Mechanism Accounting For The Mipomersen Induced Lipid Effects
Apolipoprotein B 100 is the main structural protein of VLDL and LDL and is required for the formation of VLDL and LDL . Familiar Hypobetalipoproteinemia is a genetic disorder due to a mutation of one apolipoprotein B allele that is characterized by very low concentrations of LDL and apolipoprotein B due to the decreased production of lipoproteins by the liver . Mipomersen, an apolipoprotein B antisense oligonucleotide, mimics Familiar Hypobetalipoproteinemia by inhibiting apolipoprotein B 100 production in the liver by pairing with apolipoprotein B mRNA preventing its translation . This decrease in apolipoprotein B synthesis results in a decrease in hepatic VLDL production leading to a decrease in LDL levels.
Effect Of Bile Acid Sequestrants On Clinical Outcomes
The Lipid Research Clinics Coronary Primary Prevention Trial of cholestyramine vs. placebo was the first large drug study to explore the effect of specifically lowering LDL-C on cardiovascular outcomes . LRC-CPPT was a multicenter, randomized, double-blind study in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia. The treatment group received cholestyramine 24 grams per day and the control group received a placebo for an average of 7.4 years. In the cholestyramine group total and LDL-C was decreased by 8.5% and 12.6% as compared to the placebo group. In the cholestyramine group there was a 19% reduction in risk of the primary end point accounted for by a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The reduction in events correlated with the decrease in LDL-C levels . Of note, compliance with cholestyramine 24 grams per day was limited with many patients taking much less than the prescribed doses. These results indicate that lowering LDL-C with bile acid sequestrant monotherapy will reduce cardiovascular disease.
What Is High Cholesterol And Who Should Care
High cholesterol raises your risk of atherosclerosis, which is the buildup of plaque in your arteries. Arteries are the blood vessels that supply nutrients and oxygen to your body.
Atherosclerosis, in turn, raises your risk of developing cardiovascular disease, or disease of the heart and blood vessels.
Statins are prescription medications that lower your cholesterol levels. Examples include atorvastatin, simvastatin, rosuvastatin, and pravastatin. Statins block an enzyme that normally allows your body to make cholesterol. By blocking the enzyme, statins lower the amount of cholesterol in your blood.
Lovastatin, the first statin available in the U.S., was approved by the Food and Drug Administration in 1987.
Lowering cholesterol with a statin is beneficial for people who:
Already have cardiovascular disease, like a heart attack or stroke
Are at high risk for cardiovascular disease due to diabetes or other reasons
Have very high cholesterol levels
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Mechanisms Accounting For Inclisiran Induced Lipid Effects
The mechanism of action of inclisiran is the same as for PCSK9 monoclonal antibodies . Briefly, decreasing the production of PCSK9 in the liver, the primary source of circulating PCSK9, leads to a decrease in plasma PCSK9 levels resulting in a decrease in in LDL receptor degradation . An increase in the number of hepatic LDL receptors increases the clearance of LDL leading to a decrease in LDL-C levels .
Cholesterol Medications Effect On Your Body
Heres a list of some of the common side effects associated with Lipitor:
Lipitor block the HMG-CoA enzyme. Which stops your bodys internal cholesterol production. But this also stops a huge range of other processes from taking place.
Vitamin D, all your sex hormones , and even co-enzyme Q10 production are impacted by statin use. Vitamin D deficiency is known to cause fatigue. Hormone imbalance are known to cause fatigue. And coQ10 deficiency is most certainly associated with fatigue!
Co-enzyme Q10 deficiency is responsible for a number of the side-effects associated with statin drugs. And it could be the main cause of your cholesterol medication-induced fatigue!
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Atorvastatin May Cause Side Effects Tell Your Doctor If Any Of These Symptoms Are Severe Or Do Not Go Away:
- swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
Atorvastatin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.
If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration’s MedWatch Adverse Event Reporting program online or by phone .
