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A PANEL DISCUSSION ONHYPERLIPOPROTEINAEMIAS
Bhavin Dalal*, Tarak Shah**, Urmi Jhaver**,Brinder Vij**, Linu Jacob**
Assistant Prof.; **Resident; Dept. Of Medicine, MP Shah Medical College and Guru Gobind Singh Hospital, Jamnagar, Gujarat, India.
Q. 1. How are Indians different from Western people in lipid status and why?Ans. Indians show high levels of TGS and LP (a) and low level of HDL - while Westerns show high amounts of LDL and low levels of LP (a).[1] This can be explained by :
1.Dietary habits : Indians consume high amounts of saturated fatty acids and fats rich in omega six fatty acids and less fish in their staple diet.
2.Gene - environment interaction resulting in variable phenotypic expression of same gene defects.
3.Sedentary life leading to low level of HDL.
Q. 2. Is hypertriglyceridaemia an independent risk factor for CHD?
Ans. Yes :
After study in animal models and various genetically mediated hyperlipidaemias, datas show, that TGS are as bad as LDL in their atherogenicity and can cause CHD.[2] Important mechanism by which TGs contribute to CHD are: (1) They are directly atherogenic, (2) They affect the coagulation system independently and cause increased platelet aggregability, increased factor VII and X activity and increased levels of plasminogen activator inhibitor factors thus contributing to a procoagulant state.
Q. 3. What are the normal values for the different types of lipids?
Ans. The normal values of the various serum lipoprotein and cholesterol are[3] :
Total cholesterol 180-200 mg%
Triglycerides < 200 mg%
LDL cholesterol < 130 mg%
HDL cholesterol < 35 mg%
Lipoprotein (a) or Lp (a)[4] < 30 mg%Q. 4. What are the ideal values of the various lipoproteins and blood cholesterol in a patient of CHD?
Ans. In a patient of CHD, the desired values of the various lipoproteins are
Total cholesterol < 200 mg%
LDL cholesterol < 100 mg%
HDL cholesterol > 45 mg%Infact an HDL cholesterol > 60 mg%is a negative risk factor for CHD; i.e. you can subtract one risk factor.
Q. 5. What are the indications for lipid profile in a person?
Ans. Based on total cholesterol values, the NCEP-II (National Cholesterol Education Programme)[5] has given guidelines for doing lipid profile in the normal.
Total cholesterol
Desirable < 200 mg/dl
Borderline high 200-239 mg/dl
High > 240 mg/dlA person having cholesterol level < 200 mg/dl need not go for total lipid profile. A person having cholesterol > 240 mg/dl should definitely go for detailed lipid profile evaluation. And a person having cholesterol between 200-239 mg/dL should go for lipid profile if there are 2 or more associated risk factors. Apart from this, the usual indications for doing lipid profile in a person can be broadly classified into two categories.
1.Conditions which are caused by dyslipidaemias e.g. In known patients of CHD or persons with high risk for CHD like hypertension, obesity, smoking, alcoholism, premature CHD in one of the relatives etc. or in a patient of CVA or PVD.
2.Conditions which cause dyslipidaemias e.g.
- Hypothyroidism o CRF
- Familial hypercholesterolaemia
- Unexplained pancreatitis
In a person with evidence of hyslipidaemia like tendon xanthomas, xanthelesmas, tuberous xanthomas, arcus juvenalis etc.
Q. 6. How do you go for lipid profile estimation?
Ans. Lipid profile should be performed after overnight fasting as the cholesterol synthesis occurs maximum at night.
In a patient of MI lipid profile should be done within 24 hours and if not possible then after six weeks because in between there is increased sympathetic activity which can alter the results.
Q. 7. What are the NCEP[5] guidelines for treatment of hyperlipidaemia?
Ans. The US national cholesterol education programme (NCEP) in its second report (1994) has advocated general guidelines for the treatment of dyslipidaemias. The decision to treat hypercholesterolaemia depends not only on the LDL level but also on the associated CAD risk factor(s) in an individual patient.
Risk factors for coronary heart disease
oMen > 45 years, women > 55 years not receiving HRT
Family history of MI, sudden cardiac death before 55 years age for males and < 65 years for females in first degree relative.
