New lipid-lowering drugs provide greater CV risk reduction

10 Jan 2018
New lipid-lowering drugs provide greater CV risk reduction

A new batch of apolipoprotein B (apoB)-lowering drugs that capitalize on statins’ ability to lower lipids will further benefit patients at high cardiovascular (CV) risk who need to be treated more aggressively.

“The sobering reality is, as good as statins have been, there remains a considerable risk of clinical events,” said Professor Stephen Nicholls of the South Australian Health & Medical Research Institute in Adelaide, Australia. “The best relative risk reduction with statins thus far has been 45 percent. That means more than half of the clinical events continue to occur despite statin therapy. We need to find additional agents.” [Nicholls S, AHA 2017, abstract AT.ME.2398]

“The success of adding the cholesterol absorption inhibitor ezetimibe to statin therapy to achieve CV risk reduction gave researchers hope that other therapies might offer as much or more benefit,” Nicholls said.

In particular, proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors have shown promising results in clinical trials. Improved plaque regression with the PCSK9 inhibitor evolocumab (64 percent of patients vs 47 percent of those on placebo) in the GLAGOV trial, for example, suggested that evolocumab could slow atherosclerosis progression and promote its regression when added to statin therapy. [JAMA 2016;316:2373-2384]

“A novel approach that targets RNA synthesis of PCSK9 has also been promising, as demonstrated in the ORION-1 trial,” said Nicholls.

ORION-1 was a double-blind, placebo-controlled trial in which treatment with the PCSK9 synthesis suppressor inclisiran reduced LDL-cholesterol (LDL-C) by 27.9–41.9 percent at 180 days, compared with a 2.1 percent LDL-C increase with placebo. The trial was conducted in patients at high CV risk with elevated LDL-C levels. [N Engl J Med 2017;376:1430-1440]

“The ability to directly target these agents to the hepatocyte and actually have a very complementary approach in reducing PCSK9 synthesis presents an attractive therapeutic alternative. The administration of these agents 3–4 times a year may achieve a robust and durable degree of LDL-C lowering,” Nicholls said.

Focusing on triglyceride reduction as a pathway to reduce CV risk has led to apolipoprotein C-III and angiopoietin-like 4 as potential targets for new drug development, based on the triglyceride-modulating effects with loss-of-function mutations.

“This is fundamentally a balance between atherogenic lipoproteins and atheroprotective lipoproteins,” Nicholls said. “These agents need to move forward in clinical development for us to understand not only their impact on CV events but, importantly, safety. It’s an exciting time forward.”
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