As in the non-diabetic population, epidemiological studies have shown that increased LDL cholesterol and decreased HDL cholesterol levels increase the risk of cardiovascular disease in patients with diabetes. In patients with diabetes, elevations in serum triglyceride levels also are associated with an increased risk of cardiovascular disease. With regards to triglycerides, it is not clear whether they are an independent risk factor for cardiovascular disease or whether the elevation in triglycerides is a marker for other abnormalities, such as decreased HDL cholesterol levels. As discussed above, while epidemiology can provide great insights, because of the potential for unrecognized confounding variables, randomized controlled trials are required to demonstrate that reductions in lipid levels will result in a decrease in cardiovascular disease.

With the exception of one study, CARDS, the large randomized statin outcome studies have not specifically focused on the effect of statins on cardiovascular disease in patients with diabetes. As shown in Table 1, these diverse statin trials, including both primary and secondary prevention trials, have consistently shown the beneficial effect of statins on cardiovascular disease, presumably primarily by lowering LDL levels. The reduction in cardiovascular disease observed was of a similar magnitude in the diabetic subjects as in the non-diabetic subjects. Thus, the available data indicates that statins are beneficial in reducing cardiovascular disease in subjects with diabetes. Because of the large number of patients with diabetes included in the Heart Protection Study (HPS) and CARDS we will discuss these two studies in greater depth.

The HPS was a double blind randomized trial that focused on patients at high risk for the development of cardiovascular events including patients with a history of myocardial infarctions, other atherosclerotic lesions, diabetes, and/or hypertension. Patients were between 40 and 80 years of age and had to have a total serum cholesterol levels greater than 135mg/dl (thus very few patients were excluded because they did not have a high enough cholesterol level). The major strength of this trial was the large number of patients studied (>20,000). The diabetes subgroup included 5,963 subjects and thus was as large as many trials. The study was a 2x2 study design comparing simvastatin 40mg a day vs. placebo and anti-oxidant vitamins (vitamin E 600mg, vitamin C 250mg, and beta-carotene 20mg) vs. placebo and lasted approximately 5 years. Analysis of the group randomized to the anti-oxidant vitamins revealed no beneficial or harmful effects. In contrast, simvastatin therapy reduced cardiovascular events, including myocardial infarctions and strokes, by approximately 25% in all participants and to a similar degree in the diabetic subjects (total cardiovascular disease reduced 27%, coronary mortality 20%, myocardial infarction 37%, stroke 24%). Further analysis of the subjects with diabetes revealed that the reduction in cardiovascular events with statin therapy was similar in individuals with diabetes diagnosed for a short duration (<6 years) and for a long duration (>13 years). Similarly, subjects with diabetes in good control (HbA1c <7%) and those not in ideal control (HbA1c >7%) also benefited to a similar degree with statin therapy. Moreover, both Type 1 and Type 2 diabetic patients had a reduction in cardiovascular disease with simvastatin therapy (this is the only trial that included Type 1 diabetics and suggests that if Type 1 patients are over the age of 40 years of age that they will benefit from statin therapy similar to Type 2 diabetics). In general, statin therapy reduced cardiovascular disease in all subgroups of subjects with diabetes (females, males, older age, renal disease, hypertension, high triglycerides, low HDL, ASA therapy, etc) i.e. statin therapy benefited all patients with diabetes. Of particular note subjects with diabetes with baseline LDL cholesterol levels less than 116mg/dl treated with simvastatin had a reduction in cardiovascular events. Moreover, analysis of all study patients similarly demonstrated that subjects with LDL cholesterol levels less than 100mg/dl benefited from statin therapy. These results are of particular clinical importance because they demonstrate that high-risk patients with LDL cholesterol levels at goal (LDL< 100mg/dl) would nevertheless benefit from statin therapy. Because of the results of this and other studies (see below) guidelines for treating patients have recently been up dated.

