Cardiovascular Risks & Insights from ACR Convergence 2021

ACR CONVERGNCE 2021—Controlling inflammation—in addition to lowering cholesterol levels and other strategies—is an increasingly recognized component of managing cardiovascular (CV) risk. Also, targeting changes to the function and structure of high-density lipoprotein (HDL) in the setting of inflammation may improve CV outcomes for people with rheumatic disease. Speakers at ACR Convergence 2021 offered these insights and more in a session that explored how to manage risk and outcomes related to cardiovascular disease.

Targeting LDL

Dr. Jorge Plutzky

Jorge Plutzky, MD, director of preventive cardiology at Brigham and Women’s Hospital, Boston, and associate professor of medicine at Harvard Medical School, offered a cardiologist’s perspective during the presentation. When it comes to low-density lipoprotein (LDL) levels, the field has gone from “lower is better” to “lowest is best,” according to Dr. Plutzky, especially with regard to patients reaching a certain level of CV risk.

“Cardiologists’ broad view is that this is an incredibly common problem, that patients go through a very long preclinical phase before CV complications of atherosclerosis are manifest[ed], and that provides an opportunity to intervene during those early phases,” he said. “Many aspects of cardiovascular risk are modifiable and that represents a chance to avoid some chronic sequelae and even some particularly adverse outcomes, like CV death.”

Efforts to get LDL lower and lower are seen in recent therapy development beyond statins. Example: Inclisiran—approved in Europe and under review in the U.S.—uses small interference RNA to target production of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that degrades LDL receptors and leads to higher LDL levels. Alirocumab and evolucumab, which also target PCSK9, have shown positive effects in clinical trials when they are added to statin therapy.^1,2

In another study, a specific type of omega-3 fatty acid, icosapent ethyl, was found to have a “striking benefit” when added to statin therapy in patients with high CV risk.³ Questions have been raised about the placebo used in the study, but Dr. Plutzky noted the 25% risk reduction suggests the benefit is likely real.

Bempedoic acid, alone or with ezetimibe, reduces LDL, as well as C-reactive protein levels, raising “an intriguing question” for rheumatologists.⁴ “Is there an anti-inflammatory effect here and may that contribute to benefits in the clinical trial? We’ll have to wait and see,” said Dr. Plutzky. Results from a phase 3 study are expected in spring 2022.

Canakinumab, an antibody to interleukin (IL) 1b, produced reductions in inflammation and CV events, but no change in LDL.⁵ “One can point to this as a proof of concept that inflammation matters. Whether this is a therapy for cardiovascular disease isn’t clear, but it highlights important issues,” Dr. Plutzky said.

“All of these issues are relevant for really all patients, and all Americans, in terms of their CV risk,” he said, “but perhaps in particular those with rheumatologic disorders, where inflammation may be contributing to their increased cardiovascular risk.”

LDL, HDL & Rheumatic Disease

LDL levels in the setting of rheumatic disease is a tricky matter, said Christina Charles-Schoeman, MD, MS, professor of medicine and chief of rheumatology at the University of California, Los Angeles.

For patients with systemic inflammation from rheumatoid arthritis (RA), lower LDL and total cholesterol levels have been associated with higher, rather than lower, CV risk. This situation has come to be known as the lipid paradox.

Work by Dr. Charles-Schoeman and her group found this paradox may be caused by the effect of disease activity degrading cholesterol esters, leading to lower serum cholesterol levels. Treatment with tofacitinib decreases this degradation and increases cholesterol levels, researchers have found.⁶

Investigators have begun to focus on non-traditional lipid parameters, such as the effects of rheumatic disease activity on the function and structure of high-density lipoprotein (HDL). HDL has two major functions that combat atherosclerosis: its antioxidant function and its effect on reverse cholesterol transport, the removal of excess cholesterol from the peripheral tissues.

HDL, researchers have found, doesn’t adhere only to cholesterol, but to many proteins, some of which can be modified in active RA. The protein profile of dysfunctional, pro-inflammatory HDL is different compared with anti-inflammatory HDL, including some involved in immune response, complement regulation and other functions important in inflammatory disease, Dr. Charles-Schoeman said.

One trial, TEAR, found that—regardless of the therapy involved—“if you decrease inflammation, you have improvements in the HDL function profile,”⁷ she said. This finding points to an important new direction in treatment.

“Treatment of active RA, while associated with increases in traditional cholesterol levels, may be associated with improvement in non-traditional lipid parameters including HDL function and structure,” Dr. Charles-Schoeman said. “Further CV studies are certainly warranted to evaluate further the relationship of these lipid changes to CV events.”

Thomas Collins is a freelance medical writer based in Florida.

References

1. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1489–1499
2. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017 May 4;376(18):1713–1722.
3. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11–22.
4. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019 Mar 14;380(11):1022–1032.
5. Ridker PM, Everett BM, MacFadyen JG, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017 Sep 21;377(12):1119–1131.
6. Charles-Schoeman C, Fleischmann R, Davignon J, et al. Potential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib. Arthritis Rheumatol. 2015 Mar;67(3):616–625.
7. Charles-Schoeman C, Yin Lee Y, Shahbazian A, et al. Improvement of high-density lipoprotein function in patients with early rheumatoid arthritis treated with methotrexate monotherapy or combination therapies in a randomized controlled trial. Arthritis Rheumatol. 2017 Jan;69(1):46–57.