What Else Should I Know About Atherosclerosis And Statins
Statins are used specificially for preventing and treating atherosclerosis that causes chest pain, heart attacks, strokes, and intermittent claudication . Lupus, medications such as corticosteroids, family history, and other factors can predispose a person to atherosclerosis however, only your doctor can decide whether statins are the right choice for you based on your total cholesterol level, LDL level, and other risk factors. Most people are placed on statins only if lifestyle changes are not sufficient enough in reducing their cholesterol levels. However, keep in mind that if you begin taking a statin, you may be on it for the rest of your life.
Eating a low-fat, low-calorie diet is also essential in preventing or slowing atherosclerosis. Focus on what you can eat, not what you cant. For example, fish, vegetables, fruits, whole grains, and legumes are all great choices. In addition, try to limit stress and exercise regularly. Walking, biking, stretching, yoga, and Tai chi are all great activities for people with lupus because they are easier on your joints but help to improve muscle, bone, and heart health. If you are overweight, weight loss can help to reduce your cholesterol.
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Effect Of Evinacumab On Clinical Outcomes
There are no cardiovascular outcome studies.
Homozygosity for loss-of-function mutations in ANGPTL3 is associated with significantly lower plasma levels of LDL-C, HDL-C, and triglycerides . Heterozygous carriers of loss-of-function mutations in ANGPTL3, which occur at a frequency of about 1:300, have significantly lower total cholesterol, LDL-C, and triglyceride levels than noncarriers . Moreover, patients carrying loss-of-function variants in ANGPTL3 have a significantly lower risk of coronary artery disease . Additionally, in an animal model of atherosclerosis treatment with evinacumab decreased atherosclerotic lesion area and necrotic content . Taken together these observations suggest that inhibiting ANGPTL3 with evinacumab will reduce cardiovascular disease.
Mechanisms Accounting For Bile Acid Sequestrants Induced Lipid Effects
Bile acid sequestrants bind bile acids in the intestine, preventing their reabsorption in the terminal ileum leading to the increased fecal excretion of bile acids . This decrease in bile acid reabsorption reduces the size of the bile acid pool, which stimulates the conversion of cholesterol into bile acids in the liver . This increase in bile acid synthesis decreases hepatic cholesterol levels leading to the activation of SREBPs that up-regulate the expression of the enzymes required for the synthesis of cholesterol and the expression of LDL receptors . The increase in hepatic LDL receptors results in the increased clearance of LDL from the circulation leading to a decrease in serum LDL-C levels . Thus, similar to statins and ezetimibe, bile acids lower plasma LDL-C levels by decreasing hepatic cholesterol levels, which stimulates LDL receptor production and thereby accelerates the clearance of LDL from the blood.
The mechanism by which treatment with bile acid sequestrants improves glycemic control is unclear .
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Before Taking This Medicine
You should not use atorvastatin if you are allergic to it, or if you have:
liver disease or
if you are pregnant or breastfeeding.
Atorvastatin can harm an unborn baby or cause birth defects. Do not use if you are pregnant. Stop taking this medicine and tell your doctor right away if you become pregnant. Use effective birth control to prevent pregnancy while you are taking this medicine.
Atorvastatin may pass into breast milk and could harm a nursing baby. Do not breastfeed while you are taking this medicine.
To make sure this medicine is safe for you, tell your doctor if you have ever had:
a thyroid disorder or
if you drink more than 2 alcoholic beverages daily.
Atorvastatin can cause a condition that results in the breakdown of skeletal muscle tissue, potentially leading to kidney failure. This condition may be more likely to occur in older adults and in people who have kidney disease or poorly controlled hypothyroidism .
Atorvastatin is approved for use in adults and children who are at least 10 years old.
