Prevention & Treatment of Dyslipidemia (high blood lipids, i.e., fats, such as cholesterol & triglycerides)
‘Prevention is better than cure’ (Hippocrates, ancient Greek doctor – the father of western medicine, 460 – 370 B.C.)
Primary hyperlipidemias – Fredrickson classification
Source: Dr D.S. Fredrickson: Founding father of the field of lipidology
Secondary causes of hyperlipidaemia
-Excessive alcohol consumption
-High energy diet, especially saturated diet
-Type 2 diabetes (less common in type 1)
-Renal disease, especially with proteinuria – nephrotic syndrome
-Cholestatic liver disease – biliary obstruction
-Other (anorexia nervosa, paraproteinaemia, lipodystrophy, autoimmune, pancreatitis etc.)
Medications that may cause hyperlipidaemia
-Beta – blockers
-Oestrogen replacement therapy
-Androgen replacement in men
-Cyclosporine and other immunosuppressants
-Antidopamine agents (antipsychotics, metoclopramide etc.)
-HIV antiretroviral regimens (HAART)
-Isotretinoin analogs (used to treat acne)
Dietary changes. The Mediterranean diet
The Mediterranean Diet (MedDiet) is a nutritional model characterized by:
-the abundant consumption of olive oil (oleic acid as monοunsaturated fatty acid)
-high consumption of plant foods (fruits, vegetables, pulses, cereals, nuts, and seeds)
-the frequent and moderate intake of wine (mainly with meals)
-the moderate consumption of fish, seafood, yogurt, cheese, poultry and eggs
-and the low consumption of red meat, processed meat products, and seeds.
Several epidemiological studies have evaluated the effects of a Mediterranean pattern as protective against several diseases associated with chronic low-grade inflammation such as cancer, diabetes, obesity, atherosclerosis, metabolic syndrome and cognition disorders.
The adoption of this dietary pattern could counter the effects of several inflammatory markers, decreasing, for example, the secretion of circulating and cellular biomarkers involved in the atherosclerotic process.
The omega -6 to omega -3 ratio
-Excessive amounts of omega-6 polyunsaturated fatty acids (PUFAs such as various seed oils) and a very high omega-6/omega-3 ratio, as is found in today’s Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects.
-In the secondary prevention of cardiovascular disease, a ratio omega-6/omega-3 ratio of 4/1 was associated with a 70% decrease in total mortality.
Omega – 3 fatty acids – fish oil
-Omega-3 fatty acids are beneficial for the heart. Positive effects include anti-inflammatory and anti-blood clotting actions, lowering cholesterol and triglyceride levels, and reducing blood pressure. They may also reduce the risks and symptoms for other disorders including diabetes, stroke, some cancers, and the age – related cognitive decline.
-Omega – 3 fatty acids are contained in fish oil of fatty fish (EPA & DHA)
-The linseed oil contains another omega – 3 fatty acid: alpha-linolenic acid (ALA). The value of ALA has recently emerged, although most companies that sell supplements of omega -3 use fish oil EPA and DHA as sources for omega – 3 polyunsaturated fatty acids, and do not include ALA.
-They are useful at lowering triglycerides in the blood (the only FDA indication).
-They are used in Europe as secondary prevention after cardiovascular events
Plant sterols (phytosterols) & stanol esters
-Phytosterol (plant sterol; including beta – sitosterol) is a plant-based compound that can compete with dietary cholesterol to be absorbed by the intestines, resulting in lower blood cholesterol levels.
-Phytosterols may also have some effect in cancer prevention.
-Patients with hypercholesterolemia (increased blood cholesterol) can eat phytosterols and stanols found in nuts, seeds, vegetable oils, and fortified food products, such as orange juice, yogurt, margarine spreads, and salad dressing.
-Studies show that eating spreads enriched with phytosterols per day reduced total cholesterol by up to 11% and LDL cholesterol (‘bad’ cholesterol) by up to 15%.
-Statins (simvastatin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin & rosuvastatin), also known as HMG-CoA reductase inhibitors, inhibit HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) an enzyme involved in the synthesis of cholesterol especially in the liver. Decreased cholesterol production leads to an increase in the number of LDL (low – density lipoprotein) membrane receptors, which increases the clearance of LDL cholesterol from circulation.
-Statins are used to treat hyperlipidemia and are the most effective drugs in lowering LDL (‘bad’) cholesterol.
-Adverse effects: statins may cause liver problems. Rarely, severe and sometimes fatal liver problems have been reported in patients taking “statin” medicines, including lovastatin. The risk of developing liver problems may be greater if the patient drinks alcohol daily or in large amounts or if he/she has a history of liver problems. Statins may also cause muscle problems (myopathy), or even rhabdomyolysis (destruction of muscle cells), which can in turn result in life-threatening kidney injury.
-Also, as previously referred, statins may increase the risk for diabetes mellitus.
Coenzyme Q10 & statins
-Coenzyme Q10 (CoQ10, ubiquinone) levels are decreased in statin use, so some suggest coenzyme Q10 supplementation on people taking statins. CoQ10 is often added on multivitamins.
