There is good evidence for at least some methods of achieving dramatic reductions in blood cholesterol in humans to be safe and reduce the risk of age-related cardiovascular issues. To pick one of the underlying mechanisms involved in these benefits, the common age-related condition of atherosclerosis is at root caused by interactions between damaged cholesterol and the cells of blood vessel walls. Cells become irritated by the presence of that cholesterol, and this begins a series of overreactions and unfortunate events that leads to the generation of fatty plaques that narrow blood vessels and weaken blood vessel walls. In conjunction with the raised blood pressure present in older individuals, this eventually leads to the dramatic structural failure of a stroke or heart attack, when a large blood vessel is blocked or ruptures. If there is less cholesterol in the bloodstream, however, the whole chain of cause and effect slows down. That slowing isn't as good as fixing the issue, such as by effectively sabotaging any one of the bad cellular behaviors that combine to lead to the growth of plaques, but it is certainly a lot better than nothing.
Statins are the obvious item to point out when thinking about cholesterol, aging, and cardiovascular disease. The widespread use of this class of drug has done much to reduce the incidence and mortality of cardiovascular disease. These days, however, researchers are looking into more targeted means of reducing cholesterol levels, forms of therapy that suppress specific genes to achieve much larger reductions than is possible with statins. There are a number potential targets for gene therapies, RNA interference approaches, and the like, such as an ASGR1 mutation that occurs in small number of humans, who have less cholesterol and much lower rates of atherosclerosis. The story is much the same for an ANGPTL4 mutation, also present in a small number of people and associated with significantly reduced cholesterol and cardiovascular risk. For today, however, I'll note a brace of publicity materials on recent attempts to target PCSK9 with the aim of permanently lowering blood cholesterol by a large amount. Several distinct teams appear to have timed their press for the same scientific conference, so all the results appeared in public at much the same time.
The first in a new class of gene-silencing drugs, known as inclisiran, has halved cholesterol levels in patients at risk of cardiovascular disease. The findings come from the largest trial yet to test the safety and effectiveness of this kind of therapy. The technique, known as RNA interference (RNAi) therapy, essentially 'switches off' one of the genes responsible for elevated cholesterol, PCSK9. The twice-a-year treatment could be safely given with or without statins, depending on individual patient needs. Eventually, inclisiran could help to reduce the risk of heart attacks and stroke related to high cholesterol. "We appear to have found a versatile, easy-to-take, safe, treatment that provides sustained lowering of cholesterol levels and is therefore likely to reduce the risk of cardiovascular disease, heart attacks, and stroke. These reductions are over and above what can be already be achieved with statins alone or statins plus ezetemibe, another class of cholesterol-lowering drug."
In the study, researchers gave 497 patients with high cholesterol and at high risk of cardiovascular disease either inclisiran at varying doses, or placebo. Seventy-three per cent of these patients were already taking statins, and 31 per cent were taking ezetimibe. Participants, who were recruited from Canada, USA, Germany, Netherlands, and the UK, were excluded if they were taking monoclonal antibodies for cholesterol lowering. Patients were given different doses of inclisiran or placebo via subcutaneous injection, either via a single dose, or via a dose on day one and another at three months. They were followed up regularly for a subsequent eight months and tested for blood cholesterol and side effects. The researchers found that just one month after receiving a single treatment of inclisiran, participants' LDL cholesterol levels had reduced by up to 51 per cent.
A new class of cholesterol lowering drugs known as PCSK9 inhibitors has emerged as an effective treatment for drastically lowering LDL cholesterol beyond what is possible with statin therapy alone. Previous research demonstrated that evolocumab, a member of this new class of drugs, effectively reduces LDL cholesterol by approximately 60 percent. Evolocumab is a fully human monoclonal antibody that works by blocking proprotein convertase subtilisin-kexin 9 (PCSK9), a protein that reduces the liver's ability to remove LDL cholesterol from the blood. The FOURIER trial (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) was designed to determine whether evolocumab, when added to statin therapy, would reduce adverse cardiovascular events.
