Case study 67CVD risk: guiding lipid management
Ric is a 49-year-old IT consultant who has come to see you concerned that he is at risk of a heartattack. Ric has type 2 diabetes, diagnosed 2 years ago, which is well controlled. He has a familyhistory of type 2 diabetes and his father died recently of a heart attack at age 73. There is no othersignificant family history.Ric has 6 or 7 alcoholic drinks per week and smokes 10 cigarettes a day (he has tried to quit anumber of times without success). Ric’s only exercise is his weekly social game of squash, and hislunch often consists of take-away meals. Ric takes controlled-release metformin 1000 mg in theevening. On-examination his waist circumference is 100 cm, blood pressure 130/82 mmHg, restingpulse 75 beats per minute with regular rhythm.Ric’s total cholesterol is 6.1 mmol/L, HDL-cholesterol 1.6 mmol/L, LDL–cholesterol 3.85 mmol/L andtriglycerides 1.4 mmol/L. Renal function, liver function tests, full blood count, glucose levels andHBA
are all within normal range.
1. a) What is Ric’s calculated absolute cardiovascular risk over the next 5 years?
low (<10%) moderate (10% to 15%) high (>15%)
b) Which cardiovascular risk tool/calculator did you use to calculate your answer?c) Are there any additional risk factors not considered by this cardiovascular tool that youwould include in Ric’s formal CV risk assessment? (Please list)
2. List three lifestyle interventions (in order of importance) that you would recommend to assistRic in reducing his cardiovascular risk.
3. a) Would you consider statin therapy appropriate for Ric? Please provide a reason for youranswer.
yes (give details) noStatin: ____________________________ Dose: __________________ Frequency: _________________Reason: ______________________________________________________________________________
b) List three clinical parameters that you would monitor if starting Ric on a statin:
A 45-year-old man presented to the emergency with chest pain. The chest pain lasted for approximately 15 minutes then subsided on its own. He also noticed that he was nauseated and was sweating during the pain episode. He had no medical problems and had not been to a physician for several years.
On examination, he was in no acute distress with normal vital signs. His lungs were clear to auscultation bilaterally, and his heart had a regular rate and rhythm with no murmurs. An electrocardiogram(ECG) revealed slight ischemic changes. The blood biochemistry revealed raised serum total cholesterol and LDL cholesterol levels. He was placed on a low-fat diet and Lovastatin therapy.
He was without complaints and was feeling well on his subsequent follow-up visit. On repeat serum cholesterol screening, a decrease in the cholesterol level was noted.
What is the mechanism of action of this drug?
What are the potential side effects?
What are the alternative options to treat this patient?
The patients had an episode of IHD (Ischemic heart disease), and had hyperlipidemia.
Hyperlipidemia is one of the most treatable risk factors of coronary heart disease. Initially, when the fasting low-density lipoprotein (LDL) cholesterol is found elevated, life style modification is recommended such as dietary adjustments, exercise, and weight loss. If the LDL cholesterol level is again found above threshold, pharmacological therapy is initiated. Since the patient in the given case had a mild attack of IHD, hence without trial he had been put on low-fat diet and statins.
A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), and the remainder is provided by the average diet. The liver and intestine account for approximately 10% each of total synthesis in humans. Virtually all tissues containing nucleated cells are capable of cholesterol synthesis, which occurs in the endoplasmic reticulum and the cytosol. LDL-C is a transporter of cholesterol from liver to peripheral tissues, while HDL is a transporter of cholesterol from peripheral tissues to liver for degradation. Excess LDL is responsible for Atherosclerosis and is a risk factor for IHD ( Ischemic heart disease), that is why it is considered “Bad cholesterol”. HDL-C on the other day acts as a scavenger to lower serum cholesterol level, because of this, it is cardio protective and is considered ‘Good cholesterol”.
Biosynthesis of cholesterol
The biosynthesis of cholesterol may be divided into five steps: (1) Synthesis of Mevalonate from acetyl-CoA. (2) Formation of isoprenoid units from Mevalonate by loss of CO2. (3) Condensation of six isoprenoid units form squalene. (4) Cyclization of squalene gives rise to the parent steroid, lanosterol. (5)Formation of cholesterol from lanosterol.
Hypercholesterolemia and the consequences
Atherosclerosisis characterized by the deposition of cholesterol and cholesteryl ester fromthe plasma lipoproteins into the artery wall. Diseases in which prolonged elevated levels of VLDL, IDL, chylomicron remnants, or LDL occur in the blood (e.g.,diabetes mellitus, lipid nephrosis, hypothyroidism, and other conditions of hyperlipidemia) are often accompanied by premature or more severe atherosclerosis. There is also an inverse relationship between HDL (HDL2) concentrations and coronary heart disease, making the LDL: HDL cholesterol ratio a good predictive parameter. This is consistent with the function of HDL in reverse cholesterol transport.
Diet Can Play an Important Role in Reducing Serum Cholesterol
Hereditary factors play the greatest role in determining individual serum cholesterol concentrations; however, dietary and environmental factors also play a part,and the most beneficial of these is the substitution in the diet of polyunsaturatedand monounsaturated fatty acids for saturated fatty acids. Plant oils such as corn oil and sunflower seed oil contain a high proportion of polyunsaturated fatty acids, while olive oil contains a high concentration of monounsaturated fatty acids. On the other hand, butter fat, beef fat, and palm oil contain a high proportion of saturated fatty acids. Sucrose and fructose have a greater effect in raising blood lipids, particularly triacylglycerols, than do other carbohydrates.
