How Pcsk9 Inhibitors Work
PCSK9 inhibitors work to lower cholesterol in patients whove been diagnosed with coronary artery disease, have a genetic propensity for high cholesterol or are at high risk for heart attack or stroke. PCSK9 inhibitors may also be effective alone for certain patients who cant tolerate a statin or cant achieve goal cholesterol levels while on other cholesterol-lowering medications.
This new class of drugs successfully lowers LDL by 50 to 70% when taken alone or in combination with a statin, says Brook, citing a study in the New England Journal of Medicine that shows PCSK9 inhibitors can actually prevent heart attacks and strokes. This benefit was shown even in patients taking statins who had LDL levels below 100 mg/dL who were previously thought to be well controlled, says Brook.
These PCSK9 inhibitors target PCSK9 proteins in the liver that destroy the livers receptors responsible for removing excess cholesterol from the blood. Because these proteins are destroyed, more receptors are then able to do their job, successfully lowering the amount of LDL cholesterol in the blood.
The PCSK9 inhibitor is injected in the skin of the abdomen or upper thigh every two to four weeks. Despite promising results, a major drawback for many patients is the cost.
Know The Dangers Of Trans Fats
Trans fats are dangerous for your heart, because they raise low-density lipoprotein cholesterol and triglyceride levels. The chief culprit youll see on product labels is partially hydrogenated oil. Trans fats are the result of adding hydrogen to liquid vegetable oils to increase shelf life. This may make some baked and fried foods taste better, but trans fats are very unhealthy, particularly for people with high triglycerides. In fact, trans fats should make up less than 1 percent of your total calories, according to the World Health Organization. Check your food labels: If a food contains trans fats or hydrogenated oils, leave it on the shelf.
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Natural Ways To Lower Your Cholesterol Levels
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Cholesterol is made in your liver and has many important functions. For example, it helps keep the walls of your cells flexible and is needed to make several hormones.
However, like anything in the body, too much cholesterol creates concerns.
Like fat, cholesterol does not dissolve in water. Instead, to move around the body, it depends on molecules called lipoproteins. These carry cholesterol, fat, and fat-soluble vitamins in your blood.
Different kinds of lipoproteins have different effects on health. For example, high levels of low-density lipoprotein results in cholesterol deposits in blood vessel walls, which can lead to (
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Mechanism Accounting For The Statin Induced Lipid Effects
Statins are competitive inhibitors of HMG-CoA reductase, which leads to a decrease in cholesterol synthesis in the liver. This inhibition of hepatic cholesterol synthesis results in a decrease in cholesterol in the endoplasmic reticulum resulting in the movement of sterol regulatory element binding proteins from the endoplasmic reticulum to the golgi where they are cleaved by proteases into active transcription factors . The SREBPs then translocate to the nucleus where they increase the expression of a number of genes including HMG-CoA reductase and, most importantly, the LDL receptor . The increased expression of HMG-CoA reductase restores hepatic cholesterol synthesis towards normal while the increased expression of the LDL receptor results in an increase in the number of LDL receptors on the plasma membrane of hepatocytes leading to the accelerated clearance of apolipoprotein B and E containing lipoproteins . The increased clearance of LDL and VLDL accounts for the reduction in plasma LDL-C and triglyceride levels. In patients with a total absence of LDL receptors statin therapy is not very effective in lowering LDL-C levels.
Effect Of Pcsk9 Inhibitors On Clinical Outcomes
It should be noted that that the duration of the FOURIER trial was very short and it is well recognized from previous statin trials that the beneficial effects of lowering LDL-C levels takes time with only modest effects observed during the first year of treatment. In the FOURIER trial the reduction of cardiovascular death, myocardial infarction, or stroke was 16% during the first year but was 25% beyond 12 months. Thus, long-term benefit may be greater than observed during the study.