Smoking > 10 cigarettes / day)
Hypertension (even if controlled with medications)
Diabetes mellitus
Low HDL (< 35 mg/dL)
Guidelines for LDL action limits
Die Drugs GoalNo CHD and less than
two risk factors> 160 > 190 < 160 No CHD but two
or more risk factors>130 > 160 <130 Presence of CHD >100 >130 <100 Therapeutic approaches based on plasma TG levels are less precise. The NCEP guidelines are :
Serum TG (mg/dL) Intervention < 200 (Normal) Nil : some recommend life style measures to lower it to < 150 mg/dL 200-400 Life style modification : drugs may (Borderline high) be considered if (i) CAD present, (ii) Family history of CAD present, (iii) total blood CH > 240 mg/dL and HDL < 35 mg/dL, (iv) Genetic dysbetalipoproteinaemia (Type III) or familial combined hyperlipidaemia (Type V), (v) Multiple risk factors present 400-1000 (High)
(Borderline high)Treatment as in previous category; emphasis on controlling causes of Secondary hypertriglyceridaemia; drug therapy is a must if history of acute pancreatitis Is positive. > 1000 (Very high) Vigorous measures to lower TG levels since risk of acute pancreatitis is high; control diabetes (if present), institute very low fat diet, curtail alcohol, use drugs. Q. 8. What are the various treatment modalities for dyslipidaemias?
Ans. There are 2 broad ways of treating hyperlipidaemias.
I. Non pharmacological
II. Pharmacological
Of the two, the non pharmacological measures if timely done are the best. The various measures include :
(i) Dietary advice : Diet just adequate to maintain ideal body weight based on age and gender alongwith other risk factors should be advised.
The two step approach to treat hypercholesterolaemia as per NCEP recommendations is as follows :
Nutritent Step 1diet Step 2 diet Total fat < 30% calories < 30% calories Fatty acids saturated < 10% calories < 7% calories Polyunsaturated < 10% calories < 10% calories Monounsaturated 0-15% calories 0-15% calories Carbohydrates 50-60% calories 50-60% calories Protein 10-20% calories 10-20% calories Cholesterol < 300 mg/day < 200 mg/day Such changes can be brought about by replacing whole milk, dairy products, egg yolk, meat, palm oils, ghee etc. with fresh fruits, vegetables complex carbohydrates and low fat dairy products.
(ii) Increased physical activity. On regular basis this should be advised because it burns up calories and helps to maintain ideal body weight and ideal lipoprotein values and secondly it increases HDL values.
Q. 9. What are the various drugs used in lipid lowering therapy?
Ans. The drugs used in lipid lowering therapy can be broadly classified as first line agents and second line agents.[6]
First line agents include :
1.Bile acid sequestrants or resins like cholestyramine and colestipol
2.Niacin or nicotinic acid and
3.HMGCoA reductase inhibitors or statins like lovastatin, simvastatin, atorvastatin etc.
Second line agents are the fibric acid derivatives or the fibrates like gemfibrozil, clofibrate, fenofibrate, benzafibrate.
Depending on the clinical condition in which used drugs can be classified as
Elevated LDL and normal TG (< 200 mg/d/L) Hypercholesterolaemia) oHMGCoA reductase inhibitors. o Bile acid sequestrants
oNicotinic acid.
HRT (in women)oHMGCoA reductase inhibitor and bile acid sequestrant and ninacin
HMCGoA reductase inhibitor + NinacinElevated LDL and TG (200-400 mg/dL) (combined hyperlipidaemia) o HMGCoA reductase inhibitors.
o Gemfibrozil oNicotinic acid.oHMGCoA reductase inhibitor and Gemfibrozil
oHMGCoA reductase inhibitor and Nicotinic acid
oBile acid sequestrant and Nicotinic acid
o Gemfibrozil Nicotinic acid.TG > 400 mg/dL
(Hypertriglyceridaemia)o Gemfibrozil oNicotinic acid. in addition there are other lipid lowering agents like probucol, neomycin, guggulipid etc. which are nowadyas not widely used.
Q. 10. Brief mechanism of action of lipid lowering agents.
Ans. Bile acid sequestrants act by interfering with reabsorption of bile acids from the intestine. As bile acids are lost, more is to be produced, for which cholesterol is utilised, leading to a decrease in the blood cholesterol level.
Niacin acts by inhibiting the secretion of lipoproteins from the liver thereby reducing blood cholesterol.
