Abstract
Lowering low-density lipoprotein-cholesterol (LDL-C) is the prime strategy to prevent or treat atherosclerotic cardiovascular diseases (ASCVD). Fourier’s trial showed that cardiovascular events are the least when LDL levels are close to 25 mg%. All professionals now endorse the targets to be 50-55 mg% to address the residual risk in the very high-risk groups and manage familial hypercholesterolemia patients. Despite realizing the need for intensive reduction of LDL majority of patients, even in the US or Europe, are not achieving the guideline-recommended LDL goals. 1 Some of them have true statin intolerance or significant unpleasant side effects preventing maintenance of prescribed station doses on a long-term basis.
The proprotein convertase subtilisin/kexin type 9 (PCSK 9) inhibitors came into existence as a boon to fill these gaps in current therapy of dyslipidemia. These monoclonal antibodies inhibit the action of PCSK9 and make more LDL receptors available on the surface of hepatocytes. The abundance of LDL receptors enhances elimination of LDL-C from circulation. In robust clinical trials like Fourier and Odyssey outcomes, they had proven their safety and efficacy with 40%-60% reduction in LDL over and above what can be achieved with baseline statins-ezetimibe therapy. Based on these results FDA approved two PCSK9 inhibitor agents—Evolocumab and Alirocumab that can be used as subcutaneous injections twice a month for intense lowering of LDL levels. The need to inject them every two weeks is a bit of a challenge for long-term usage. 2
Before fully experiencing these two wonderful molecules, Inclisiran has made its entry with a bang. Inclisiran is a siRNA that inhibits the production of PCSK9 protein thus sparing the LDL receptors from degradation; resulting in enhanced elimination of LDL-c from circulation. In a series of ORION trials, it proved as a promising molecule- efficacious and safe with an attractive dosing pattern—six monthly SC injections that could help in maintaining steady lower levels of LDL in blood. After a single dose LDL-C is reduced by 50% an effect that is sustained for six months. FDA and European EMA have approved Inclisiran in 2023. It was initially introduced into market with trade name-leqvio. Injection site reactions were reported in about 5%, most often minor. The local site reactions further reduced with the second and further repeat injections. Other side-effects were not much different from those seen with placebo. Diarrhea and headache are occasionally reported. Its impact on diabetes and insulin resistance has to be further observed.3, 4
The 2018-Task force on clinical practice guidelines
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defined the “Very high-risk group” to priorities our resources in the management of dyslipidemia and identify the group that may be best served with PCSK9 inhibitors, including Inclisiran.
More than one of the four major ASCVD events: (a) recent ACS (within 12 months), (b) History of MI, (c) History of ischemic stroke, (d) symptomatic peripheral artery disease.
Or
One of the above events plus two or more of the nine high-risk conditions: (a) Age >65 years, (b) Heterozygous familial hypercholesterolemia, (c) History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major events cited before, (d) Diabetes mellitus, (e) Hypertension, (f) CKD, (g) current smoking, (h) Persistently elevated LDL-C (>100 mg%) despite maximally tolerated statin and ezetimibe use, (i) history of congestive heart failure.
Over the last six months, Inclisiran appeared in the Indian market after the DCGI approval. The first product is—Novartis-Sybrava PFS 284 mg (1.5 ml) injection, costing 1.2 lakh per injection in pre-filled auto-injectors. A few other companies in India are fast entering the market almost at the same price. Initial experience shows that it has the potential to be a great game-changer due to its efficacy and use in subcutaneous route once in six months—a schedule that sounds like vaccination. It will improve patient acceptability, compliance and confidence. The price has to settle down further, for greater adaptability in the economically compromised communities. The long-term effects are yet to be studied. It looks like great times are ahead in the management of difficult-to-treat dyslipidemia patients.
