who were heterozygous for loss-of-function variants accounted for 246 participants in the cohort.
Those who were carriers of loss-of-function variants had 27% lower triglyceride levels vs. noncarriers (P = 2.8 x 10-21). After adjustment for covariates, participants who were carriers also had 4% lower HDL (P = .02).
Of the 13,102 participants with CAD, 43 participants were carriers of the loss-of-function variant (cumulative carrier frequency = 0.33%). The variant was also seen in 183 participants in the control group (n = 40,430; cumulative carrier frequency = 0.45%).
After an adjustment for sex, age and principal components of ancestry, and the ANGPTL3 loss-of-function variant was linked to 41% lower odds of CAD (adjusted OR for any loss-of-function variant = 0.59; 95% CI, 0.41-0.85). The association was also seen for odds of MI, but it was not as significant (carrier frequencies, 0.36% among participants with MI and 0.45% among the control group; OR = 0.66; 95% CI, 0.39-1.06).
Further evidence of connection
Researchers analyzed additional evidence of the connection between ANGPTL3 loss-of-function variants and CAD with data from 23,317 participants with CAD and 107,116 participants in a control group from four other studies. Carriers of the variants had numerically lower odds for CAD, although it was not significant (OR = 0.63; 95% CI, 0.39-1.02).
In a separate evaluation, researchers assigned 83 patients with mildly to moderately elevated triglyceride or LDL levels to evinacumab (Regeneron) or placebo. Patients assigned 20 mg/kg of evinacumab had a decrease in triglycerides at 4 days (–76%), LDL at 15 days (–23.2%) and HDL at 15 days (–18.4%).
Evinacumab was also administered to mice to evaluate its effect on atherosclerosis. The therapy decreased atherosclerotic lesion size more than the control antibody (difference, –39%; P < .001). Evinacumab also contributed to a greater decrease of necrotic content in severe lesions vs. the control antibody (difference, –45%; P = .001).
“Collectively, these findings confirm that the ANGPTL3 pathway is important in regulating lipids and [CVD],” Robert Pordy, MD, vice president of cardiovascular and metabolism therapeutics at Regeneron Pharmaceuticals, said in a press release. “Evinacumab, our antibody to ANGPTL3, has been designated a breakthrough therapy by the [FDA] for [homozygous familial hypercholesterolemia], and we plan to move to phase 3 for this indication. We are also planning to initiate additional studies in people with other severe forms of dyslipidemia.” – by Darlene Dobkowski
Disclosure: This study was partially funded by Regeneron Pharmaceuticals. Dunbar reports receiving grants and nonfinancial support from Regeneron Pharmaceuticals during the conduct of the study, and grants from Ionis and UniQure outside the submitted work. Pordy is an employee of Regeneron Pharmaceuticals and reports receiving other support from Regeneron Pharmaceuticals outside the submitted work. Please see the full study for a list of the other researchers’ relevant financial disclosures.