Update on Lipid-Lowering Therapies for CVD

Atherosclerotic cardiovascular disease (ASCVD) represents the top global cause of morbidity and mortality, and elevated plasma levels of lipids have been identified as one of the strongest predictive risk factors for ASCVD.^1-3 Thus, lipid-lowering therapy remains an essential component of CVD management, with statins as the first-line treatment.

For patients who are intolerant or have contraindications for statins, and for those on maximally tolerated statin therapy who do not reach low-density lipoprotein (LDL) target levels, ezetimibe and PCSK9 inhibitors may be used as monotherapy or in combination with statins to augment their lipid-lowering impact. Each of these guideline-recommended therapies have been associated with improvements in lipid profiles, reduced risk for ischemic events and cardiovascular mortality, and improvements in endothelial function and inflammatory blood markers.³

Monotherapy with ezetimibe was found to be associated with an 18% reduction in LDL, an 8% reduction in triglycerides, and a 3% increase in high-density lipoprotein (HDL). When combined with statins, ezetimibe led to a further reductions in LDL (15%) and triglycerides (5%), and an additional 1.6% increase in HDL.³

PCSK9 inhibitors have been shown to reduce plasma LDL by 65% and 34% compared with placebo and statin therapy, respectively. In combination with statins, PCSK9 inhibitors led to reductions in plasma LDL of 70% compared with placebo. In addition, PCSK9 inhibitors were associated with a 25% to 30% reduction in lipoprotein(a), a 17% reduction in triglycerides, compared with placebo, and a 7% increase in HDL.³

Emerging therapies

In a review published in Pharmacology and Therapeutics, several novel lipid-lowering agents under investigation are described, including inclisiran, a synthetic small interfering RNA that inhibits the synthesis of hepatic PCSK9. Results from phase I and phase II trials indicate 50% reductions in LDL compared with placebo, with no increase in adverse effects.³ Results from phase III trials thus far indicate that bempedoic acid may confer LDL-lowering benefits when combined with statins or ezetimibe.

Evinacumab, a monoclonal antibody that inhibits angiopoietin-like protein 3 (ANGPTL3), was found to reduce LDL by 20% to 90% and triglycerides by 50% in patients with familial hypercholesterinemia. Antisense oligonucleotides (ASO) targeting ANGPTL3 have shown dose-dependent reductions in triglycerides of 30% to 60% and favorable effects on LDL and HDL in healthy individuals, as well as decreased progression of atherosclerosis in rodent models.

Volanesorsen, an ASO directed against apolipoprotein C-III (ApoC-III) mRNA, was found to lower triglycerides by 70% in healthy individuals and in patients with familial chylomicronemia syndrome and hypertriglyceridemia, but was associated with more adverse events than other existing and emerging therapies.

In a recent phase II trial, an ASO that inhibits the synthesis of apolipoprotein(a) in hepatocytes led to dose-dependent reductions in lipoprotein(a) levels in patients with baseline levels of apolipoprotein(a) >60 mg/dl, with few reported adverse events.⁴

We spoke with the following experts to further gauge challenges and developments in the realm of lipid-lowering therapies: Robert S. Rosenson, MD, professor of medicine and director of Cardiometabolic Disorders at the Icahn School of Medicine at Mount Sinai in New York, New York; and Seth Shay Martin, MD, MHS, associate professor of medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland, and director of the Advanced Lipid Disorders Program of the Ciccarone Center at Johns Hopkins.  

What are some of the current challenges of lipid management in CVD?

Dr Rosenson: The main challenges are therapies that lower LDL cholesterol in patients with familial hypercholesterolemia and patients with statin muscle intolerance. Other challenges include lowering lipoprotein(a), a genetically determined atherogenic lipoprotein associated with early-onset ASCVD.

Dr. Martin: One major challenge is that our patients are often unaware of the risks associated with high lipids. For example, there are more than 1 million patients estimated to have familial hypercholesterolemia in the US and 30 million around the globe, but more than 90% remain undiagnosed.⁵ 

Furthermore, it has been shown that even in patients who have had heart attacks, lipid panels are often not followed up, and drug therapy is not optimized.

