Jaslok Hospital and Research Centre,
Macrovascular disease is a well known complication of diabetes mellitus. Atherosclerotic changes appear in a diabetic at a much earlier age, occur in a more severe form and progress at an extremely accelerated pace. Even today, in spite of modern therapeutic modalities, the most common cause of death in a diabetic prior to the age of 30-35, years is that from myocardial infarction. Coronary artery disease (CAD), cerebrovascular accidents and peripheral vascular disease are more common in the patient with diabetes as compared to the general population.
The presence of diabetes is indeed a well known risk factor leading to atherosclerosis, but, hyperglycemia is but one of several other factors which predispose people with diabetes to accelerated atheroma formation. Whilst, many of the other risk factors can occur independently and therefore are seen in the general non-diabetic population, it is now known that some of these important risk factors are seen in the diabetic population at a frequency which precludes mere chance association. In fact, many of these are now included in the "Metabolic" syndrome.
Hypertension is one such factor which is seen much more often in a person with diabetes than in the general population. Lipid disorders are also seen more frequently associated with the diabetic state and add significantly to the propensity for getting macrovascular disease to which a person with diabetes is so prone.
Lipid disorders do occur in the general population and I do not intend to discuss the various dyslipidemic syndromes here, but confine the discussion to the type of dyslipidemia frequently encountered in a person with diabetes.
Raised levels of serum triglycerides with a decrease in the levels of the good HDL-cholesterol are thought to be characteristic of the diabetic state. Although the levels of the bad LDL-cholesterol may not be significantly elevated, we now know that that there is a qualitative change in the composition of the LDL particles (smaller, denser particles), which increase atherogenicity even if the absolute concentration of LDL-C is not significantly increased. The combination of elevated levels of small, dense LDL-C particles and high triglyceride levels represents a lethal cholesterol abnormality known as pattern B well known to be associated with accelerated atherosclerosis.
Epidemiologic evidence suggests that high total triglyceride, as well as high VLDL-C levels and VLDL-related triglyceride levels, and low HDL-C levels may be even stronger risk factors for CAD in people with diabetes than in the nondiabetic population. In fact, there are many studies which support the independent benefits of lowering triglyceride levels and raising HDL-C levels in a patient with diabetes. In addition, the combination of elevated total cholesterol level, hypertension, and uncontrolled hyperglycemia is implicated in the development of nephropathy.
The increase in the levels of these lipids and the hypertension seen relatively more frequently in a diabetic surely plays a very important role in the accelerated atherosclerosis seen in a diabetic and enforces the concept that diabetes is a disorder which is much more than a simple disorder of raised blood glucose levels. It is a syndrome complex and unless all these other risk factors are also managed, one cannot talk of good or optimal diabetic management.
Lipid abnormalities may be the result of the unbalanced metabolic state of diabetes (ie, hyperglycemia and insulin resistance). Treatment with glucose-lowering agents reduces triglyceride levels in patients with type 2 diabetes and does not change, or only modestly raises, HDL-C levels. Small reductions (10% to 15%) in LDL-C levels may be achieved through optimal glycemic control. Thus, whilst improved control of hyperglycemia does moderate diabetes-associated dyslipidemia, elevated cholesterol levels persist and need to be specifically treated. Therefore, lipid-modifying treatment is warranted in many patients.
In this section, I will discuss the approach to a patient with a lipid disorder. Although the focus will be towards the management of these problems in the diabetic patient, I do not think that the basic approach and management differ so drastically that the discussion should not hold good for the general population at large.
Every patient, at the initial evaluation and thereafter on a regular basis must undergo testing for his lipid profile. One must be clear of what is exactly meant by a lipid profile. because most of the doctors as well as laboratories do so many tests, most of which do not give any worthwhile information but only add to the amount that the patient has to pay! In fact, so many investigations are included in what is supposed to be a lipid profile that besides not offering any relevant information, it tends to confuse the doctor as well as the patient. When a lipid profile is called for, all that one needs to know in the vast majority of cases are the levels of serum triglycerides (TG), the levels of total Cholesterol (T-C) and HDI.-C. These three parameters give enough information about the lipid status in most patients especially if seen along with a simple observation of the stored serum which can be a pointer towards the presence of chylomicronemia.
