SAN DIEGO — Intensive lipid lowering is linked to fewer cardiovascular events in diabetic patients with established cardiovascular disease—and, as in nondiabetics, “lower is better.”
That was the message from a subanalysis of 1,501 patients with diabetes who were among the 10,001 participants in Pfizer's Treating to New Targets (TNT) study, reported by James Shepherd, M.D., at the annual scientific sessions of the American Diabetes Association.
“The results suggest to me that we really should be quite aggressive with our intervention in our diabetic patients, not only with their glucose control, but also with their cardiovascular risk control,” said Dr. Shepherd, professor of pathological biochemistry at the University of Glasgow, Scotland.
In the original study, first reported in March at the American College of Cardiology meeting, 10,001 patients with stable, established coronary heart disease (CHD) and a starting LDL cholesterol level of 130 mg/dL or less were randomized to receive either 10 mg or 80 mg of atorvastatin per day and were followed for a mean of 4.9 years, lowering mean LDL levels to 101 mg/dL and 77 mg/dL, respectively.
The high-dose regimen not only resulted in a 22% relative reduction in risk of major cardiovascular events, but also significantly reduced the relative risk of stroke by 35% and of heart failure by 26% (N. Engl. J. Med. 2005;352;1425–35).
In the TNT study, 753 diabetics were randomized to 10-mg atorvastatin, while the other 748 received 80 mg. At baseline, the two groups were well matched, with an average age of 63 years.
Compared with the overall study cohort, the diabetics were heavier and had a higher proportion of women.
They also were more likely to have hypertension, peripheral vascular disease, and a history of previous cerebrovascular accidents. However, their diabetes was relatively well controlled, with a hemoglobin A1c of 7.4%, as was their mean blood pressure, at 135/77 mm Hg, Dr. Shepherd said.
At baseline, their mean LDL cholesterol level was about 150 mg/dL. After an 8-week open-label run-in period of 10-mg atorvastatin, that level was reduced to just under 100 mg/dL.
The 753 who remained on 10-mg atorvastatin for the rest of the study had a final LDL cholesterol level of 98.6 mg/dL, compared with 76.7 mg/dL in the 748 randomized to 80 mg.
During the trial, the average triglyceride level was 177.9 in the 10-mg group, compared with 145.1 mg/dL in those on 80 mg/day. Levels of HDL cholesterol were not appreciably different between the two groups.
Differences in the rates of major cardiovascular events between the high- and low-dose atorvastatin appeared soon after randomization and remained significant the entire 4.9 years, with a relative risk reduction of 25%. Overall, 17.9% of the 10-mg group had a major event, compared with 13.8% of those taking 80 mg.
Although the numbers for each individual end point were too small to reach statistical significance, most showed the same trend: 4.1% vs. 3.1% died of coronary heart disease, 8.1% vs. 6.6% had a nonfatal, nonprocedure-related MI, and 5.7% vs. 3.7% experienced a fatal or nonfatal stroke, Dr. Shepherd reported.
Cerebrovascular events were reduced by 31% overall, occurring in 10% and 7% of the 10-mg and 80-mg groups, respectively. Reductions were seen in both fatal and nonfatal stroke (5.8% vs. 4.3%) and in transient ischemic attacks (4.1% vs. 2.7%).
Although overall event rates were higher among the diabetics, the pattern of benefit with aggressive lipid lowering was similar to that of the entire TNT cohort, in whom overall major cardiovascular event rates were 10.9% with 80 mg and 8.7% with 10 mg, 2.5% vs. 2% for CHD deaths, 6.2% vs. 4.9% for nonfatal, nonprocedure-related MI, and 3.1% vs. 2.3% for fatal or nonfatal stroke.
In the diabetic participants, similar patterns were also seen for secondary event rates and clearly illustrated that having diabetes increases vascular disease risks across the board: The proportions experiencing any cardiovascular event, for example, were 44.1% of the diabetics with 10-mg atorvastatin and 39.8% of those taking 80 mg, compared with 33.5% and 28.1%, respectively, for the nondiabetics.
Peripheral arterial disease occurred in 8.9% vs. 9.1% of the diabetics, compared with 5.6% and 5.5% of the nondiabetics.
Current guidelines from the National Cholesterol Education Program, which consider diabetes a coronary risk equivalent, advise an LDL cholesterol level below 100 mg/dL for all diabetic patients.
An NCEP update published last year suggested that in patients at very high risk, including those with “multiple major risk factors (especially diabetes),” an LDL target of less than 70 mg/dL might be considered as a therapeutic option (Circulation 2004;110:227–39).