Pharmacokinetics And Drug Interactions
Statins have different pharmacokinetic properties which can explain clinically important differences in safety and drug interactions . Most statins are lipophilic except for pravastatin and rosuvastatin, which are hydrophilic. Lipophilic statins can enter cells more easily but the clinical significance of this difference is not clear. Most of the clearance of statins is via the liver and GI tract . Renal clearance of statins in general is low with atorvastatin having a very low renal clearance making this particular drug the statin of choice in patients with significant renal disease. The half-life of statins varies greatly with lovastatin, pravastatin, simvastatin, and fluvastatin having a short half-life while atorvastatin, rosuvastatin, and pitavastatin having a long half-life . In patientâs intolerant of statins, the use of a long-acting statin every other day or 2 times per week has been employed. Short acting statins are most effective when administered in the evening when HMG-CoA reductase activity is maximal while the efficacy of long-acting statins is equivalent whether given in the AM or PM . In patients who prefer to take their statin in the morning one should use a long-acting statin.
Thus, despite the excellent safety record of statins, careful attention must be paid to the potential drug-drug interactions. For additional information see Kellick et al .
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What Statins Are Available To Treat High Cholesterol
Available statin drugs
- Increased blood glucose levels.
- Reversible memory issues.
If youre unable to take statins because of the side effects, youre said to be statin-intolerant. If you are taking a statin, you should avoid grapefruit products because they can increase side effects. You should limit the amount of alcohol that you drink because combining alcohol and statin usage can increase your risk of liver damage. You may want to talk with your provider or pharmacist if you are concerned about any other types of interactions.
PCSK9 inhibitors are designed to attach to a particular liver protein, which results in lowered LDL cholesterol. This class of drug can be given with statins and is usually for people at high risk of heart disease who have not been able to lower their cholesterol enough through other means.
Effect Of Statin Therapy On Clinical Outcomes
A large number of studies using a variety of statins in diverse patient populations have shown that statin therapy reduces atherosclerotic cardiovascular disease. The Cholesterol Treatment Trialists have published meta-analyses derived from individual subject data. Their first publication included data from 14 trials with over 90,000 subjects . There was a 12% reduction in all-cause mortality in the statin treated subjects, which was mainly due to a 19% reduction in coronary heart disease deaths. Non-vascular causes of death were similar in the statin and placebo groups indicating that statin therapy and lowering LDL-C did not increase the risk of death from other causes such as cancer, respiratory disease, etc. Of particular note there was a 23% decrease in major coronary events per 1 mmol/L reduction in LDL-C. Decreases in other vascular outcomes including non-fatal MI, coronary heart disease death, vascular surgery, and stroke were also reduced by 20-25% per 1 mmol/L reduction in LDL-C. Additionally, analysis of these studies demonstrated that the greater the reduction in absolute LDL-C levels the greater the decrease in cardiovascular events. For example, while a 40mg/dl decrease in LDL-C will reduce coronary events by approximately 20%, an 80mg/dl decrease in LDL-C will reduce events by approximately 40%. These results support aggressive lipid lowering with statin therapy.
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What Are Statins And Why Are They Used In The Treatment Of Lupus
Statins are medications that lower the level of cholesterol in your blood by reducing the production of cholesterol in the liver. Cholesterol is a natural component of the fats in your blood stream and the cells of your body. However, people with high levels of cholesterol in their blood face an increased risk of cardiovascular disease, which can lead to chest pain, heart attack, stroke, and peripheral vascular disease.
When too much cholesterol circulates in the blood, the substance can cause deposits to form on your artery walls. Plaque is dangerous because it can block the flow of blood to various parts of your body, including your heart and brain. Studies have shown that people with lupus are more likely to have clogged arteries that can lead to heart attack and stroke at a younger age. This increased risk is caused by elevated cholesterol levels, high blood pressure, diabetes, and inflammation, conditions that occur often in people with lupus. Certain medications, such as corticosteroids can provoke or compound these symptoms. For this reason, the cholesterol-lowering properties of statins are commonly called upon for lupus patients.