HMGCoA reductase inhibitors inhibit the rate limiting step in cholesterol synthesis; i.e. the conversion of HMGCoA to mevalonate which is subsequently converted to cholesterol.
Fibrates act by increasing or stimulating the enzyme lipoprotein lipase which hydrolyses triglyceride thereby decreasing the blood triglyceride level.
Q. 11. Classify statins?
Q. 12. Are all statins the same?
Ans. As far as the mechanism of action is concerned, all statins are the same; i.e. they are all HMGCoA reductase inhibitors. However they differ in their pharmacokinetics, half life, lipid solubility, potency and lipid and nonlipid mechanisms.
- Statins have a half life of 2-3 hours except atorvastatin which has half life of 14-20 hours.
- Simvastatin is the most lipophilic and fluvastatin the most hydrophilic.
- Atorvastatin is the most potent and fluvastatin the least potent.
- Atorvastatin > Simvastatin > Lovastatin > Fluvastatin.
- The only stain that decreases, Lp(a) is atorvastatin.
Q. 13. What are the other effects of statins?
Ans. Apart from their excellent lipid lowering action statins have other important effects which include[7]
1.Atherosclerotic plaque stabilisation. This is by decreased release of inflammatory cytokines and procoagulant factors along with a reduction in local inflammation and macrophage stimulation.
2.Amelioration of endothelial dysfunction by increasing nitric oxide production, decreasing superoxidation of lipoproteins and decreasing expression of leucocyte adhesion molecule.
3.Improved coronary artery compliance.
4.Prevention of plaque rupture and thrombus formation.
By these mechanisms statins provide stability to atheromatous plaque and decreases the incidence of MI, unstable angina and all cause mortality in CAD and CVA.
Q. 14. How do you utilise statins?
Ans. Statins are usually started as a single dose in the evening (as max. cholesterol synthesis occurs at night). The dose is then titrated according to the response at intervals of 4-6 weeks till the desired response or to the respective max. doses.
The levels of cholesterol start falling over 4-6 weeks. Mortality benefits appear after 2 years of continuous medication. Further continuation of the drug should be individualised (No definite guide lines or studies are available to date). If the dyslipidaemia continues to be a major risk for the CHD of the patient and if it cannot be controlled by life style modifications, then perhaps statins should be continued life long.)
Drug Initial dose Maximum dose Lovastatin 10-20 mg/day 80 mg/day Atorvastatin 10-20 mg/day 80 mg/day Simvastatin 5-10 mg/day 40 mg/day Pravastatin 10 mg/day 40 mg/day Fluvastatin 20 mg/day 40 mg/day Q. 15. What are the side effects of statins?
Ans. Statins, as a group, are relatively safe drugs. However certain adverse effects can occur especially with high doses.
Constipation was the most common side effect in lovastatin trial.
Other side effects include :
- Headache, nausea, rashes
- Sleep disturbances especially with simvastatin
- Rise in serum transaminases. Mild transient elevations occur with all statins. However elevations to more than three times the upper limit of normal is an indication for discontinuation of therapy. Hence baseline LFT with followup LFTs every four monthly is advised
- Muscle tenderness and rise in CPK levels. Rarely myopathy and rhabdomyolysis especially when statins are combined with gemfibrozil, niacin, erythromycin and cyclosporin
- High doses of statins can induce tumours in animals. However the clinical importance of this potential in humans is not known.
- Statins are contraindicated in pregnancy because it interferes with cholesterol and there by steroid hormone synthesis in foetus.
Q. 16. Can fibrates be combined with statins?
Ans. Statins if possible should not be combined with fibrates because of the risk of myopathy; but in special situations like diabetes with dyslipidaemia may be used with close monitoring.
Q. 17. What is cardiac dysmetabolic syndrome?
Ans. Cardiac dysmetabolic syndrome [8],[9] also known as syndrome X is named by Dr. Raven after his excellent work on peripheral insulin resistance. It consists of
Procoagulant state
Hypertension
Obesity
Lipid triad (High level of TGs, high LDL and low HDL)[8],[9]
Diabetes (Increased insulin resistance)
(Mnemonic PHOLD)
If syndrome X is associated with hyperuricaemia / microalbuminuria / salt sensitivity then it is known as syndrome X plus.
Q. 18. Should post unstable angina and post CABG patients receive statins?
Ans. Yes, Statins should be given to patients of unstable angina and post acute coronary syndrome as[7] :
- Endothelial dysfunction is removed.
