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Hot Topic at ENDO 2022: Novel Medication Targeting PCSK9 for LDL Cholesterol Reduction

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Statins lower Low-Density Lipoprotein (LDL) cholesterol by 30-50%, have well-known cardiovascular benefits, a well-established safety profile and, in combination with ezetimibe, may reduce LDL-C by about 65%. However, some patients need additional LDL-C reduction to reduce atherosclerotic cardiovascular disease (ASCVD) risk. These include patients with established ASCVD or patients with genetic familial hypercholesterolemia, which is associated with lifelong elevations in LDL-C and increased risk of cardiovascular disease at a young age. At the annual scientific meeting of the Endocrine Society, ENDO 2022, held in Atlanta, two sessions highlighted the new medication inclisiran, including a small interfering RNA which is approved in the U.S. and Europe for LDL-C reduction in high-risk patients taking statins. One of the benefits of inclisiran is that it is long-acting. Only three injections in the first year and two more in the second year and subsequent years, will lower LDL-C by 50%, on top of a statin. Inclisiran, approved by the FDA in late 2021, is indicated for statin-treated persons at high risk of cardiovascular events, specifically those with ASCVD or heterozygous familial hypercholesterolemia.

Inclisiran targets PCSK9 (proprotein convertase subtilisin/Kexin type 9) messenger RNA (mRNA). PCSK9 is a protein that binds to the hepatic LDL receptor and escorts the LDL receptor to the hepatic lysosome, where it degrades. This degradation leads to fewer LDL receptors and thus reduced cholesterol uptake in the liver and higher plasma concentrations of LDL-C. Studies of people with loss of function mutations of the PCSK9 gene have reported lower levels of LDL-C and lower risk of ASCVD.

The first medications to target PCSK9 were monoclonal antibodies to PCSK9, which reduce LDL-C by about 50-60% on top of statins and reduce ASCVD events (heart attack, stroke, CVD death, coronary revascularization procedures) in high-risk patients. The monoclonal antibodies are administered subcutaneously either every two weeks or every month. Adverse effects are generally injection site reactions. To date, an increase in diabetes as seen with statin therapy primarily in patients at risk of diabetes, 0.2% per year, has not been observed. 

Inclisiran affects the PCSK9 pathway by a genetic mechanism of action. It is a double-stranded RNA that directs the breakdown of the mRNA for PCSK9, this reducing translation of the mRNA. Lower levels of PCSK9 in the liver increase recycling (rather than degradation) of LDL-C receptors, which increase LDL-C uptake by the liver, and excretion of cholesterol by the bile. After injection of 284 mg inclisiran at days 1 and 90, PCSK9 levels were significantly reduced by 75% at four months and 69% at six months. In two placebo-controlled randomized trials (ORION 10 and 11) in over 3000 participants with ASCVD taking statins, subcutaneous injection of inclisiran at day one, three months, nine months, and 18 months reduced LDL-C by more than 50 %. Inclisiran has been approved in combination with a statin at a dose of 284 mg subcutaneously at one month, three months, and then every six months. Adverse effects are mainly injection site reactions that occurred in clinical trials in about 8% of patients in the inclisiran group and 2% of patients in the placebo group. Other adverse effects with an excess incidence in the inclisiran group compared to placebo included arthralgia (5% versus 4%, respectively) and bronchitis (4.3% versus 2.7%, respectively). Dose adjustment is not needed in people with mild, moderate, and severe renal impairment or those with mild or moderate liver disease.

A cardiovascular outcomes trial is ongoing. The cost of inclisiran today is about $3,250 per dose without insurance. However, it can be less if the patient has Medicare Part B or commercial insurance and is eligible for a copay program. Currently, this medication is available through a buy and bill model at the practitioner’s office, a specialty pharmacy, or an Alternate Injection Center.

In summary, medications targeting PCSK9 reduce LDL-C markedly and provide additional LDL-C reduction in people taking statins or statins and other LDL-C lowering medications. Inclisiran, delivered subcutaneously three times the first year and then every six months, has the potential, provided it is affordable, to change the way we treat patients with increased ASCVD risk.

Dr. Newman has no conflicts of interest to report.

Image by Denis Novikov / GettyImages

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