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14th March 2023
Merck has reported that its investigative, oral, once-daily, PCSK9 inhibitor, MK-0616, gave rise to significant reductions in LDL cholesterol in adult patients with hypercholesterolaemia.
Increased levels of PCSK9 elevate plasma LDL cholesterol and conversely, lowering PCSK9 reduces LDL cholesterol. As a result, inhibition of PCSK9 represents a therapeutic target and drugs such as evolocumab have been recommended in the treatment of primary hypercholesterolaemia or mixed dyslipidaemia and in patients with a high or very high risk of cardiovascular disease, where LDL cholesterol levels remain above 3.5 mmol/l. However, to date all PCSK9 inhibitors are only available as an injectable form, whereas MK-0616 is an oral PCSK9 inhibitor.
In a study of healthy patients with hypercholesterolaemia, the use of once daily MK-0616 (dose 10 to 300 mg), exhibited a dose dependent increase in plasma exposure and a > 90% mean maximum reduction of free plasma PCSK9 levels from baseline at all dose levels studied.
The recent findings are from a phase 2b clinical trial in which MK-0616 was given at varying doses (6, 12, 18 and 30 mg) to adult patients with hypercholesterolaemia and who were divided into one of three categories, in which fasting LDL cholesterol levels ranged from > 1.81 to < 6.48 mmol/l.
In addition, participants were either stable on one or more lipid lowering therapies or who had not received any such treatments for more than 30 days before screening. Individuals were then randomised 1:1:1:1:1 (i.e., each dose and placebo) and the treatment continued for 16 weeks and the primary objective of the study was to evaluate the percent change in LDL cholesterol from baseline to week 8.
MK-0616 and reduction in LDL cholesterol
A total of 380 participants with a median age of 62 years (49% female) with hypercholesterolaemia and a moderate to high risk of atherosclerotic cardiovascular disease were included.
At week 8, all four doses of MK-0616 significantly reduced LDL-C compared to placebo and the placebo-adjusted reduction from baseline ranged from 41.2% with the 6 mg dose to 60.9% with the 30 mg dose (p < 0.001 for each dose).
The drug was well tolerated and the proportion of participants experiencing greater than one adverse event was similar (ranging from 39.5% to 44.2%) between the different doses and placebo (44%).
The findings of the phase 2b study have been published in the Journal of the American College of Cardiology.
20th December 2022
PCSK9 inhibitor persistence in patients with familial hypercholesterolaemia (FH) appears to be very high over time and associated with achievement of low-density lipoprotein cholesterol (LDL-C) goals as well as an improvement in quality-of-life according to an analysis of clinical practice data by Spanish researchers.
Familial hypercholesterolaemia is associated with premature atherosclerotic cardiovascular diseases and is inherited as an autosomal dominant trait. Due to the presence of dysfunctional low-density lipoprotein (LDL) receptors because of a genetic mutation, serum LDL-C levels are considerably increased from birth. Within the general population, a recent meta-analysis of 62 studies estimated a pooled FH prevalence of 1:311. According to the 2019 ESC/EAS Guidelines for the management of dyslipidaemias, patients with FH are categorised as being at very high risk of cardiovascular disease. Consequently, the guidelines recommend a therapeutic regimen that achieves ≥50% LDL-C reduction from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL). In addition, studies have suggested that the use of a PCSK9 inhibitor led to a 54.9% mean reduction in LDL-C from baseline in those with severe heterozygous FH. Nevertheless, information on the persistence or adherence to treatment with PCSK9 inhibitors in patients with FH, which is required to reduce the burden of atherosclerotic disease over time, is lacking. In the current study, researchers set out to examine the persistence to treatment, efficacy and impact on quality of life of PCSK9 inhibitor use in FH patients within a real-world clinical setting.
The researchers used data from the Spanish Familial Hypercholesterolaemia cohort study (SAFEHEART), an open, prospective study in genetically defined FH patients in Spain. They included patients on stable lipid-lowering therapy and who were managed and with a PCSK9 inhibitor (PCSK9i), although the choice of which agent was decided by the treating clinician. For the study, researchers measured persistence as the % of patients staying on a PCS9Ki at the end of each year of follow-up and quality of life was assessed with the EuroQol 5D.
PCSK9 inhibitors persistence and effectiveness over time
A total of 696 patients with a median age of 56.4 years (46% female) were included and followed for a median of 3.7 years with the median baseline LDL-C being 3.8 mmol/L. Background lipid lowering therapy was a statin and ezetimibe in 74.6% of cases and statin monotherapy in 17.5% of cases.
