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

Recommendations and Future Directions

The continuum of health before the overt development of CAD can be classified into 2 groups: those who do not yet have the risk factors that confer an increased risk for developing CVD, and those who already have them. From a primordial prevention perspective, preserving a state of health before the onset of DM, hypercholesterolemia, or HTN has the greatest potential for decreasing CVD morbidity and mortality. However, strategies to achieve this are resource intensive.

With regard to primary prevention of CVD, it is clear that for DM and HTN, there is no role for pharmacological interventions in individuals without overt disease, and rather, changes in lifestyle should be encouraged. Aggressive glycemic control (HgA1c <6.5%) should be considered in diabetic patients without CAD and especially in those without evidence of microvascular disease. Importantly, extrapolating the experience from ACCORD, although glycemic control is important, targets should be achieved slowly. Similarly, in individuals without CVD or DM, once individuals become hypertensive by current guidelines (SBP ≥140 mm Hg), pharmacological interventions should be initiated with a target SBP of <130 mm Hg (Figure 2).

Figure 2.

Recommendations for Modulating Risk Factors for the Primary Prevention of Cardiovascular Disease
This figure summarizes the treatment recommendations for HTN, DM, and hyperlipidemia in the primary prevention of CVD before and after development of the risk factor. Pharmacological intervention should only be initiated in HTN and DM after the risk factor has developed. This is in contrast to hyperlipidemia, where risk stratification will determine whether statin therapy is warranted. DM = diabetes mellitus; HgA1c = hemoglobin A1c; hsCRP = high-sensitivity C-reactive protein; HTN = hypertension; SBP = systolic blood pressure; other abbreviations as in Figure 1.

Interestingly, unlike DM and HTN, even in the absence of overt hyperlipidemia, there appears to be an opportunity to reduce CVD events by initiating statin therapy in individuals who are at intermediate CVD risk. Accurate identification of individuals with subclinical disease allows not only earlier lifestyle interventions or risk factor modifications but also the reclassification of patients and discontinuation of a therapy where the risk–benefit ratio may not have been favorable. Developing a model that correctly discriminates between a nonmodifiable versus a modifiable disease state is challenging. As a result, identifying new methods and variables that improve our estimation of risk should be a priority.

Furthermore, given the evidence that the atherosclerotic process begins early in infancy, current risk calculators may not completely identify who would benefit from lipid-lowering therapy.[2,90] As a result, starting treatment earlier than indicated by conventional risk calculators must be considered. Different calculators could possibly be developed that are based on genetics, additional markers of disease (proteinuria, glucosuria, ankle-brachial index, or left ventricular hypertrophy), data from bioimaging (coronary artery calcium and the presence of carotid and peripheral plaques), or biomarkers (CRP, troponin, brain natriuretic peptide, and lipoprotein [a]). Regarding bioimaging, coronary artery calcium and carotid plaque quantification have been shown to improve discrimination of risk using the ASCVD Pooled Cohort equation.[91–93] Additionally, 1 study that measured carotid, aortic, and iliofemoral disease by ultrasound and coronary artery calcification in individuals without a prior history CVD found that disease in the iliofemoral region was strongly correlated with coronary artery calcification and aortic disease.[94] Given the high prevalence of iliofemoral disease, if incident CVD events can be correlated with its presence, iliofemoral disease may help with future risk stratification.[94] A recent CVD risk prediction model, which combined variables derived from multiple modalities (left ventricular hypertrophy determined by ECG, coronary artery calcification, N-terminal prohormone of B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity CRP) into a base risk calculator that included the ASCVD risk variables and statin use, significantly improved model discrimination (C-statistic: 0.79).[95] Although this model has not been validated, it suggests that there are opportunities to improve our current risk prediction models.

The idea of primordial prevention is what drives the efforts to target lower levels of risk and disease-specific targets in the primary prevention of CVD. The genetic risk of an individual is essentially a primordial CVD risk score or a baseline lifetime CVD risk that may be mitigated or amplified by environmental factors. Two studies have derived different genetic CVD risk scores.[96,97] The first study examined the effect of lifestyle on CVD and found that within the highest genetic-risk group, a favorable lifestyle decreased CVD events compared with an unfavorable lifestyle.[96] The second study compared the effect size of statin therapy on CVD events by genetic risk group and found a relative risk reduction of 46% in the highest-risk group compared with 26% in all others (p = 0.05).[97] Genetic risk scores that characterize an individual's genetic CVD risk would identify individuals who would benefit from risk reduction therapies at the earliest time point.

Although it is attractive to consider pharmacological therapies in lower-risk patients, adverse effects and physiological barriers may make the risk–benefit ratio unfavorable, particularly if adherence to medications is affected. Appropriate selection of individuals who will benefit from more aggressive pharmacological therapies will hinge on the accuracy of CVD risk calculators. Lifestyle and behavioral interventions, although difficult to implement and adopt, do not have this lower limit and should be the intervention for the lowest-risk groups.