A clinical perspective on PCSK9 inhibition: What do we know and what can we expect?
As of the discovery of statins in the prevention of CHD in 1994, treatment of cardiovascular (CV) disease and LDL-c reduction rapidly advanced. Today we have many potential new medications beyond statins and the question now is, should we use them, in whom and to what purpose.
Should we use the new potential medications, in whom and to what purpose?Literature - Paul M Ridker, MD - Brigham and Women’s Hospital, Harvard Medical School, Boston, USA - PACE-CME symposium held at ESC 2016, Rome
It is all in the last 35 years that we have seen a remarkable advance and understanding of apolipoproteins, the mechanisms of heart disease and the rapid development of drugs affecting these processes, said Paul Ridker. As of the discovery of statins in the prevention of CHD in 1994, treatment of cardiovascular (CV) disease and LDL-c reduction rapidly advanced. Today we have many potential new medications beyond statins and the question now is, should we use them, in whom and to what purpose.
Statin therapy is the fundamental background therapy for hyperlipidaemia but even when LDL-c levels are lowered to 1.8 mmol/L, still many patients have ‘residual risk’ for coronary disease and need further cholesterol reduction. With this in mind, and the knowledge that quite some patients are statin intolerant or have a moderate (<80% reduction) response6, there is a need for additional cholesterol treatment options, such as PCSK9 inhibitors.
PCSK9 inhibitors have been shown to be effective as monotherapy or as add-on to statin therapy, in statin-intolerant patients, in heterozygous FH patients with residual LDL-R activity and interestingly also in some homozygous FH patients with a defective receptor, for whom so far lipoprotein apheresis was the only suitable therapeutic option. It took only 10 years from the discovery of the importance of the PCSK9 pathway, to development of drugs and their approval in the US and Europe in 2014 and 2015 respectively. CV outcome studies are, however, still ongoing and Ridker emphasises the importance of full completion of the trials that are currently running.
Three major large PCSK9 clinical trials are currently in progress and they together comprise over 70.000 patients (Fourier, ODYSSEY and SPIRE I and II4). These trials will show us how broad the use of PCSK9 inhibitors can be. Preliminary data of the ODYSSEY and OSLER trials5 show large LDL-c and CV risk reductions. However, we have to keep in mind that the total number of events in these studies so far is very low and that only half of the patients in ODYSSEY and 27% of the OSLER patients are on high-dose statins. Furthermore, it is encouraging that no major safety concerns have been observed so far.
Overall, over the last years we see a clear reduction of cholesterol levels worldwide among men and women. That is good news. This reflects better therapies but also improved primary prevention. But according to Ridker, we need to think more about the meaning of residual CV risk. He proposes to discriminate between ‘residual cholesterol risk’, ‘residual inflammation risk’ (those with high hsCRP levels) and ‘residual triglyceride risk’, as further LDL-c-lowering may not be effective in patients in whom LDL-c levels may already have been substantially decreased by prior statin therapy.