KEYSTONE, COLO. — The size and composition of lipids in type 1 diabetics—rather than classically abnormal lipid levels—may explain the dyslipidemia of many such patients and why they end up with cardiovascular disease, Dr. Robert H. Eckel said at a conference on the management of diabetes in youth.
Case in point: HDL cholesterol levels in persons with type 1 diabetes are typically normal or even elevated. Moreover, their HDL cholesterol is particularly rich in the large, buoyant subfraction believed to be particularly cardioprotective, according to Dr. Eckel, immediate past president of the American Heart Association and professor of medicine, physiology, and biophysics at the University of Colorado.
So why, then, do diabetic patients have cardiovascular disease rates so high that the National Cholesterol Education Program has deemed diabetes a coronary disease equivalent?
The answer isn't known, but Dr. Eckel believes the work of Dr. Alan M. Fogelman and colleagues at the University of California, Los Angeles, provides strong clues. They have shown the HDL cholesterol in patients with CAD and high HDL cholesterol levels is modified so as to be proinflammatory. In vitro studies have found that this HDL cholesterol stimulates production of cytokines that enhance lipid oxidation, vascular inflammation, and plaque growth.
“I'm wondering if the HDL present in type 1 diabetes is defective in its ability to act as an antioxidant, making it noncardioprotective. I think it's a hypothesis that has not been adequately addressed,” Dr. Eckel said at the conference sponsored by the University of Colorado and the Children's Diabetes Foundation, Denver.
Danish investigators have demonstrated that type 1 diabetic patients have increased transcapillary escape rates of LDL cholesterol from the intravascular space into the arterial wall (Atherosclerosis 2003;170:163–8). Under such circumstances, a person could have a normal plasma LDL cholesterol value—as do many type 1 diabetic patients—and yet faster LDL cholesterol transit into the vessel wall would lead to accelerated atherosclerosis.
Although Dr. Eckel emphasized he is a strong proponent of aggressive lipid modification in patients with type 1 diabetes—“an LDL below 100 mg/dL should be considered the ceiling,” he said, adding that surprisingly, there is “almost zero” evidence that favorably modifying lipids improves cardiovascular outcomes in these high-risk patients.
For example, the Heart Protection Study—widely hailed as a landmark clinical trial—included 615 type 1 diabetic subjects among its more than 20,000 participants. In striking contrast to the study's overall results, the 5-year cardiovascular event rate in type 1 diabetic patients was not significantly better with aggressive LDL cholesterol lowering with 40 mg/day of simvastatin than placebo, although a favorable trend was noted (Lancet 2003;361:2005–16).
On the other hand, intriguing preliminary evidence suggests lipid-modifying therapy may reduce the risk of various forms of diabetic microangiopathy. For example, Indian physicians have reported that simvastatin slowed progression of retinopathy in hypercholesterolemic diabetic patients (Diab. Res. Clin. Pract. 2002:56:1–11).
This result is lent credence, Dr. Eckel said, by a prospective study of 1,441 type 1 diabetic participants in the Diabetes Control and Complications Trial (DCCT) conducted by investigators at Harvard University. They found subjects in the highest quartile for LDL cholesterol had an adjusted 3.8-fold greater risk of developing clinically significant macular edema than those in the lowest quartile (Diabetes 2004;53:2,883–92).
In addition, University of Pittsburgh investigators have reported simvastatin therapy was associated with trends toward slower progression of both neuropathy and nephropathy, compared with placebo in a small study of 39 type 1 diabetic patients without overt nephropathy (J. Diabetes Complications 2001;15:113–9).
“That's an interesting observation that requires many more interventional trials,” Dr. Eckel commented.
He added that despite the absence of firm proof of the efficacy of preventive strategies in type 1 diabetic patients, their extremely high cardiovascular risk warrants aggressive measures. In addition to an LDL cholesterol of less than 100 mg/dL—and a target of 55–70 mg/dL or less in those with CAD—he supports a target triglyceride level below 130 mg/dL and an HDL cholesterol greater than 40 mg/dL.
The triglyceride goal can be achieved by improved glycemic control, weight reduction, exercise, a high-fiber Step-II AHA diet, fibrates, and fish oil capsules sufficient to provide 2.7–7.7 g of omega-3 fatty acids per day, he added.
'I'm wondering if the HDL present in type 1 diabetes is defective in its ability to act as an antioxidant.' DR. ECKEL