-A study concluded that coenzyme Q10 supplementation (50 mg twice daily) effectively reduced statin-related mild-to-moderate muscular symptoms, causing lower interference of statin-related muscular symptoms with daily activities (Sourcehttp://www.ncbi.nlm.nih.gov/pubmed/25375075 )
Statin therapy & insulin resistance
Statins are evidence – based drugs to prevent cardiovascular disease. However, their benefits have been disputed by a statin – related increased risk of new onset diabetes (NOD) in randomized controlled trials (RCTs) and meta-analyses. NOD risk seems to be more relevant with high – intensity rather than low –intensity statin treatment. Also, this risk is particularly increased in patients at risk for the development of diabetes
In 2012, United Sates Food & Drug Administration (FDA) released changes to statin safety label to include that statins have been found to increased glycosylated hemoglobin and fasting serum glucose levels. Many studies on patients with cardiovascular (CV) disease risk factors have shown that statins have diabetogenic potential (i.e., predispose for the development of diabetes mellitus) and the effect varies as per the dosage and the type used. The various mechanism for this effect have been proposed and one of them includes the downregulation of the glucose transporters by the statins. The recommendations by the investigators are that though statins have a diabetogenic risk, they have more long – term benefits which can outweigh the risk. In the elderly patients and those with metabolic syndrome, as the risk of diabetes increase, the statins should be used cautiously Other than a subset of population with risk for diabetes; statins still have a long – term survival benefits in most of the patients (Reference:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360430/ ).
In a study, the authors investigated the effects of statin treatment on blood glucose control and the risk for type 2 diabetes in 8,749 nondiabetic men 45 to 73 years old in a 6-year follow-up of the population-based metabolic syndrome in men trial, based in Kuopio, Finland. During the follow-up, 625 of the participants were diagnosed with diabetes. Indices derived from oral glucose tolerance tests were used to assess insulin sensitivity and secretion. A total of 2412 individuals were taking statins. The drugs were associated with an increased risk for type 2 diabetes even after adjustment for age, body mass index, waist circumference, physical activity, smoking, alcohol intake, a family history of diabetes, and beta-blocker and diuretic treatment, at a hazard ratio (HR) of 1.46. The risk was found to be dose dependent for simvastatin and atorvastatin, which were taken by 388 and 1409 participants, respectively. High-dose simvastatin was associated with an HR of 1.44 for diabetes vs 1.28 for low-dose therapy, whereas the HR for diabetes with high-dose atorvastatin was 1.37. Statin therapy was also associated with a significant increase in 2-hour glucose and the glucose area under the curve at follow-up, as well as a nominally significant increase in fasting plasma glucose levels. Moreover, individuals taking statins had a 24% decrease in insulin sensitivity and a 12% reduction in insulin secretion compared with those not receiving the drugs. These increases were again dose dependent for atorvastatin and simvastatin. Although pravastatin, fluvastatin, and lovastatin were found to be less diabetogenic (that predispose to diabetes mellitus) than atorvastatin and simvastatin, the number of participants taking these agents was too small to reliably estimate their individual effects on the risk for diabetes, the research team notes. In conclusion statin therapy appears to increase the risk for type 2 diabetes by 46%, even after adjustment for confounding factors. This suggests a higher risk for diabetes with statins in the general population than has previously been reported, which has been in the region of a 10% to 22% increased risk (Reference (Retrieved: October 11, 2015): http://www.medscape.org/viewarticle/843980 ).
An overview on the published data about statin therapy (used as lipid – lowering agents) and its correlation with insulin showed that clinical evidence suggests a worsening effect of statins on insulin resistance and secretion, anyway basic science studies did not find a clear molecular explanation, providing conflicting evidence regarding both the beneficial and the adverse effects of statin therapy on insulin sensitivity. The overview concluded that although most of the clinical studies suggest a worsening of insulin resistance and secretion, the cardiovascular benefits of statin therapy outweigh the risk of developing insulin resistance, thus the data suggest the need to treat dyslipidemia and to make patients aware of the possible risk of developing type 2 diabetes or, if they already are diabetic, of worsening their metabolic control (Reference: http://www.ncbi.nlm.nih.gov/pubmed/25208056).
-The fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia, and there are hypolipidemic agents. Commonly prescribed fibrates include bezafibrate, ciprofibrate, clofibrate (largely obsolete due to side-effect profile, e.g. gallstones), gemfibrozil & fenofibrate.
-Fibrates are used in accessory therapy in many forms of hypercholesterolaemia, usually in combination with statins. Clinical trials do also support their use as monotherapy agents.
-Although less effective in lowering LDL (‘bad’) – cholesterol & triglyceride levels, by increasing HDL levels and decreasing triglyceride levels, they seem to reduce insulin resistance when the dyslipidemia is associated with other features of the metabolic syndrome (hypertension, & type 2 DM) and are therefore used in many hyperlipidemias.
-Fibrates are not suitable for patients with low HDL – cholesterol levels.
