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Vol 26, No. 02, February 2022   |   Issue PDF view/purchase
SPOTLIGHTS
Managing Cholesterol With siRNA Therapy
An interview with Dr. Prashanth Subramanian, Chief Scientific Officer for Novartis Singapore on their newly approved cholesterol drug.

High cholesterol has been associated with increased cardiovascular risk and stroke. The World Health Organization estimates that 2.6 million people die each year from diseases caused by high cholesterol. In this interview, we have here with us Dr. Prashanth Subramanian, Chief Scientific Officer for Novartis Singapore, to share more with us on the situation in Singapore and a recently approved therapy for managing cholesterol levels.

1. (a) In 2017, around 33.6 per cent of Singaporean residents aged between 18 to 69 were reported to suffer from high bad cholesterol, contributing to the rise of cardiovascular diseases such as heart disease and stroke. What is the current state of disease burden of bad cholesterols in Singapore and why is this the case?

High cholesterol is the highest prevalent risk factor for coronary artery disease among Singaporeans aged 18 to 69. According to the Ministry of Health, Singapore, the prevalence of hyperlipidaemia (high levels of fats in the blood, which include cholesterol and triglycerides) was 33.6 per cent in 2017.1 If left untreated, it can lead to other health conditions such as heart attack, stroke, and atherosclerotic cardiovascular disease (ASCVD).

Although the incidence of ASCVD locally is uncertain, it is the most common cause of acute myocardial infarction (AMI), frequently known as a heart attack. AMI is a type of ischaemic heart disease, where heart problems are caused by reduced blood supply due to the narrowing of heart arteries and were associated with 4,523 out of 22,054 deaths in Singapore in 2020.2

Singapore’s rapidly ageing population and the increasingly sedentary lifestyle for both the elderly3 and the young due to the pandemic4 predisposes individuals to chronic health problems, leading to a rising prevalence of risk factors for ASCVD.

(b) What are some causes of high cholesterol that we should be aware of?

One’s cholesterol level is primarily influenced by two factors: genetics and lifestyle. Under certain medical conditions, some patients may also have elevated blood cholesterol levels. These include diabetes mellitus (also known as diabetes), chronic kidney disease, and hypothyroidism. Ageing can also contribute to elevated cholesterol levels as the liver is less effective in removing the bad cholesterol from the blood circulation.

There are some patients with a genetic predisposition to high cholesterol levels (familial hypercholesterolemia) and have a strong family history of premature coronary artery disease.

There are some medicines such as steroids5 or oral contraceptives,6 which the patient may be taking, that can increase cholesterol levels as well.

An unhealthy lifestyle is also a contributing factor such as bad dietary habits, obesity, lack of exercise, smoking, and excessive alcohol consumption.

An elevated cholesterol level is considered the most readily modifiable risk factor of ASCVD. With ASCVD as the underlying cause of heart attacks and stroke, Novartis recently launched the “Invisible Nation” programme. A partnership with Global Heart Hub, Invisible Nation is a worldwide network of patient organisations committed to driving a decline in cardiovascular (CV) death by effecting systemic change in ASCVD care.

2. Is hyperlipidaemia hereditary? Why are certain individuals unable to control the level of bad cholesterol?

Hyperlipidaemia can be hereditary if one has the condition familial hypercholesterolemia, a genetic disorder that causes the liver to remove bad cholesterol from the blood less efficiently.7

There are several factors that results in one’s inability to control the level of bad cholesterol.

Firstly, it could be due to genetic influence.6 For example, the bad cholesterol levels for people with familial hypercholesterolemia could be significantly elevated to a point where it cannot be controlled regardless of lifestyle changes and medicines.

Other common reasons for failure to control cholesterol levels are an inadequate dose/strength of the prescribed medicines, not adhering to a self-administered regimen or intolerance towards cholesterol-lowering medicines amid -undesirable side effects.8

Additionally, there are patients who believe that medications alone are sufficient to control their cholesterol levels without making lifestyle changes. A study suggested that patients with high cholesterol tend to gain more weight and exercise less once they were prescribed statins, a common orally administered cholesterol-lowering medicine.9

Despite the effectiveness of statins and other cholesterol-lowering medications, it should not be the only means to manage high cholesterol. Patients still need to adhere to a diet low in saturated fat, trans-fats and cholesterol (e.g. red and processed meats like sausage, butter, and full-fat dairy products) and stick with a heart-healthy diet (e.g. lean proteins such as chicken and fish).

