Learning outcomes:
European Society of Cardiology (ESC) guidelines have consistently pointed to the lowering of LDL-C as a cornerstone in the prevention of atherosclerotic cardiovascular events.
Statins are the mainstay of treatment for lowering cholesterol through inhibition of HMG-CoA reductase in the liver, with biosynthesis being responsible for approximately 70-80% of the body’s total cholesterol, and 20-30% being attributable to diet. For this reason, many patients, particularly those in the high and very-high risk categories, will not achieve LDL-C lowering goals through diet alone, and will therefore require pharmacological intervention. Statins are divided into high-intensity, moderate-intensity and low-intensity, based on their percentage predicted reduction in LDL-C, summarised in Table 2 and available in the British National Formulary (BNF).
Table 1: Statin intensity classification and percentage predicted reduction in LDL-C
| Statin Intensity | Medication | Dose (LDL-C reduction) |
| High-intensity | Atorvastatin | 20 mg (43%) |
| 40 mg (49%) | ||
| 80 mg (55%) | ||
| Rosuvastatin | 10 mg (43%) | |
| 20 mg (48%) | ||
| 40 mg (53%) | ||
| Simvastatin | 80 mg (42%) | |
| Moderate-intensity | Atorvastatin | 10 mg (37%) |
| Fluvastatin | 80 mg (33%) | |
| Rosuvastatin | 5 mg (38%) | |
| Simvastatin | 20 mg (32%) | |
| 40 mg (37%) | ||
| Low-intensity | Fluvastatin | 20 mg (21%) |
| 40 mg (27%) | ||
| Pravastatin | 10 mg (20%) | |
| 20 mg (24%) | ||
| 40 mg (29%) | ||
| Simvastatin | 10 mg (27%) |
Source: British National Formulary
Ezetimibe acts by inhibiting cholesterol absorption and is typically prescribed as an adjunct to statin therapy where LDL-C goals are not reached with a statin alone, or also as monotherapy where stains are not tolerated. When added to ongoing statin therapy, Ezetimibe has been shown to give an additional 21 – 27% reduction in LDL-C levels.
Ezetimibe can be taken at any time of the day, and with or without food, but combination products with statins that require night-time dosing (i.e. simvastatin) are best taken at nighttime. Ezetimibe combination products with atorvastatin or rosuvastatin can be taken at either nighttime or daytime, owing to the relatively longer half-lives of these two statins.
For patients also taking a bile acid sequestrant such as colestyramine, it is advised that ezetimibe should be taken either ≥ 2 hours before or ≥ 4 hours after administration of the bile acid sequestrant as bile acid sequestrants can bind to ezetimibe and significantly lower its absorption.
The BAS colestyramine (Questran) and colesevelam (Cholestagel) reduce the absorption of cholesterol and bile acids into the circulation. This in turn increases demand by the liver for cholesterol, thereby lowering circulating LDL-C. Maximum daily dosing with colestyramine and colesevelam has shown a reduction in LDL-C of 18- 25%. BAS are not absorbed but can have a variety of gastrointestinal side effects such as constipation and can significantly lower absorption of fat-soluble vitamins A, D E and K. Some patient groups may require vitamin supplementation particularly with water-miscible forms. BAS are indicated for hypercholesterolaemia, as adjunct treatments or as monotherapy, but in guidelines and practice their role is limited as a second or third-line option.
Bempedoic acid, like statins, is an inhibitor of cholesterol biosynthesis in the liver. Bempedoic acid’s site of inhibition, however, is further upstream to that of HMG-CoA Reductase (at the adenosine triphosphate citrate lyase (ACL) site). Bempedoic acid also lowers circulating LDL-C through the upregulation of LDL receptor expression in the liver.
There is a reduced risk of muscle-related side effects with bempedoic acid compared with statins, which is probably attributable to the fact that bempedoic acid is a prodrug that is activated in the liver rather than in the muscles. Bempedoic acid is however known to increase plasma concentrations of statins. Concomitant use with simvastatin > 40 mg daily is contraindicated, and patients taking other statin regimens with bempedoic acid should be monitored for muscle-related side effects.
Bempedoic acid may increase serum uric acid levels, increasing the risk of gout attacks in at-risk patients, thereby warranting increased monitoring. Hyperuricaemia with gout attack requires discontinuation of bempedoic acid.
