For lipid control, there have been several important primary-prevention and secondary-prevention trials.
For primary prevention, seven studies with diabetic patients are noteworthy:
1. The Prevention Study/Texas Coronary Atherosclerosis Prevention Study (3). This study randomly assigned patients with average cholesterol levels of 221 mg/dL, LDL of 150 mg/dL, and lower than normal HDL of 36 mg/dL for men and 40 mg/dL for women, to 20-40 mg/day of lovastatin or placebo, and followed them for an average of 5.2 years. Of these patients, 155 were diabetic. In this study, lovastatin led to a relative risk (RR) reduction of 0.56% for any arteriosclerotic event (fatal or nonfatal myocardial infarction, unstable angina, or sudden death) and an absolute risk reduction of 0.04. Despite LDL levels of 115 mg/dL and HDL levels of 39 mg/dL at the end of the study, the differences in the patients with diabetes were not statistically significant.
2. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial-Lipid Lowering Trial (ALLHAT-LLT) (4) randomly assigned patients 55 years and older who had hypertension and at least one other risk factor to 40 mg/day of pravastatin or to placebo. There were 3638 patients with diabetes in the subgroup analysis. The relative risk reduction was 0.89 for coronary heart disease (CHD).
3. The Helsinki Heart Study (5) randomly assigned men aged 40-55 years with elevated non-HDL cholesterol levels to 600 mg of gemfibrozil twice daily or to placebo. The starting mean total cholesterol was 290 mg/dL and the mean HDL was 47.6 mg/dL. There were 135 patients with diabetes in this study, and the incidence of CHD was 3.45% in the gemfibrozil group and 10.5% in the placebo group at 5 years. The relative risk was 0.32 and the absolute risk was 0.07; neither was statistically significant.
4. The landmark Heart Protection Study (HPS) (6) included both primary-prevention and secondary-prevention data in patients with diabetes who were at risk for cardiovascular disease. The objective was to study the effects of a fixed dose of simvastatin across a wide range of lipid abnormalities, from lipid levels below, at, and above goal. This study enrolled 3982 diabetic patients and treatment with 40 mg of simvastatin led to reduced risk for CHD events of statistical significance, with relative risk reductions of 0.74 and absolute risk reductions of 0.05.
5. The Prospective Study of Pravastatin in the Elderly at Risk study (7) randomly assigned men and women 70-82 years of age with a history of cerebral or peripheral vascular disease to 40 mg/day of pravastatin or placebo. In the primary-prevention group, 396 patients had diabetes. Pravastatin led to a trend toward harm with interaction between the diabetes and the treatment group, suggesting that patients with diabetes did substantially worse than patients without diabetes.
6. The Anglo-Scandinavian Cardiac Outcome Trial-Lipid Lowering Arm (8) randomly assigned patients aged 40-79 years with CHD and hypertension to 10 mg/day of atorvastatin. In the diabetes subgroup, 2532 patients who had hypertension and at least two other risk factors had lower event rates (3.6% in the control group and 3% in the intervention group). The absolute and relative risk reductions were not significant in the diabetes group.
7. The Collaborative Atorvastatin Diabetes Study (CARDS) (9) evaluated 2838 patients with type 2 diabetes, aged 40-75 years, without high LDL cholesterol, to determine the efficacy of 10 mg of atorvastatin to placebo in the primary prevention of major cardiovascular events. The average duration of follow up was 3.9 years. The primary end point was time to first occurrence of acute coronary heart disease events, coronary revascularization of stroke. Atorvastatin reduced acute CHD events by 36% coronary revascularizations by 31%; and rate of stroke by 48%. Treatment with atrovastatin would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years.
For secondary prevention, eight trials are noteworthy:
1. The landmark Scandinavian Simvastatin Survival Study (4S) randomly assigned patients with coronary disease to 20 mg/day of simvastatin, or placebo. There were 202 patients with diabetes included in a subgroup analysis. The 4S had the highest event rate of any of the control groups studied, indicative of a very high-risk population. Statistically significant absolute and relative risk reductions of 0.23 and 0.50, respectively, were seen. Of all of the data from the secondary-prevention trials, the 4S was particularly impressive. The 4S represented the first randomized, double-blind, placebo-controlled, mortality study that was powered to examine the effects of long-term simvastatin therapy and total mortality and coronary events in patients with a previous myocardial infarction and/or angina pectoris and mild to moderate elevations in serum cholesterol (10).