The CARDS trial is the only statin trial that specifically focused on subjects with diabetes. The subjects in this trial were males and females with Type 2 diabetes between the ages of 40 to 75 years of age who were at high risk of developing cardiovascular disease based on the presence of hypertension, retinopathy, renal disease, or current smoking. Of particular note the subjects did not have any evidence of clinical atherosclerosis (myocardial disease, stroke, peripheral vascular disease) and hence this study is a primary prevention trial. Inclusion criteria included LDL cholesterol levels less than 160mg/dl and triglyceride levels less than 600mg/dl. Of note is that the average LDL cholesterol in this trial was approximately 118mg/dl indicating relatively low LDL cholesterol levels. A total of 2838 Type 2 diabetic subjects were randomized to either placebo or atorvastatin 10mg a day. Atorvastatin therapy resulted in a 40% decrease in LDL cholesterol levels with over 80% of patients achieving LDL cholesterol levels less than 100mg/dl. Most importantly, atorvastatin therapy resulted in a 37% reduction in cardiovascular events. In addition strokes were reduced by 48% and coronary revascularization by 31%. As seen in the HPS, subjects with relatively low LDL cholesterol levels (LDL <120mg/dl) benefited to a similar extent as subjects with higher LDL cholesterol levels (>120mg/dl). CARDS, in combination with the other statin trials, provide conclusive evidence that statin therapy will reduce cardiovascular events in patients with diabetes. Of note the benefits of statin are seen in patients with diabetes in both primary and secondary prevention trials.

Very few studies have compared the effect of different magnitudes of lipid lowering on the reduction in cardiovascular events in patients with diabetes. The Post-CABG study compared very low dose lovastatin (2.5-5.0mg per day) vs. high dose lovastatin (40-80mg per day) in 1,351 subjects post bypass surgery. Starting LDL cholesterol levels were between 130-174mg/dl. As expected the high dose of lovastatin reduced LDL cholesterol levels to a much greater degree than the low dose lovastatin (low dose LDL approx 135 vs. high dose LDL approx 95). The main comparison in this trial was the change in atherosclerosis in the grafts measured by comparing baseline angiography to angiography after 4.3 years. In the entire population the mean percentage of grafts with progression of atherosclerosis was 27 percent in the high dose lovastatin group and 39 percent in the low dose lovastatin group. Additionally, the rate of revascularization was reduced by 29 percent in the high dose lovastatin group. When the patients with diabetes were analyzed separately, similar beneficial effects were observed. These results indicate that lowering LDL to less than 100mg/dl would slow the angiographic changes to a greater extent than lowering the LDL to 135mg/dl. Of note though is that even with LDL levels less than 100mg/dl progression of atherosclerosis still occurred.

Recent studies have compared reductions of LDL to approximately 100mg/dl to more aggressive reductions in LDL. The Reversal Trial studied 502 symptomatic coronary artery disease patients with an average LDL of 150mg/dl. Patients were randomized to moderate LDL lowering therapy with pravastatin 40mg per day or to aggressive lipid lowering with atorvastatin 80mg per day. As expected LDL levels were considerably lower in the atorvastatin treated group (pravastatin LDL= 110 vs. atorvastatin LDL= 79mg/dl). Additionally, C-reactive peptide was reduced by 36.4% in the atorvastatin group vs. 5.2% in the pravastatin group. Most importantly, when one analyzed the change in atheroma volume determined after 18 months of therapy using intravascular ultrasound, the group treated aggressively with atorvastatin had a much lower progression rate than the group treated with pravastatin. Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden (i.e. there was a very slight regression of lesions), whereas patients treated with pravastatin showed progression of lesions. When one compares the extent of the reduction in LDL cholesterol to the change in atheroma volume, a 50% reduction in LDL (LDL levels of approximately 75mg/dl) resulted in the absence of lesion progression. This study suggests that lowering the LDL to levels well below 100mg/dl is required to prevent disease progression as measured by intravascular ultrasound.

The Prove-It trial determined in patients recently hospitalized for an acute coronary syndrome whether aggressively lowering of LDL cholesterol with atorvastatin 80mg per day vs. moderate LDL lowering with pravastatin 40mg per day would have a similar effect on cardiovascular end points such as death, myocardial infarction, documented unstable angina requiring hospitalization, revascularization, or stroke. As expected the on-treatment LDL cholesterol levels were significantly lower in patients aggressively treated with atorvastatin compared to the moderate treated pravastatin group (atorvastatin LDL= approximately 62 vs. pravastatin LDL= approximately 95mg/dl). Of great significance, death or major cardiovascular events was reduced by 16% over the two years of the study in the group aggressively treated with atorvastatin.

In the treat to new target trial (TNT) patients with stable coronary heart disease and LDL cholesterol levels less than 130mg/dl were randomized to either 10mg or 80mg atorvastatin and followed for 4.9years. As expected LDL cholesterol levels were lowered to a greater extent in the patients treated with 80mg atorvastatin (77mg/dl vs. 101mg/dl). Impressively, the occurrence of major cardiovascular events was reduced by 22% in the group treated with atorvastatin 80mg (p<0.001).

