Initial treatment of lipid disorders should focus on lifestyle changes. There is little debate that exercise is beneficial and that all patients with diabetes should, if possible, exercise for at least 30 minutes 4-5 times per week. Exercise will decrease serum triglyceride levels and increase HDL cholesterol levels. Diet is debated to a greater extent. Everyone agrees that weight loss in obese patients is essential. But how this can be achieved is hotly debated with many different "experts" advocating different approaches. The wide diversity of approach is likely due to the failure of any approach to be effective in the long term for the majority of obese patients with diabetes. If successful weight loss will decrease serum triglyceride levels, increase HDL cholesterol levels, and modestly reduce LDL cholesterol.

It is also hotly debated whether a low fat, high complex carbohydrate diets vs. a high monounsaturated fat diet is ideal for patients with diabetes. One can find "experts" in favor of either of these approaches and there are pros and cons to each approach. I think it is essential to recognize that both approaches reduce saturated fat and cholesterol intake and it is likely that these changes are the most important dietary alterations that our patients need to make. The high carbohydrate diet will increase serum triglyceride levels in some patients and if the amount of fat in the diet is markedly reduced serum HDL levels may decrease. In obese patients it has been postulated that a diet high in monounsaturated fats, because of the increase in caloric density, will lead to an increase in weight gain. Both diets reduce saturated fat and cholesterol intake that will result in reductions in LDL cholesterol levels. Additionally, both of these diets also reduce trans-fatty acid intake, which will have a beneficial effect on LDL and HDL cholesterol levels. Recently there has been increased interest in low carbohydrate, increased protein diets. Short-term studies have indicated that weight loss is superior with this diet however longer studies have demonstrated a similar weight loss to that observed with conventional diets. The major concern with the low carbohydrate, high protein diet is that they tend to be high in saturated fats and cholesterol. In the short-term studies during active weight loss this has not resulted in major perturbations in serum cholesterol levels but there is concern that when weight becomes stable these diets might adversely affect serum cholesterol levels. In general while weight loss and diet therapy are beneficial, in clinical practice they are seldom sufficient because long-term life style changes are very difficult for most patients to sustain. With the currently available weight loss drugs only modest effects on weight have been observed. In some patients weight loss drugs may be a useful adjuvant to diet therapy.

Lastly, some "experts" advocate the addition of fish oil. Fish oil will lower serum triglyceride levels and studies in non-diabetic subjects indicate a reduction in cardiovascular events. Most studies of fish oil in patients with diabetes have demonstrated that this is a safe approach but an occasional study has reported worsening of glycemic control in patients with diabetes treated with fish oil. Additionally, in some patient's fish oil increases LDL cholesterol levels.

The effect of statins, fibrates (TRICOR), niacin, ezetimibe and bile resin binders on lipid levels in patients with diabetes is virtually identical to that seen in the non-diabetic patients (Table 7). Statins, ezetimibe, and fibrates are easy to use and generally well tolerated by patients with diabetes. Bile resin binders are difficult to take due to GI toxicity (mainly constipation). Diabetic subjects have an increased prevalence of GI symptoms and it is likely that this will be exacerbated by the use of bile resin binders. In diabetic patients with diarrhea the use of bile resin binders may be advantageous. Bile resin binders may increase serum triglyceride levels, which can be a problem in some patients with diabetes who are already hypertriglyceridemic. An additional difficulty in using bile resin binders is their potential for binding other drugs. Other drugs should be taken either two hours before or four hours after taking a bile resin binder to avoid the potential of decreased drug absorption. Diabetic patients are frequently on multiple drugs for glycemic control, hypertension, etc., and it can sometimes be difficult to time the ingestion of bile resin binders to avoid other drugs. Lastly, niacin reduces insulin sensitivity (i.e., causes insulin resistance), which can worsen glycemic control. Recent studies have shown that low doses of niacin (<2000mg/day) are well tolerated in diabetic subjects who are in good glycemic control. In patients with poor glycemic control, niacin is more likely to adversely impact glucose levels. High doses of niacin are also more likely to adversely affect glycemic control. Niacin can also increase serum uric acid levels and induce gout, an abnormality that is already common in obese patients with Type 2 diabetes. However, niacin is the most effective drug in increasing HDL cholesterol levels, which are frequently low in patients with diabetes.