A case in point is the lipoprotein electrophoresis which many patients are routinely subjected to. Whilst, in the rare patient, some information may be forthcoming from this, in the vast majority of the cases, the same information is available through estimating the three parameters which I have enumerated above. Unfortunately, advantage is taken of the relatively poor knowledge of lipids which most of us have to make the patient pay for additional tests. To give an example, we are told the levels of alpha lipoproteins. This gives the same information as the HDL-C values, but in any case, the HDL-C levels are also estimated! So not only does the patient pay for unnecessary tests, but the picture gets confused with the additional introduction of terms like alpha, beta, pre-beta, etc. lipoproteins. All this makes the management of lipid disorders, (which in the final analysis is what is of importance and not the number and volume of tests done) all that much more confusing. In reality, if one understands the basics, the specific treatment of hyperlipidemias is quite simple. I do not mean to imply that such a detailed lipid study should never be carried out. There are some patients with severe lipid problems who would merit such a detailed analysis, but the vast majority of patients have no need for undergoing such a detailed testing as a routine.
The LDL cholesterol level can be measured directly or can be calculated by using the Friedwald formula (measurement is expressed in milligrams per deciliter):
LDL=total cholesterol - HDL - (triglyceride / 5)
There is some evidence to suggest that dividing the serum triglyceride values by 5 may underestimate the levels of LDL-C, and I usually divide the values by a factor of 6. LDL-C plays such an important role in atherosclerosis, that it would be better to err on the side of caution and bring it down to absolutely optimal values rather than risk keeping it at a slightly higher level. Utilising 6 as the dividing factor, allows us to err on the side of caution. One more point that I would like to mention is that levels of LDL-C calculated in this manner are valid only if the values for serum triglycerides are under 400mg%. Levels above this would give possibly erroneous readings for the LDL-C values, but in my opinion, this is an academic point. When faced with such a high TG value, one would definitely have to accept that both the TG and the LDL-C are much higher than acceptable and have to be brought down.
The serum T-Cholesterol (T-C) levels can be measured at any time of the day irrespective of the meals etc., since they do not change significantly even after a meal full of fats. But as we need to measure the TG and the HDL-C as well, the blood should be collected after a 12 hour fast. 'There is no evidence to suggest that drinking water or even having black tea or coffee (without sugar) will significantly alter the results. I allow my patients to have water and in some cases, even insist that they take adequate quantities of water especially in patients with borderline renal function, where dehydration should always be avoided. In such instances I tell the patient that when he does go to the laboratory, he should insist that he has come fasting, or some technician will no doubt ask him to come again on a completely fasting stomach. Patients who are acutely ill, are rapidly losing weight, are pregnant or have had a myocardial infarction within the past three months should have the tests rescheduled as the levels of serum cholesterol estimated may not be the usual levels of the patient which is what we are interested in.
The patient must be on his usual diet, which can either be a free diet, a diabetic diet or a diet prescribed to him for a previously diagnosed lipid problem. He should not make any drastic changes in his diet in the few days previous to the test. The blood should be collected without stasis, and thus, I always instruct the laboratory that the blood be collected after the patient has been sitting for around five minutes, and the tourniquet, if used, should be tied for the shortest possible duration. The blood may be collected either as serum (no anticoagulant) or as plasma in an EDTA bulb. If the blood is obtained without any anticoagulant, it should be allowed to clot for about 30 minutes at room temperature and the clot should be detached from the wall of the bulb before centrifugation. The report must mention whether the estimation was done on serum or plasma. Plasma values must be multiplied by 1.03 to give the equivalent serum readings which are used in the calculations LDL-C.
The estimation of serum lipids should ideally be carried out at a good laboratory which is interested in metabolic work rather than one in which such work is just routine. I usually feel that the levels should be estimated at a couple of good laboratories and the results averaged out before a definite decision is taken about further treatment. Unless the values obtained are clearly in the mid-normal range or, for that matter, in the very high range, it would be prudent to repeat the tests in different laboratories or even in the same laboratory and use the average of the values obtained to judge the correct levels. The reason for this is that there is quite a significant day to day variation in the levels of LDL-C and the T-C in the same patient. This change can be as large as 20mg% and in borderline cases, this may make quite a difference whilst analysing the results. Values of the T-C and the LDL-C also show an annual variation with the levels in the winter months being lower than the usual values by around 20%! This too must be taken into account when analysing the data and especially when judging the efficacy of treatment.
