|Year : 2018 | Volume
| Issue : 3 | Page : 135-136
Novel lipid-lowering agents proprotein convertase subtilisin-kexin type 9 inhibitors: Do they show mortality benefits?
Department of Pharmacology, Adesh Institute of Medical Sciences and Research, Bathinda, Punjab, India
|Date of Web Publication||27-Jul-2018|
Dr. Rajiv Mahajan
Department of Pharmacology, Adesh Institute of Medical Sciences and Research, Bathinda - 151 101, Punjab
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mahajan R. Novel lipid-lowering agents proprotein convertase subtilisin-kexin type 9 inhibitors: Do they show mortality benefits?. Int J App Basic Med Res 2018;8:135-6
|How to cite this URL:|
Mahajan R. Novel lipid-lowering agents proprotein convertase subtilisin-kexin type 9 inhibitors: Do they show mortality benefits?. Int J App Basic Med Res [serial online] 2018 [cited 2020 Apr 5];8:135-6. Available from: http://www.ijabmr.org/text.asp?2018/8/3/135/237716
Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a hepatic protease that binds to low-density lipoprotein receptors (LDLRs) and causes their internalization into the lysosomes thus promoting destruction of LDLR. Seidah et al. discovered that PCSK9 regulates LDLR degradation and could potentially be a target for modulating LDLR expression and consequently LDL-cholesterol (LDL-C) levels. Destruction of LDLR, in a way stops removal of LDL-C from the blood, leading to an increase in blood LDL levels. Drugs which inhibit PCSK9 will act to increase LDL receptors levels thus lowering the levels of LDL-C.
Hyperlipidemia is one of the most common and best-established risk factors for cardiovascular disease (CVD). Although guidelines recommend the use of statins for treatment of individuals at increased risk for developing CVD events; there are limited options for patients who either develop intolerable side effects to statins or develop CVD despite being on maximally tolerated statin therapy. In these patients, a new modality of treatment, PCSK9 inhibitors will definitely prove useful.
The Food and Drug Administration (FDA) has already approved PCSK9 inhibitors for lipid lowering. Alirocumab was approved by the FDA in July 2015. The approved indications for alirocumab are as follows:
- For adult patients with heterozygous familial hypercholesterolemia
- In patients with clinically significant atherosclerotic CVD requiring additional LDL lowering after being on diet control and maximally tolerated statin therapy.
Evolocumab was also approved by the FDA in August 2015, with indications as:
- For the use in adult patients with heterozygous familial hypercholesterolemia
- For the use in adult patients with homozygous familial hypercholesterolemia
- For the use in adult patients with clinical atherosclerotic CVD requiring additional lowering of LDL cholesterol after being on a controlled diet and maximally tolerated statin therapy.
Earlier in clinical trials, Alirocumab has been found to reduce LDL-C in a dose-dependent manner by up to 43% with a maximum dose of 300 mg every 4 weeks; and even a greater reduction of up to 70% was seen at a dosage regimen of 150 mg every 2 weeks. Evolocumab, when added to maximally tolerated dose of statins, showed LDL reduction up to 65% with 70–140 mg of drug every 2-week regimen and approximately 50% LDL reduction with 280–420 mg drug every 4-week regimen. As monotherapy, evolocumab has shown a reduction in LDL values by 40%–50% at doses of 420 mg every 4 weeks.
Nasopharyngitis, upper respiratory tract infection, back pain, and nausea are commonly seen adverse effects with PCSK9 inhibitors. The most common adverse events leading to drug discontinuation include myalgia, nausea, and dizziness. Notable serious adverse events are cardiac disorders including palpitations, angina pectoris, and ventricular extrasystoles.
Although no major life-threatening adverse effect has been reported, the development of one of PCSK9 inhibitor bococizumab has been shelved off by Pfizer in 2016. Although in trials, bococizumab met all the trial-related endpoints, a press release by company briefed that it observed a set of patients with an unanticipated attenuation of LDL-C lowering over time, as well as a higher level of immunogenicity and higher rate of injection-site reactions with bococizumab than shown with the other agents in this class. This event should be read along with the results of meta-analysis which concluded that despite favorable early indications from lipid-lowering trials, the available clinical data do not demonstrate a mortality benefit with PCSK9 inhibitors, though significant reduction in myocardial infarction, stroke, and coronary revascularization incidences were seen with a PCSK9 inhibitor treatment.
Thirty-five randomized controlled trials (RCTs) were included in the analysis of all-cause mortality in the meta-analysis. Compared with no treatment with a PCSK9 inhibitor, treatment with a PCSK9 inhibitor was not associated with a statistically significant change in all-cause mortality (crude rate 1.9% vs. 2.2%; odd ratio: 0.71 [95% confidence interval, 0.47–1.09]; P = 0.12, I2 = 18%, heterogeneity P = 0.26). Similarly, 34 RCTs were included in the analysis of cardiovascular mortality in this meta-analysis. Compared with no treatment with a PCSK9 inhibitor, treatment with a PCSK9 inhibitor was not associated with a statistically significant change in cardiovascular mortality (crude rate 1.1% vs. 1.3%; odd ratio: 1.01 [95% CI, 0.85–1.19]; P = 0.95, I2 = 0%, heterogeneity P = 0.74). As such, PCSK9 inhibitors have no effect on all-cause mortality and cardiovascular mortality.
Due to these obvious reasons coupled with cost factors, though PCSK9 inhibitors are welcome innovation in controlling hyperlipidemia in patients intolerant to statins, they should be used cautiously, and efforts should be made to identify more subset of patients where they can prove useful.
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