Mechanisms Accounting For The Volanesorsen Induced Lipid Effects
Volanesorsen binds to apo C-III mRNA leading to increased degradation and thereby inhibits the hepatic synthesis of apo C-III protein resulting in a reduction in plasma apo C-III levels . Apo C-III has a number of important effects on the metabolism of TG rich lipoproteins . Apo C-III is an inhibitor of LPL and therefore decreasing apo C-III levels will enhance LPL activity. In patients with FCS this will not be important because patients with this disorder have defects in components of the LPL complex that result in the inability to increase LPL activity. Studies have shown that apo C-III stimulates the production and secretion of VLDL by the liver. This effect is also not likely to be of primary importance in patients with FCS as the very high TG levels are primarily due to chylomicrons and not VLDL. Whether apo C-III regulates chylomicron secretion by the intestine is unknown. Finally, and most importantly, Apo C-III inhibits the binding of TG rich lipoproteins to hepatic LDL receptors and LDL receptorrelated protein 1 decreasing the clearance of TG rich lipoprotein particles. A decrease in apo C-III will accelerate the clearance of TG rich lipoproteins, which likely accounts for the ability of volanesorsen to decrease TG levels in patients with FCS.
How Are Fats And Cholesterol Connected In Cats
Fats, including cholesterol, are carried in the blood in complex compounds that also contain protein: so-called lipoproteins.
These include triglycerides, cholesterol and phospholipid linked to apopproteins, which are manufactured in cells of the liver and intestines. Apolipoproteins are synthesized in the liver or in intestinal cells.
There are four major lipoprotein classes in cats, as follows:
Chylomicrons and Very low density lipoproteins carry triglycerides in the blood
Low density lipoproteins and High density lipoproteins carry cholesterol in the blood. In cats, HDL outnumbers LDL by 5:1, while in humans, LDL is the main carrier of cholesterol.
Many humans are aware of these abbreviations from their own blood test results, but its important to remember that the significance of abnormal levels is very different in humans compared to cats.
Plant Sterols And Stenols
Plant sterols and stenols can reduce the amount of cholesterol absorbed by your body. Theyre found in many plant foods in small amounts. Larger amounts are found in plant sterol and stenol-fortified foods, including:
Usually, two servings of a fortified food will provide the FDA-recommended amount of plant stenols or sterols each day.
Plant stenols and sterols are thought to be able to reduce cholesterol by as much as 8 to 12 percent. But more evidence is needed to understand their long-term safety and efficacy.
Side effects can include diarrhea and fat in the stool.
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What Are Normal And High Triglyceride Levels
The National Cholesterol Education Program sets guidelines for triglyceride levels:
- Normal levels: Less than 150 milligrams per deciliter
- Borderline high:150 to 199
- High: 200 to 499
- Very high: 500 or more
Elevated levels may lead to heart disease, especially in people with low levels of “good” cholesterol and high levels of “bad” cholesterol. The same is true if you have type 2 diabetes.
Experts once debated how important triglycerides are, but it now seems clear that higher levels are linked to problems such as heart disease.
One thing is clear, though: A good diet and exercise plan can lower triglyceride levels, improve cholesterol, and decrease the chance of heart disease.
Risk Factors For High Triglycerides
Research shows that triglyceride levels predict cardiovascular disease, a principal cause of morbidity and mortality in Western society. People with high triglycerides may be at significant risk for cardiovascular disease even if their LDL cholesterol levels are at goal.
A 2010 study conducted at Harvard Medical School evaluated the relative contributions of triglyceride and HDL cholesterol in the risk of coronary heart disease after LDL cholesterol levels were reduced. The study, involving 170 cases and 175 controls, suggests that high triglycerides and low HDL cholesterol levels were associated with coronary heart disease even in patients with lower LDL cholesterol levels. The odds of coronary heart disease increased by approximately 20 percent per 23 milligrams per deciliter increase in triglycerides.
Having high triglycerides also makes you more likely to develop type 2 diabetes. Its not that high triglycerides actually causes diabetes, but it shows that the body isnt turning food into energy properly. Normally, the body makes insulin, which escorts glucose into the cells where its used for energy. The insulin allows the body to use triglycerides for energy, but when someone is insulin-resistant, the cells wont let insulin or glucose in, thereby causing both glucose and triglycerides to build up in the blood.
Conventional Treatment for High Triglycerides
Statins
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Pharmacokinetics And Drug Interactions
Omega-3 ethyl esters and fatty acids are absorbed by the GI tract similar to other dietary lipids. It is worth noting that omega-3-free fatty acids are directly absorbed by the small intestine and are not dependent on pancreatic lipases for absorption. Thus, absorption of omega-3-fatty acids is not decreased in patients with pancreatic insufficiency and therefore may be preferred in patients with pancreatic disease. Additionally, the bioavailability of omega-3-fatty acids with a low fat diet was greater than omega-3-ethyl esters while there was little difference between these different formulations with a high fat diet .
Drug interactions have not been seen with omega-3-fatty acids .