SUMMARY OF OUTCOME TRIALS
It should be noted that that the duration of the PCSK9 outcome trials were relatively short and it is well recognized from previous statin trials that the beneficial effects of lowering LDL-C levels takes time with only modest effects observed during the first year of treatment. In the FOURIER trial the reduction of cardiovascular death, myocardial infarction, or stroke was 16% during the first year but was 25% beyond 12 months. In the ODYSSEY trial the occurrence of cardiovascular events was similar in the alirocumab and placebo group during the first year of the study with benefits of alirocumab appearing after year one. Thus, the long-term benefits of treatment with a PCSK9 inhibitor may be greater than that observed during these relatively short-term studies.
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How Quickly Can I Lower My Cholesterol
Your cholesterol levels may lower as quickly as a few weeks to a few months, depending on your treatment plan.
If your levels are very high, your healthcare provider may recommend taking medications at the start of your treatment plan. This may help lower your cholesterol levels more quickly. The sooner you can lower your bad cholesterol levels, the sooner you can lower your risk for plaques to form.
You can also lower your cholesterol through lifestyle and diet changes alone, but it may take three to six months to see results. Talk with your healthcare provider to figure out the best treatment plan for you.
Effect On Evinacumab On Lipid And Lipoprotein Levels
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
A double-blind, placebo-controlled trial randomly treated patients with Homozygous Familial Hypercholesterolemia with an intravenous infusion of evinacumab 15 mg/Kg every 4 weeks or placebo . The individuals in this trial were on lipid lowering therapy and the mean baseline LDL-C level was approximately 250-260mg/dL. After 24 weeks of treatment patients in the evinacumab group had a 47% reduction in LDL-C levels vs. a 1.9% increase in the placebo group . This decrease in LDL-C levels was observed after 2 weeks of therapy and was observed regardless of concomitant use of other lipid lowering drugs or apheresis. Notably, in individuals with null-null LDL receptor variants evinacumab resulted in a 43% decrease in LDL-C levels indicating that evinacumab therapy was effective in the absence of functional LDL receptors. As expected, total cholesterol, non-HDL-C cholesterol, and apo B levels were also decreased. Moreover, triglyceride levels decreased 55% and HDL-C levels decreased 30% with evinacumab administration while Lp levels were unchanged.
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Triglycerides And Cardiac Risk
Many clinical studies have shown that having a high triglyceride blood level a condition called hypertriglyceridemia is also associated with a substantially elevated cardiovascular risk. While this association is generally accepted by experts, it is not yet agreed that elevated triglyceride levels are a direct cause of atherosclerosis, as LDL cholesterol is thought to be. There is no generally accepted triglyceride hypothesis.
Still, there is no question that hypertriglyceridemia is strongly associated with elevated cardiovascular risk. Furthermore, high triglyceride levels are a prominent feature of several other conditions known to increase cardiac risk. These include obesity, sedentary lifestyle, smoking, hypothyroidism and especially metabolic syndrome and type 2 diabetes.
This latter relationship is particularly important. The insulin resistance that characterizes metabolic syndrome and type 2 diabetes produces an overall metabolic profile that tremendously increases cardiac risk. This unfavorable metabolic profile includes, in addition to hypertriglyceridemia, elevated CRP levels, high LDL cholesterol levels, and low HDL cholesterol levels. People with insulin resistance also tend to have hypertension and obesity. Their overall risk of heart disease and stroke is very high.
Lower Your Ldl Cholesterol And Triglycerides
High blood LDL cholesterol and triglyceride levels are the main risk factors associated with heart disease, which is still the most common cause of death in Britain and the United States. But you dont need to resort to dangerous drugs to lower your levels, as some simple diet and lifestyle changes can do the job even more effectively. So in this article Ill explain how you can lower your LDL cholesterol and triglycerides without drugs, and so reduce your risk of heart disease dramatically.
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What Are The Types Of Fibrate Drugs
There are several types of fibrates. You may take:
Last reviewed by a Cleveland Clinic medical professional on 02/10/2022.
- American Heart Association. Cholesterol Medications. Accessed 2/10/2022.
- Blais JE, Kin Yi Tong G, et al. Comparative efficacy and safety of statin and fibrate monotherapy: A systematic review and meta-analysis of head-to-head randomized controlled trials. 2021 Feb-. PLoS ONE 16: e0246480. Accessed 2/10/2022.
