Dr. James Manos (MD)
January 22, 2016
January 22, 2016
Prevention & treatment of high blood fats
‘Prevention is better than cure’ (Hippocrates, ancient Greek doctor – the father of Western medicine, 460 – 370 B.C.)
Prevention & treatment of dyslipidemia (high blood lipids, i.e., fats, such as cholesterol & triglycerides)
Primary hyperlipidemia – Fredrickson classification
See https://en.wikipedia.org/wiki/Hyperlipidemia
Secondary causes of hyperlipidemia
-Hypothyroidism
-Excessive alcohol consumption
-Obesity
-High-energy diet, especially a saturated diet
-Type 2 diabetes (less common in type 1)
-Metabolic syndrome
-Renal disease, especially with proteinuria–nephrotic syndrome
-Cholestatic liver disease – biliary obstruction
-Other (anorexia nervosa, paraproteinemia, lipodystrophy, autoimmune, pancreatitis, etc.)
Medications that may cause hyperlipidemia
-Beta-blockers
-Corticosteroids
-Estrogen 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 monounsaturated 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.
Adopting 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. In contrast, increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects.
-In the secondary prevention of cardiovascular disease, the omega-6/omega-3 ratio of 4/1 was associated with a 70% decrease in total mortality.
Source: http://www.ncbi.nlm.nih.gov/pubmed/12442909
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 of other disorders, including diabetes, stroke, some cancers, and age-related cognitive decline.
-Omega – 3 fatty acids are contained in fish oil of fatty fish (EPA & DHA)
-The linseed oil contains alpha-linolenic acid (ALA), another omega-3 fatty acid. 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 on 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%.
Medications
Statins
-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 increases 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.
-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 in people taking statins. CoQ10 is often added to 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 (Source http://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 more relevant with high–intensity rather than low–intensity statin treatment. Also, this risk is particularly increased in patients at risk for developing diabetes.
(Reference: http://www.ncbi.nlm.nih.gov/pubmed/26437128)
In 2012, the United States Food & Drug Administration (FDA) released changes to the statin safety labels to include that statins have been found to increase 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). The effect varies as per the dosage and the type used. Various mechanisms for this effect have been proposed, including 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 that can outweigh the risk. In elderly patients and those with metabolic syndrome, as the risk of diabetes increases, statins should be used cautiously. Other than a subset of the population at risk for diabetes, statins still have long–term survival benefits in most patients.
(Reference: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360430/ )
(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 assessed 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 dose-dependent for simvastatin and atorvastatin, which 388 and 1409 participants took, 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 and 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 predisposes 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 increases the risk of 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, with a 10% to 22% increased risk.
(Reference (Retrieved: October 11, 2015): http://www.medscape.org/viewarticle/843980 )
(Reference (Retrieved: October 11, 2015): http://www.medscape.org/viewarticle/843980 )
An overview of 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. 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)
(Reference: http://www.ncbi.nlm.nih.gov/pubmed/25208056)
Fibrates
-The fibrates are a class of amphipathic carboxylic acids. They are used for various metabolic disorders, mainly hypercholesterolemia, and there are hypolipidemic agents. Commonly prescribed fibrates include bezafibrate, ciprofibrate, clofibrate (obsolete due to side-effect profile, e.g., gallstones), gemfibrozil & fenofibrate.
-Fibrates are used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins. Clinical trials 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 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:
-Induction of lipoprotein lipolysis
-Induction of hepatic fatty acid (FA) uptake and reduction of hepatic triglyceride production
-Increased 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
-Increases HDL-cholesterol (‘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 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 the blood. Therefore, it is sometimes prescribed for people with low HDL, who are also at elevated risk of a heart attack.
-Mechanisms of action: Niacin's 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 the fat breakdown in adipose (fat) tissue and free fatty acids available for the liver to produce triglycerides, VLDL, and consequently LDL (‘bad’) – cholesterol.
-Decrease in free fatty acids also suppresses the hepatic expression of apolipoprotein c3 (APOC3) and PGC-1b, thus increasing VLDL turnover and reducing its production.
-It also inhibits diacylglycerol acyltransferase – 2, which is important for 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, 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 eye's retina, which is reversible after niacin intake ceases.
Thanks for reading!
Reference
Bibliography & External Links
Bibliography
· 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. McGraw-hillmedical.com
· Screening in the future, p. 160 – 161, Oxford Handbook of General Practice, C. Simon, H. Everitt, T. Kendrick, 2nd edition, Oxford University Press,2005. www.oup.com
Additional Bibliography
Additional Bibliography
- 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, 20
Links
(Retrieved January 18, 2015)
• http://www.ncbi.nlm.nih.gov/pubmed/18672019
• http://www.ncbi.nlm.nih.gov/pubmed/18003755
• http://www.ncbi.nlm.nih.gov/pubmed/16531786
• http://www.ncbi.nlm.nih.gov/pubmed/25375075
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