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The role of LDL-C and Type 2 Diabetes How Omega3 EPA fish oil reduces LDL-C

Sunday, April 29th, 2012

The role of LDL-C and Type 2 Diabetes

The U.K. Prospective Diabetes Study (UKPDS) established the importance of tight glycemic control in patients with diabetes. Yet in isolation, control of hyperglycemia is not sufficient to decrease the high burden of cardiovascular disease (CVD) in this population.Efforts to reduce cardiovascular morbidity and mortality in people with diabetes have therefore focused on overall or global risk factor management, including weight loss and increased physical activity, tight control of blood pressure and blood glucose, and intensive management of diabetic dyslipidemia. The typical lipid disorder in patients with diabetes, diabetic dyslipidemia, is characterized by elevated triglycerides, low levels of HDL cholesterol, and increased numbers of small, dense LDL particles.

Managing the high risk for cardiovascular morbidity and mortality in diabetic patients is a challenge for practicing clinicians. Reducing the burden of cardiovascular disease in diabetes should begin with assessment and treatment of elevated LDL cholesterol.The typical lipid disorder in patients with diabetes, diabetic dyslipidemia, is characterized by elevated triglycerides, low levels of HDL cholesterol, and increased numbers of small, dense LDL particles. The achievement of the intensive LDL cholesterol goals recommended by both the NCEP and the American Diabetes Association (ADA) has the potential to substantially improve long-term cardiovascular outcomes To this end, this review addresses three key issues related to lowering the risks associated with diabetic dyslipidemia: 1) the substantial CHD risk associated with relatively normal LDL cholesterol; 2) the value of lowering LDL cholesterol and normalizing atherogenic LDL particles in reducing cardiovascular risk; and 3) the role of intensive statin therapy in achieving aggressive LDL cholesterol goals.

Patients with diabetes frequently have lipid profiles that appear more benign than those of other high-risk people without diabetes. In general, LDL cholesterol levels in people with diabetes are not higher than those in people without diabetes who are matched for age, sex, and body weight. In fact, the most common LDL cholesterol level in diabetes is “borderline high” (130-159 mg/dl).12 Moreover, high LDL cholesterol levels (≥ 160 mg/dl) do not occur at higher-than-average rates in people with diabetes. Nonetheless, LDL cholesterol does not play less of a role in cardiovascular risk in people with type 2 diabetes. In fact, LDL cholesterol levels may understimate cardiovascular risk in diabetes. A large number of small, dense particles characterize the LDL fraction in diabetic individuals. These particles contain less cholesterol than normal-sized LDL particles, but they are exceptionally atherogenic.Thus, levels of LDL may appear deceptively “normal” in cholesterol measurements.

Small, dense LDL particles are considered more atherogenic than the larger, buoyant LDL particles because they are more readily oxidized and glycated, which make them more likely to invade the arterial wall.This can initiate atherosclerosis or lead to increased migration and apoptosis of vascular smooth muscle cells in existing atherosclerotic lesions. As a consequence, elevated or “normal” LDL cholesterol may be more pathogenic in people with diabetes.

Beyond the importance of even modest elevations in LDL cholesterol in people with diabetes, it also appears that LDL cholesterol interacts with risk factors of the metabolic syndrome to magnify the risk of CVD.The strong association between increased small, dense LDL particles and elevated triglycerides, for example, appears to be linked to the altered insulin sensitivity common in the metabolic syndrome and type 2 diabetes. Insulin resistance in skeletal muscle promotes the conversion of energy from ingested carbohydrate into increased hepatic triglyceride synthesis, which in turn generates large numbers of atherogenic triglyceride-rich lipoprotein particles, such as very-low-density lipoprotein (VLDL). As a further consequence, through the action of cholesteryl ester transfer protein, a significant amount of the triglyceride content of VLDL is exchanged for cholesterol in LDL particles, leading to the formation of triglyceride-enriched (and cholesterol-depleted) LDL These LDL particles are now primed to become smaller and denser through the actions of hepatic lipase-mediated triglyceride hydrolysis.Thus, adverse changes in LDL particles occur as triglyceride levels increase. Once triglyceride levels exceed 100 mg/dl, small, dense LDL particles predominate

Why eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—both components of omega-3 fatty acids—have differential effects on LDL cholesterol.

Presenting the results of the laboratory study here at the National Lipid Association (NLA) 2011 Scientific Sessions, senior investigator Dr Preston Mason (Brigham and Women’s Hospital, Boston, MA) said that EPA is an inhibitor of lipid oxidation at normal and elevated cholesterol levels in the presence and absence of DHA, while DHA seems to have no real effect on lipid peroxidation. This trial was one of a number of studies that attempted to address the clinical question as to why LDL-cholesterol levels increase in patients treated with the triglyceride-lowering omega-3 fatty acids. In his trial, Mason et al compared the effects of EPA and DHA—alone or in combination with statins—on lipid peroxidation in polyunsaturated fatty-acid- and cholesterol-enriched vesicles.