What are the acceptable levels of these lipids? The latest recommendations state that in adults with diabetes, the optimal LDL-C level is less than 100 mg/dL and the optimal HDL-C level is more than 45 mg/dL; triglyceride levels of less than 200 mg/dL are desirable.
You will realize that these recommendations are much more stringent than those evolved in the past. A few years back, levels of LDL-C greater than 160mg% were considered as being in the "high risk" category. Levels between 130 and 159mg% were in the "borderline risk" category whilst levels of LDL-C below the 139mg% value are felt to be safe. Levels of HDL-C below 35mg% were are considered to be in the "high risk" category for the development of atherosclerosis. It has been shown that even changes of as small a magnitude as 5-10mg% in the HDL-C levels will bring about significant change in the relative risk involved.
It was also felt in the past that fasting triglyceride levels below 250mg% were safe and should not merit active therapy unless the associated levels of LDL-C were more than 160mg% Levels, between 250mg% and 500mg% were considered "borderline" high whilst those above 500% are considered as being in the "high risk" category. I do not accept these values and feel that the serum triglycerides should be kept below the 200mg% mark at the very least. In fact, for a diabetic patient, active efforts must be made to lower the TG values as much as is possible and I feel that the aim of treatment should be to lower the TG levels to around 150mg%, especially in view of the recent evidence that TG itself is an independent risk factor for macrovascular disease.
After estimating the lipid levels, I then evaluate the patient for the presence of any other additional risk factors predisposing that patient to atherosclerosis. These additional risk factors are shown in the following Table.
|Risk Factors for Atherosclerosis other than high LDL-C levels.|
|Cigarette smoking (more than 10 per day);|
|High Blood pressure;|
|Raised BMI and/or Waist-Hip Ratio;|
|HDL-C levels below 45mg%;|
|Serum triglycerides above 200mg%;|
|Definite prior myocardial infarction, or a definite episode of angina;|
|History of cerebrovascular or peripheral vascular disease;|
|Family history of premature CHD (death before 55 years age);|
Evaluating the presence of the additional risk factors helps in two ways. Firstly, it should be obvious that whichever risk factor is correctable should be actively treated. The second reason for knowing about the presence of these risk factors is to help in planning the treatment strategy in patients with "borderline" elevation of the lipids. How actively should one treat these "borderline" values? No one denies that the lipid levels well beyond the "acceptable" range should be treated, but some controversy exists about treating borderline levels. There are many doctors who feel that unless additional risk factors are present, then it is not necessary to take strong measures to optimise the borderline levels, but the patient should just be closely monitored, after giving him some basic dietary advise. I am totally against this attitude. I feel that in all patients definite steps need to be taken to bring the levels down to optimal and "safe" values irrespective of the presence or absence of any other risk factor. Of course, the other factors should be treated insofar as they are correctable.
In any case, if we are consider people with diabetes, then one important risk factor is already present. Male patients would inevitably have two risk factors which should merit the most active management in lowering the raised lipid levels to as safe a value as is possible. I feel that the presence of diabetes removes the protective influence that the female sex confers on women. Importantly, many diabetics tend to be overweight and the prevalence of high blood pressure is significantly increased in diabetes. In view of this, people with diabetes are "sitting ducks" for the development of atherosclerosis and all active efforts MUST be made to bring the lipid levels to as low a level as is possible.
There is enough evidence to suggest that a reduction in the serum cholesterol levels considerably lowers the risk for developing atherosclerosis especially CAD. In an excellent study it was shown that reductions of 8% in the serum cholesterol levels brought about a lowering of the incidence of CAD by 19 % over the next seven years. A reduction of 25% in the T-C values lowered the incidence by 49% as compared to control subjects. Taking into consideration the results of many other studies, it has been estimated that for patients with a raised T-C levels, EVERY 1% REDUCTION IN THE LEVELS OF T-C, LOWERS THE RISK FOR CAD BY 2%!
Before commencing therapy for hyperlipidemias, one should always keep in mind that occasionally the raised lipid levels may be secondary to other medical conditions and optimal management of these conditions may lower the raised lipid values. Diabetes is a classic example of this. Increases in the serum TG levels and a lowering of the HDL-C levels are known to occur along with disturbances in glucose homeostasis and correction of the diabetic state may lead to a lowering of the TG levels with an increase in the HDL-C levels. It must be added, that optimal control of the blood glucose does not lower the raised levels of LDL-C and may not change the other lipid levels to optimal values, thus neccesitating additional specific therapy. Hypothyroidism is another such example. The correction of the hypothyroid state with a judicious use of replacement therapy often allows the raised lipid levels to come down to acceptable values.