- Singh G, Correa R. Fibrate Medications. Treasure Island : StatPearls Publishing 2021 Jan-. Accessed 2/10/2022.
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Hyperlipidemia High Cholesterol High Triglycerides How To Treat
The treatment of hyperlipidemia, high cholesterol, and high triglyceride is mainly divided into two parts: drug treatment and adjustment of daily eating habits.
If the necessity of medication is not reached, most doctors will generally recommend starting with non-medication.
Improve by adjusting the patients life and eating habits. If the blood lipids do not return to normal after 3-6 months, medical treatment should be performed.
The general treatment drugs are Statins, cholic acid-binding resin, nicotinic acid, and fibrate derivatives four kinds, to achieve control to reduce the risk of cardiovascular disease caused by arteriosclerosis.
The treatment of drugs still needs to be discussed with the doctor, so in the next paragraph, I will mainly focus on the second focus of treatment, which is also the root of the daily diet and life maintenance.
Note. Taking the relevant therapeutic drugs requires taking the medicine according to the instructions of the doctor. All kinds of drugs have side effects.
You should discuss with the doctor and design a prescription label according to your own situation. Do not judge the consumption by yourself.
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Effect Of Alipogene Tiparvovec On Lipid And Lipoprotein Levels
In patients with plasma TG levels > 880mg/d, treatment with alipogene tiparvovec resulted in an approximately 40% decrease in fasting plasma TGs with half of the patients having > 40% decrease in fasting plasma TG levels at 3-12 weeks post treatment . By week 16-26, fasting TG levels returned to baseline values but chylomicron levels were reduced . While fasting TG levels returned to baseline, postprandial TG levels were reduced by approximately 60% suggesting that there are long term effects that are not reflected by fasting TG levels . In fact, in some patients treated with alipogene tiparvovec, lipoprotein lipase expression was demonstrated in muscle biopsies at 26 weeks .
Mechanisms Accounting For The Niacin Induced Lipid Effects
Early studies demonstrated that niacin inhibited the release of free fatty acids from cultured adipocytes and decreased circulating free fatty acid levels . The ability of niacin to inhibit adipose tissue lipolysis is mediated by the activation of GPR109A , a G protein-coupled receptor that is highly expressed in adipose tissue . It was initially thought that the decrease in plasma TGs induced by niacin therapy was due to niacin inhibiting lipolysis in adipose tissue resulting in a decrease in the transport of fatty acids to the liver leading to the decreased availability of fatty acids for hepatic TG synthesis. However, studies have shown that while niacin acutely decreases plasma free fatty acid levels this inhibition is not sustained . Additionally, studies in mice lacking GPR109A have shown that niacin does not inhibit lipolysis but still decreases plasma TG and LDL-C levels . Moreover, studies in humans using GPR109A agonists lowered plasma free fatty acid levels but did not cause the expected effects on plasma TGs and LDL-C . Thus, the effects of niacin on adipose tissue lipolysis are no longer thought to mediate the niacin induced decrease in plasma TG levels.
LOW DENSITY LIPOPROTEIN
The decrease in plasma LDL-C with niacin therapy is thought to be secondary to a reduction in VLDL and LDL formation and secretion by the liver .
HIGH DENSITY LIPOPROTEIN
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Who Could Benefit From Pcsk9 Inhibitors
When To Seek Treatment
Deciding on whether you ought to be treated for high cholesterol or high triglyceride levels, whether that treatment ought to include drug therapy, and which drugs ought to be used is not always entirely straightforward. Still, if your cardiovascular risk is elevated, the right treatment aimed at your lipid levels can substantially reduce your chances of having a heart attack, or even of dying prematurely. So when it comes to treating cholesterol and triglycerides, it is important to get it right. You can read about current thinking on when and how treatment for blood lipids should be chosen.
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What Causes High Triglycerides
Aside from consuming a high-fat and/or high-carb diet, other lifestyle factors can contribute to high triglycerides, specifically excess weight, lack of exercise, drinking too much alcohol and smoking. Dr. Malaney adds that it can also be a side effect of certain medications, such as some birth control pills, beta blockers, antipsychotics medications, and corticosteroids.