3. Hyperlipidaemia is defined as having more than 4.1 mmol/L of LDL-cholesterol. What are some consequences of uncontrolled bad cholesterol levels and how severe could they become if left untreated?

Persistently elevated cholesterol levels are a significant risk factor for the development of cardiovascular disease (CVD).10 If left untreated, this can increase one’s risk of developing CVD in those without established cardiovascular disease or can further increase the risk of CVD events in patients who already have a history of heart attacks, strokes, or have undergone coronary stenting or coronary artery bypass surgery.

4. When a healthy lifestyle, diet, and exercise are not enough to prevent or reverse hyperlipidaemia, patients may require pharmacological interventions. What are some currently available treatments for bad cholesterol levels?

Statins are the first-line therapy for patients with high cholesterol and are the most commonly used orally administered cholesterol-lowering therapy.11 They are prescribed to reduce one’s risk of illness and mortality.

Ezetimibe is another agent commonly prescribed with statins to lower bad cholesterol by preventing the absorption of cholesterol from food intake in the gut.12

Oral fibrates are effective for patients with high triglyceride levels.13 Those that find them ineffective could also be initiated on prescription-strength omega-3 fatty acid (fish oil) at higher doses.14

5. In recent years, new innovations such as small-interfering (siRNA) therapies and nanomedicine have shown great promise to tackle high cholesterol. Could you share the latest developments in treating and managing LDL-cholesterol levels?

In 2015, hepatic translation proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, which are monoclonal antibodies administered by injection every two weeks, were approved for use by the US Food and Drug Administration (FDA).15 These drugs are effective and together with statins, lower LDL-cholesterol and cardiovascular risks more effectively.

The latest therapy approved in Singapore for treatment of high cholesterol is Inclisiran (Leqvio®). It is available for patients with non-Familial Hypercholesterolemia (non-FH) and Heterozygous Familial Hypercholesterolemia (HeFH). Inclisiran is currently available in 54 countries and has recently received US FDA approval as well. Using small interfering RNA (siRNA),16,17 it prevents the synthesis of PCSK9 protein, thereby increasing the number of LDL-receptors on the hepatocytes,18 which are the chief functional cells of the liver that plays a pivotal role in cholesterol metabolism.

It is suitable for patients with high cholesterol levels who are either unable to achieve their target LDL level with maximally tolerated statin therapies needed to prevent cardiovascular disease, or are intolerant towards cholesterol-lowering medicines amid undesirable side effects.19,20

This medicine is administered as an initial dose, another one at three months and then just once every six months21 thereafter. Together with statins, it can effectively lower cholesterol levels.22

