UC Davis researchers have shown that statins not only improve cholesterol levels, but also dramatically reduce disease-causing inflammation in patients with metabolic syndrome — a condition defined by symptoms that include abdominal obesity and high blood pressure.
The study, published online in the September 12 issue of the Journal of Clinical Endocrinology & Metabolism, offers new hope to the one in four Americans with metabolic syndrome who have double the risk of developing heart disease and are five times more likely to develop diabetes.
“Changes in diet and exercise, resulting in weight loss are still the treatment of choice for preventing the consequences of metabolic syndrome,” said Kenny Jialal, a professor of internal medicine at UC Davis Health System and director of the Laboratory for Atherosclerosis and Metabolic Research. “However, people don't always adhere to those changes. Our results suggest that statin may be a way to forestall the deadly complications of metabolic syndrome.”
Statins are a class of drugs used to prevent and treat heart disease. They work by lowering cholesterol levels and preventing atherosclerosis, the blockage of blood vessels due to plaque build-up. Previously, Jialal's group showed that statins, as a class of drugs, are anti-inflammatory. Since the metabolic syndrome, is characterized by low-grade inflammation and insulin resistance, they decided to look at the direct effect of statins on inflammation in these patients.
The UC Davis team conducted a double-blind, randomized, placebo-controlled study in which they gave a standard daily dose of a statin (Simvastatin or placebo) to 50 patients with metabolic syndrome. After eight weeks, they measured cholesterol levels, as well as biomarkers of inflammation in the circulation, but more importantly, in cells pivotal in all stages of plaque formation, the monocytes. They found, as expected, that statin lowered low-density-lipoprotein- cholesterol and non-high-density-lipoprotein-cholesterol levels, both of which the American Heart Association guidelines target for treatment of metabolic syndrome.
Jialal and his colleagues also found marked reductions in two pivotal biomarkers of inflammation: C-reactive protein (CRP) and interleukin-6. While these markers are typically elevated in insulin resistance, a condition that precedes the development of diabetes, statin therapy reduced these levels by 36 percent and 44 percent, respectively.
“We showed a direct anti-inflammatory effect of statins in monocytes,” said Jialal, who also is a staff endocrinologist at the Sacramento VA Medical Center.
Inflammation is not only predictive of heart disease, he said. But, it is involved in a complicated metabolic cycle of changes that results in resistance to insulin, the hormone that regulates blood sugar. Insulin resistance, in turn, is a precursor to diabetes.
Jialal said the current finding suggests that physicians can now consider treating metabolic syndrome with statins, a class of drugs with a proven safety record. In fact, six of the 25 participants on statin therapy could no longer fit the medical definition of metabolic syndrome by the end of the study.
A person is diagnosed as having metabolic syndrome if they have excessive abdominal fat, high LDL (bad) cholesterol and low HDL (good) cholesterol levels, high blood pressure, an inability to regulate blood sugar (insulin resistance), and high levels of biomarkers of inflammation, such as CRP, which is associated with heart disease. While it affects 25 percent of Americans, it disproportionately affects particular age and ethnic groups. An estimated 36 percent of Mexican-American women battle metabolic syndrome, as do 50 percent of Americans over the age of 60.
While genetic factors contribute to the incidence of metabolic disorder, poor nutrition and sedentary lifestyles are important factors, as well, he said.
“Metabolic syndrome is a major health problem of our time. We need strategies to fight this epidemic,” Jialal said.
Jialal's team also made important discoveries about the way statins work at the molecular level. Compared to the placebo group, monocytes from patients exposed to statin produced less interleukin-6 and TNF, two critical molecules in insulin resistance and the development of cardiovascular disease. In addition, the researchers made the novel observation that in patients with metabolic syndrome, statin therapy interfered with cell signaling and transcription by inhibiting the “master switch” in the inflammatory process, a protein called NFkb.
“We also showed for the first time an increased production of a key enzyme, PI 3-kinase, related to insulin activity and vascular health,” said Sridevi Devaraj, associate professor of pathology and lead author of the study.
Jialal and his colleagues will next look at the fat cells of patients with metabolic syndrome for more clues as to how statins work and what goes wrong in patients with the disorder. “We also need long-term studies that look at the effects of statins on insulin resistance and diabetes prevention,” he said. “We have much more work to do.”
This study was funded by the National Institutes of Health and Merck Medical School grant.
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