Venice, Italy - Results from a study presented this week at the Drugs Affecting Lipid Metabolism 2004 meeting have shown that in a cohort of type 2 diabetic patients, statin therapy with cerivastatin for two years had no effect on mean common carotid intima-media thickness (IMT), despite an LDL cholesterol reduction of 25% [1]. According to investigators, other diagnostic tools may be necessary to assess cardiovascular risk in patients with type 2 diabetes.

"Typically, patients with diabetes have a higher IMT than normal patients, but we found there was no progression, despite expecting to see some," said Dr Edith D Beishuizen (Leiden University Medical Center, Leiden, the Netherlands). "You also see no regression on statin therapy despite the reduced cardiovascular event rate. We think that once you have type 2 diabetes, there have been years of exposure to other cardiovascular risk factors, such as dyslipidemia, hypertension, obesity, and metabolic syndrome. Once you reach this final stage, the vessel wall may be irreversibly damaged and the drugs are unable to exert a beneficial effect."

In an interview with heartwire, Beishuizen explained that the study was designed in 1997 and at that time it wasn't clear if primary prevention with statin therapy was effective in diabetic patients, thus leading investigators to design the trial to assess the effects of statin therapy on the vascular wall in type 2 diabetics. "Now we have CARDS and the diabetic subgroups from the Heart Protection Study, so we know that statin therapy is effective in diabetic patients. What we still didn't know was if this was due to the LDL-cholesterol lowering or if there were other effects on the vascular wall," said Beishuizen.

Investigators initially randomized 250 type 2 diabetic patients to cerivastatin 0.4 mg or placebo. In August 2001, when cerivastatin was withdrawn from the market, patients taking the statin were switched to simvastatin 20 mg without unblinding the study. The primary end point was the mean change in common carotid IMT, as measured by B-mode ultrasound, over two years. Secondary end points included changes in the IMT of the other carotid and femoral segments and cardiovascular events.

At two years, there was no effect of statin therapy on the mean common carotid IMT, despite the significant reductions in LDL cholesterol. There were also no statistically significant changes in the IMT of other carotid and femoral segments. According to Beishuizen, although they observed a significantly lower cardiovascular event rate in patients on statin therapy, the natural history of IMT was "milder" than anticipated. There was also no progression of IMT in patients randomized to placebo, causing investigators to speculate that statins are unable to exert an influence on the irreversibly changed glycosylated extracellular matrix.

"We've seen in other studies, such as ARIC and other IMT studies in diabetic patients, that progression on IMT is not as fast as you would think when you look at clinical events," said Beishuizen. "Also, in this trial, clinical events were very high in the placebo group in comparison with the statin group, so there must be some other mechanism apart from IMT that is causing this."

Beishuizen said it was surprising and somewhat disappointing not to find any correlation. However, once the results are considered, she said, they lead to the intriguing possibility that in terms of risk stratification, IMT may not be an effective tool in diabetic patients.

"We believe the value of statin therapy in diabetic patients is not to be debated, based on the evidence from CARDS and the other trials," said Beishuizen. "But other tools may need to be used, such as MRI or other noninvasive tools to assess cardiovascular risk. I suppose you could argue that everybody with diabetes has a high risk and that they should all be treated as high-risk patients. But we don't think that's correct, because even within the diabetic subgroup there are patients that do very well and progress very slowly. We still think there is a need for risk stratification."