In lipid management, statins are most commonly used, but their use can be limited by associated side effects. 

What are the most notable recent and emerging developments in the area of lipid-lowering therapy, and what are the remaining needs?

Dr Rosenson: Emerging developments include monoclonal antibodies, small interfering mRNA inhibitors, and CRISPR approaches.^3,7 Emerging therapies include evinacumab, a fully human monoclonal antibody directed against ANGPTL3. This therapy lowers LDL cholesterol by 50% by an LDL-independent mechanism. In patients with loss-of-function mutations in the LDL receptor, response to this therapy is similar to that in patients with less severe abnormalities in the LDL receptor.⁶

The results in patients with severe elevations in LDL cholesterol and heterozygous familial hypercholesterolemia were reported at the American Heart Association Scientific Sessions 2020 on November 15, 2020 as a late breaking clinical trial.⁸ [Editor’s note: Dr Rosenson was the lead investigator of this trial, in which evinacumab was shown to reduce LDL levels by >50% in patients with refractory hypercholesterolemia.] 

There is an ongoing phase 3 trial in patients with cardiovascular events (Horizon, Novartis) and a phase 2 trial in patients with high lipoprotein(a) and established atherosclerotic vascular disease (Amgen).

Other remaining needs include triglyceride-lowering therapies that prevent the risk for acute pancreatitis. Another emerging therapy is the ApoC-III inhibitor vupanorsen.

Dr Martin: In the area of lipid-lowering therapy, PCSK9 inhibitors were a major breakthrough for LDL cholesterol lowering to reduce cardiovascular risk. However, burdensome prior authorization requirements have impeded their use in practice. There are multiple other promising lipid therapies in the pipeline, such as those aiming at lipoprotein(a), ANGPTL3, and ApoC-III. 

What are the key recommendations regarding this topic in terms of clinical practice?

Dr Rosenson: Recommendations for clinicians should emphasize the mandate to achieve minimal acceptable LDL cholesterol goals with high intensity or maximally tolerated statins, ezetimibe, and PCSK9 inhibitors. 

Dr Martin: The tools for lipid management are ever-expanding, and we have the potential to partner effectively with our patients to substantially lower LDL-C and cardiovascular risk. However, there is a need to do the fundamentals. At present we are too often mopping up the floor when we should be turning off the faucet. By that, I mean implementing effective lipid management and prevention as early as possible. We need to increase diagnosis of familial hypercholesterolemia early in life, cascade test family members, and follow up lipid panels regularly in patients at risk and optimize therapy.

References

1. World Health Organization. The top 10 causes of death. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death Accessed online November 16, 2020.
2. GA Fishbein, MC Fishbein, LM Buja. Chapter 7 – Myocardial Ischemia and Its Complications. Cardiovascular Pathology (Fourth Edition). Academic Press. 2016;239-270. doi:10.1016/B978-0-12-420219-1.00007-0
3. Mourikis P, Zako S, Dannenberg L, et al. Lipid lowering therapy in cardiovascular disease: From myth to molecular reality. Pharmacol Ther. 2020;213:107592. doi:10.1016/j.pharmthera.2020.107592
4. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al; AKCEA-APO(a)-LRx Study Investigators. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020;382(3):244-255. doi: 10.1056/NEJMoa1905239
5. WVU Medicine. WVU Medicine Children’s marks Familial Hypercholesterolemia Awareness Day to reduce premature heart disease. Accessed online November 16, 2020.
6. Raal FJ, Rosenson RS, Reeskamp LF, et al; ELIPSE HoFH Investigators. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med. 2020;383(8):711-720. doi:10.1056/NEJMoa2004215
7. Furgurson M, Lagor WR. CRISPR: a promising tool for lipid physiology and therapeutics. Curr Opin Lipidol. 2019;30(3):172-176. doi:10.1097/MOL.0000000000000591
8. Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in patients with refractory hypercholesterolemia. Published online November 15, 2020. N Engl J Med. doi:10.1056/NEJMoa2031049