The Benefits And Risks Of Statins
The main benefit of statins is that they lower the risk of cardiovascular disease. But the size of this benefit is not the same for everyone. If your risk of cardiovascular disease is high, then the benefit of taking a statin is greater than if your risk were very low. In other words, you have much more to gain from a statin if your risk of heart disease is high.
What about the risks? Every drug can cause side effects. The most well-studied side effects of statins are:
Muscle pain and weakness
Taking a statin every day can also weigh on ones finances, even though theyre available as generics.
When deciding who should take a statin, the key question is: Do the benefits of statins outweigh the risks?
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Medical Guidelines And Recommendations
In 2015, the United States Department of Agriculture Dietary Guidelines Advisory Committee recommended that Americans eat as little dietary cholesterol as possible, because most foods that are rich in cholesterol are also high in saturated fat and thereby may increase the risk of cardiovascular disease. For over 2 decades, the Dietary Guidelines for Americans recommended that dietary cholesterol be no more than 300 mg per day. In a 2014 draft, DGAC dropped this recommendation because evidence showed no appreciable relationship between dietary and serum cholesterol. This caught the eye of the Physicians Committee for Responsible Medicine , which sued DGAC due to concerns of conflicts of interest which prompted the final draft to recommend eating “as little dietary cholesterol as possible”. A 2013 report by the American Heart Association and the American College of Cardiology recommended to instead focus on healthy dietary patterns rather than cholesterol limits as they are hard for clinicians and consumers to implement. They recommend the DASH and Mediterranean diet, which are low in cholesterol. A 2017 review by the American Heart Association recommends switching saturated fats for polyunsaturated fats to reduce cardiovascular disease risk.
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Medications For High Triglycerides
Many people who have high cholesterol also have high triglycerides . Some medications can help lower this type of fat directly. Once these levels go down, the total amount of cholesterol is often lowered.
A common prescription for high triglycerides is niacin or vitamin B-3. Niacin can help lower bad cholesterol and increase good cholesterol .
This is a good option for people who dont respond well to other medications because the side effects of niacin are mild. People taking this medication might experience the following:
- flushing of the face
When more aggressive treatment is necessary to treat high triglycerides, a class of medications called fibrates is often prescribed.
Also, dietary supplements of omega-3 fatty acids found in fish oil have been shown to reduce triglyceride levels.
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Truths About Statins And High Cholesterol
For every drop of scientific evidence that statins are safe and effective, there is a tidal wave of misinformation. Our patients are concerned about statin side effects theyve heard about from family or friends, or read about on the Internet.Statins are the gold-standard for high cholesterol treatment. Theyre a powerful medication, and theyve been proven to save the lives of many men and women living with or having a high risk of heart attack or stroke.But if statins are so effective, why are some people afraid to take them?As with any medication, there are risks associated with taking statins, but the benefits far outweigh the risks for the vast majority of high-risk patients.In an effort to put statin side effects into context and provide honest, scientific answers about statins and their use, weve put together a list of common questions our patients ask us:
Regulation Of Cholesterol Synthesis
Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, whereas lower intake from food has the opposite effect. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the proteinSREBP . In the presence of cholesterol, SREBP is bound to two other proteins: SCAP and INSIG-1. When cholesterol levels fall, INSIG-1 dissociates from the SREBP-SCAP complex, which allows the complex to migrate to the Golgi apparatus. Here SREBP is cleaved by S1P and S2P , two enzymes that are activated by SCAP when cholesterol levels are low.
Cholesterol synthesis can also be turned off when cholesterol levels are high. HMG-CoA reductase contains both a cytosolic domain and a membrane domain. The membrane domain senses signals for its degradation. Increasing concentrations of cholesterol cause a change in this domain’s oligomerization state, which makes it more susceptible to destruction by the proteasome. This enzyme’s activity can also be reduced by phosphorylation by an AMP-activated protein kinase. Because this kinase is activated by AMP, which is produced when ATP is hydrolyzed, it follows that cholesterol synthesis is halted when ATP levels are low.
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