“We know that EPA and DHA have different effects on LDL-cholesterol levels,”. “One of the things that affect LDL clearance is its oxidative state. Oxidized LDL is not cleared. One of the concepts is that EPA might preferentially prevent LDL oxidation, so even though it’s not affecting its synthesis, it would help its clearance.”

EPA inhibited lipid hydroperoxide (LOOH) formation by 42% and 54% in vesicles with normal and elevated cholesterol levels, respectively. DHA, on the other hand, inhibited LOOH by 28% in vesicles with elevated cholesterol levels only. The separate effects of EPA, DHA, and EPA/DHA were enhanced when used in combination with statin therapy, including atorvastatin, atorvastatin metabolite, simvastatin, or rosuvastatin. The most potent antioxidant capacity was observed with EPA and the active metabolite of atorvastatin.

In another analysis, Dr Terry Jacobson (Emory University School of Medicine, Atlanta, GA) and colleagues reviewed 21 clinical trials that systematically evaluated the effects of EPA and DHA as monotherapy on LDL-cholesterol, HDL-cholesterol, triglyceride, and non-HDL-cholesterol levels.

In studies that directly compared DHA and EPA, mean placebo-corrected triglyceride levels decreased by 22.4% and 15.6%, respectively. In head-to-head comparisons, DHA increased LDL cholesterol by 2.6% whereas EPA decreased LDL cholesterol by 0.7%. In trials comparing each agent alone, 10 of the 14 monotherapy trials with DHA showed increases in LDL cholesterol ranging from 5.4% to 16.0% vs control, while none of the EPA trials showed any increase. The changes in LDL-cholesterol levels significantly correlated with baseline triglyceride levels for DHA-treated patients, but this was not observed for patients treated with EPA, the group reported.

Speaking with heartwire, Dr William Harris (University of South Dakota, Sioux Falls), who was not involved in the research, said the issue is clinically important because numerous studies have shown that long-chain omega-3 fatty acids lower triglycerides, but randomized, clinical trials with compounds containing EPA and DHA have also shown increases in LDL-cholesterol levels. Lovaza / Omacor (omega-3 fatty acid ethyl esters, GlaxoSmithKline) is currently approved for the treatment of elevated triglyceride levels, but its use often results in an increase in LDL cholesterol. Harris noted that other drugs, including fibrates, have the potential to increase LDL cholesterol..

Omega 3 EPA reduces LDL cholesterol levels –

New clinical study results presented at the American Heart Association Scientific Sessions show that the long-chain omega-3 fatty acid EPA (eicosapentaenoic acid), helped significantly reduce small dense LDL (bad) cholesterol levels.

“This study suggests that supplementation with the omega-3 fatty acid EPA may present unique benefits for cardiovascular health,” said Sujata K. Bhatia, M.D., Ph.D., research associate with DuPont. “EPA was shown to have advantageous effects on several biomarkers, including LDL cholesterol, small dense LDL, and lp-PLA2.”

EPA is a long-chain fatty acid that is found primarily in cold water, fatty fish like sardines anchovies mackerel as well as some omega-3 fatty acid such as TakeOmega3 which has 750 mg EPA per capsule and is the highest grade omega 3 available in UK . A growing body of evidence suggests that EPA is the long-chain omega-3 that supports heart health.

The study, conducted by Cardiovascular Research Associates and sponsored by DuPont, was conducted among 110 healthy individuals comparing the effects of EPA supplements to DHA (docosahexaenoic acid) supplements on cardiovascular health. The participants were placed into four study groups and examined over a six week period. During that time, each group was monitored while taking: EPA 600 mg per day; EPA 1,800 mg per day; DHA 600 mg per day; and an olive oil placebo.

The study found that in the 1,800mg EPA group, there were significant reductions of 7 percent for small dense low density lipoprotein (LDL) cholesterol, and 6 percent for lipoprotein-associated phospholipase A2 (lp-PLA2). lp-PLA2 is an enzyme involved in vascular inflammation.

In contrast, the 600mg DHA group showed a significant increase in total small dense LDL cholesterol in both the fasting and fed state of 14.2 percent and 16.3 percent respectively.

The study results will be featured during the American Heart Association Conference poster session in Chicago

Omacor contains 375mg DHA just two capsules exceeds the 600mg DHA level that shows an increase in LDL C – on a 4 capsule per dose dose that would deliver 1500 mg of DHA which is more than double the dose that showed a 14.2 % and 16.3% increase in small dense LDL

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