How should I advise a patient on the pros and cons of inclisiran?

Clinical conundrum: GP Dr James Chambers discusses handling a patient enquiry about inclisiran, including how to explain current evidence for its benefits and recommendations for its appropriate use  

The case: A 59-year-old man tosses his medication onto your desk and says, with some exasperation, ‘These don’t seem to be working’. He had a myocardial infarct six years previously and has been on various statins, over the intervening years, either because of failure to reach target or because of intolerance. His medication concordance is good. This attendance was prompted by him seeing online that his latest LDL-C level remains stubbornly above target, despite him now being on atorvastatin 80mg/day plus ezetimibe. He asks you about inclisiran, saying that he’d heard a radio programme about it the other day. ‘How good is it, and is it safe?’ he asks. ‘And could my younger brother have it, too? He’s not had any heart trouble yet, but he’d like to prevent it.’

1. When is inclisiran indicated – how does it fit into the hierarchy of other lipid-lowering therapies? Would it be used alone, or in combination with other treatments?

Inclisiran (brand name Leqvio) was first recommended by NICE guidelines in 2021.¹

NICE strictly defines its use within primary care as being for secondary prevention in patients with a history of cardiovascular disease who, despite maximum tolerated lipid lowering therapies, continue to have persistently high LDL-C levels (defined as >2.6mmol/L).^1,2

The term ‘maximum tolerated lipid lowering therapies’ refers to its use alongside the maximum dose of statins a patient can tolerate, with or without other lipid lowering medications such as ezetimibe or bempedoic acid.¹ In patients who cannot tolerate statins at all, it can also be used alongside other lipid lowering medications, such as ezetimibe, if the target is not met.^1,2

Unlike these other lipid lowering medications, inclisiran is delivered as an injection and, following its initial loading doses given three months apart, requires only twice-yearly doses within a healthcare setting. The recommended dose is 284 mg for the initial dose, then 284 mg after 3 months for the second and then 284 mg every 6 months.³

In the case described above, the patient would be eligible to start on inclisiran. He is already on the maximum dose of conventional oral medications (atorvastatin and ezetimibe), has a history of MI and uncontrolled LDL-C levels – assuming these are above 2.6mmol/L. It is worth noting that, even if he was not on the maximum dose of atorvastatin, with his history of previous intolerances, he could be considered for inclisiran on his personal maximum tolerated dose, with or without the ezetimibe.

The choice to start inclisiran before ezetimibe or any other additional oral medications (such as bempedoic acid) should be made as a shared decision alongside the patient’s preferences. However, unlike the other additional lipid-lowering medications, inclisiran is recommended only if the LDL-C is greater than 2.6mmol/L. Therefore it may be wise to consider inclisiran before these other choices to avoid the patient being ‘locked out’ of it as a treatment option later – for example, if their LDL-C dropped below that threshold but did not reach the 2mmol/L target for secondary prevention.

In practices who are unable to offer inclisiran locally, I would encourage a referral or advice and guidance request to lipid clinics in patients whose LDL-C remains above 2.6mmol/L despite maximum oral medications. In Scotland, the advice remains for patients suitable or eligible for inclisiran to be referred to a lipid clinic.⁴

2. How effective is it and what are the main side effects? Some time ago, the RCGP and BMA put out a joint statement pointing out the lack of long-term data on cardiovascular outcomes and safety – has the situation changed since then?

The effectiveness of inclisiran for lipid lowering has been shown in a series of clinical trials called the ORION trials which were first published in 2017. The initial trial found a 50% reduction in LDL-C levels within its test group compared to placebo, sustained over its 6-month trial period.⁵ This trial laid the groundwork for further phase 3 trials, the most recent demonstrating ongoing sustained efficacy for up to 4 years. Importantly, it also found no significant differences in adverse reactions compared to the placebo group, except for some local injection site reactions.^6,7

It was in this context that NHS England launched its first ever ‘population health agreement’ in September 2021, aiming to deliver inclisiran to over 300,000 patients over a 3-year period. This was the first deal of its type, demonstrating the faith NHS England had in this drug for cardiovascular disease prevention. However, by the end of 2024, only 30,000 patients have been prescribed inclisiran, reaching only one in ten patients that NHS England had set out for.⁸

So why, despite this evidence and NHS leaders’ commitment, did inclisiran not catch on? Pulse readers may remember after the government announced its plans, the RCGP and BMA published a joint statement about inclisiran.^9,10  It emphasised the gaps in long-term cardiovascular outcome data, a lack of evidence about potential long-term safety and interaction risks, as well as concerns about whether primary care had sufficient capacity to deliver the treatment in the first place. This likely significantly discouraged uptake by clinicians at that time.

To address some of these concerns, the ORION-4 trial is currently looking at long-term cardiovascular outcomes in patients on inclisiran compared to placebo groups.¹¹ It is hoped this trial will demonstrate robust evidence that the reduction in LDL-C seen in previous trials will translate into reduction in cardiovascular events. The results are due to be released later this year, with the RCGP/BMA stating they will review their proposal then.

