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Ahmed M Salem
Cardiology ST8 – Oxford University Hospitals NHS Foundation Trust
Atherosclerotic Cardiovascular Disease (ASCVD) remains a leading cause of mortality in Europe, accounting for over 4 million deaths annually.1 Prevention strategies should be tailored to an individual’s overall cardiovascular risk. This is especially pertinent in type 2 diabetes, where dyslipidaemia is a key contributor to the two- to threefold increase in cardiovascular risk compared with non-diabetic individuals. 2,3
In this high-risk populations, statins remain the cornerstone of both primary and secondary prevention of cardiovascular disease (CVD). Robust evidence supports their efficacy in reducing major adverse cardiovascular events (MACE).4,5
However, an unintended consequence of statin therapy is its association with a modestly increased risk of diabetes.6 This was first observed in 2008 with rosuvastatin, and has since been supported by meta-analyses of randomised trials showing around 10–12% increased incidence of diabetes with statin therapy compared to placebo.7,8 Though mechanisms are unclear—potentially involving altered insulin sensitivity and metabolic signaling—this diabetogenic effect remains outweighed by statins’ cardiovascular benefits.
Despite their efficacy, real-world data show that statin monotherapy often fails to achieve LDL-C targets in high-risk patients, even at maximal doses.9,10 Moreover, perceived or true statin intolerance continues to limit optimal lipid control. In these cases, adjunctive lipid-lowering therapies play a vital role in reducing residual risk.
Agents that inhibit cholesterol synthesis, such as ezetimibe, or block proprotein convertase subtilisin/kexin type 9 (PCSK9) activity, have proven effective. When used alone or in conjunction with statins, both drug classes significantly improve LDL-C levels and cardiovascular outcomes.11,12 However, cost-effectiveness remains debated. For instance, early economic analyses of evolocumab from the FOURIER trial suggested costs exceeded conventional thresholds.13
This concern is reflected in differences between guidelines. While the European Society of Cardiology (ESC) recommends PCSK9 inhibitors for patients with LDL-C levels >1.8 mmol/L (high-risk) or >1.4 mmol/L (very high-risk) despite lipid-lowering therapy14, NICE sets more conservative thresholds of >4.0 mmol/L and >3.5 mmol/L, respectively.15
Bempedoic acid (180 mg daily) is a novel oral lipid-lowering drug that inhibits ATP citrate lyase, enhancing LDL receptor activity. Because it is a prodrug activated only in the liver, muscle exposure is minimal—reducing risk of myotoxicity compared with statins.16
Phase III trials show a 21% LDL-C reduction with monotherapy and ~30% when combined with ezetimibe.17 The CLEAR —the first cardiovascular outcomes trial for bempedoic acid—trial demonstrated a significant reduction in MACE in statin-intolerant patients over 41 months.18 As such, NICE now recommends bempedoic acid with ezetimibe when statins are contraindicated or not tolerated.19
While LDL-C remains the main therapeutic target, elevated triglycerides and low HDL-C also contribute to residual risk.20
Pemafibrate, tested in the PROMINENT trial, achieved >25% triglyceride reduction in diabetic patients but did not lower cardiovascular events. However, its favourable hepatic profile suggests possible benefit in metabolic liver disease.21
Omega-3 fatty acids (eicosapentaenoic acid [EPA] and/or docosahexaenoic acid [DHA]) have traditionally been employed for hypertriglyceridaemia management. However, multiple trials have reported mixed results regarding their impact on cardiovascular outcomes.22 These discrepancies likely stem from heterogeneity in patient populations, formulations, and dosages used.
In contrast, icosapent ethyl—a highly purified form of EPA—has emerged as a promising agent. In the REDUCE-IT trial, icosapent ethyl (2 g twice daily with food) reduced cardiovascular events by 25% and cardiovascular mortality by 20% over nearly five years in statin-treated patients with elevated triglyceride levels and established cardiovascular risk.23 Interestingly, the magnitude of benefit exceeded what would be expected based on triglyceride reduction alone, suggesting additional non-lipid mechanisms.
These may include anti-inflammatory effects (as suggested by reductions in high-sensitivity C-reactive protein), plaque stabilisation, and possible antithrombotic properties, as hinted by a (non-significant) increase in bleeding events compared to placebo (2.6% vs. 2.1%; P = 0.06).
Based on these results, NICE recommends icosapent ethyl for:
– Secondary prevention: CVD patients with triglycerides ≥1.7 mmol/L
– Primary prevention: Diabetic patients with additional risk factors and optimised LDL-C (statins ± ezetimibe) 24
ESC guidelines echo these recommendations.25
| Clinical Scenario | Therapy Recommendation |
| High LDL-C | Start statin (maximally tolerated). If inadequate → add ezetimibe. If still above target → consider PCSK9 inhibitor (or bempedoic acid if cost or tolerance issues). |
| Statin intolerance | Ezetimibe ± bempedoic acid. PCSK9i if LDL-C remains high. |
| Elevated triglycerides (≥1.7 mmol/L) | Optimise LDL-C first (statin ± ezetimibe). Then add icosapent ethyl if established CVD or high-risk diabetes. |
| Mixed dyslipidaemia / Diabetes | Comprehensive risk reduction with statins + lifestyle + triglyceride management. Consider pemafibrate or icosapent ethyl depending on profile. |
Pharmacological lipid-lowering therapy remains central to CVD prevention, complementing lifestyle modification. As newer agents emerge, clinicians must understand their mechanisms, indications, and limitations. The evolution toward personalised, multi-target lipid management—addressing both LDL-C and triglyceride-rich lipoproteins—reflects modern precision medicine in cardiovascular prevention.
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