In this randomized, double-blind, placebo-controlled multinational clinical trial, 27,564 patients aged 40-85 were studied. All trial participants had stable atherosclerotic vascular disease, defined as a medical history of heart attack, stroke or symptomatic peripheral artery disease. On a background of high or moderate intensity statin therapy patients had a LDL cholesterol level of at least 70 mg/dl. Patients received either evolocumab (140mg every two weeks or 420mg every month) or placebo. Similar to data from previous lipid lowering trials, researchers report that evolocumab reduced LDL cholesterol by 59 percent, in this case from a median of 92 mg/dL to a median of 30 mg/dL. The LDL cholesterol lowering effect remained constant over the duration of the trial.
Researchers report that patients treated with evolocumab had a 15 percent reduction in the risk of major cardiovascular events, defined as the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization (occurring in 9.8 percent of patients treated with evolocumab vs. 11.3 percent of patients treated with placebo). Additionally, evolocumab reduced the more serious key secondary endpoint, which was a composite of heart attack, stroke or cardiovascular death, by 20 percent (occurring in 7.9 percent of patients treated with evolocumab vs. 9.9 percent in the placebo group). This reduction in risk improved over time, increasing from 16 percent in the first year to 25 percent after the first year.
New results from the clinical trial program, SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular Events), which sought to determine the effect of bococizumab, a PCSK9 inhibitor, on LDL cholesterol levels and clinical outcomes in high-risk patients already taking statin therapy, have been presented. Researchers report that bococizumab had short-term benefits on lowering cholesterol levels and significantly reduced the risk of cardiovascular events by 21 percent compared to placebo among those who had baseline LDL cholesterol levels of greater than 100 mg/dL. However, the cholesterol lowering effect tended to diminish over time in some patients and bococizumab did not reduce cardiovascular event rates among those with LDL levels lower than 100 mg/dL.
The SPIRE program involved eight double-blind, placebo controlled clinical trials that were conducted simultaneously. Six lipid-lowering trials randomized 4,449 patients, who previously had a heart attack or stroke or had extremely high baseline cholesterol levels and were on statin therapy, to receive either bococizumab (150 mg subcutaneously every 2 weeks) or placebo to determine the effects on LDL levels. Two other multi-national trials randomized 27,438 patients to either bococizumab or placebo and were designed to evaluate the impact of the drug on cardiovascular outcomes, including nonfatal heart attack and stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death. Almost all the patients were on statin therapy.
On November 1, 2016, the entire SPIRE clinical trials program was stopped when the sponsor, Pfizer, who manufactures bococizumab, discontinued the development of the drug when initial results from the LDL cholesterol lowering trials indicated that some trial participants had developed anti-drug antibodies, an immunologic response to the drug. Further analysis indicated that bococizumab effectively reduced LDL cholesterol levels by an average of 56 percent after 14 weeks; however, the immunologic reaction attenuated the reduction in LDL cholesterol in approximately 15 percent of those who received the drug. Data also show that there was a wide variation in the magnitude of cholesterol reduction that patients achieved with bococizumab, even among patients who did not develop the immunologic response. Bococizumab is a humanized antibody therapy that works by blocking proprotein convertase subtilisin-kexin 9 (PCSK), a protein that reduces the liver's ability to remove LDL cholesterol from the blood. "We believe that the attenuation of LDL lowering over time in the treatment group was likely due to the fact that bococizumab, a humanized antibody, led to an immunologic response in some patients. The alternative PCSK9 inhibitors evolocumab and alirocumab, which have already been approved for use, are fully human antibodies and do not have this adverse effect."
If this were a better world, the next stage in this process would be the development of one-off gene therapies for use by all adults, carried out long before old age rolls around. That is unlikely to happen any time soon within the bounds of the present regulatory environment, however. Waiting until the damage is underway and the disease process in its comparatively late stages before acting is the great failing of modern medicine and regulation of its use. So much more could be done to slow down and prevent aging by intervening sooner with these new technologies, in adults who are still young and healthy. Acting too late is always a poor strategy in comparison.