Launching Medscape Cardiology's "Risk Factor Management" (RFM) News Center

Christopher P. Cannon, MD


March 10, 2006

Risk Factors and the Metabolic-Vascular Disease Continuum

There are several unmodifiable risk factors, such as age, where even the advances of modern medical science will not allow us to directly intervene. However, even when patients present with these factors (eg, the aged – meaning almost all of us, at some point), this should merely alert those of us in the healthcare community to those groups where we have to concentrate our efforts in order to manage the other, modifiable risk factors. For example:


There are multiple studies, dating back to the mid 1990s[3] and unfortunately continuing even today, repeatedly documenting underutilization of known beneficial therapies in the elderly. This is all the more paradoxical since the absolute benefit in terms of cardiovascular events prevented is much greater in this high-risk group.[4] Thus, efforts to expand the application of risk factor management to this group would be very beneficial to both the patients and the community, and represents time and effort well spent.


Hypertension is a huge risk factor, especially as it often represents the "first step" in the development of multiple types of vascular disease, including cerebrovascular disease (ie, stroke), coronary disease (both ischemic and nonischemic dilated cardiomyopathy), and the long, slow, costly process of congestive heart failure (both diastolic and systolic). Heart failure afflicts more than 50 million people in the United States alone, and, especially in light of the cost burden it places on the healthcare system, represents a widely prevalent disease that needs aggressive management of its risk factors to hopefully prevent or at least ameliorate recourse to treatment.

Hyperlipidemia -- and the "Statin Decade"

Hypercholesterolemia is one of the most important modifiable risk factors on the list, and there has been a flurry of data in the past year showing that being more aggressive than we have been will provide even further benefit.

There are many lipid parameters that can be modified. The first and foremost is low-density lipoprotein (LDL) cholesterol. The past decade has firmly established that reducing LDL is a very potent way to reduce the risk of cardiovascular events. This was first shown in the Scandinavian Simvastatin Survival Study (4S) trial comparing standard-dose simvastatin vs placebo.[5] Figure 1 illustrates the series of trials that have been conducted since then that make up what could be termed "The Statin Decade."

Figure 1.

"The Statin Decade."

The notion that "lower is better" has been firmly established by this series of trials, most recently the Pravastatin or Atorvastatin Evaluation and Infection Therapy - Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22)[6] and Treating to New Targets (TNT) trials,[7] which found a benefit of high-dose statins compared with standard-dose statins (Figure 2). The Coordinating Committee of the National Cholesterol Education Program (NCEP)[8] has come up with "therapeutic options" that entail much lower levels than the prior NCEP Adult Treatment Panel III (ATP III)[9] guidelines recommend, aiming for an LDL < 70 mg/dL in very high-risk patients.

Figure 2.

Benefits of intensive vs standard statin therapy.

But LDL is not the only lipid parameter. One of the most interesting new frontiers in lipid management focuses on raising high-density lipoprotein (HDL), for which potent drugs are now becoming available. But further understanding of assessing and managing other lipid subfractions will continue to advance our ability to manage risk in these patients.


Diabetes is a well-documented and quite severe risk factor for all types of vascular disease. Its debilitating effects are pervasive and are generally associated with much more diffuse and serious coronary disease than in otherwise similar patients without diabetes. Peripheral arterial disease is also very prevalent in diabetic patients.[10]

We have all hoped that aggressive management of glucose levels would lead to fewer cardiac events, and preliminary evidence of this has now been documented in studies presented this year at the American Diabetes Association meeting. But risk management in diabetic patients is now understood to be much broader than just controlling glucose. The importance of blockade of the renin-angiotensin system has been documented in numerous studies of diabetic patients -- both for protection against cardiac events and for renal protection.[2] The benefits of most therapies tend to be amplified in these high-risk patients with diffuse disease,[11] thus emphasizing the need to use all effective preventive medications in these patients.

The Metabolic Syndrome

The metabolic syndrome is related to diabetes in that glucose intolerance is a major component, but it also includes other factors such as obesity, low HDL, high tryglycerides, and hypertension. Our cardioprotective medications have not been able to target many of these issues to date, but several promising new agents, including endocannabinoid receptor blockers, such as rimonabant, may offer a means of treating several components of the disease.[12]

Lifestyle -- Smoking and Obesity

Several lifestyle factors are also important risk factors. Smoking is the largest cause of death worldwide. Fortunately, smoking cessation appears to lead to marked reduction in death.[13] Although rates of smoking have been falling in Western countries, it has been rising in less developed countries. Thus, smoking continues to be a major cause of death and disability worldwide.

Obesity is the next leading cause of death in a recent estimate in the United States. Indeed, with the increase in the "Western lifestyle" that is, unfortunately, accompanying increasing industrialization throughout the world, obesity is becoming the biggest risk factor after tobacco use for the health of humankind. The healthcare community will be remiss if clinicians do not aggressively address this risk factor, and with that will go the need to stay current on new data and alternatives for management of this highly modifiable risk factor.

Other Risk Factors

Finally, there are markers of risk, such as C-reactive protein, which serve as potent indicators of risk of cardiovascular disease.[14] CRP levels, which correlate with degree of vascular inflammation, have been shown to predict the risk of death, myocardial infarction, peripheral arterial disease, and stroke in populations that are previously healthy[15]; those with prior vascular disease; and in high-risk acute coronary syndrome patients.[16] Recently, it has also been shown that treatment to achieve lower CRP levels is associated with lower risk of recurrent cardiac events.[17] Thus, CRP may be a reasonable marker of inflammation and as such could be a means of monitoring risk in patients on treatment. There are many additional markers of inflammation, and of the other processes in vascular disease, that add to risk stratification. Many of these may prove useful in profiling a patient's risk for vascular disease and in choosing appropriate therapies. The future is bright for risk markers to assist in targeting appropriate therapies.[18]