Reviews

Secondary Prevention Trials

Secondary Prevention Trials: Statins

The Scandinavian Simvastatin Survival Study (4S Study) trial was a cholesterol lowering study with simvastatin in 4,444 subjects (of whom 5% were diabetic) with prior myocardial infarction followed for an average of 5.4 years. The investigators have recently presented the results of subgroup analysis in the 202 subjects with diabetes in the 4S study. This study is very important for a number of reasons. Although the diabetic subgroups analyses are post hoc, the investigators have been the first to show that a modification of dyslipidemia significantly decreases the risk of new CHD events in diabetes subjects with CHD. Particularly impressive is the magnitude in the reduction of risk of CHD (55%) in diabetic subjects, which is actually greater than in nondiabetic subjects (32%). One important implication of 4S data is 2.5-fold higher CHD risk in diabetic subjects than in the nondiabetic subjects. Thus the results suggests that the absolute clinical benefit achieved by cholesterol lowering with simvastatin may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events. Simvastatin was also effective in each of the lipid subgroups examined. Indeed, simvastatin appeared to be possibly more effective in subjects with low HDL cholesterol or high triglyceride levels, although the tests of statistical interaction were not significant. Thus, at least in diabetic subjects with CHD, very aggressive LDL, lowering may be beneficial.

Recently limited data have become available with respect to the Cholesterol And Recurrent Events (CARE) Study (11% of the study subjects were diabetic). In this study, the average LDL cholesterol was 139 mg/dl. In 586 subjects with diabetes and CHD, 40 mg of pravastatin was associated with a 25% decrease in major CHD events and revascularization procedures, which was similar to a 23% decrease observed in nondiabetic subjects.

Secondary Prevention Trials: Fibrates

Gemfibrozil and Bezafibrate are the fibric acid agents that have undergone clinical trials. In the recently reported Bezafibrate Coronary Angiographic Intervention Trial (BECAIT), bezafibrate reduced coronary events in 92 men over a 5-year period. The Diabetes Atherosclerosis Intervention Study (DAIS) is a multicenter, double- blind, randomized, placebo-controlled trial with the primary objective to determine whether fenofibrate (200 mg micronized) will reduce progression of pre-existing atherosclerotic lesions (angiographically proved) over 36 months. If these new fibric acid agents show reduction in overall mortality as well as CHD, the safety issue mortality of fibric acids (observed in Helsinki Heart Study) will need to be revised. Bezafibrate, like fenofibrate, also has an advantages of greater reduction in LDL cholesterol than gemfibrozil.

In a study designed to compare the efficacy of statin and fibrate in diabetic patients, 400 mg bezafibrate or 10 mg simvastatin was given to diabetic patients with dyslipidemia in a double-blind fashion. It was found that bezafibrate mainly increases HDL cholesterol and lowers serum triglycerides but at the expense of an increase in LDL cholesterol whereas simvastatin lowers LDL cholesterol more effectively but has a smaller effect on HDL cholesterol and triglycerides.

Primary Prevention Trials

Primary Prevention Trials: Statins

Primary prevention trials on diabetic subjects with statins are scarce. But primary prevention trial with prevastatin was conducted in the West of Scotland Coronary Prevention Study (WOSCOPS), and has shown significant reductions in CHD in hypercholesterolemic nondiabetic subjects.

Primary Prevention Trials: Fibrates

In the Helsinki Heart Study, gemfibrozil was associated with a significant reduction of CHD events in subjects free of CHD at baseline, especially in those with elevated triglyceride levels and lower HDL cholesterol levels. There was effect on mortality. Of the subjects, 135 had diabetes at baseline. In these subjects, gemfibrozil reduced the risk of CHD by 60%, the result statistically was not significant.

In a primary prevention trial with bezafibrate in hyperlipidemic type 1 diabetes, serum cholesterol, triglyceride and fibrinogen decreased to a significant extent, whereas serum apolipoprotein B, apolipoprotein a and HDL cholesterol showed no significant change.