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Effect Of Niacin On Cardiovascular Outcomes
COMBINATION WITH FIBRATES
In the Stockholm Ischemic Heart Disease Secondary Prevention Study survivors of a myocardial infarction below 70 years of age were randomized to a control group and a group treated with clofibrate and immediate release nicotinic acid . Serum cholesterol and TG was lowered by 13% and 19%, respectively, in the treatment group compared to the control group. Recurrent myocardial infarction was reduced by 50% within one year . Total mortality was decreased by 26% in the group treated with clofibrate + niacin while ischemic heart disease mortality was decreased by 36% . Notably, the benefit of clofibrate + niacin was only observed in patients with a baseline TG level > 143mg/dl. In the age of statins, the clinical implications of this early study are unclear.
COMBINATION WITH STATINS
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Moderate Hypertriglyceridemia Prevention Of Cardiovascular Disease
In the era of statin therapy, it is uncertain whether lowering TG levels in patients on statin therapy will further reduce cardiovascular events. As discussed in detail in the sections on individual drugs, the studies carried out so far have not shown that adding niacin or fibrates to statin therapy is beneficial with regards to cardiovascular disease. As also discussed, the available studies have major limitations because many of the patients in these outcome studies did not have substantial elevations in TGs and therefore the issue is an open question that requires additional studies. Notably, the REDUCE-IT trial, which tested the effect of high dose EPA in patients with elevated TG levels and the JELIS trial which tested the effect of EPA 1.8 grams per day in patients with high cholesterol levels demonstrated a reduction in cardiovascular events. However, in both of these trials the decrease in cardiovascular events was considerably greater than one would expect based on the reduction in TG levels suggesting that the decrease in cardiovascular events was not solely due to lowering TG levels and that other effects of EPA likely played a role.
Treatment For High Cholesterol
Making lifestyle changes, especially changing some of the foods you eat, and regular physical activity, are very important to help reduce high LDL cholesterol.
- Move more. Regular physical activity is one of the best things you can do for your heart health. Increasing your physical activity from as little as 10 minutes a day to the Australian governments recommended 30 to 45 minutes a day, five or more days of the week, can help manage your cholesterol levels and reduce your risk of heart disease.
- Quitting smoking reduces the risk of heart disease and can help reduce cholesterol levels. The most effective way to stop smoking is with a combination of stop-smoking medicines and support from a service like Quitline . Speaking to your GP is also a great first step.
- Drinking alcohol doesnt have any health benefits. Alcohol contributes unnecessary kilojoules and is of low nutritional value. Alcohol is not a necessary or recommended part of a heart-healthy eating pattern. If you do drink, to reduce your risk of alcohol-related harm, healthy women and men should drink no more than 10 standard drinks a week and no more than four standard drinks on any one day.
- You may also need to take cholesterol-lowering medicines to help manage your cholesterol and reduce your risk of having a heart attack or stroke. Talk to your doctor about finding the most appropriate treatment for you.
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Effect On Inclisiran On Lipid And Lipoprotein Levels
HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
The effect of inclisiran on LDL-C levels was determined in patients with heterozygous familial hypercholesterolemia who were randomized to receive subcutaneous injections of inclisiran 284mg or placebo on days 1, 90, 270, and 450 . The mean baseline LDL-C level was 153Â±54mg/dl and 90% of the patients were receiving statins with most on high intensity statins . At day 510 LDL-C levels were reduced by 47.9% compared to placebo . The reduction in LDL-C was similar in all genotypes of familial hypercholesterolemia. Total cholesterol was reduced by 33%, non-HDL-C by 44%, Lp by 17.2%, and triglycerides by 12%. HDL-C and hsCRP were not markedly altered.
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
A small study reported that inclisiran treatment lowered LDL-C levels in 3 of 4 patients with homozygous familiar hypercholesterolemia but less than that seen in individuals with fully functioning LDL receptors .