Aggressive statin therapy and the risk of malignancy.

The advent of pharmacologic agents which partially inhibit the rate limiting enzyme in cholesterol synthesis (3-hydroxy-3-methylglutaryl Co-A reductase) provided a major advance in preventive medicine. Clinical trials in both primary and secondary prevention have demonstrated reduction in cardiovascular events by statin therapy. However, early epidemiologic studies proposed an inverse relationship between cholesterol levels and mortality. While the epidemiologic studies were controversial and did not establish a cause and effect relationship, concern was raised that aggressive lipid lowering by pharmacological means may be associated with increased risk for noncardiac mortality, including malignancy. The theoretical concern was intensified by meta-analysis of statin trials, which confirmed the reduction in cardiovascular mortality but also demonstrated a potential increase in cancer risk. This review evaluates the epidemiologic and prospective trial data which address the potential relationship between aggressive statin therapy and the risk of malignancy.

Metabolic syndrome in South Asians.

Metabolic syndrome (MS) is a cluster of multiple cardio-metabolic risk factors in the same individual. People with MS are at high risk for the development of cardiovascular disease (CVD), chronic kidney disease (CKD), and cerebrovascular disease (CeVD). The excessive presence of MS in South Asians is likely responsible for significant morbidity in this population. This review discusses the scope of MS in South Asians and measures to combat its effects by preventive and therapeutic measures.

Evolving concepts of the role of high-density lipoprotein in protection from atherosclerosis.

High-density lipoprotein (HDL) is classified as a negative risk factor due to the inverse relationship between elevated levels of HDL cholesterol and atherosclerosis. The mechanism by which HDL can mediate protection from atherosclerosis is complex and multifactorial. The primary role of reverse cholesterol transport in the reduction of risk for coronary artery disease is supported by a considerable amount of experimental data. HDL is able to interact with and remove cholesterol from the lipid-laden foam cells in the peripheral vasculature with subsequent transportation to the liver for excretion. However, HDL has multiple other physiologic effects that may play a significant role in protection from atherosclerosis. HDL has been demonstrated to exhibit multiple beneficial effects on the coagulation system. Platelet function is improved by both direct and indirect mechanisms. HDL has a complex interaction with the protein C and protein S system. Thrombolytic balance is also improved by HDL. HDL has been demonstrated to have a significant natural antioxidant effect that inhibits the oxidative step required for low-density lipoprotein uptake by the macrophage. Additionally, HDL has also been demonstrated to exert multiple beneficial effects on endothelial function, including decreased apoptosis and endothelial repair.

Statins as adjunctive therapy in the management of hypertension.

The effective optimization of the modifiable risk factors for the development of atherosclerosis is the cornerstone preventive cardiology. Risk factor clustering has been demonstrated to occur in a higher prevalence than would be expected by chance alone. The common cardiovascular risk factors frequently share metabolic pathways. Inflammation and oxidative stress are demonstrable in the major cardiovascular risk factors. Hypertension and dyslipidemia frequently co-exist in an individual. The advent of statin therapy has allowed optimization of the lipid profile and achievement of therapeutic goals advocated by the Adult Treatment Panel of the National Cholesterol Education Program. Statin therapy has been demonstrated to exhibit a wide variety of nonlipid or pleiotropic effects. Observational studies have demonstrated that statin therapy may cause a small but statistically significant alteration of blood pressure. Prospective clinical trials have demonstrated that statin therapy reduces this cardiovascular risk in both hypertensive and normotensive individuals. The potential role of statin therapy in blood pressure reduction is compatible with several pleiotropic mechanisms of statin therapy. However, a significant body of data from prospective, well-designed, controlled clinical trials that have analyzed the effect of statin therapy on blood pressure as the primary end point is lacking. This review examines the observational relationship between hypertension and dyslipidemia, the potential mechanisms by which statin therapy may lower blood pressure, and selected clinical trial data.

Dysfunctional high-density lipoprotein and atherosclerosis.

High-density lipoprotein (HDL) is well established as a negative risk factor for the development of atherosclerosis. Epidemiologic, pathologic, and experimental studies have demonstrated a role for HDL in protection from coronary artery disease. HDL has been demonstrated to reduce the risk from atherosclerosis by multiple pathophysiologic mechanisms. Low-density lipoprotein is a metabolic end product that can be recognized and cleared by specific hepatic receptors with excretion into the bile. However, low-density lipoprotein may also be scavenged in the periphery by the monocyte-macrophage system, with subsequent generation of lipid-laden foam cells. HDL may reduce the atherosclerotic burden by multiple potential mechanisms. HDL can interact with the foam cell to remove cholesterol via receptor-mediated binding, passive diffusion, and alteration of intracellular cholesterol trafficking by ATP binding cassettes. The process of reverse cholesterol transport is a major mechanism by which HDL can remove cholesterol from the periphery, allowing it to be cleared by the liver and then excreted into the bile. However, HDL exhibits multiple additional potential beneficial physiologic effects. Endothelial function and repair is potentiated by HDL. Normal HDL has significant anti-inflammatory and antioxidant activity. Prostacyclin production and improvement in fibrinolytic balance is also attributed to normally functioning HDL. HDL is also intimately related to the metabolism of other circulating lipoproteins. However, multiple clinical studies have identified individuals with a significant atherosclerotic burden despite normal or elevated levels of HDL cholesterol. Clinical conditions associated with inflammation and oxidative stress have adversely altered the normal functions of HDL. Clinical assays have been developed to assess the functionality of HDL. Dysfunctional HDL may be returned to normal by diet, exercise, degree of fat intake, and pharmacologic approaches. Orally active mimetic proteins are in development and have shown clinical promise.

