How Low to Go With Glucose, Cholesterol, and Blood Pressure in Primary Prevention of CVD

Kimberly N. Hong, MD, MHSA; Valentin Fuster, MD; Robert S. Rosenson, MD; Clive Rosendorff, MD, PHD; Deepak L. Bhatt, MD, MPH


J Am Coll Cardiol. 2017;70(17):2171-21-85. 

In This Article

Abstract and Introduction


Diabetes, hyperlipidemia, and hypertension are modifiable risk factors that predict cardiovascular disease events. The effect of these risk factors on incident cardiovascular disease increases with progressively higher levels of glucose, low-density lipoprotein cholesterol, and blood pressure. The thresholds for initiating treatment of these modifiable risk factors and the optimal goals of risk factor modification are a focus of primary prevention research. Although an aggressive approach is appealing, adverse events may occur, and potential physiological barriers may exist. This paper discusses primary prevention of coronary heart disease that may be achieved through modification of diabetes, hyperlipidemia, and hypertension by summarizing current guidelines and pertinent clinical trial data from intervention trials that included a primary prevention cohort.


Deaths from atherosclerotic cardiovascular diseases (CVD) have declined in the past 3 decades; however, CVD remains the leading cause of death, accounting for nearly 1 in 3 deaths.[1] The increasing incidences of obesity and type 2 diabetes mellitus (DM) contribute to this high rate.[2,3] The INTERHEART (Effect of Potentially Modifiable Risk Factors Associated with Myocardial Infarction in 52 Countries) study investigated risk factors associated with CVD death rates. INTERHEART measured 9 risk factors prior to a first myocardial infarction (MI) and found that they contributed to over 90% of the risk for a first MI. These 9 risk factors included DM, hypertension (HTN), and lipoprotein profile represented by varying apolipoprotein (Apo) B/A1 ratio strata.[3,4] These data suggest that there is a significant opportunity for affecting public health by reducing CVD events through risk factor modification and prevention.

Prevention may be categorized as primordial, primary, secondary, and tertiary (Central Illustration). Primary prevention refers to the modification of risk factors associated with disease development, secondary prevention to the control of disease progression once present, and tertiary prevention to mitigating the consequences of advanced disease on functional status and quality of life. Primordial prevention refers to achieving a state of health that prevents risk factors for disease from developing. Although the opportunity for societal benefit is the greatest if this "time zero" before disease develops is preserved, this would require population-based strategies and systems-wide collaboration, which are difficult to achieve.[2,5–7]

Central Illustration.

Cardiovascular Disease Prevention and Health Promotion
This figure depicts the tiered approach to preventing CVD. Primordial prevention makes up the base and optimizes health behaviors to reduce the development of CVD risk factors. The second tier is primary prevention, which targets CVD risk factors to prevent the development of CVD. Last, the apex is secondary and tertiary prevention, where CVD is targeted to prevent progression and development of additional CVD. Adapted with permission from Vaduganathan et al.(5). CAD = coronary artery disease; CVD = cardiovascular disease; PVD = peripheral vascular disease.

Epidemiological studies conducted in the past 4 to 5 decades have identified DM, hyperlipidemia, and HTN as predictors of CVD risk. The consistency of these data has resulted in CVD risk calculators that integrate multiple risk factors.[2,3] In addition to there being significant pathophysiological interplay between these risk factors, another common denominator is their effect on the microvasculature. The microcirculation regulates blood flow and oxygen delivery via vasodilation and vasoconstriction of arterioles downstream of the macrovasculature. The coronary arteriolar bed increases coronary flow by modulating >55% of the total coronary vascular resistance. This is referred to as coronary flow reserve, which in the absence of epicardial (pre-arteriole) disease serves as a functional assessment of the coronary microcirculation.[8,9] Impaired vasoreactivity of the microvasculature can affect the pressure and flow gradients that match perfusion to metabolic demand, causing myocardial ischemia.[8] Resultantly, coronary microvascular disease was first used to explain anginal symptoms in patients without overt macrovascular disease.[10,11] Postulated mechanisms for coronary microvascular disease that are shared between HTN, DM, and the metabolic syndrome include endothelial and smooth muscle dysfunction, dysregulation of nitric oxide synthesis, and the production of growth factors including angiotensin and endothelins.[10,11] Microvascular disease in diabetic patients has been correlated with increased CVD events.[12] In another observational study that included asymptomatic diabetic patients without coronary artery disease (CAD), a coronary flow reserve <2.5 was associated with a composite endpoint, which included mortality, acute coronary syndrome, or revascularization.[13] This suggests a correlation between microvascular disease in diabetic patients and CVD. Furthermore, there are studies that have found lower coronary flow reserve in patients with HTN and hypercholesterolemia.[9,14] A potential opportunity for averting the significant morbidity and mortality associated with CVD may be targeting prevention efforts at a stage before microvascular disease has developed.

This paper discusses the primary prevention of CAD through the modification of 3 risk factors—DM, hyperlipidemia, and HTN—by summarizing the current guidelines and the varying perspectives and controversies regarding these guidelines that stem from an evolving evidence base.