Bempedoic acid comes in two formulations: Nilemdo 180 mg film-coated tablets (bempedoic acid 180mg); or Nustendi 180 mg/10 mg film-coated tablets (180 mg of bempedoic acid and 10 mg of ezetimibe), with both products subject to Managed Access Protocols for reimbursement on the Community Drug Schemes. GPs and hospital prescribers may submit an application on an individual patient basis, through the special drug request (SDR) section on the ‘GP Application Suite’ or under ‘Services for Hospitals’ on the PCRS website.
The combination product Nustendi should be taken either at least two hours before or at least four hours after taking colestyramine, as the bile acid sequestrant can lower the serum concentration of ezetimibe significantly. ESC 2025 guidance states that the addition of bempedoic acid to the maximally tolerated dose of statin, with or without ezetimibe, should be considered in patients at high or very high risk in order to achieve the LDL-C goal.
PCSK9 inhibitors lower circulating LDL-C by preventing the degradation of LDL-receptors on liver surface cells. PCSK9 protein normally degrades LDL-receptors after LDL-C has been taken up into the liver. Therefore, inhibition on PCSK9 allows for more LDL-receptors to be recycled back to the liver surface, increasing the liver’s ability to remove further LDL-C from circulation.
Evolocumab (Repatha) is an injectable monoclonal antibodies that inhibit PCSK9, reducing LDL-C levels by an average of 60%, TG levels by 26% and increasing HDL-C by 9%. The LDL-C lowering by evolocumab is additive to that achieved by statins. PCSK9 inhibitors are prescribed under the High-Tech Arrangements through the HSE’s Medicine Management Programme and a Managed Access Protocol is in place. Repatha is indicated for patients with hypercholesterolaemia or mixed dyslipidaemia or in patients with established ASCVD to lower LDL-C levels. Repatha is also indicated for FH. Reimbursement of evolocumab is confined to adults with established ASCVD with an LDL-C persistently ≥ 3.5 mmol/L, or adults with a confirmed diagnosis of heterozygous familial hypercholesterolaemia (HeFH) with a LDL-C persistently ≥ 4 mmol/L. The ESC states that PCSK9 inhibitors are recommended in very-high-risk patients with FH if the treatment goal is not achieved on maximal tolerated statin plus ezetimibe, and also in FH patients who cannot tolerate statins. An alternative PCSK9 inhibitor, Alirocumab (Praluent) is no longer marketed in Ireland by Sanofi due to commercial reasons.
In July 2026, the FDA approved the first oral PCSK9 inhibitor, which is known as enlicitide and marketed as Lipfendra. Enlicitide is indicated as an adjunct to diet and exercise to reduce LDL-C and is taken as an oral dose once-daily. In trials, enlicitide reduced LDL-C by 56% compared to placebo but is not yet approved for use in the EU.
Inclisiran (Leqvio), is a small interfering ribonucleic acid (RNA) molecule that lowers LDL-C by inhibiting the synthesis of PCSK9 in the liver. Inclisiran has been shown to lower LDL-C levels by approximately 50% and is administered as a subcutaneous injection every six months, once treatment has been initiated. Leqvio is licensed within the EU by the EMA but is not yet reimbursed within Ireland.
ESC guidance advises that recommended lifestyle modifications have the greatest magnitude and highest level of evidence to reduce TGs.
Pharmacological treatment to lower TG levels should only be considered in high-risk patients when TGs are >2.3 mmol/L and TGs cannot be lowered by lifestyle modifications. Statins are the ESC’s first line recommendation and mainstay of treatment to reduce CVD risk in high-risk individuals with hypertriglyceridaemia (>2.3 mmol/L).
Regarding the evidence base, triglyceride lowering with fibrates in reducing CV risk is not well established. The evidence of LDL-C reduction by statins is far more robust. The fibrates gemfibrozil, fenofibrate, bezafibrate (unlicensed in Ireland) have only moderate triglyceride-lowering effects. Furthermore, the 2019 ESC guidance states statin combination with gemfibrozil enhances the risk of myopathy and must be avoided. Overall, ESC guidance states that fenofibrate or bezafibrate may be considered for lowering of triglycerides, but that risk reduction of ASCVD has not been established.
