The FDA approved alirocumab (Praluent), the first monoclonal antibody to inhibit a protein called PCSK9 that was discovered a decade back. Cholesterol is cleared by receptors in the liver and these receptors are degraded by PCSK9. So if you block PCSK9, the cholesterol clearing receptors remain intact and active, pulling down cholesterol levels from the body.
Statins work by reducing production of cholesterol and by up regulating the number of clearance receptors. The PCSK9 blocker is far more powerful and effective than a statin, and is capable of lowering low-density lipoprotein cholesterol (LDL) levels to below 40 mg%. They may even bring down LDL levels to 10 mg %.
The PCSK9 inhibitor differs from a statin by prolonging the life of the receptor that clears cholesterol and thereby reduce LDL, and by being injectable. The injection is taken once a fortnight or once a month. Alirocumab is given once every 2 weeks while evelocumab is injected once a month.
The FDA has approved the drug for homozygous hypercholesterolemia. These people have very high levels of cholesterol, up to 500-600 mg % of LDL-C. Actually evelocumab has been approved for the above condition. Both evelocumab and alirocumab can be used in people with heterozygous hypercholesterolemia as an addition to statins and diet. The PCSK9 inhibitor can also be used in patients intolerant to statins. The FDA has explained intolerance to statin as when there is failure of 40 mg of atorvastatin to bring down cholesterol to desired level.
It is crucial to remember at this point that life style modification is of the greatest importance in prevention of cardiovascular disease. The “Magnificent Seven” need constant attention: –
- Cessation of smoking.
- Exercise
- Reduction of weight.
- Healthy heart diet.
- Correcting blood pressure.
- Correcting high cholesterol.
- Managing diabetes.
The patient has to be persuaded to change his life style to the better before embarking on any drug therapy. The PCSK9 blockers do not come cheap. The approximate cost of one year’s therapy is $13,000. The cost of the new drug will be outside the reach of most Indian patients.
The drug is not without side effects. Muscle aches as seen with statins have been observed in patients injected PCSK9 blockers. Memory loss was noticed in 0.9% treated patients in the OSLER trials, and alirocumab in the ODDESEY trial produced cognition problems in 1.2% vs. 0.5% (placebo). The third adverse effect observed with PCSK9 blockers is development of cataract when LDL is reduced <20mg %. We should not be surprised if more side effects are noticed in further trials. Moreover more trials are needed to confirm whether lowering of LDL to levels below 40-50 mg% reduce incidence of heart attack, stroke and death.
It is mandatory that PCSK9 inhibitors, apart from homozygous hypercholesterolemia, be tried after life style modification and optimal statin use. Often when atorvastatin does not work or is not tolerated, rosuvastatin proves effective. Ezetimibe should not be forgotten, because ezetimibe is freely available in India and has been shown to reduce cardiovascular events when added to a statin (IMPROVE-IT trial).
The Circulation published an interesting paper a few weeks ago, which showed that in a prospective study of 4000 people, all of whom were more than 60 years and free of heart disease baseline PCSK9 levels predicted future cardiovascular events in a follow-up extending 15 years. It was also observed that high levels of PCSK9 with low LDL led to clinical events, high LDL level with low PCSK9 also were associated with events, but high baseline levels of both PCSK9 and LDL did not predict future cardiac events.
There are rumors that PCSK9 blockers are being developed as oral medication and that research is going on to produce a once a year vaccine. We have very interesting times ahead of us as we wait for large- scale randomized trials to document clinical efficacy and safety of this new class of cholesterol lowering drug. It would be premature to endorse these drugs till then.