Hypertriglyceridemia

Hypertriglyceridemia, defined as fasting serum triglyceride levels of 150 mg per dL or higher, is associated with increased risk of cardiovascular disease. 

Hypertriglyceridemia can be classified as moderate (greater than 500 mg/dL) or severe (greater than 1000 mg/dL), with the latter almost always involving a genetic component.

Triglycerides up to 500 mg/dL or carried by VLDL which entails a mild to modern risk or increase atherogenocity and risk for an acute cardiovascular event.

At levels above 500 mg per/dL, triglycerides are carried by chylomicrons, which exponentially increased the risk for pancreatitis.

 

Hypertriglyceridemia  risk factors include:  obesity, metabolic syndrome, and type 2 diabetes mellitus.

 

Less common risk factors include: excessive alcohol use, physical inactivity, being overweight, use of certain medications, and genetic disorders. 

 

Severely elevated triglyceride levels (500 mg per dL or higher) increase the risk of pancreatitis. 

Whether it causes coronary artery disease or is a marker for lipoprotein abnormalities that causes premature coronary artery disease is controversial.

Correlates with the presence of small, dense particles of LDL cholesterol and reductions in the HDL2 component of HDL cholesterol, both of which are associated with premature coronary artery disease.

Predicts for coronary artery disease, but not after adjustment of LDL or HDL cholesterol subfractions.

Triglycerides do not accumulate with atherosclerotic disease plaque to any significant degree.

TG‘s are mostly found in chylomicrons, which transport dietary fatty acids and cholesterol from the intestine and very low density lipoprotein particles, which transport TG’s from the liver.

Serum TG measurements assess the total mass of TG‘s, not the number or type of particles carrying those TGs.

When TG levels are elevated due to isolate the elevations in chylomicrons, which are too large to enter the arterial wall, atherosclerotic risk is not increased.

Beyond chylomicrons, measured TG levels can also be elevated with either an increase in the TG content of VLDL particles or an increase in the total number of VLDL particles.

Both triglycerides and cholesterol arecarried in plasma by apolipoprotein B (ApoB) containing lipoprotein particles.

Hyperypertriglyceridemia is not a single disease but rather a heterogeneous collection of disorders, with potentially different degrees of cardiovascular risk.

Treatment guidelines do not recommend lowering plasma triglyceride levels because randomized trials have not provided consistent evidence that lowering plasma triglyceride levels reduce the risk of cardiovascular events.

Management of high triglyceride levels (150 to 499 mg per dL) starts with dietary changes and physical activity to lower cardiovascular risk. 

 

Lowering carbohydrate intake, especially refined carbohydrates and increasing fat, especially omega-3 fatty acids, and protein intake can lower triglyceride levels. 

The Helsinki Heart Study showed little benefit of treatment with gemfibrozil in terms of cardiovascular risk reduction in patients with triglyceride levels greater than 200 mg/dL unless their LDL-C to HDL-C ratio was five or greater.

Disorders associated with premature coronary artery disease include familial combined hyperlipidemia, dyslipidemia in type 2 diabetes, familial hypoalphalipoproteinemia.

Familial combined hyperlipidemia and familial hypoalphalipoproteinemia each affect 1% of the population and type 2 diabetes affects 5% of the population, and these three disorders account for 50% of premature coronary artery disease events.

An inherited form, monogenic familial hypertriglyceridemia is not associated with premature coronary artery disease and affects up to 1% of the population.

Typically polygenic, heterozygotes familial hypertriglyceridemia, is an autosomal dominant disorder either monogenic or polygenic, and is associated with moderate elevation and fasting serum triglyceride level of 200-500 mg/dL.

Insulin resistance, obesity, hyperglycemia, hypertension, often a accompany familial hypertriglyceridemia.

Familial hypertriglyceridemia is associated with coronary artery disease risk and is common in patients with premature coronary artery disease.

How many first-degree relatives of patients with familial hypertriglyceridemia the serum triglyceride level predicts cardiovascular mortality, independent of cholesterol levels.

Homozygous mutations typically results in triglyceride levels greater than 1000 mg/dL, which resulted in significant elevated risk of cardiovascular and pancreatic complications compared with the heterozygous form.

HDL cholesterol particle catabolism is enhanced in the setting of hypertriglyceridemia.

In familial hypertriglyceridemia with heterozygous disease inactivated mutations of the lipoprotein lipase gene, LPL, and typically have a low serum HDL level.

Familial hypertriglyceridemia occurs in approximately 1% of the general population.

Familial hypobetaloproteiemia is associated with mutations that may occur at multiple genetic loci.

Familial hypobetaloproteiemia may show links to mutations in the gene encoding Apo B.

apo B is the integral protein found in chylomicrons as well as in their remnants, including very low density lipoprotein cholesterol.

LPL mutations raise serum triglyceride levels by 20 to 80%.

