This persistent or residual CV risk has prompted clinicians to broaden their assessment of dyslipidaemia and consider additional markers of atherogenic burden. This webinar was presented by Dr Christel Olivier, director of Diabetes Care Centurion, and sponsored by Austell.
Atherosclerosis develops when LDL cholesterol and other apolipoprotein B (ApoB)-containing lipoproteins penetrate the arterial wall, initiating an inflammatory cascade that ultimately leads to plaque formation and cardiovascular events. Importantly, these lipoproteins are not merely markers of disease but direct contributors to the atherosclerotic process. While LDL cholesterol remains the primary therapeutic target, it does not always reflect the total number of circulating atherogenic particles, particularly in patients with complex metabolic disorders.
Recent European guidance has reinforced the importance of intensive lipid lowering by introducing an additional ‘extreme high-risk’ category for patients with established ASCVD and multiple cardiovascular events or polyvascular disease. For these individuals, the recommended LDL cholesterol target has been reduced to <1mmol/l, highlighting the increasingly aggressive approach required for patients at greatest risk.
Understanding atherogenic dyslipidaemia
Patients with type 2 diabetes (T2DM), metabolic syndrome, obesity and severe insulin resistance frequently exhibit a characteristic pattern known as atherogenic dyslipidaemia. Rather than isolated LDL cholesterol elevation, these patients typically present with elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol and an excess of small, dense LDL particles. Even when LDL cholesterol targets are achieved with statin therapy, this lipid profile may continue to drive CV risk.
This pattern is particularly relevant in South Africa, where >4-million people are living with diabetes. About 60% of these individuals demonstrate features of atherogenic dyslipidaemia, making it the most commonly encountered lipid disorder in everyday clinical practice. These observations suggest that focusing solely on LDL cholesterol may underestimate CV risk in a substantial proportion of patients.
ApoB and lipoprotein(a): Emerging markers of risk
Apolipoprotein B has emerged as a valuable marker of overall atherogenic particle burden. Each LDL, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and lipoprotein(a) particle contains a single ApoB molecule. Measuring ApoB therefore provides a direct estimate of the total number of circulating atherogenic lipoproteins rather than simply quantifying the cholesterol they carry.
High density lipoprotein (HDL) cholesterol does not contain ApoB, making the test highly specific for atherogenic particles. Current evidence suggests that ApoB is a more accurate predictor of ASCVD risk than LDL cholesterol alone and should be considered as a secondary treatment target in patients at high CV risk receiving statin therapy.
Lipoprotein(a), or Lp(a), represents another important risk marker. Structurally similar to LDL cholesterol, Lp(a) contains an additional apolipoprotein(a) component that confers independent CV risk.
Unlike conventional lipid parameters, Lp(a) concentrations are largely genetically determined and are minimally influenced by lifestyle interventions or statin therapy. Measuring Lp(a) at least once during a patient's lifetime can therefore assist in identifying individuals with inherited CV risk that might otherwise remain undetected.
Residual risk despite statin therapy
Evidence from South African clinical practice demonstrates that residual dyslipidaemia remains common despite widespread statin use. The Dyslipidemia International Study showed that >50% of statin-treated patients failed to achieve recommended LDL cholesterol targets, while >45% continued to have elevated triglycerides and reduced HDL cholesterol. These findings emphasise the need not only to optimise statin therapy but also to consider combination treatment and broader lipid assessment beyond LDL cholesterol alone.
Fenofibrate: Addressing residual atherogenic risk
Fibrates have long been used to improve triglyceride and HDL cholesterol levels, but recent evidence suggests that not all fibrates produce equivalent effects on atherogenic lipoproteins. A large meta-analysis of 63 randomised controlled trials demonstrated that while fibrates consistently reduced triglycerides and produced modest reductions in LDL cholesterol, fenofibrate was unique in maintaining reductions in both ApoB and non-HDL cholesterol when used either as monotherapy or in combination with statin therapy.
These findings suggest that fenofibrate targets the overall atherogenic particle burden more effectively than other fibrates, making it particularly relevant for patients with residual CV risk despite statin treatment.