The first priority in treating lipid disorders in patients with diabetes is to lower the LDL cholesterol levels to goal. LDL is the first priority because the database linking LDL with cardiovascular disease is extremely strong and we now have the ability to markedly decrease LDL cholesterol levels. Dietary therapy is the initial step but in most patients will not be sufficient to achieve the LDL goals. If patients are willing and able to make major changes in their diet it is possible to achieve remarkable reductions in LDL cholesterol levels but this seldom occurs in clinical practice. Statins are the first choice drugs to lower LDL cholesterol levels and the majority of diabetic patients will require statin therapy. There are six statins currently available in the US and one should be sure to choose a statin that is capable of lowering the LDL to goal. The effect of different doses of the various statins on LDL cholesterol levels is shown in Table 8. If a patient is unable to tolerate statins or statins as monotherapy are not sufficient to lower LDL to goal the second choice drug is ezetimibe. Ezetimibe can be added to any statin and is now available in a combination pill with simvastatin (Vytorin). If additional LDL lowering is required or a patient cannot tolerate ezetimibe one could add a bile resin binder. Both ezetimibe and bile resin binders additively lower LDL cholesterol levels when used in combination with a statin because the mechanism of action of these drugs is to increase hepatic LDL receptor levels thereby resulting in a reduction in serum LDL levels. Niacin and the fibrates also lower LDL cholesterol levels (see table 7).

The second priority should be non-HDL cholesterol (total cholesterol – HDL cholesterol = non-HDL cholesterol), which is particularly important in patients with elevated triglyceride levels. Non-HDL cholesterol is a measure of all the pro-atherogenic apolipoprotein B containing particles. Numerous studies have shown that non-HDL cholesterol is a strong risk factor for the development of cardiovascular disease. The non-HDL cholesterol goals are 30mg/dl greater than the LDL cholesterol goals. For example, if the LDL goal is <100mg/dl then the non-HDL cholesterol goal would be <130mg/dl. Drugs that reduce either LDL cholesterol or triglyceride levels will reduce non-HDL cholesterol levels.

The third priority in treating lipid disorders is to increase HDL cholesterol levels. There is strong epidemiologic data linking low HDL cholesterol levels with cardiovascular disease but unfortunately our ability to increase HDL cholesterol levels is relatively limited. Life style changes are the initial step and include increased exercise, weight loss, and stopping cigarette smoking. The role of recommending ethanol is controversial but in patients who already drink moderately there is no reason to recommend that they stop. The first choice drug for increasing HDL levels is niacin (see Table 7). Fibrates and statins also raise HDL cholesterol levels but the increases are modest (usually less than 15%). Unfortunately, given the currently available drugs it is very difficult to significantly increase HDL levels and in many of our diabetic patients we are unable to achieve HDL levels in the recommended range.

The fourth priority in treating lipid disorders is to decrease triglyceride levels. Initial therapy should focus on glycemic control. Improving glycemic control can have profound effects on serum triglyceride levels. Fibrates, niacin, statins, and fish oil all reduce serum triglyceride levels (see Table 7).

Many diabetic patients have multiple lipid abnormalities. As discussed in detail above life style changes is the initial therapy. If life style changes are not sufficient in patients with both elevations in LDL and triglycerides (and elevations in non-HDL cholesterol) my approach to drug therapy is based on the triglyceride levels (Figure 1). If the serum triglycerides are very high (greater than 500mg/dl), where there is an increased risk for pancreatitis and hyperviscosity syndromes, initial pharmacological therapy is directed at the elevated triglycerides and the initial drug choice is either a fibrate or niacin. If the serum triglycerides are less than 500mg/dl, statin therapy to lower the LDL level to goal is the initial therapy (see Figure 1). Studies have clearly demonstrated that statins are effective drugs in lowering triglyceride levels in patients with elevated triglycerides. In patients with normal triglyceride levels statins do not greatly affect serum triglyceride levels. If the triglyceride levels remain above goal one can then consider combination therapy.

Often monotherapy is not sufficient to completely normalize the lipid profile. For example, often with statin therapy one lowers the LDL to goal but the HDL and triglycerides remain in the abnormal range. Currently, there are no randomized controlled trials demonstrating that combination therapy reduces cardiovascular disease to a greater extent than monotherapy. However, many experts believe that further improvements in the lipid profile will be beneficial. When using combination therapy one must be aware that the addition of either fibrates or niacin to statin therapy increases the risk of myositis. The increased risk of myositis is greatest when gemfibrizol is used in combination with statins. Fenofibrate seems to have a lower risk. The increased risk with niacin appears to be very modest and there is even a combination pill containing lovastatin and niacin available (Advicor). It is my opinion that the risks of combination therapy are relatively modest if patients are carefully selected and that in many patients at high risk for cardiovascular disease combination therapy is appropriate. One should be aware of the steps listed in Table 9 that can reduce the potential for toxicity when one uses combination therapy. As with many decisions in medicine one needs to balance the benefits of therapy with the risks of therapy and determine for the individual patient the best approach.

In summary, modern therapy of patients with diabetes demands that we normalize lipid levels to reduce the high risk of cardiovascular disease in this susceptible population.