The atherogenic dyslipidaemia (AD) complex responsible for residual risk, (Duran,2020) involves:

• Elevations in small dense low-density lipoprotein (sdLDL) particles with normal or slightly increased LDL-cholesterol
• Elevations in triglycerides (TGs) and triglyceride-rich lipoprotein (TRL) (remnant cholesterol; non- high-density lipoprotein cholesterol (HDL-C), chylomicrons, interleukin).
• Reduced HDL-C.

Question: Why is cardiovascular risk Increased in diabetic patients?
Answer: Because of the residual risk remaining even after LDL control in diabetic patients.

Diabetes and dyslipidaemia

Qualitative or compositional changes include oxidised lipoproteins, glycated lipoproteins, oxidised, glycated, or small-sized lipoprotein particles, which are poor ligands for LDL receptors and are shifted to the non-receptor (scavenger pathway). They penetrate the artery wall and form foam cells. This has more atherogenic potential.

Atherosclerosis in diabetes

Atherosclerosis in diabetes leads to more CVD events and worse outcomes. It can lead to:

• Plaque burden
• Complexity of lesions
• Vulnerability decreasing stability
• Coronary calcification
• Extent of coronary ischaemia:
• More diffuse disease
• More multi-vessel disease
• More significantly-affected vessels
• Fewer normal vessels
• Reduced collateral recruitment.

Atherogenic dyslipidaemia management

The following comprise the modern concept of lipid-lowering strategies to reduce cardiovascular diseases.

• Start Early. Less ‘lipid exposure’ leads to prevention of lesion formation.
• Treat (much more) aggressively. From desirable target to LDL-C elimination in the blood.
• Use combination therapy. Statin + ezetimibe (+/- PCSK9mAb)-induced LDL-C lowering reduces CV risk.
• Add therapy for atherogenic dyslipidaemia: Fibrates in those with high TG and low HDL-C.

Fibrates

Fenofibrate is the most studied, with lower risk of rhabdomyolysis and is recommended in most guidelines. Gemfibrozil increased risk of rhabdomyolysis. Bezafibrate has few outcome studies. An additional benefit of fibrates is improvements in diabetic retinopathy, shown in several studies.

Empirical combination therapy (statin/fibrate) doesn’t improve CVD outcomes  and is generally not recommended. Consider therapy with statin and fenofibrate in those with both trigs >2.3mmol/L and HDL ≤0.9mmol/L. Treatment targets and goals for cardiovascular disease prevention

 LDL-C:

• Very high risk: <1.4mmol/L
• High risk: <1.8mmol/L
• Moderate risk: <2.6mmol/L
• Low risk: <3mmol/L.

Non-HDL-C:

• Very high risk: < 1.8mmol/L
• High risk: <2.2mmol/L
• Moderate risk: <2.mmol/L
• Low risk: <3.4mmol/L.

There is no treatment goal for triglycerides but <1,7mmol/L indicates lower risk. Higher levels indicate a need to look for other risk factors. Diabetes HbA1C: <7% (<53 mmol/mol).

Take-home messages

Atherogenic dyslipidaemia is commonly found in diabetes and the metabolic syndrome. The primary goal is to lower LDL-C: Statin+/- ezetimibe+/- PCSK9 inhibitor. Do not overlook non-HDL-C (a measure of residual risk). If non-HDL-C is above target and TG>2.3, add fibrate.