What is likely to remain unchanged, even if results of the ORION-4 trial are positive, is the increasing pressure in general practice, which makes the likelihood of GPs wanting to take on additional, unfunded, work increasingly unlikely.

NHS England hopes to overcome this through its population health agreement, which funds inclisiran centrally, and provides reimbursement to practices for the full fee of the medication plus £15 (increased up from £5 in March 2025) alongside the standard personal administration fee.¹²

This, combined with the greater allocation of points within lipid management for the latest QOF year, shows NHS England’s commitment towards providing financial reward for practices engaged in cardiovascular prevention. The question remains as to whether the financial incentive is enough to make this additional work, and potential uncertainty, worth it.

In terms of our patient above, the latest evidence would allow us to reassure him inclisiran remains a safe and effective choice for lowering his cholesterol, particularly in the context of avoiding side effects he may have experienced with his previous intolerance to statins. However, it would be prudent to inform him that trials are still ongoing regarding the long-term benefits of the medication, although initial results are promising. 

3. What is the current situation regarding inclisiran and primary prevention of cardiovascular disease?

While the focus is on the use of inclisiran for secondary prevention at this time, there remains a potential for its use in primary prevention too. The ORION-11 trial has shown inclisiran to be just as effective at lowering LDL-C levels in a primary prevention population as it is for secondary prevention patients.¹³ At this time, NICE suggests its cost-effectiveness in primary prevention would be an ‘unacceptable’ use of NHS resources.¹⁴ Its use for this purpose is restricted to clinical trials only, which are currently underway, so this may change in future depending on their long-term outcomes.¹⁵ Interestingly in Scotland and Wales, guidelines already extend its use to primary prevention in patients with heterozygous familial hypercholesterolemia and LDL-C >5mmol/L – either in combination with a statin (with or without other lipid-lowering therapy), or (if statin intolerant) alone or with other lipid-lowering therapy.^5,16,17

Overall, inclisiran currently remains a divisive medication, with many uncertainties around its long-term data, as well as concerns about the unorthodox political influence behind its initial approval.¹⁸ However, it’s clear that the medication has potentially considerable benefits. It has a very favourable infrequent dosing regime which will be popular with patients, it has clear evidence for its ability to lower LDL-C levels effectively and it gives clinicians something new to reach for when statins aren’t enough or our patients just can’t tolerate them at all.

With a quarter of all deaths in the UK resulting from cardiovascular disease and cardiovascular disease costing the NHS £15 billion a year,^19,20 action needs to be taken. We can only hope that inclisiran is the revolutionary new advancement that we all hope, and were promised, it would be.

Dr James Chambers is a GP in Staffordshire

References

1. NICE. Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia. [TA733]. 2021
2. NICE. Cardiovascular disease: risk assessment and reduction, including lipid modification. [NG238]. 2023
3. Electronic Medicines Compendium. Leqvio 284 mg solution for injection in pre filled syringe. Summary of Product Characteristics.
4. Marrs J, Anderson S. Inclisiran for treatment of hypercholesterolaemia. Drugs Context 2024;13:2023-12-3
5. NHS Scotland. NHS Right Decisions. Coronary Heart Disease and Stroke, Primary and Secondary Prevention Guideline (Cholesterol). 2022
6. Ray K et al. Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial. JAMA Cardiol 2019;4(11):1067-75 
7. Ray K et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med 2020;382(16):1507-19
8. Ray K et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol 2023 Feb;11(2):109-19
9. Mahase E. Drug rollout aimed to show UK still a “science superpower” only reaches 10% of target. BMJ 2025;391:r2579
10. Potter C. ‘Serious concerns’ over cholesterol-lowering injection rollout, warn GP leaders. Pulse Today; December 2021
11. RCGP. Inclisiran position statement. December 2021
12. NHS Health Research Authority. Research summaries: ORION-4. 2018
13. NHS England. Funding and supply of inclisiran (Leqvio). March 2025
14. Ray K et al. Effect of inclisiran on lipids in primary prevention: the ORION-11 trial. Eur Heart J 2022;43(48):5047-57
15. NICE. Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia: Committee discussion. [TA733]. 2021
16. Healthcare Improvement Scotland/Scottish Medicines Consortium. Inclisiran (Leqvio®) is accepted for restricted use within NHS Scotland. 2021
17. NHS Wales. All Wales Therapeutics and Toxicology Centre. Accessing medicines. Medicines advice: Inclisiran (Leqvio®). 2022
18. McCartney M, Cohen D. Inclisiran: the ‘extremely unusual’ political influence behind the novel drug’s approval. 2023
19. British Heart Foundation. Facts and Figures.
20. NHS Digital. Cardiovascular Disease Prevention Audit (CVDPREVENT Audit): Summary.