The other conditions which can show a secondary rise in the serum cholesterol levels are nephrotic syndrome, obstructive liver disease and importantly drugs which may raise the LDL-C levels like progestins and anabolic steroids. Many of the drugs which are commonly used for treating high blood pressure like thiazide diuretics and beta blockers also bring about detrimental changes in the lipid levels with a rise in the TG and T-C levels and a lowering of the HDL-C values. This aspect has been discussed in detail in the chapter dealing with the management of high blood pressure.
Having ruled out/treated any other secondary cause for the increase in the lipid levels, the next step is to initiate specific treatment to optimise the lipid levels.
|Approach to treatment of adults with diabetes according to LDL-C levels|
|Patient status||Medical nutrition therapy||Drug therapyl|
|Initiate when LDL-C level is||LDL-C goal||Initiate when LDL-C level is||LDL-C goal|
|CAD, PVD, or CVD present||>100 mg/dL||<100 mg/dL||>100 mg/dL||<100 mg/dL|
|CAD, PVD, or CVD not present||>100 mg/dL||>100 mg/dL||>130 mg/dL*||>100 mg/dL|
CAD, coronary artery disease; CVD, cerebrovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PVD, peripheral vascular disease.
*For diabetic patients with multiple CAD risk factors (HDL-C level, <35 mg/dL; hypertension; smoking; family history of CVD, microalbuminuria, or proteinuria), some authorities recommend initiation of drug therapy when LDL-C levels are between 100 and 130 mg/dL.
The next step in the management of lipid disorders is the prescription of a specific diet therapy. This is quite simple as we shall see. Unfortunately, many of the so-called "diet experts" here, blindly follow the American method of prescribing diets and talk of the "One Step" and the "Two Step" methods. This really shows that they do not have any idea about the traditional eating habits of the local population. As a matter of interest, in the One Step method, used as the initial diet therapy to lower the serum cholesterol, the total amount of fats are reduced to 30% of the total calory intake for the day. The saturated fatty acids are restricted to 10% of the daily calories and the daily intake of cholesterol in food to 300mg per day. In the second step, that is the "Two Step" method, the calories derived from saturated fatty acids are further reduced to around 7%, whilst the daily intake of dietary cholesterol is limited to 200 mg.
Most of us eat a traditional indian diet, and this constitutes the vast majority of the indian population, including the so called sophisticated urbanites, and in this sort of a diet, the amount of fats is rarely, more than 30% of the total calories. Therefore asking these patients to follow the "One Step" diet and reduce the fat content of the diet to 30% of the total daily calories really has no meaning! As I has discussed whilst detailing the prescription of diet to a patient, most patients are not interested in knowing details about the calory content and the fat content of their foods. Neither are they interested in knowing the cholesterol content of foodstuffs! What they would appreciate is being give certain broad guidelines which they would find easy to follow. As a matter of interest, just as we have discussed about the diabetic diets, there are those who are at the other end of the spectrum. Instead of detailing the calory, fat and cholesterol content of foods and giving detailed charts about the exact type and amount of foods which the patient should eat, they ask the patient to follow a "Fat Free" diet! Is this ever possible? Most of the foods including vegetables, legumes and pulses, leave alone the meats and related products contain fats which have been called as the "invisible" fat. Thus what is meant by a so-called fat free diet is that no visible fat should be eaten. In other words, the food should be basically boiled and all foods which have a high fat content should be AVOIDED! It is not humanly possible for any person to follow such a "boiled" diet for any period of time. It should also be realised that the fats in the foods are necessary to give bulk, and taste, to the food and help in satiety. Fats also are the source of essential fatty acids and a completely "fat free" diet would invariably lead to a deficiency of these essential fatty acids.
The basic guidelines that I give the patients is that I would like them to decrease the fat content in their food as far as is possible, keeping in mind that they should get an adequate amount of fats which will supply the essential fatty acids, satisfy the "taste buds" and help in satiety. The amount of saturated fats should be decreased and foods very rich in cholesterol should be avoided or eaten only occassionally. As these are also the basic principles that I follow in prescribing a diabetic diet, I have discussed these aspects about the diet in the chapter "Diet in Diabetes", especially the section called the "The Oil Crisis!" and I would appreciate it if the relevant pages could be referred to for a detailed discussion.