-Mechanisms of action:
-Ιnduction of lipoprotein lipolysis
-Ιnduction of hepatic fatty acid (FA) uptake and reduction of hepatic triglyceride production
-Ιncreased removal of LDL particles
-Reduction in neutral lipid (cholesteryl ester and triglyceride) exchange between VLDL and HDL may result from decreased plasma levels of TRL
-Increase in HDL (‘good’) – cholesterol production and stimulation of reverse cholesterol transport.
-Adverse effects: fibrates may cause muscle problems (myopathy), or even rhabdomyolysis (destruction of muscle cells), which can in turn result in life-threatening kidney injury. The risk is increased especially when combined with statins. They may also cause gallstones and acute kidney injury (AKI).
Niacin (Nicotinic acid; vitamin B3)
-Niacin is an organic compound, and one of the 20 to 80 essential human nutrients.
-A review of niacin did not find that it affected either cardiovascular disease or risk of death in those already taking a statin. Niacin alone appears to reduce the risk of cardiovascular disease.
-The National Cholesterol Education Program (NCEP) in 2002 recommended niacin alone for cardiovascular and atherogenic dyslipidemia in mild or normal LDL (‘bad’) – cholesterol levels or in combination for higher LDL levels. By lowering VLDL levels, niacin also increases the level of HDL (‘good’) – cholesterol in blood, and therefore it is sometimes prescribed for people with low HDL, who are also at high risk of a heart attack.
-Mechanisms of action: Niacin therapeutic effect is mostly through its binding to G protein – coupled receptors, niacin receptor 1 (NIACR1) and niacin receptor 2 (NIACR2) that are highly expressed in adipose (fat) tissue, spleen, immune cells and keratinocytes.
-NIACR1 inhibits cAMP production and thus fat breakdown in adipose tissue and free fatty acids available for the liver to produce triglycerides and VLDL and consequently LDL (‘bad’) – cholesterol.
-Decrease in free fatty acids also suppress the hepatic expression of apolipoprotein c3 (APOC3) and PGC-1b, thus increase VLDL turnover and reduce its production.
-It also inhibits diacylglycerol acyltransferase – 2, important on hepatic triglyceride synthesis.
-Side effects include dermatological (skin) conditions such as skin flushing and itching, dry skin, and skin rashes including eczema exacerbation and acanthosis nigricans. Nausea and liver toxicity – even fulminant liver failure have also been reported. Side effects of hyperglycemia, cardiac arrhythmia, birth defects in experimental animals, hyperuricemia and gout have also been reported.
-Although high doses of niacin may elevate blood sugar, thereby worsening diabetes mellitus, recent studies show the actual effect on blood sugar to be only 5–10%. Patients with diabetes who continued to take anti-diabetes drugs containing niacin did not experience major blood glucose changes. Thus overall, niacin continues to be recommended as a drug for preventing cardiovascular disease in patients with diabetes.
-Niacin, particularly the time-release variety, at extremely high doses can cause acute toxic reactions. Extremely high doses of niacin can also cause niacin maculopathy on the macula of the retina of the eye that is reversible after niacin intake ceases.
Bibliography & External Links
Longo D.L., Fauci A.S., Kasper D.L., Hauser S.L., Jameson J.L., Loscalzo J.L., Harrison’s manual of medicine, 18th edition, McGraw – Hill, 2013.
Longmore M., Wilkinson I.B., Davidson E.H., Foulkes A., Mafi A.R., Oxford Handbook of Clinical Medicine, 8th edition, Oxford University Press, 2010.
Ahmed N., Clinical Biochemistry, Oxford University Press, 2010.
Simon C., Everitt H., Kendrick T., Oxford Handbook of General Practice, Oxford Medical Publications, 2nd edition, 2005.
Longmore M., Wilkinson I., Turmezei T., Kay Cheung C., Oxford Handbook of Clinical Medicine, Oxford Medical Publications, 7th edition, 2008.
Collier J., Longmore M., Brinsden M., Oxford Handbook of Clinical Specialties, Oxford Medical Publications, 7th edition, 2006.
Stone C.K., Humphries R.L., Current Diagnosis and Treatment in Emergency Medicine, McGraw – Hill LANGE, 6th edition, 2008.
Disease prevention & health maintenance, p. 1103 – 1130, Harrison’s Manual of Medicine, Fauci A.S., Braunwald E.B., Kasper D.L., Hauser S.L., Longo D.L., Jameson J.L., Loscalzo J., 17th edition, Mc Graw Hill Medical, 2009.
Screening in the future, p. 160 – 161, Oxford Handbook of General Practice, C. Simon, H. Everitt, T. Kendrick, 2nd edition, Oxford University Press,2005.
Reference – Links
(Retrieved January 18, 2015)
Source for the image: http://markstengler.com/health-risks/oxidized-ldl-cholesterol-the-better-heart-risk-indicator/ and http://www.3dbioprintingconference.com/medical/new-3-d-printing-developments-include-blood-vessels-back-braces/
http://en.wikipedia.org/wiki/Metabolic_syndrome#mediaviewer/File:Obesity6.JPG(free to use picture)
Dr. James Manos (MD)
Medical Microbiologist & Hospital lab doctor (microbiology, haematology & biochemistry department)
- Sydney, New South Wales, Australia
- Hospital & Health Care