Hypertriglyceridemia is an important cause of acute and recurrent pancreatitis in patients with familial lipid metabolic disorders, diabetic ketoacidosis, excessive alcohol use, hypothyroidism, hormone supplementation, medication use, and pregnancy.

Hypertriglyceridemia causes 1-4% of cases of acute pancreatitis.

Serum triglyceride levels greater than 1000 mg/dL are necessary to diagnose hypertriglyceridemia-induced acute pancreatitis.

Therapy for hypertriglyceride induced acute pancreatitis include: diet, anti-hyperlipidemic agents,

Heparin infusion, intravenous insulin, and plasmapheresis.

In randomized trials extended release niacin and fiibrates have not reduce the rates of cardiovascular events when administered in addition to appropriate medical therapy including statins.

n-fatty acid products have not shown a benefit patients receive a statin therapy.

Moderate- to high-intensity physical activity lowers triglyceride levels, as well as improve body composition and exercise capacity. 

Elevated triglyceride management includes:

Weight loss, dietary modification, moderate exercise as first-line lifestyle modification treatments.

 For hypertriglyceridemia, restriction of carbohydrates, specifically fructose and fat in the diet and the consumption of omega-3 fatty acids from algae, nuts, fish and seeds are recommended.

Medications are recommended in those with high levels of triglycerides that are not corrected with lifestyle modifications, with fibrates being recommended first.

Omega-3-carboxylic acids is another prescription drug used to treat very high levels of blood triglycerides.

Statins are considered for patients with high triglyceride levels who have borderline or intermediate risk. 

 

Dyslipidemia and cardiovascular disease are common in shift workers and eating at night may contribute to this pathophysiology: postprandial lipid metabolism, which leads to hypersensitivity in triglyceride responses when eating at night.

 

When individuals eat at night, levels of TG are  similar to eating during the day, however, these levels at night were reached with consuming approximately half the calories. 

 

24-hour levels of TG were 10% higher when meals were consumed hourly across 24 hours compared to consuming a typical 3-meal schedule while awake during the day and sleeping at night. 

 

Endogenous circadian rhythms of TG, peak at night, were shifted earlier by ~10 hours under baseline conditions whereas the rhythms in total cholesterol, HDL-C or LDL-C remained unchanged and peaked in the afternoon.

 

The time-of-day dependency on postprandial lipid metabolism, which leads to hypersensitivity in TG responses when eating at night, may underlie the dyslipidemia and elevated cardiovascular disease risk observed in shift workers.

 

For patients at high risk or continue high triglyceride levels despite statin use, high-dose icosapent can reduce cardiovascular mortality.

Treatment of hyper triglyceridemia currently is with weight reduction, physical exercise, improved macronutrient diet, correction of coexistent secondary causes of obesity, diabetes, excessive alcohol consumption, and medications that increase triglyceride levels.

In patients with hypertriglyceridemia and high risk of atherosclerotic, cardiovascular disease should be treated with high intensity statin combined with ezetimbe, a proprotein converttaste, subtilisin-kexin type 9 inhibitor, or both to attain guideline recommended LDL cholesterol goal: with persistent hypertriglyceridemia, the use for high-dose pure eicopentanoic acid should be considered.

With severe or extreme hyper triglyceridemia, a diet very low in saturated fats, with consideration of a fibrates  in a high dose n– 3 fatty acids to achieve a plasma triglyceride level below 500 mg/dL, as well as a statin-based regimen, if the risk of atherosclerotic cardiovascular disease is high, and LDL cholesterol is not a goal.

Icosapent ethyl (Vascepa)is a highly purified and stable eicosapentaenoic acid (EPA) ethyl ester that lowers triglyceride levels and is used in adjunct to diet in adult patients with triglyceride levels of at least 500 mg/dL.

In the REDUCE-IT trial the risk of primary endpoint of cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina was significantly lower by 25% among patients who receive 2 g of Icosapent ethyl twice daily and among those who receive placebo, corresponding to an absolute difference of 4.8 percentage points in the rate of endpoint.

Icosapent ethyl, a highly purified eicopentatonic acid was recently shown to reduce cardiovascular events by 25% and was not associated with triglyceride lowering.(STRENGTH trial)

Evidence against triglyceride lowering and reducing cardiovascular risk should guide other therapeutic strategies to lower risk(Mason RP).

Elevated triglycerides are associated with increase cardiovascular risk, however current triglyceride lowering therapies are in effective in reducing such risk.

Studies show that no relationship exists between triglyceride lowering and cardiovascular risk,consistent with previous fibrate and niacin trials.

Among patients with type two diabetes, mild to moderate hyper triglyceridemia and a low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received permafibrate then among those who received placebo,: although the drug lowered triglyceride, VLDL cholesterol, and apo-lipoprotein C- III levels (PROMINENT investigators).

Olezarzen a ligand, conjugated anti-sense oligonucleotide targeting  APOC3 messenger RNA has been shown to lower plasma, triglyceride levels in patients with extreme hypertriglyceridemia.