What Should I Know About Storage And Disposal Of This Medication
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat and moisture .
Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA’s Safe Disposal of Medicines website for more information if you do not have access to a take-back program.
It is important to keep all medication out of sight and reach of children as many containers are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location â one that is up and away and out of their sight and reach.
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Hypertriglyceridemia Management According To The 2018 Aha/acc Guideline
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The 2018 AHA/ACC Guideline on the Management of Blood Cholesterol was a welcome update from the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.1 Our new guideline reinforces the importance of a heart-healthy lifestyle, the use of statins as the first line agent in primary and secondary cardiovascular prevention and the importance of risk stratification to identify those who benefit most from these measures. Also of note, our new guideline features a specific section on hypertriglyceridemia. This section is composed of one class I and three class IIa recommendations followed by a synopsis and supportive text to assist clinicians in recognising and treating patients with hypertriglyceridemia.
Identify and Address Secondary Factors
The class I recommendation first identifies a population 20 years of age or older who have moderate hypertriglyceridemia defined as fasting or nonfasting triglycerides 175-499 mg/dL and advises searching for and treating secondary factors . The remaining three recommendations build on this.
Table 1: Secondary Factors
Use of Statin Therapy in Moderate Hypertriglyceridemia
Use of Statin Therapy in Severe Hypertriglyceridemia
The third recommendation endorses the initiation of statins in those with severe hypertriglyceridemia with ASCVD equal to or greater than 7.5% in concert with addressing secondary factors.
Other Therapies in Severe Hypertriglyceridemia
Drug Administration And Pharmacokinetics
The recommended starting dose is 285 mg injected subcutaneously once weekly for 3 months after which the dose should be reduced to 285 mg every 2 weeks. If serum TGs decrease by less than 25% or are not below 2000 mg/dl after 3 months on volanesorsen 285 mg weekly, treatment should be discontinued .
After 6 months of treatment one can consider increasing the dose frequency back to 285 mg weekly if the serum TG response has been inadequate and the platelet counts are in the normal range. Patients should return to 285 mg every 2 weeks if the higher 285 mg once weekly dose does not provide a significant additional TG reduction after 9 months .
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Acute Pancreatitis Associated With Significant Hypertriglyceridemia: A Special Situation
Treatment of acute pancreatitis in patients with massive hypertriglyceridemia comprises strict fasting and intravenous fluid replacement as basic measures. Whether plasmapheresis is indicated has to be decided on a case-by-case basis. With this approach TG levels can be lowered rapidly, which may interrupt the underlying pathomechanism so that the pancreatitis takes a milder course . However, there are no randomized studies on this topic . Moreover, a recent analysis showed that TG levels decline quickly without plasmapheresis . Furthermore, patients with acute pancreatitis frequently present with various triggering factors , making it difficult to distinguish the role played by hypertriglyceridemia from those of other factors. In addition, plasmapheresis is not suitable as a long-term treatment in patients with hypertriglyceridemia because TG levels quickly rebound after hemofiltration.
Patients with FCS in whom hypertriglyceridemia is apparently a key factor in the pathogenesis of acute pancreatitis should immediately be treated with plasmapheresis. In the long term, a diet change from standard fats to medium-chain TG may be beneficial, as MCTs are metabolized independent of chylomicrons and do not result in an increase in TG levels after a meal . This is all the more relevant when women with hereditary disorders such as FCS become pregnant, as estrogens can trigger a significant increase in TG levels .
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Dos And Donts In Managing High Triglycerides:
- DO exercise regularly.
- DO eat more fruits and vegetables and high-fiber foods such as oat bran. Cook with monounsaturated fatsolive, peanut, and canola oils.
- DO stop smoking.
- DO lose weight by changing your diet and doing aerobic exercise, such as walking, jogging, bicycling, or swimming. Exercise at least 30 minutes daily.
- DONT forget to treat other medical conditions such as diabetes and underactive thyroid.
- DONT drink more than two alcoholic drinks per day.
- DONT change your diet or medicines without your doctors approval.
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Effect Of Fibrates In Combination With Other Lipid Lowering Drugs On Lipid And Lipoprotein Levels
STATINS
Statins are the primary drugs used to treat most patients with dyslipidemia. Statins are very effective in lowering LDL-C levels but have only modest effects on TG and HDL-C levels. Therefore, it is appealing to add a fibrate to patients who on statin therapy have LDL-C levels at goal but still have elevated non-HDL-C and TG levels and decreased HDL-C levels. Therefore, there have been numerous studies examining the effect of the combination of statins and fibrates on lipid and lipoprotein levels. An example is the Safari Trial which compared the effect of simvastatin only vs. simvastatin + fenofibrate in patients with combined hyperlipidemia . The results of this trial are shown in . As anticipated, adding a fibrate results in a further lowering of LDL-C, non-HDL-C, and TG levels with a further increase in HDL-C.
How To Lower Triglycerides
Your doctor will determine if you need treatment to lowering triglycerides by talking with you about your current diet and lifestyle, and evaluating your triglyceride level, your LDL cholesterol level, and your potential risk factors for coronary heart disease.