I usually take a little time to discuss with the patient certain "finer" aspects of his diet. Milk and milk derived products form a major part of most indian diets. Milk has a high content of saturated fats and I advise the patient that he should use milk from which most of the fat and cream has been removed. This does not mean the use of "skim" milk. I ask the patients to boil the milk and let it cool. Cream will form at the top and this should be removed. The milk should then be reboiled and allowed to cool again. One will be surprised to see that more cream does form at the top. This should be removed too! I ask the patients who use skimmed milk to also boil the milk and remove the cream that appears at the top. One would be surprised at the amount of cream that forms even with skimmed milk. It is a fallacy to feel that skimmed milk is fat free. It is this milk from which the cream has been removed by boiling it twice which should be used for drinking and for making milk based items like dahi, etc.
Only lean cuts of meat should be used and all the visible fat should be cut carefully away. After cooking, all the oil should be allowed to drain away. The skin of the chicken should not be eaten, consumption of egg yolks and organ meats (liver, brain) should be curtailed or may need to be avoided. Processed foods like salami, bacon and sausages should be avoided. Shellfish such as shrimps are relatively high in cholesterol but not in fats and can be occasionally eaten. The use of coconuts in the cooking should preferably be avoided. The type and amounts of oils to be used has been discussed in the section "The Oil Crisis" in the Diet chapter.
The cooking should be done by methods that use little or no extra oil. This includes steaming, baking, broiling, grilling and stir frying. Foods can be cooked in microwave ovens (which many urban households now have) or in non stick pans without adding oil. Soups, stews and gravies should be cooled after cooking. This allows the fats to come up to the surface in a congealed form and this can be removed. The soups and the gravy can then be reheated before serving without losing out on the taste or the nutrients.
Theoretically, after the diet is prescribed, one should follow up the patients for three to six months to see whether the goal of optimising the lipid levels is reached. As far as I am concerned, optimal levels, especially in a diabetic are those that are well within the "safe" ranges mentioned above. It is only after this that thought is given to the use of drugs to bring down the levels further, if indicated. Whilst, I subscribe to this view and insist on the patient following certain dietary restrictions, I usually start of with drug therapy along with the diet, especially if any macrovascular complications already present. Even otherwise, if the lipid levels are in the high risk group, then I feel that one should start the drug therapy at the earliest. The Table given above allows a more clinical approach.
It is always possible to monitor the lipid levels and decrease the dose of the drugs at a later stage and even stop them completely to see whether diet by itself will maintain the lipid levels. From a practical viewpoint, although this may not be accepted under strict medical norms, patients feel gratified on seeing a reduction in the lipid levels and they are more likely to continue following the diet thereafter. If it happens that diet alone does not bring about the necessary changes in the lipid levels and recourse is then taken to drugs to optimise the lipid levels, then patients, feel that dieting does not help them. The feeling would be to give up on dieting and depend on the drugs only.
Drug therapy should be initiated after behavioral interventions have been tried, except for patients with clinical CAD or very high LDL-C levels (>200 mg/dL), who should receive drug therapy when behavior therapy is initiated. In adults with diabetes, the optimal LDL-C level is less than 100 mg/dL and the optimal HDL-C level is more than 45 mg/dL; triglyceride levels of less than 200 mg/dL are desirable.
Four different classes of hypolipidemic drugs are currently available.
Bile acid sequestrants (resins)
The anion exchange resins cholestyramine and colestipol bind cholesterol-containing bile acids in the intestines, producing an insoluble complex that prevents reabsorption, and thus depleting the body's supply of cholesterol. These agents decrease LDL cholesterol levels by up to 20 percent. The problem is that these resins may cause an increase in triglyceride levels
Because of their gritty texture and side effects, compliance may be a problem. Side effects include constipation, abdominal discomfort, flatulence, nausea, bloating and heartburn. A dosage reduction, increased dietary fiber, taking bile acid sequestrants with meals and letting the resin stand in liquid for 10 minutes before taking it are strategies that minimize the side effects.