The reason for the cholesterol-lowering effect of polyunsaturated fatty acids is still not fully understood. It is clear, however, that one of the mechanisms involved is the up-regulation of LDL receptors by poly- and monounsaturated ascompared with saturated fatty acids, causing an increase in the catabolic rate of LDL, the main atherogenic lipoprotein. In addition, saturated fatty acids cause the formation of smaller VLDL particles that contain relatively more cholesterol, and they are utilized by extrahepatic tissues at a slower rate than are larger particles—tendencies that may be regarded as atherogenic.
Lifestyle and the Serum Cholesterol Level
Additional factors considered to play a part in coronary heart disease include high bloodpressure, smoking, male gender, obesity (particularly abdominal obesity), lack of exercise, and drinking soft as opposed to hard water. Premenopausal women appear to be protected against many of these deleterious factors, and this is thought to be related to the beneficial effects of estrogen. There is an association between moderate alcohol consumption and a lower incidence of coronary heart disease. This may be due to elevation of HDL concentrations resulting from increased synthesis of apo A-I. It has been claimed that redwine is particularly beneficial, perhaps because of its content of antioxidants.Regular exercise lowers plasma LDL but raises HDL.
When diet changes fail, hypolipidemic drugs are prescribed to reduce Serum Cholesterol & Triacylglycerol levels. Few of the commonly used drugs to lower cholesterol level are as follows-
1) Statins (Lovastatin)
A family of drugs known as statins, have proved highly efficacious in lowering plasma cholesterol and preventing heart disease.
Mechanism of action of drug -Lovastatin is a member of a class of drugs (Atorvastatin, fluvastatin, pravastatin and Simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase.
These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins arebound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Effective treatment with Lovastatin, along with low fat diet, decreases levels of blood cholesterol. The lowering of cholesterol also lowers the amounts of the lipoproteins that transport cholesterol to peripheral tissues i.e. low density lipoproteins(LDL).
Side effects of therapy –The potential side effects include elevated liver function tests,increased muscle creatine phosphokinase (CPK) secondary to Myopathy and rarely rhabdomyolysis.
2) Alternative treatment options-Other agents that may be considered include bile acid sequestrants,Niacin, fibric acid, and fish oils.
a) Niacin is a vitamin that is used in high doses to treat hypercholesterolemia. Niacin acts to decrease VLDL and LDL plasma levels.Its mechanism of action is not clearly understood but probably involves inhibition of VLDL secretion, which in turn decreases the production of LDL. Niacin inhibits the release of free fatty acids from adipose tissue which leads to a decrease of free fatty acids entering the liver and decreased VLDL synthesis in the liver. This decreases the availability of VLDL for conversion to LDL (containing cholesterol esters). Niacin also increases high-densitylipoprotein (HDL) (the “good cholesterol”) by an unknown mechanism.
b) Fibrates such as Clofibrate and gemfibrozil act mainly to lower plasma triacylglycerols by decreasing the secretion of triacylglycerol and cholesterol-containing VLDL by the liver.
c) Ezetimibe– a new drug, Ezetimibe, which reduces blood cholesterol levels by inhibiting the absorption of cholesterol by the intestine, has recently been introduced. Ezetimibe belongs to the azetidinone class of cholesterol absorption inhibitors.
d) Bile Acid Sequestrants (Resins)-Bile acid sequestrants bind bile acids in the intestine and promote their excretion in the stool. To maintain the bile acid pool size, the liver diverts cholesterol to bile acid synthesis. The decreased hepatic intracellular cholesterol content results in up regulation of the LDL receptor and enhanced LDL clearance from the plasma. Bile acid sequestrants include Cholestyramine, colestipol, and colesevelam.
e) Omega 3 Fatty Acids (Fish Oils)-ω-3 polyunsaturated fatty acids (ω -3 PUFAs) are present in high concentration in fish and in flax seeds. The most widely used ω -3 PUFAs for the treatment of hyperlipidemia are the two active molecules in fish oil: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish oils can result in an increase in plasma LDL-C levels in some patients. Fish oil supplements can be used in combination with Fibrates,niacin, or statins to treat hypertriglyceridemia. In general, fish oils are well tolerated and appear to be safe, at least at doses up to 3–4 g. A lower dose of omega 3 (about 1 g) has been associated with reduction in cardiovascular events in CHD (Chronic Heart Disease) patients and is used by some clinicians for this purpose.
Management of Low HDL-C
Causes of low HDL levels
· Severely reduced plasma levels of HDL-C(<20 mg/dL) accompanied by triglycerides <400 mg/dL usually indicate the presence of a genetic disorder, such as a mutation in apoA-I, LCAT(Lecithin Cholesterol Acyl Transferase) deficiency,or Tangier disease.
· HDL-C levels <20 mg/dL are common in the setting of severe hypertriglyceridemia, in which case the primary focus should be on the management of the triglycerides.
· HDL-C levels <20 mg/dL also occur in individuals using anabolic steroids.
· Secondary causes of moderately low levels of plasma HDL (20–40 mg/dL) should be considered in conditions like smoking, Type 2 Diabetes mellitus, Gaucher’s disease and malnutrition.
1) Smoking should be discontinued.
2) Obese persons should be encouraged to lose weight, sedentary persons should be encouraged to exercise.
3) Diabetes should be optimally controlled.
4) When possible,medications associated with reduced plasma levels of HDL-C should be discontinued.
5)The presence of an isolated low plasma level of HDL-C in a patient with a borderline plasma level of LDL-C should prompt consideration of LDL lowering drug therapy in high-risk individuals.
6) Statins increase plasma levels of HDL-C only modestly (~5–10%).
7) Fibrates also have only a modest effect on plasma HDL-C levels (increasing levels ~5–15%), except in patients with coexisting hypertriglyceridemia, where they can be more effective.
8) Niacin is the most effective available HDL-C–raising therapeutic agent and can be associated with increases in plasma HDL-C by up to ~30%, although some patients do not respond to niacin therapy.