Here are some of the reasons your doctor might discuss medications to lower triglycerides with you:
- You have metabolic syndrome. This condition includes a combination of abdominal obesity, high triglycerides, and high blood pressure. If you have metabolic syndrome and tried diet and lifestyle changes for three months without success, triglyceride-lowering medications may be needed.
- Previous medication lowered your total cholesterol but not your triglycerides. If your cholesterol is well controlled, but your triglyceride level is still too high, at or above 200 mg/dL, triglyceride-lowering medications may help.
- You have very high triglycerides. If your triglyceride level is at or higher than 500 mg/dL, you may need to start medications to lower triglycerides even before reaching lower cholesterol levels.
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Will A Keto Diet Lower Triglycerides And Cholesterol
No, keto diets have been shown to increase cholesterol levels. The Mediterranean diet, however, has been shown to lower cholesterol levels and reduce the risk of cardiac events.
The Mediterranean diet promotes eating vegetables, fruits, whole grains, and healthy fats daily eating fish, poultry, beans, and eggs weekly reducing portions of dairy and limiting red meat.
Skip The Sweet Drinks
One of the easiest things you can do to lower your triglycerides is to cut out sweetened drinks. Sodas and other sugary drinks are packed with fructose, a known offender when it comes to boosting triglycerides. Drink no more than 36 ounces of sweet sippers per week — that means three 12-ounce cans of soda.
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How To Take Your Cholesterol
When youre taking medicines, its important to follow your healthcare providers advice carefully. If you dont take medicines exactly as prescribed, they can harm you. For example, you could unknowingly counteract one medicine by taking it with another one. Medicines can make you feel sick or dizzy if not taken properly.
Taking your cholesterol meds correctly
Medicine can only help you reduce cholesterol if you take it correctly.
- You should take all medicines the way your provider instructs you to do.
- Dont decrease your medication dosage to save money. You must take the full amount to get the full benefits. If your medicines are too expensive, ask your provider or pharmacist about finding financial assistance. Some companies provide discounts for certain medications.
- Dont hesitate to let your provider know if you dont think the medication is working or if you have side effects of cholesterol medicine that concern you.
Working with your pharmacy
Your pharmacy can be your partner in ensuring youre sticking with your cholesterol meds.
Keeping track of your high cholesterol medication
There are now many ways to keep track of medication schedules.
When traveling, keep your medicines with you so you can take them as scheduled. On longer trips, take an extra week’s supply of medicines and copies of your prescriptions in case you need to get a refill.
A note from Cleveland Clinic
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 .
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What Are Triglycerides And What Is Considered A Healthy Level
Triglycerides are sort of like cholesterol: Both are types of fat found in your blood. But while cholesterol is used to make cells and certain hormones, the job of triglycerides is to store unused calories to give your body energy between meals.
Triglycerides get stored after you eat. If you take in any calories that arent needed for energy right away, theyre converted into triglycerides and transferred to your fat cells for later use.
Eating more calories than you need on the reg can lead to high triglycerides over time, which can up your risk for heart disease. Triglycerides are usually measured along with cholesterol, and numbers over 150 mg/dL are usually considered high.
Some Side Effects Can Be Serious If You Experience Any Of These Symptoms Call Your Doctor Immediately:
- muscle pain, tenderness, or weakness
A medication called clofibrate , which is similar to gemfibrozil, has been known to cause cancer, gallbladder disease, and stomach pain leading to appendectomy. Talk to your doctor about the risks of taking this medication.
Gemfibrozil 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 .
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How Often Should I Have My Cholesterol Tested
Adults should have their blood lipids measured every 5 years, starting at 45 years. Aboriginal and Torres Strait Islander people should start lipid blood tests at 35, because on average heart and blood vessel disease such as heart attacks and stroke happen 10 to 20 years earlier in Indigenous people.
All Australians in these age groups are eligible for a regular 20-minute heart health check with their doctor. This checks your blood pressure, cholesterol and blood sugar levels. Your doctor can then assess your risk of having a heart attack or stroke in the next 5 years.
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Limit Your Sugar Intake
Added sugar is a big part of many peoples diets.
While the American Heart Association recommends consuming no more than 100150 calories of added sugar per day, one study found that the average American eats about 308 calories of added sugar daily .
Added sugar is commonly found in sweets, soft drinks, and fruit juice.
Extra sugar in your diet may be turned into triglycerides, which can lead to an increase in blood triglyceride levels, along with other heart disease risk factors.
A 2020 review that included data on 6,730 people found that those who consumed sugar-sweetened beverages regularly were over 50% more likely to have high triglycerides, compared with those who did not drink them regularly .
Another study found that consuming high amounts of added sugar is also associated with higher blood triglyceride levels in children .
Fortunately, several studies have shown that low carb diets can lead to a decrease in blood triglyceride levels .
Even a simple change such as replacing sugar-sweetened beverages with water could decrease triglycerides in some people .
Summary
Minimizing added sugar in your diet from sugary beverages and sweets can reduce your blood triglyceride levels.
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