Bile acid sequestrants can bind with warfarin, digitalis, thyroxine, thiazides, furosemide, tetracycline, penicillin G, phenobarbital, iron, propranolol, acetaminophen and nonsteroidal anti-inflammatory agents, as well as oral phosphate supplements and hydrocortisone. Ingesting such agents at least an hour before or four to six hours after a resin dose reduces the potential for drug interactions. They may be a good choice in patients with hepatic disease because they do not affect hepatic metabolism. They are also a good choice in very young patients and women of childbearing age. These drugs are available in the form of powders (cholestyramine in 9 gm. sachets containing 5 gms. of the drug and 4 gms. of a orange flavoured filler, whilst colestipol is available in 5 gm. sachets. They are also available in the form of premixed liquid drinks.) The powders have to be mixed with water to an accepted consistency and then taken in twice daily doses with meals. One could use unsweetened lime juice to flavour the powders or even mix the powder with pulpy fruit juices to make them more palatable. One usually starts with a very small dose and then depending on the response builds it up to the maximum dose of 16-24 gms. per day of cholestyramine and 12-20 gms. of colestipol.
It lowers LDL-C and triglycerides and raises HDL-C, and thus may be particularly useful in diabetes. This agent increases the HDL level by 15 to 35 percent, reduces total and LDL cholesterol levels by 10 to 25 percent, and decreases the triglyceride level by 20 to 50 percent.
Nicotinic acid therapy should be used with caution in patients with diabetes mellitus because it tends to worsen glycemic control. It can worsen insulin resistance and aggravate glucose intolerance.
Side effects of nicotinic acid include flushing, pruritus, gastrointestinal discomfort, hyperuricemia, gout, elevated liver function tests and glucose intolerance. Taking 325 mg of aspirin 30 minutes before the drug is ingested may minimize flushing. Frequently, however, flushing and pruritus resolve spontaneously with continued use. Nicotinic acid should be taken with meals to reduce the occurrence of gastrointestinal upset.
Hepatotoxic side effects are more common with sustained-release nicotinic acid preparations than with regular formulations. A hepatitis-like syndrome, manifested by weakness and a lack of appetite, may develop in patients receiving sustained-release preparations.
Other side effects of nicotinic acid include atrial fibrillation, hypotension, transient headaches and activation of peptic ulcer disease.
Unfortunately, the incidence of side effects tends to be high when the vitamin is not taken under optimal conditions (ie, a gradually increased bedtime dose preceded by low-dose aspirin). As a result, many patients are reluctant to remain on this treatment for any significant length of time.
Extended-release niacin is a prescription form of the vitamin that is released evenly into the blood. This decreases the incidence of flushing, which is niacin's most common--and annoying--side effect. However, even with the extended-release formulation, it is prudent to gradually increase the bedtime dose over time and to encourage the patient to take a baby aspirin 30 minutes before taking the niacin.
On average, HDL cholesterol increases by about 20% in patients who take extended-release niacin. Treatment usually starts with 500 mg of extended-release niacin each night and is increased by 500 mg each month. The usual maintenance dose is 1,500 to 2,000 mg.
These drugs are well known for lowering triglyceride levels by up to 50%. They also raise HDL levels by 10% to 15%. Their effect on LDL levels varies, but most data show that fibric acid derivatives do not influence or only slightly reduce LDL levels, but LDL-C levels may increase in patients with significant and predominant hypertriglyceridemia;
Fibric acid derivatives are generally well tolerated. The most common adverse effect is gastrointestinal intolerance (eg, abdominal pain, nausea, vomiting, diarrhea, constipation, dyspepsia, gallstone formation). Neuromuscular symptoms (eg, headache, dizziness, vertigo, arthralgias) and dermatologic problems have also been reported with this class of drugs. Monotherapy with fibric acid derivatives is rarely associated with myalgias and rhabdomyolysis, but the incidence of myalgias and rhabdomyolysis increases when these agents are used with statin drugs. Therefore, thoughtful consideration should be given to prescribing these two drug classes together.
Lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and cerivastatin are HMG-CoA reductase inhibitors, or statins, that inhibit cholesterol synthesis. To varying degrees, all of these agents lower total, LDL and triglyceride cholesterol components and slightly raise the HDL fraction. These agents typically reduce total cholesterol levels by 10% to 15%, LDL-C by 20% to 40%, and triglycerides by 10% to 20%. Statins also modestly increase HDL-C levels by 5% to 10%. A doubling of the dose above the minimal effective dose decreases serum LDL cholesterol concentrations by an additional 6 percent. The maximal reduction in serum LDL cholesterol concentrations induced by treatment with a statin ranges from 24 to 60 percent.