Other Agents

Obesity is an important risk factor in diabetes and is a contributory factor in the adverse cardiovascular outcome and dyslipidemia. Sibutramine, (anti-obesity drugs), a selective reuptake inhibitor of serotonin and noradernaline (SNRI), has been shown to produce weight loss significantly decrease triglyceride levels and increase HDL cholesterol levels in type 2 diabetes. Orlistat, a pancreatic lipase inhibitor was assessed in a multicenter study on its effect on dyslipidemia. It was noted that orlistat causes improvement of lipid profile in obese type 2 diabetics compared to placebo. Metformin is an effective antihyperglycaemic agent. It improves lipid profile particularly by decreasing LDL and total cholesterol levels and increasing HDL cholesterol levels in obese type 2 diabetes.

Nicotinic acid is a very useful agent in the treatment of dyslipidemia. It reduces triglycerides to significant extent, and decreases LDL cholesterol and significantly is the only agent known to decrease Lp(a), but is contraindicated in diabetes because of its tendency to worsen the glycemic control.

Fish oil contain eicosapentaenoic acid and docosahexaenoic acid is known to decrease triglycerides. A mate-analysis on 26 published trials on diabetic have shown that fish oils decrease triglyceride to a significant extent of about 30% in type 2 diabetic subjects and it has no significant adverse effect on glycemia.

Dietary treatment of Dyslipidemia in Diabetes

Dietary treatment of dyslipidemia is a necessary foundation of drug treatment. Depending on the degree of hyperlipidemia, the Step I or Step II diets can be introduced sequentially, or the step II diet can be begun immediately (or when the drug therapy is begun) if the patient is already restricting his or her intake of saturated fatty acids to less than 10 percent of total calories and if the risk of cardiovascular disease is high. The Step I diet contains no more than 30 percent of calories from fat, less than 10 percent of calories from saturated fatty acids, and less than 300 mg of cholesterol per day. The Step II diet contains no more than 30 percent of calories from fat, less than 7 percent of calories from saturated fatty acids, and less than 200 mg of cholesterol per day.

In long term studies the Step II diet decreased serum LDL cholesterol concentrations from 8 to 15 percent. In additions diet can help to reduce weight to an ideal level, reduce blood pressure and insulin resistance. Diets more restricted in fat than Step II diet result in little additional reduction in serum LDL cholesterol concentrations, rather it raises serum triglyceride concentrations and lower serum HDL cholesterol concentrations.

Treatment Goals for Lipoprotein Therapy

The National Cholesterol Educations Program (NCEP) Adult Treatment Panel II suggests targets for LDL lowering that are dependent on the categories of CHD risk. For subjects with established CHD (i.e. for secondary prevention), the goal for target LDL cholesterol is less than 100 mg/dl, while for high risk primary prevention, the goal is 130 mg/dl and for low risk primary prevention, the goal is 160 mg/dl. Two or more risk factors compromise high risk, and diabetes itself counts as a single risk factor in the algorithm. However, the text of the NCEP suggests that diabetic women may be at as high risk as diabetic men (suggesting that perhaps all diabetic subjects should have an LDL cholesterol less than 130 mg/dl). Furthermore, the panel suggested that diabetic subjects might be treated as if they had CHD (i.e. goal less than 100 mg/dl). The latter recommendation is strongly indicated by the high case fatality rate in diabetic subject with CHD.

The optimal LDL cholesterol level in adults with diabetes is less than 100 mg/dl, optimal HDL cholesterol level is more than 45 mg/dl, and desirable triglycerides is less than 200 mg/dl. Since clinical trials provide data on the benefit of LDL lowering, the primary emphasis is placed on it, rather than on HDL raising and triglyceride lowering which theoretically seems more attractive. Raising HDL cholesterol levels pharmacologically is very difficult in diabetic patients since the most effective agent in raising HDL cholesterol is nicotinic acid which is relatively contraindicated in diabetes because of its potential to worsen the glycemia. Fibrates causes a modest elevation of HDL cholesterol in addition to their potential for significant triglyceride lowering. Amongst the statins, simvastatin and atorvastatin increases HDL by about 8%.