Finally, the IDEAL trial was a randomized study that compared atorvastatin 80mg vs. simvastatin 20-40mg in 8,888 patients with a history of cardiovascular disease. As expected LDL cholesterol levels were reduced to a greater extent in the atorvastatin treated group than the simvastatin treated group (approximately 104mg/dl vs. 81mg/dl). Once again the greater reduction in LDL cholesterol levels was associated with a greater reduction in cardiovascular events. Specifically, major coronary events defined as coronary death, nonfatal myocardial infarction, or cardiac arrest was reduced by 11% (p=0.07) while nonfatal acute myocardial infarctions were reduced by 17% (p=0.02).

Combining the results of the Heart Protection Study, CARDS, Reversal, Prove-It, TNT, and IDEAL leads one to the conclusion that aggressive lowering of LDL cholesterol with statin therapy will be beneficial and suggests that in high risk patients lowering the LDL to levels well below 100mg/dl is desirable. As will be discussed below guidelines have recently been updated to reflect the results of these studies.

The beneficial effect of fibrates (e.g. gemfibrizol, Tricor) on cardiovascular disease in patients with diabetes in shown in Table 2. While the data are not perfect, the results of these randomized trials suggest that this class of drug also reduces cardiovascular events in patients with diabetes. The largest trial was the Field Trial which was recently published. In this trial, patients with type 2 diabetes between the ages of 50 and 75 not taking statin therapy were randomized to fenofibrate or placebo and followed for approximately 5 years. Fenofibrate therapy resulted in a 12% decrease in LDL cholesterol, a 29% decrease in triglycerides and a 5% increase in HDL. Coronary events (coronary heart disease death and non-fatal MI) were reduced by 11% in the fenofibrate group (p= 0.16). However, there was a 24% decrease in non-fatal MI in the fenofibrate treated group (p=0.01) and a non-significant increase in coronary heart disease mortality. Total cardiovascular disease events (coronary events plus stroke and coronary or carotid revascularization) were reduced 11% (p=0.035). These beneficial effects of fenofibrate therapy on cardiovascular disease were observed in patients without a previous history of cardiovascular disease. In patients with a previous history of cardiovascular disease no benefits were observed. Interestingly, fenofibrate treatment was associated with a decreased development of retinopathy requiring laser therapy and the progression of albuminuria was decreased. The mechanism by which fibrates reduce cardiovascular events is unclear. These drugs lower serum triglyceride levels and increase HDL cholesterol but it should be recognized that the beneficial effects of fibrates could be due to other actions of these drugs. Specifically, these drugs activate PPAR alpha, which is present in the cells that comprise the atherosclerotic lesions, and it is possible that these compounds directly effect lesion formation and development. In addition, fibrates are anti-inflammatory. In fact, analysis of the VA-HIT study suggested that much of the benefit of the fibrate was not due to changes in serum lipoprotein levels. To summarize, while in general the data to date indicates that fibrates reduce cardiovascular disease in patients with diabetes, the results are not as robust or consistent as seen in the statin trials.

A single randomized trial, the Coronary Drug Project, has examined the effect of niacin monotherapy on cardiovascular outcomes. This trial was carried out from 1966 to 1974 in men with a history of a prior myocardial infarction and demonstrated that niacin therapy reduced cardiovascular events. Recently the results of this study were re-analyzed to determine the effect of niacin therapy in subjects with varying baseline fasting and 1-hour post meal glucose levels. It was noted that 6 years of niacin therapy reduced the risk of coronary heart disease death or nonfatal MI by approximately 15-25% regardless of baseline fasting or 1 hour post glucose challenge glucose levels. Particularly notable is that reductions in events were seen in the subjects who had a fasting glucose levels >126mg/dl or 1 hour glucose levels >220mg/dl (i.e. patients with diabetes). Thus, based on this single study, niacin reduces cardiovascular events both in normal subjects and patients with diabetes.

With regards to ezetimibe and the bile resin binders there have been no randomized studies that have examined the effect of these drugs on cardiovascular end points in subjects with diabetes. In non-diabetic subjects bile resin binders have reduced cardiovascular events. Since bile resin binders have a similar beneficial impact on serum lipid levels in diabetic and non-diabetic subjects one would anticipate that these drugs would also result in a reduction in events in the diabetic population. There are no outcome studies with ezetimibe (studies are in progress) but given that this drug reduces LDL cholesterol levels one would anticipate that ezetimibe will also reduce cardiovascular events.