Of all of the lipid trials, the patients in the 4S were at greatest risk of an event when we compare event rates in the placebo group. The 4S involved 4444 men and women, 35-70 years of age, in 94 clinical centers in five countries. The 4S patients had established histories of myocardial infarction and/or angina pectoris. Triglyceride levels were less than 221 mg/dL and total cholesterol ranged from 212 to 309 mg/dL. Treatment with simvastatin significantly improved survival over a median of 5.4 years. The risk of total mortality was reduced by 30%, and the risk of coronary mortality was reduced by 42% by the end of the study. This 42% reduction in coronary mortality accounted for the improvement in overall survival. The risk of major coronary events was reduced by 34% at the end of the study. Major coronary events included coronary death and nonfatal death, myocardial infarction, or resuscitated cardiac arrest (10).
The results are even more remarkable in the post hoc subgroup analysis in the simvastatin trial. The post hoc subgroup analysis included 202 diabetic patients at baseline with a mean age of 60 years; 72% of these patients were male. In this diabetic group, 12% were treated with insulin, 39% were on oral hyperglycemic drugs, and 50% were on diet therapy alone. Mean baseline glucose levels were 154.9 mg/dL in the placebo group and 154.2 mg/dL in the simvastatin group. Total cholesterol was 259.9 mg/dL in the placebo group and 259.5 mg/dL in the simvastatin group; LDL was 185.6 mg/dL in the placebo group and 186.0 mg/dL in the simvastatin group; and triglycerides were 157.7 mg/dL in the placebo group and 149.7 mg/dL in the simvastatin group (10).
Over the course of the trial, the simvastatin-treated diabetic patients had a reduction of 27% in total cholesterol, a reduction of 36% in LDL cholesterol, an increase of 7% in HDL, and a reduction of 11% in triglycerides. The major revelation was the reduction in coronary events: the risk of major CHD events was significantly reduced by 54% in patients with diabetes, with a p value of 0.002!
There were equally significant reductions for the risk of any CHD events (p = 0.015), and of any atherosclerotic event (p = 0.018). The 6-year probability of escaping a major coronary disease event was 50.7% in the placebo group and 75.1% in the simvastatin group, representing a 55% risk reduction in the diabetic cohort, even more impressive than the 32% risk reduction in the nondiabetic cohort. The risk of major CHD events was significantly reduced in patients with diabetes and the risk of any CHD was also substantially reduced (to a statistically significant degree). The diabetic patients included in the 4S tended to have a longer duration of CHD and a higher prevalence of chest pain on exertion than their nondiabetic cohorts (10).
Based on the data from the 4S, the potential benefit of simvastatin treatment for 6 years in 100 patients would prevent an expected major CHD event in 9 of 29 nondiabetic patients, compared with 24 of 49 patients with diabetes. Thus, there is a significant benefit, in addition to the lipid-lowering effects, in using simvastatin in the diabetic patient population.
This post hoc subgroup analysis on patients with diabetes provided the first trial-based evidence that cholesterol lowering significantly and convincingly reduced the risk of major CHD events and other atherosclerotic events in diabetic patients (10).
The treatment effect did not seem to depend on baseline total cholesterol or LDL cholesterol levels. This data has suggested that the clinical benefit was greater in diabetic patients than nondiabetic patients because of their underlying increased risk.
In addition to the 4S, an expanded 4S diabetes post hoc subgroup analysis trial was published by Haffner (11) in the Journal of Diabetes Care. In this study, subjects with known baseline fasting glucoses were evaluated using updated 1997 American Diabetes Association diagnostic criteria. This added an additional 281 subjects to the diabetic subcohort. In addition to the 202 diabetes subjects previously identified, an additional 281 subjects met the American Diabetes Association criteria of having fasting glucoses greater than 126 mg/dL. Of the remaining individuals, 678 met the criteria for impaired fasting glucose (fasting glucose between 110 mg/dL and 125 mg/dL) and 3237 patients still were within the normal range. Interestingly, the event rate in the placebo groups was similar to the data obtained in previous cohorts, showing that the patients with normal fasting glucoses had a 5-year event rate of approximately 26%. Patients with impaired fasting glucose had an event rate of 30%, patients with diabetes with elevated fasting glucoses had an event rate of 32%, and patients who were known to have diabetes had a 5-year event rate of 45%.
