Controversies in Lipids – is the role of statins now clear, are there alternatives, and what’s in the pipeline?News - Mar. 31, 2017
SPECIAL INVITED PLENARY - Professor John Chapman (Paris, France)
Controversies in Lipids – is the role of statins now clear, are there alternatives, and what’s in the pipeline?
Multiple studies have shown a clinical benefit of statin treatment over time, although mixed patterns of the type of benefit have been observed, depending on baseline levels and the duration of the study. CV event reduction is seen, but not all studies revealed a mortality benefit. The mechanism through which LDL-c lowering is thought to reduce events, may be that it favours stabilisation of vulnerable plaques.
Effective LDL-c lowering treatment can be hindered by adverse effects, of which muscle problems are most frequently experienced. If patients experience muscle symptoms, it is worth trying to rechallenge with the same statin after a break, or to try a reduced dose or another statin. Statins are pharmacologically distinct, for instance with regard to half-life (simvastatin and pravastatin have a short half-life of about 2-3 hours, while atorvastatin, rosuvastatin and pitavastatin have a longer half-life of about 20 hours). It has been suggested that the pathophysiological basis for statin-associated muscle symptoms arises from inefficient uptake of statins by the liver, allowing the statin to ‘escape’. As a consequence, elevated levels of statins are present in the circulation with prolonged residence time, which leads to increased peripheral tissue exposure to statins. In skeletal muscles, it inhibits mitochondrial electron transport. This can cause muscular symptoms, possibly aggravated by intense exercise. Considering the different half-lifes, these effects may depend on the specific statin used.
Chapman stressed that the benefit should be optimised, appreciating that the CV benefit far outweighs possible adverse effects.
New lipid-lowering therapies are now available, namely PCSK9 inhibitors. PCSK9 normally targets the LDL-receptor for degradation, which prevents its action on lowering plasma LDL-c levels. Thus, when PCSK9 is inhibited, more LDL-receptors remain available to take LDL-c out of the circulation. Statins increase PCSK9 levels, thereby minimising its own LDL-c lowering effect via reducing LDL-receptor levels. The fact that both agents lower LDL-c via different routes, suggests that PCSK9 inhibition can be a good complimentary add-on therapy to statins.
Ideas about a ‘normal’ LDL-c level and classifications in guidelines may change based on recent insights that very low LDL-c can now be achieved with novel and more potent LDL-lowering therapy. Newborns show an average level of 0.7 mg/dL or about 30 mmol/L, with the brain being richest in cholesterol. Does this mean that this is the minimum LDL-c level needed? A lot of cholesterol in needed in the brain at the start of life, but the brain can synthesise cholesterol. In fact, every organ can synthesise cholesterol, albeit at different rates. Hence, very low LDL-c levels do not confer a problem, and we certainly do not need all the cholesterol we have as adults.
Prof. Chapman therefore concluded by emphasising the newly emerging concept that lowest for longest is the best approach as far as LDL-c levels are concerned.