- Coronary vasodilatory capacity is improved and
- Plaque rupture and thrombus formation is prevented by plaque stabilisation.
Thus stain therapy in early stages of CHD can prevent disease progression and even cause regression of lesions.
In post CABG the role of statins is to prevent the progression of atherosclerosis in venous grafts. The main aim is to maintain the LDL levels < 100 mg% which is consistent with NCEP guidelines.[10]
Q. 19. How lipid status is affected in diabetes?
Ans. Dyslipidaemias are quite complex and addition of diabetes makes them even more complex. Changes occurring in diabetic dyslipidaemias can be classified into two categories[11]
Quantitative and Qualitative
Quantitative changes include :
(i) Increase in VLDL as compared to normal due to increased availability of glucose for VLDL synthesis (glucose Ä FFAS Ä VLDL) and decrease in lipoprotein lipase activity leading to decreased clearance of VLDL from peripheral circulation.
(ii)Increased LDL levels and
(iii)Decreased HDL levels due to increased hepatic lipase activity, decreased lipoprotein lipase activity and decreased VLDL clearance.
Qualitative changes include :
(i)Increased amounts of TGs in VLDL, LDL and HDL.
(ii) Non enzymatic glycation of LDLs. (Glycated LDLs are more atherogenic than normal LDL) and
(iii)Non enzymatic glycation of HDLs. (Glycated HDL is less efficient in cholesterol clearance).
In both IDDM and NIDDM changes in lipid status are almost the same both quantitatively and qualitatively except that in IDDM, the changes vary with glycaemic control. In IDDM the lipoprotein constituent values come in the favourable range with strict euglycaemia whereas in NIDDM the changes continue even with well controlled euglycaemia.
Q. 20. How will you manage dyslipidaemia in diabetes?
Ans. Hyperlipidaemias are to be treated with more aggressiveness in diabetics as cholesterol is abnormally distributed among different lipoportein constituents in diabetes. The non HDL cholesterol level should be the guideline for treatment.
Non HDL cholesterol = (Or Total CH - HDL)
The following are the goals for diabetics (Garg and Grundi)
Ideal goal Total cholesterol < 200 mg% < 170 mg% LDL cholesterol < 130 mg% 100 mg% Non HDL cholestrol holesterol < 160 mg% 130 mg% The treatment modalities include :
I.Non pharmacological measures : under these come
1.Dietary measures which include the same two step approach with careful contribution from carbohydrates to maintain euglycaemia. Protein rich, that too animal protein rich food, with roughage is the message here.
2.Physical activity. For physical activity the council on exercise of ADA (American Diabetes Association) has clear cut recommendations for both IDDM and NIDDM patients.
(i) For IDDM patients exercise is recommended to maintain ideal body weight; but taking care of things like hypoglycaemia, ketosis, cardiovascular ischaemia, arrhythmias, exacerbation of retinopathy and injury to lower limbs which may be associated with very heavy exercise programme.
(ii) For NIDDM patients exercise regimen is even more important to decrease insulin resistance and hence hyperlipidaemias. Such patients need thorough examination for retinopathy, hypertension and silent ischaemia which should include stress echocardiography as well for all > 35 years of age.
II. Pharmacological measures : Out of the first line drugs, though nicotinic acid has beneficial effect on HDL levels, hyperglycaemia as their side effects should make their use guarded and cautions one.
Same is the case with bile acid sequestrants which increase triglycerides which are already high in Indian diabetics.
However HMGCoA reductase inhibitors or statins can be used in diabetics without much worry though their other side effects like liver toxicity and myositis should be taken care of. Out of the second line drugs or the fibric acid derivatives, clofibrate is the preferred drug because it has the least effect on glycaemic control with TG decreasing effect which is the case in diabetic dyslipidaemias. Combination therapy with bile acid sequestrants and fibrates or bileacidsequestrants and statins can be tried especially in severe diabetic hyperlipidaemias. Even nicotinic acid can be added as a triple drug therapy.
In conclusion euglycaemia along with statins or fibrates should be the ideal initial approach to diabetic dyslipidaemias.
Q. 21. Can statins be given in stroke.
Ans. Yes. Statins reduce the incidence, recurrence and all causes of mortality of stroke as shown in CARE (Cholesterol and Recurrence Event Study) similarly in a way that it reduces morbidity and mortality in CHD.[12]
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