Compared with the 335 placebo-treated, impaired fasting glucose subjects, the 343 simvastatin-treated, impaired fasting glucose subjects had significantly reduced coronary mortality; with a relative risk reduction of 56%, a relative risk reduction in total mortality of 46%, a 40% risk reduction of major coronary events, and a 43% risk reduc tion in revascularizations, all of which were statistically significant. The study also demonstrated improved survival, with reduced major coronary events and fewer revascularizations in the simvastatin-treated 4S patients with impaired fasting glucose. The 251 simvastatin-treated diabetic patients had significantly fewer major coronary events and revascularizations compared with placebo, and a reduction of coronary events of 42% and revascularizations 47% in the diabetic cohort (10).
In fact, if we look at all the CHD prevention trials with statins in diabetic patients, including the Heart Protection Study, data with simvastatin in the 4S trial, in terms of CHD risk reduction, demonstrates more robust and statistically significant reductions than seen with any other statin trial to date (10).
2. The Lescol Intervention Prevention Study (12) was conducted in patients who had undergone percutaneous coronary intervention. Patients were randomly assigned to 80 mg/day of fluvastatin or placebo. There were 202 patients with diabetes, who had an absolute risk reduction of 0.16 with a relative risk reduction of 0.53 in preventing CHD events.
3. The Long Term Intervention with Pravastatin in Ischemic Disease trial (13) randomly assigned patients with known heart disease to 40 mg/day of pravastatin or placebo. There were 782 patients with diabetes in the subgroup. There was a relative risk reduction of 0.84 and an absolute risk reduction of 0.04 for cardiovascular events, but neither was significant.
4. The Prospective Study of Pravastatin in the Elderly at Risk trial (7) randomly assigned elderly patients (over 70 years of age) to pravastatin. The secondary-prevention arm involved 227 patients with diabetes. A harmful trend in secondary prevention was also noted in this study.
5. The Post-Coronary Artery Bypass Graft trial (14) randomly assigned patients who had undergone coronary artery bypass grafting to aggressive (60-85 mg/dL) or moderate (130-140 mg/dL) LDL targets. Lovastatin was used, and 116 patients had diabetes. Aggressive lowering led to nonsignificant reductions in absolute and relative risks.
6. The Cholesterol and Recurrent Events trial (15) randomly assigned patients with previous myocardial infarction to 40 mg/day of pravastatin or placebo. In this study, 586 patients had diabetes, and achieved an absolute risk reduction of 0.08 and a relative risk reduction of 0.78.
7. The HPS trial (16) looked at the effects of simvastatin in 20,536 patients between the ages of 40 and 80 years, with coronary artery disease, myocardial infarction in the past, hypertension, or diabetes. In this trial, more than 8000 patients were diabetic. Doses were not adjusted. The relative risk reduction was 0.89 for any cardiovascular event and the absolute risk reduction was 0.04, both statistically significant. These individuals were all given 40 mg of simvastatin with no titration. This study demonstrated that this dose safely reduced the risk of heart attack, stroke, and revascularization by approximately one-third. The number needed to treat for major vascular events was seven in diabetic patients. Another important conclusion from the HPS trial was that reduction rates in major vascular events decreased even below the previously held threshold level of 100 mg/dL of LDL, demonstrating that lower is better for LDL reduction in both the diabetic and nondiabetic patient populations (5).
8. The Veterans Administration High-Density Lipoprotein Cholesterol Intervention Trial (17) targeted male patients with the low HDL and low LDL syndrome. HDL levels were less than 40 mg/dL and the LDL levels were less than 140 mg/dL. This study enrolled only patients with documented coronary disease. In the diabetes subgroup, the RR for cardiovascular events was 0.76 and the absolute risk reduction was 0.08. Including patients with undiagnosed diabetes reduced risks further to a RR of 0.68 and an absolute risk reduction of 10%.