During the follow-up, persistence with PCSK9i was 96.1% for the whole period. At the last follow-up visit, the median LDL-C had reduced by 58%. In addition, at the last follow-up visit, 48% of patients had achieved the 2019 ESC/EAS LDL-C goal.
There were also improvements in quality of life after the first year and this remained stable over time.
The authors concluded that there was long-term persistence with PCSK9i in patients with FH patients within a clinical practice setting and that use of a PCSK9i vastly increased attainment of LDL-C goals.
Alonso R et al. Persistence with long-term PCSK9 inhibitors treatment and its effectiveness in Familial Hypercholesterolemia: data from the SAFEHEART study. Eur J Prev Cardiol 2022
20th May 2022
Adding PCSK9 inhibitors and ezetimibe to maximally tolerated statin therapy in patients at a high risk of a cardiovascular event reduces the risk of a non-fatal myocardial infarction (MI) and non-fatal stroke but does not significantly reduce either all-cause mortality or cardiovascular mortality.
This was the main finding from a network meta-analysis of trials by a group of US and Chinese researchers.
The 2021 European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice recommend that a high-intensity statin is prescribed up to the highest dose that can be tolerated in order to reach the LDL target for a specific risk group.
Furthermore, the joint American College of Cardiology/American Heart Association Task Force has suggested that in patients at very high cardiovascular risk and whose LDL-C level remains ≥70mg/dl (≥1.8mmol/l) on maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is a reasonable option.
Previously published data has already shown that when added to statin therapy, ezetimibe produces an incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Similarly, addition of alirocumab (a PCSK9 inhibitor) to patients receiving high-intensity statin therapy, reduced the risk of recurrent ischaemic cardiovascular events.
Whilst the benefits of both treatments cholesterol lowering agents are clear, the benefits to an individual patient depends upon their baseline risk. Moreover, the absolute incremental benefit derived from combining PCSK9 inhibitors and ezetimibe either separately or in combination, among individuals taking a maximally tolerated dose of statin or for those who are statin-intolerant and with different levels of baseline cardiovascular risk, remains to be determined.
For the present study, the authors performed a network meta-analysis of randomised controlled trials in which patients had a median baseline LDL cholesterol value > 1.8mmol/l and where they were randomised to receive PCSK9 inhibitors vs control, ezetimibe vs control, or PCSK9 inhibitors vs ezetimibe.
The researchers assessed the relative and absolute risks (per 1000 patients treated for 5 years) in terms of non-fatal MI, non-fatal stroke, all-cause mortality and cardiovascular mortality. Patients were also categorised as being at low to very high cardiovascular risk.
The authors set the minimal important difference as 12 per 1000 reductions for non-fatal MI, 10 per 10,000 for a non-fatal stroke and 8 per 1000 for all-cause or cardiovascular mortality.
PCSK9 inhibitors and ezetimibe and cardiovascular outcomes
A total of 16 trials with 111,098 patients (median age 61 years) and a median LDL cholesterol concentration of 2.71mmol/l, were followed-up for a median of 2 years and included in the analysis.
Among patients prescribed statins, addition of a PCSK9 inhibitor reduced the risk of a non-fatal MI by 19% (relative risk, RR = 0.81, 95% CI 0.76 – 0.87), non-fatal stroke by 26% (RR = 0.74) but not all-cause mortality (RR = 0.95, 95% CI 0.87 – 1.03) or cardiovascular mortality (RR = 0.95, 95% CI 0.87 – 1.03).
Similarly, the addition of ezetimibe reduced non-fatal MI and non-fatal stroke by 13% and 18% respectively but, again, there was no significant effect on all-cause or cardiovascular mortality.
Among adults with a very high cardiovascular risk, the authors calculated that adding a PCSK9 inhibitor to statins would lead to 16 fewer non-fatal MIs and 21 non-fatal strokes. Adding ezetimibe to a similar or equivalent statin patient, would lead to 14 fewer non-fatal strokes and 11 fewer MIs.
Finally, adding PCSK9 inhibitors and ezetimibe to a statin would reduce non fatal strokes by 14 per 1000 and stroke by 17 per 1000, although there was no impact on all-cause or cardiovascular mortality.
The authors also found that among patients with low to moderate risk of cardiovascular disease, adding either a PCSK9 inhibitor provided no additional benefit over statin therapy alone. In other words, it was only patients with the highest cardiovascular risk who benefited from adding either ezetimibe or a PCSK9 inhibitor to their statin.
Similar reductions, again only among high or very high risk individuals and a lack of mortality benefit, were observed in patients intolerant of statins.
The authors concluded that the benefits of adding PCSK9 inhibitors and ezetimibe were limited largely to patients only with a high or very high cardiovascular risk.