Nicotinic acid: a new look at an old drug.

Dyslipidemia is central to the process of atherosclerosis. Modification of the lipid profile by diet, exercise, or pharmacologic therapy has been demonstrated to reduce the risk from atherosclerosis in clinical studies in primary and secondary prevention. Nicotinic acid has been in clinical use for over 50 years. The administration of nicotinic acid has been demonstrated to reduce apolipoprotein B-containing lipoproteins (very low-density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein and lipoprotein (a)). Nicotinic acid also exerts significant effects on high-density lipoprotein. In addition to improving dyslipidemia, nicotinic acid has been demonstrated to induce a number of nonlipid or pleiotropic effects. The recent discovery of the nicotinic acid receptor has improved knowledge relative to the mechanism of action and the adverse effect profile of nicotinic acid. Clinical trials utilizing clinical or angiographic end points demonstrated efficacy for the use of nicotinic acid in monotherapy or in combination with bile acid resins or statins.

The role of statin therapy in the management of cardiomyopathies.

The non-lipid-lowering or pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been hypothesized to beneficially alter mechanisms involved in heart failure. Retrospective analyses of heart failure trials as well as small prospective trials with nonmortality clinical and surrogate end points appeared to confirm this presumption. However, two recently published, large, prospective randomized trials did not demonstrate any significant clinical benefit of statins in heart failure patients. This review outlines the proposed biologic effects of statins in heart failure syndrome and clinical evidence of statin use in heart failure patients.

Role of insulin signaling in maintaining energy homeostasis.

OBJECTIVE: To examine the role that insulin signaling plays in modulating metabolic functions involving both peripheral and hypothalamic systems. METHODS: We review the literature regarding insulin signaling as it relates to energy homeostasis. RESULTS: Insulin signaling in the periphery is known to affect hepatic glucose production and glucose uptake in muscle and adipose tissue. In the brain, insulin is involved in a variety of signaling pathways that control positive and negative aspects of food intake and energy metabolism. Disruption of insulin signaling can affect key cellular pathways that serve to maintain energy balance and glucose homeostasis, which can then lead to insulin resistance and progression toward various metabolic disorders, including cardiovascular disease, obesity, and type 2 diabetes. The use of exogenous insulin as therapy for patients with type 2 diabetes is traditionally associated with increases in weight. CONCLUSION: An enhanced understanding of how these insulin signaling pathways function may provide answers about how to control weight gain associated with exogenous insulin use. Pharmacologic agents, such as the long-acting insulin analogues and particularly insulin detemir, that may reduce these weight effects hold considerable advantage.

Adjunctive interventions in myocardial infarction: the role of statin therapy.

Statin therapy has reduced cardiovascular morbidity and mortality across the spectrum of atherosclerosis. The administration of statins has been demonstrated to be effective in primary and secondary prevention clinical trials evaluating patients with high and low risk-factor profiles. The presumed mechanism of benefit of hypolipidemic therapy in the prevention of atherosclerotic disease was a reduction in the deposition of atherogenic lipoproteins in vulnerable areas of the coronary vasculature. Subsequent experimental studies with statins demonstrated a variety of potentially beneficial effects that would extend clinical benefit beyond lipid-lowering per se. Statin therapy beneficially alters inflammation, coagulation and fibrinolytic parameters, endothelial function, vasoreactivity, and platelet function. The demonstration of the non-lipid or pleiotropic effects provided the theoretical basis for a possible role as an adjunctive therapy in acute coronary syndromes. Retrospective analysis of a variety of early trials indicated a potential benefit of statins during acute ischemic syndromes. Recent clinical trials have addressed this important clinical question in a prospective controlled manner. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) and the Thrombolysis In Myocardial Infarction (TIMI)-22 studies present strong clinical evidence in favor of the administration of statins as adjunctive therapy in acute ischemic syndromes.

Diabetic dyslipidemia and atherosclerosis: evidence from clinical trials.

Diabetes is a highly prevalent disease in the United States and is increasing in both incidence and prevalence. Atherosclerotic vascular disease is a major cause of morbidity and mortality in diabetic patients. Type 2 diabetes is characterized by insulin resistance and frequently co-exists with a variety of cardiovascular risk factors, including hypertension, obesity, dyslipidemia, and physical inactivity. Hygienic measures such as weight loss and exercise should form the basis of therapeutic interventions in the prevention and treatment of type 2 diabetes. The role of dyslipidemia as a causal factor in vascular disease associated with diabetes was previously downplayed because total cholesterol was frequently normal or minimally elevated. However, diabetic dyslipidemia is characterized by elevated triglycerides, low high-density lipoprotein, and small, dense low-density lipoprotein, the combination of which has been termed the "lipid triad." The role of lipid modification as a means to decrease cardiovascular risk in type 2 diabetes has recently been clarified by a number of clinical trials. Subgroup analysis in early studies implied the potential for benefit of lipid modification in diabetes. The results of these early studies prompted the design of large-scale intervention trials that employed statin and fibric acid derivatives in diabetes patients. The preponderance of data from the statin trials implicates significant clinical benefit in cardiovascular risk reduction. The fibric acid derivatives have theoretic advantages in diabetic dyslipidemia. However, the robust bulk of clinical data obtained from prospective statin studies is lacking for the fibric acid derivatives, and the results of the major trials are equivocal.