Fenofibrate exerts its effects through activation of the peroxisome proliferator-activated receptor alpha (PPAR-α), increasing lipoprotein lipase activity and enhancing triglyceride metabolism. Clinically, this translates into triglyceride reductions of 20%-50%, modest increases in HDL cholesterol, small reductions in LDL cholesterol and significant reductions in ApoB and non-HDL cholesterol. By targeting multiple lipid abnormalities simultaneously, fenofibrate offers a more comprehensive approach to managing atherogenic dyslipidaemia.
Why combine fenofibrate with pravastatin?
The available fixed-dose combination pairs fenofibrate with pravastatin, a hydrophilic statin with an established safety profile and more than two decades of cardiovascular outcome data. Pravastatin's lower propensity to penetrate muscle tissue contributes to a reduced risk of statin-associated myopathy.
It also has relatively few drug-drug interactions, making it well suited to patients with diabetes who often require multiple concomitant medications. Furthermore, its glucose-neutral profile makes it an attractive option for patients with T2DM.
Clinical evidence supports the benefits of the fixed-dose combination. In a randomised, double-blind study involving patients with mixed hyperlipidaemia who remained inadequately controlled on pravastatin alone, the addition of fenofibrate resulted in further reductions in LDL cholesterol, non-HDL cholesterol, triglycerides, total cholesterol and ApoB.
The combination also reduced inflammatory and coagulation markers, including high-sensitivity C-reactive protein and fibrinogen, while favourably altering LDL particle size towards larger, less atherogenic particles.
Further support comes from the Copenhagen General Population Study, which followed >13 000 statin-treated individuals for eight years. The investigators found that patients with elevated ApoB or non-HDL cholesterol remained at significantly higher risk of myocardial infarction and all-cause mortality despite achieving recommended LDL cholesterol concentrations.
These findings reinforce the concept that LDL cholesterol alone may underestimate CV risk and that measuring ApoB or non-HDL cholesterol can identify patients who may benefit from treatment intensification.
Selecting the right patients
Not every patient receiving statin therapy requires combination lipid-lowering treatment. The greatest benefit is expected in individuals with T2DM, metabolic syndrome, obesity or mixed dyslipidaemia who exhibit the classic pattern of elevated triglycerides, reduced HDL cholesterol and increased concentrations of small, dense LDL particles.
Patients who have achieved LDL cholesterol targets but continue to demonstrate elevated ApoB or non-HDL cholesterol may also be appropriate candidates, as may selected patients who require triglyceride lowering but have concerns regarding statin tolerability.
Before initiating therapy, baseline lipid, renal and liver function testing is recommended, with repeat lipid assessment after three to six months and ongoing annual monitoring. Severe chronic kidney disease, active liver disease and known hypersensitivity remain important contraindications to treatment.
Looking beyond lipids
Although expanding lipid assessment beyond LDL cholesterol represents an important advance in CV prevention, lipid modification should never occur in isolation. Comprehensive CV risk reduction requires simultaneous optimisation of glycaemic control, blood pressure, body weight, smoking cessation and appropriate antiplatelet therapy where indicated.
The proposed treatment approach therefore begins with CV risk stratification and optimisation of statin therapy, followed by identification of persistent residual risk using triglycerides, ApoB and non-HDL cholesterol before considering combination therapy.
Conclusion
The management of dyslipidaemia is evolving beyond LDL cholesterol alone. While LDL cholesterol remains the cornerstone of lipid-lowering therapy, growing evidence indicates that ApoB and non-HDL cholesterol more accurately reflect the total burden of atherogenic lipoproteins, particularly in patients with T2DM and metabolic syndrome. For selected high-risk patients who continue to exhibit residual CV risk despite achieving LDL cholesterol targets, a fixed-dose combination of fenofibrate and pravastatin offers a rational therapeutic strategy by addressing multiple lipid abnormalities simultaneously. Incorporating broader lipid assessment into routine clinical practice may enable clinicians to identify patients who require treatment intensification and ultimately reduce the burden of residual CV disease.
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