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Inclisiran- A game changer in ASCVD management.

Atherosclerotic cardiovascular disease (ASCVD) is amongst the leading causes of death worldwide, accounting for an estimated 19 million deaths each year.1 The mortality rates are even higher in India linked with an earlier age of onset and greater severity of the disease.2-3 More than half of cardiac deaths in India occur below the age of 50 years and 25% occur below the age of 40 years. The skyrocketing rates are due to a combination of risk factors which include dyslipidemia, hypertension, impaired glucose tolerance, type 2 diabetes, metabolic syndrome, and smoking.3

Numerous clinical studies have established elevated levels of LDL-C to be the strongest risk factor for the development of cardiovascular disorders (CVD), in particular, ASCVD.4 For every 30mg/ dL change in LDL-C levels, the relative risk for CVD increases proportionately by about 30%. In South Asians increased levels of non-high-density lipoprotein-C, a type of LDL is the most important risk factor for the development of ASCVD.5

Challenges with current lipid-lowering therapies and the need for alternatives

Statins are the mainstay of therapy for lowering LDL levels as per global clinical guidelines. They can provide up to 22% proportional reductions in the risk of major vascular events. The major drawback, however, is that despite maximum tolerated statin therapy, most high-risk ASCVD patients do not achieve a clinically significant reduction in LDL levels with statins. Along with this, a considerable portion of high-risk patients are not able to tolerate statins due to their side effects.6

Other lipid-lowering drugs including monoclonal antibodies such as alirocumab and evolocumab target circulating levels of PCSK9, a protein expressed in the liver that plays a key role in keeping circulating cholesterol levels high. The treatments come with the burden of twice monthly injections as well as a question of long-term immunological safety.6

In lieu of these drawbacks, an alternative approach is required for the benefit of patients who are unable to meet LDL-C goals despite being on the maximum tolerated dose of statin, alone or in combination with other lipid-lowering treatments. Furthermore, an alternative therapy is required for those who are statin-intolerant and cannot adhere to twice-monthly injection therapies.6

Effective LDL-C reduction and cardiovascular disease prevention with Inclisiran: A breakthrough RNA therapy

With only two maintenance doses a year, Inclisiran has proven to be the first and only FDA-approved small interfering RNA (siRNA) drug for the reduction of LDL-C. It reduces the amount of LDL-C in circulation by improving the liver’s natural ability to prevent the production of PCSK9.7-9

Data from a patient-level, pooled analysis of the pivotal Phase III ORION trials (ORION-9, ORION-10, and ORION-11) over 18 months demonstrated that Inclisiran decreased LDL cholesterol levels by 50% in patients on maximally tolerated statins and kept it low during each 6-month dosing interval vs. placebo .6-7There were no severe adverse events, new-onset diabetes, neurocognitive disorders, or myalgia. The most common side effects were mild to moderate injection site reactions.9

Combined with maximal tolerated statin therapy, Inclisiran could also lead to a significant reduction in major adverse cardiovascular events such spontaneous myocardial infarction and ischemic stroke.10


While statins are the standard therapy for reducing LDL-C and preventing major cardiovascular events, many high-risk patients cannot achieve the desired results or tolerate the side effects. Monoclonal antibodies targeting PCSK9 offer an alternative but require frequent injections and raise safety concerns.6 Inclisiran, a small interfering RNA drug, provides a promising option with bi-annual dosing and proven effectiveness in reducing LDL-C without major adverse effects. Combined with statin therapy, Inclisiran may significantly reduce major adverse cardiovascular events, representing a breakthrough in ASCVD treatment.7-10

About the Author: Dr Geetika Gupta is a quirky wordsmith with a toothy grin. She has done her Bachelor of Dental surgery degree from Rajiv Gandhi University of Health sciences and is a gold medalist. Oral cancer, bone pathologies and implantology are some of her favorite topics. When she’s not busy filling cavities and perfecting smiles, she makes time to write articles on various healthcare topics. Click here to connect with Dr. Geetika Gupta on LinkedIn.


1. Vasan RS. et al. Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study. Circulation. 2022 Apr 26;145(17):1324-1338. 

2. Enas EA, Varkey B, Gupta R. Expanding statin use for prevention of ASCVD in Indians: Reasoned and simplified proposals. Indian Heart J. 2020 Mar-Apr;72(2):65-69. 

3. Duell, P.B. et al. The epidemic of atherosclerotic cardiovascular disease in India. J Clin Lipidol. 2020 Mar-Apr;14(2):170-172. 

4. Burnett, H. et al. Comparative efficacy of non-statin lipid-lowering therapies in patients with hypercholesterolemia at increased cardiovascular risk: a network meta-analysis. Curr Med Res Opin. 2022 May;38(5):777-784.

5. LDL cholesterol. Available at: Accessed: February 20, 2023.

6. Khan SA, Naz A, Qamar Masood M, Shah R. Meta-Analysis of Inclisiran for the Treatment of Hypercholesterolemia. Am J Cardiol. 2020 Nov 1;134:69-73.

7. Ray, K.K. et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017 Apr 13;376(15):1430-1440.

8. Summary of Product Characteristics: Leqvio (inclisiran), solution for subcutaneous injection.Available at .Accessed: 20 February 2023.

9. FDA approves Novartis Leqvio® (Inclisiran), first-in-class Sirna to lower cholesterol and keep it low with two doses a year (2021) Novartis. Available at: .Accessed: February 20, 2023.

10. Ray, K.K. et al. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur Heart J. 2023 Jan 7;44(2):129-138.

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