Omega-3 polyunsaturated fatty acids have been used in managing hypertriglyceridaemia, but the evidence has changed in recent times, based on different clinical trials. The STRENGTH trial, published in 2020, looked at cardiovascular outcomes of a combined formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in a 4g/day dose, in patients with dyslipidaemia and high cardiovascular risk. The STRENGTH trial failed to show any benefit of combined EPA and DHA in preventing major cardiovascular events.
Conversely, the REDUCE-IT trial, which was conducted two years earlier, demonstrated positive cardiovascular outcomes for highly purified EPA-ethyl ester (2g twice daily) given to patients with established CVD or with diabetes or other risk factors, who had been receiving statin therapy yet still had high triglyceride levels. The discrepancy in trial results may be attributable to the intervention itself (EPA/DHA mixture vs high dose purified EPA-ethyl ester), the patient cohorts or the type of placebo used. Updated ESC recommendations state that high dose EPA-ethyl ester should be considered for high-risk patients with elevated triglycerides (1.52 – 5.6 mmol/L) despite statin therapy to lower CV risks.
Familial chylomicronaemia syndrome (FCS) is a highly rare genetic disorder leading to very high triglyceride levels. Volanesorsen is an RNA-based therapy (an antisense oligonucleotide) which targets triglyceride clearance within the body. It is licensed by the EMA (but not the FDA) and marketed in Europe as Waylivra as an adjunct to diet in adults with genetically confirmed FCS and at high risk for pancreatitis in whom diet and triglyceride-lowering therapy has been inadequate. As FCS is highly rare, Waylivra is designated an ‘orphan medicine’ and is not currently marketed in Ireland.
RNA-based therapies (antisense and siRNA), and Muvalaplin (an oral small molecule) all target Lp(a) biosynthesis in the liver and are showing promising results in lowering Lp(a) by 80-98%, but these remain in clinical trials at the time of writing. While there is no specific licensed treatment available to target Lp(a), current management is through lowering of non-HDL cholesterol and other CV risk factors.
There is a lack of clinical evidence that omega-3 supplementation can lower LDL-C or CV risks, with the exception of high-dose EPA in triglyceride management, as previously discussed.
Similarly, certain red yeast rice preparations, while demonstrating cholesterol lowering effects due to the monocolin active component (chemically identical to lovastatin), have not demonstrated a clinical benefit in lowering CV risk. Furthermore, the EU has implemented a ban on red yeast rice products containing ≥3 mg/day monocolins.
Functional foods containing plant stanols and plant sterols (consumption of 2g/day) have been shown to lower LDL-C by approximately 10%, additive to diet and/or statin therapy, however trials with a clinical endpoint have not yet been undertaken.
In summary, the 2025 ESC update does not support supplementation without demonstrated safety and clinically significant LDL-C lowering.
The use of SCORE2 and SCORE2-OP calculators will help to determine CV risk for apparently healthy patients and will be useful to pharmacists when measuring lipid profiles, screening and referring patients for further assessment by their GP. Notably, patients with atherosclerotic cardiovascular disease or other high-risk conditions (for example, diabetes mellitus, chronic kidney disease), are dealt with separately within the ESC risk assessment guidance.
Guidelines and clinical practice point to LDL-C lowering as the mainstay of treatment in the prevention of atherosclerotic CV events. While statins continue to be the first choice in targeting various dyslipidaemias, a variety of additional treatment options such as ezetimibe, bile acid sequestrants, bempedoic acid and PCSK9 inhibitors are playing an increased role. Ongoing clinical trials are showing promise particularly with targeted LDL-C reduction with RNA-based therapies.
In addition to lipid profile risk-assessment, other at-risk patients will benefit from CT coronary angiogram, calcium score test and Lp(a) measurement as part of onward referral.
References available on request.
About the author: Dr. Theo Ryan is a practising pharmacist in Errigal Pharmacy, Drimnagh (Vital Pharmacy group), and a lecturer in Pharmacy Practice in the School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, where he is coordinator for the ‘Cardiology in Clinical Pharmacy Practice’ CPD course for pharmacists. The course aims to equip pharmacists with the requisite knowledge to optimise management of cardiovascular patients in both the hospital and community settings. Please contact cardioclinpharm@tcd.ie for course information.
Dr Theo Ryan B.Sc.(Pharmacy), M.Pharm, MPSI
Highlighted Articles