Stain use is also associated with other beneficial effects such as regression of atheromatous plaques and reduction of cardiovascular mortality and events; Evidence suggests that these agents reduce untoward cardiovascular events and work by mechanisms beyond the simple reduction in the LDL cholesterol level.The results of the Primary Prevention of Coronary Heart Disease with Pravastatin trial demonstrated reductions of 31 percent in first myocardial infarctions, 32 percent in cardiovascular mortality, 22 percent in total mortality and 37 percent in the need for revascularization procedures.
Very few patients discontinue use of the statins because of side effects. However, as with all drugs, adverse reactions do occur. Gastrointestinal distress, myalgias, headache, and rash are the most common patient complaints. The gastrointestinal effects often subside with continued therapy.
As with niacin, liver function abnormalities occur in about 1% of patients taking statin drugs and disappear when the drugs are discontinued. Rhabdomyolysis is a more serious adverse event, but it also is very rare (less than 0.1%). Concomitant administration of a statin drug and niacin, gemfibrozil, erythromycin, or certain antifungal agents increases the risk of rhabdomyolysis. Often used along with fibrates and/or nicotinic acid; when used in combination with these drugs, essential to closely monitor for liver dysfunction and muscle involvement.
Are all statins the same? There are differences among the statins. For example, atorvastatin has a slightly different side effect profile than the other statins. It may exert a greater effect on lowering LDL cholesterol, total cholesterol and triglycerides, but higher doses of other statins may produce the same response. However, atorvastatin as a single agent may obviate the need for multiple drug therapy in high-risk patients. In view of the numerous other mechanisms being investigated, such as plaque stabilization, antiplatelet aggregation activity and anti-arterial spasmodic effects, this particular difference may be less important than other factors. To date, no comparative studies of the statins have been performed to delineate all of the clinically important differences.
Although statins are usually only moderately effective in reducing triglyceride levels, an added benefit of atorvastatin and high-dose simvastatin is the ability to lower triglyceride levels to a greater degree than that typically observed with other statins; however, fibrates and nicotinic acid are clearly more efficacious in lowering elevated VLDL-C levels.
Because the rate of endogenous cholesterol synthesis is higher at night, all the statins are best given in the evening. Statins are eliminated in part by the kidneys and serum concentrations may be higher in patients with renal disease. Patients with hepatic disease should be given lower doses or treated with another type of drug. None of the statins should be given to pregnant women because they are teratogenic.
The category of drug used would depend on the main type of dyslipidemia present.
|Priorities for treatment of hyperlipidemia in adults with type 2 diabetes|
|1. Decrease LDL-C level
First choice: "statins"
Second choice: resins or fenofibrate
|2. Increase HDL-C level
Behavioral interventions (weight loss, exercise, smoking cessation)
Therapy with fibrates (gemfibrozil, fenofibrate) or nicotinic acid (difficult because drug is relatively contraindicated)
|3. Decrease triglyceride level
Glycemic control (first priority)
Statins (moderately effective)
|4. Treat combined hyperlipidemia,
First choice: improved glycemic control plus high-dose statin
Second choice: improved glycemic control plus statin plus fibrate
Third choice: improved glycemic control plus resin plus fibrate or improved glycemic control plus statin plus niacin (carefully monitor glycemic control) HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
Although many of the drugs are started as monotherapy, in many patients it may be necessary to use combination therapies in case the targeted levels are not reached. Which would be the second drug which should be started?
|Possible Combination Therapies If Single-Agent Therapy Is Not Effective in Reducing Lipid Levels|
|Lipid levels||First drug drug to add|
|Elevated LDL level and triglyceride level <200 mg per dL||Statin bile acidbinding resin Nicotinic acid* statin* Bile acidbinding resin nicotinic acid|
|Elevated LDL level and triglyceride level 200 to 400 mg per dL||Statin* nicotinic acid* Statin* gemfibrozil † Nicotinic acid‡ statin‡ Nicotinic acid gemfibrozil|
*--Possible increased risk of myopathy and hepatitis.
†--Increased risk of severe myopathy.
‡--The combination of nicotinic acid and lovastatin may induce rhabdomyolysis, a rare adverse drug interaction.
The importance of optimizing the lipid levels in a person with diabetes can never be minimized and one cannot say that one offers "good" diabetes management unless the dyslipidemias associated with diabetes are corrected!