The cardinal principal to be understood in reducing mortality in patients with diabetes is the reduction in ischemic and cardiovascular events. Arteriosclerotic complications from diabetes are responsible for 80% of diabetic mortality and 75% of this mortality is caused by cardiovascular disease.
Diabetes predisposes the individual to diffuse atherosclerotic cardiovascular disease, increases the severity of atherosclerotic deposition, and enhances the prevalence of multivessel cardiovascular disease, making these vessels less amenable to percutaneous transluminal coronary angioplasty.
The ongoing Framingham Heart Study shows that the data for diabetic women is even more alarming than for men, with the relative risk for heart failure, claudication, CHD, and total cardiovascular disease increased compared with men. Both diabetic men and women are more likely to have a first myocardial infarction and die within the first 5 years of an myocardial infarction than their nondiabetic cohorts (18).
The East/West Study (19) published in the JAMA in 1998 showed that the incidence of myocardial infarction in the patient with diabetes was equal to that for a second myocardial infarction in a nondiabetic patient. Although subsequent myocardial infarction occurred in 45% of the 1059 diabetic patients studied compared with 19% of the nondiabetic patients over 7 years, the Minnesota Heart Survey also indicated that the risk of death is 40% higher in diabetic individuals who had a myocardial infarction than in nondiabetic individuals after 6 years of follow-up, and that patients with diabetes are more likely to have heart failure with acute myocardial infarction (20).
There are several potential mechanisms of atherogenesis in diabetes, including abnormalities in apoprotein-particle and lipoprotein-particle distribution, procoagulant state, enhanced insulin resistance and hyperinsulinemia, glycosylation and advance glyca-tion of proteins in the plasma arterial wall, hypertension, hormone growth factor, and cytokine-enhanced smooth-muscle cell proliferation and foam cell formation, local tissue ischemia, and hypoperfusion with enhanced elaboration of angiotensin II and impaired nitric oxide release.
Proteins in the vessel wall, such as collagen, elastin, and fibrin, may become glycosylated, and these glycosylated proteins acquire properties that are different from the properties of nonglycosylated proteins. Diabetes poses a constant oxidative stress at the tissue level, with glycated LDL more easily oxidized than nonglycated LDL.
The procoagulant state increases a s insulin resistance increases. Insulin resistance is associated with elevated circulated levels of free fatty acids. These elevated free fatty acid levels have an effect on the liver levels, enhancing triglyceride content of VLDL particles, increasing the circulated levels of apolipoprotein (Apo) B, and increasing overall VLDL levels.
Triglyceride-rich VLDL particles exchange triglyceride for cholesterol with HDL, which leads to enhanced removal of Apo A-1 by the kidney, allowing the HDL particle to be more susceptible to metabolism and removal. The abnormal VLDL particles affect the composition of LDL because of the exchange of triglyceride for cholesterol.
The net result is the formation of small, dense LDL particles and a suppression of the HDL, particularly the HDL-2 fraction. The HDL-2 fraction participates more in reverse cholesterol metabolism. Clearly, the overproduction of small, dense LDL and the reduction in HDL enhances arteriosclerotic formation, resulting in decreased affinity for the
LDL receptor, increased vascular permeability, and enhanced susceptibility of oxidation and conformational changes in the Apo B, which enhances arteriosclerotic deposition. LDL lowering has a beneficial effect on endothelial function in hypercholesterolemic patients, this has important implications for myocardial ischemia, stroke, and overall cardiovascular wellness (21).
Improvement in endothelial function is critical to managing arteriosclerotic vascular disease because increased degradation of nitric oxide is a key factor in promoting endothelial abnormalities.
Oxidative stress and local tissue injury enhance the production of angiotensin II, which promotes increased catabolism of nitric oxide and vasoconstriction. Angiotensin Il-mediated generation of free radicals enhances the upregulation of leukocyte adhesion molecules and chemotaxis in cytokines, making the endothelium more likely to be a collection locale for inflammatory cells and macrophages, which degenerate into foam cells with progressive accumulation of LDL.
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