PCSK9 inhibitors and ACS

PCSK9 inhibitors:

• PCSK9 inhibitors reduce circulating LDL Cholesterol levels, and this effect can be potentially increased by a combination with statins.
• The FOURIER trial demonstrated that anti-PCSK9 reduced lipoprotein (a) levels by ≈25%–30%.
• In ORION-1 trial, a single inclisiran injection reduced mean LDL Cholesterol levels by 27.9%–41.9% after 180 days and by 28.2%–36.6% after 240 days (P <0.001). Two doses led to a mean reduction of 35.2% – 52.6% on day 180 (P <0.001).
• Similarly, ORION-10 trial showed that inclisiran reduced LDL Cholesterol levels by 52.3% after 510 days in patients with atherosclerotic cardiovascular disease (CVD).
• In ORION-11 trial, LDL Cholesterol levels reduced by 49.9% in patients with atherosclerotic CVD or an atherosclerotic CVD risk equivalent.

LDL-C management after ACS

• American College of Cardiology/American Heart Association guidelines recommend initiating a more intensive lipid-lowering therapy for patients with LDL-C ≥70 mg/dL (≥1.8 mml/L).
• ESC/EAS guidelines recommend early use of high-intensity statins and addition of ezetimibe and anti- PCSK9 antibodies in ACS patients without both LDL Cholesterol reduction ≥50% from baseline and LDL Cholesterol reduction >1.4 mmol/L (>55 mg/dL).
• Although neither evolocumab nor alirocumab significantly reduced inflammatory markers in patients with ACS, both these PCSK9 inhibitors in combination with high-intensity statins significantly reduced LDL Cholesterol levels after 8 weeks.
• In the EVACS trial, evolocumab helped >90% patients with ACS achieve LDL Cholesterol <55 mg/dL (according to ESC/EAS guidelines) compared with 11% patients receiving only statins.
• In the EVOPACS study, evolocumab on top of a high-intensity statin reduced LDL-C levels by 40.7% and helped 95.7% patients achieve LDL-C <55 mg/dL.
• In Odyssey Outcome study, alirocumab vs placebo reduced overall Mace risk by 15%, and reduced all-cause mortality risk and caused fewer deaths for CHD.

Pitfalls and future perspectives:

Although most patients receiving PCSK9 inhibitors attain the expected 50%–60% reduction in LDL-C, sporadically, a limited LDL-C-lowering response is noted.

• Proposed mechanisms for such PCSK9 inhibitor hypo-responsiveness (<15% of LDL Cholesterol reduction): (1) Impaired monoclonal antibody entry into the systemic circulation and (2) physiological impairment after monoclonal antibody absorption.

The most common cause of apparent PCSK9 inhibitor resistance is related to discontinuing concurrent lipid-lowering therapies after initiating PCSK9 inhibitors.

Novel PCSK9 inhibitors that are currently under development: Inclisiran, oral small-molecule inhibitors, vaccines, and clustered regularly interspaced short palindromic repeats.