References

  1. HealthHub, Disease Burden Statistics for Singapore, Source: https://www.healthhub.sg/a-z/health-statistics/5/disease-burden [Accessed on 20 December 2021]
  2. Report on Registration of Births and Deaths 2020 by the Registry of Births and Deaths, Immigration and Checkpoints Authority, Singapore and Ministry Of Health, Source: https://www.ica.gov.sg/docs/default-source/ica/stats/annual-bd-statistics/stats_2020_annual_rbd_report.pdf [Accessed on 23 September 2021]
  3. Ng, L.P., Koh, Y. L., Ta, N. C. (2020). Physical activity and sedentary behaviour of ambulatory older adults in a developed Asian community: a cross-sectional study. Singapore Med J 2020; 61(5): 266-271 doi: https://doi.org/10.11622/smedj.2020022 [Accessed on1 November 2021]
  4. Zheng, C., Huang, W. Y., Sheridan, S., Sit, C. H., Chen, X. K., & Wong, S. H. (2020). COVID-19 Pandemic Brings a Sedentary Lifestyle in Young Adults: A Cross-Sectional and Longitudinal Study. International journal of environmental research and public health, 17(17), 6035. https://doi.org/10.3390/ijerph17176035 [Accessed on1 November 2021]
  5. Herink M, Ito MK. Medication Induced Changes in Lipid and Lipoproteins. [Updated 2018 May 10]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. https://www.ncbi.nlm.nih.gov/books/NBK326739/
  6. Godsland IF, Crook D, Simpson R, Proudler T, Felton C, Lees B, Anyaoku V, Devenport M, Wynn V. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med. 1990 Nov 15;323(20):1375-81. doi: 10.1056/NEJM199011153232003. PMID: 2146499.
  7. Medline Plus, Familial hypercholesterolemia, Source: https://medlineplus.gov/ency/article/000392.htm [Accessed on 15 December, 2021]
  8. Fang, H.S.A., Gao, Q., Lee, M.L. et al. LDL-cholesterol change and goal attainment following statin intensity titration among Asians in primary care: a retrospective cohort study. Lipids Health Dis 20, 2 (2021). https://doi.org/10.1186/s12944-020-01427-z [Accessed on 15 December 2021]
  9. Journal of the American Heart Association, Lifestyle Changes in Relation to Initiation of Antihypertensive and Lipid-Lowering Medication: A Cohort Study, Source: https://www.ahajournals.org/doi/10.1161/JAHA.119.014168 [Last accessed on 15 December, 2021]
  10. Jeong, S.M., Choi, S., Kim, K., Kim, S.M., Lee, G., Park, S.Y., Kim, Y.Y., Son, J.S., Yun, J.M., and Park, S.M., Effect of Change in Total Cholesterol Levels on Cardiovascular Disease Among Young Adults, Journal of the American Heart Association. 2018;7:e008819, https://doi.org/10.1161/JAHA.118.008819
  11. Grundy, S., Stone, N., Bailey, A., Beam, C., Birtcher, K., Blumenthal, R., Braun, L., de Ferranti, S., Faiella-Tommasino, J., Forman, D., … 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines https://www.ahajournals.org/doi/10.1161/CIR.0000000000000625
  12. Patel, Shailendra B. “Ezetimibe: a novel cholesterol-lowering agent that highlights novel physiologic pathways.” Current cardiology reports vol. 6,6 (2004): 439-42. doi: 10.1007/s11886-004-0052-5
  13. Feingold KR. Triglyceride Lowering Drugs. [Updated 2021 Apr 1]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK425699/ [Accessed on 20 December 2021]
  14. Ito, Matthew K. “A Comparative Overview of Prescription Omega-3 Fatty Acid Products.” P & T : a peer-reviewed journal for formulary management vol. 40,12 (2015): 826-57. [Accessed on 20 December 2021]
  15. American Health & Drug Benefits, Repatha (Evolocumab): Second PCSK9 Inhibitor Approved by the FDA for Patients with Familial Hypercholesterolemia, Source: https://www.ahdbonline.com/articles/2117-repatha-evolocumab-second-pcsk9-inhibitor-approved-by-the-fda-for-patients-with-familial-hypercholesterolemia [Accessed on 20 December 2021]
  16. Ray K, Wright R, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16):1507–1519 [Accessed on 23 September 2021].
  17. Raal, F, Kallend D, Ray K, et al. Inclisiran for Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;382(16):1520–1530. [Accessed on23 September 2021]
  18. Kosmas, C. E., Muñoz Estrella, A., Sourlas, A., Silverio, D., Hilario, E., Montan, P. D., & Guzman, E. (2018). Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia. Diseases (Basel, Switzerland), 6(3), 63. https://doi.org/10.3390/diseases6030063
  19. Lansberg P, Lee A, Lee ZV, Subramaniam K, Setia S. Nonadherence to statins: individualized intervention strategies outside the pill box. Vasc Health Risk Manag. 2018;14:91-102. [Accessed on 23 September 2021]
  20. Bruckert E, Parhofer KG, Gonzalez-Juanatey JR, et al. Proportion of High-Risk/Very High-Risk Patients in Europe with Low-Density Lipoprotein Cholesterol at Target According to European Guidelines: A Systematic Review. Adv Ther. 2020;37(5):1724–1736. [Accessed on23 September 2021]
  21. Leqvio prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021.
  22. Desai CS, Martin SS, Blumenthal RS. Non-cardiovascular effects associated with statins. BMJ. 2014;349:g3743. [Accessed on23 September 2021]

About the Interviewee

Dr Galileo Violini

Dr. Prashanth Subramanian, Chief Scientific Officer for Novartis Singapore

A medical doctor specialising in Anaesthesiology, he has nearly a decade of experience as a pharmaceutical physician across diverse therapy areas and geographies. Dr Prashanth has been involved in conducting clinical trials and real-world data generation projects related to metabolic disorders and chronic kidney disease in different regions. He has a keen interest in digital healthcare initiatives and data generation projects leading to the improvement of target patient outcomes.

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