Dr. S.M.Sadikot.
Hon. Endocrinologist,
Jaslok Hospital and Research Centre,
Mumbai 400026

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.

EVALUATION

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.

LIPID RANGES

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.