Incremental Risk‐Factor Reduction Improves Overall Cardiovascular Benefit: Is It Time to Abandon the Silos?

Coronary heart disease (CHD) remains the leading cause of morbidity and mortality worldwide. Conventional CHD risk factors include smoking and elevations in blood pressure (BP), plasma lipids, and glucose. ¹ The clustering of these risk factors is being recognized more frequently in clinical medicine. Recent data support the premise that almost all patients with CHD have ≥1 of these risk factors, with at least one present to some degree in 84.6% of women and 80.6% of men. ² The number of cardiovascular (CV) risk factors present in each patient's risk profile significantly influences individual age‐adjusted rates in CV death. ³ Yet despite widespread education on the importance of detection and management of these CV risk factors, the annual decline in mortality secondary to these risk factors is slowing, while the associated morbidity is increasing. ⁴

Projections have suggested that by the year 2025, almost 30% of the world's population will have hypertension, defined as a BP ≥140/90 mm Hg. ⁵ Patients with hypertension are at a 2‐ to 4‐fold increased risk for CV disease, stroke, peripheral arterial disease, and heart failure. Clinical trials have demonstrated that long‐term reduction of BP to <140/90 mm Hg can reduce the incidence of stroke by up to 40%, myocardial infarction by as much as 25%, and heart failure by >50%. Despite this evidence, at best, slightly more than half of all patients treated for hypertension achieve the recommended BP goal of <140/90 mm Hg and, in people with diabetes, only 25% achieve the lower BP target of <130/80 mm Hg. ⁶

The role of elevated low‐density lipoprotein cholesterol (LDL‐C) levels in the pathogenesis of CV disease, especially in individuals with diabetes mellitus (DM), has emerged from many clinical trials. In the recent Veterans Affairs Diabetes Trial (VADT), ⁷ a large‐scale type 2 diabetes intervention trial investigating the effect of glucose control on CV outcomes, only 44% of participants were at the recommended LDL‐C goal of <100 mg/dL, with only 58% of patients taking statin therapy. In a recent study of more than 8000 adults with diabetes, almost all with hypertension, one half did not achieve the recommended LDL‐C level of <100 mg/dL, with one fourth not treated with a statin. ⁸ Finally, in hypertensive patients with DM, the ability to reach the recommended American Diabetes Association (ADA) target of <7% for glycosylated hemoglobin only approached 50%. ⁶

If CV disease risk is to be reduced further in hypertensive individuals, we must address multiple risk factors. Yet published guidelines in the United States for the treatment of hypertension, dyslipidemia, or DM continue to concentrate on a specific risk factor as a vertical “silo” rather than addressing global CV risk in each individual patient. ⁹ , ¹⁰ , ¹¹

For example, hypertension treatment guidelines have focused on the importance of getting patients to their BP goal rather than incorporating the evidence for utilizing statin‐based lipid‐lowering therapy in addition to the lowering of BP, as an effective means of further lowering overall CV disease risk. In no area has this silo effect been more evident than in the lipid guidelines, which have failed to address the importance of BP elevation and other CV risk factors that are often present along with dyslipidemia. While various current guidelines have tried to incorporate the use of a global CV risk score in an effort to improve the ability to predict CV events and mortality in an individual patient, ⁹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ they often fail to recognize people at high risk for CV disease ¹⁷ and often allow many patients with hypertension who would have benefited from statin‐based or other risk reduction strategies to escape “under the radar.”

The Anglo‐Scandinavian Cardiac Outcomes Trial—Lipid‐Lowering Arm (ASCOT‐LLA) ¹⁸ was a primary prevention trial performed in more than 10,000 hypertensive patients with ≥3 risk factors; all patients were hypertensive and were part of the larger ASCOT BP‐lowering trial. In this group of high‐risk subjects who would not have received lipid‐lowering therapy based on national guidelines at the time of the study, double‐blind randomization with either atorvastatin, 10 mg daily, or placebo was initiated. Baseline LDL‐C was 130 mg/dL. Atorvastatin reduced LDL‐C by 39 mg/dL. A significant 36% reduction in fatal and nonfatal CHD, as well as a significant 27% reduction in fatal and nonfatal stroke was noted. The study was stopped prematurely after 3 years. Of note, this benefit occurred in patients whose BP was well controlled to the recommended level of <140/90 mm Hg. The log‐linear relationship between reduction in LDL‐C levels and reduction in CHD risk was also seen in the Heart Protection Study (HPS), ¹⁹ a large double‐blind secondary prevention trial in 20,536 subjects with underlying CHD, CV disease, peripheral arterial disease, or diabetes. A consistent benefit on all vascular outcomes was seen in those treated with simvastatin, 40 mg daily, compared with placebo. Use of simvastatin was associated with a 30%–40% reduction in LDL‐C. Outcome improvement, as in ASCOT‐LLA, occurred regardless of the patient's baseline LDL‐C level. Prior to these 2 trials, it was thought that there was a threshold LDL‐C level that needed to be achieved to reduce CHD risk. These trial findings suggest that adding statin‐based therapy to the treatment of high‐risk patients with multiple risk factors such as hypertension, diabetes, or underlying CVD, regardless of baseline LDL‐C level, will improve CV outcome.

There is a continuous and graded increase in CV risk proportional to the severity of each primary CV disease risk factor. Incremental reduction in each risk factor proportionally reduces the CV disease risk depending on one's absolute global risk. Is it better to reduce multiple risk factors to the currently recommended guidelines or try to reduce individual risk factors to what is considered their “normal” values? One clinical trial that helps answer this question is the STENO‐2 study, ²⁰ an open‐label parallel group, 7‐year Danish trial comparing the effects of a multifactorial intervention on CV disease in 160 patients (mean age 55 years) with type 2 DM and microalbuminuria. It compared intensive with conventional treatment through stepwise implementation of behavioral and pharmacologic strategies measuring glycosylated hemoglobin (goal of <6.5% [achieved in 15% of the intensive group vs 3% of the conventional group; P=nonsignificant]), BP (goal systolic <130 mm Hg [achieved in 45% intensive vs 18% conventional; P=.001] and goal diastolic <80 mm Hg [achieved in 70% intensive vs 60% conventional; P=nonsignificant]), and dyslipidemia (goal cholesterol <175 mg/dL [achieved in 70% intensive vs 20% conventional; P<.001] and goal triglycerides <150 mg/dL [achieved in 60% intensive vs 48% conventional; P=nonsignificant]). Despite the fact that only the two goals of systolic BP <130 mm Hg and serum cholesterol <175 mg/dL were significantly different between the two strategies, the intensive multi‐risk approach reduced CV disease complications by 53%, nephropathy by 61%, retinopathy by 58%, and autonomic neuropathy by 63%. Of note, glycosylated hemoglobin <6.5% was achievable in only 15% of the intensive group.

How should the practitioner approach the challenge of risk factor management? There needs to be a renewed commitment to reduce an individual's global CV risk using an integrated treatment strategy that recognizes practical considerations of polypharmacy, patient adherence, adverse effects, economics, and efficacy. Utilization of validated CV absolute risk scores are needed that include diverse populations and additional risk factors that will allow the clinician to determine the relative importance of each individual risk factor on which to concentrate. This is the concept of incremental risk reduction. For example, in a hypertensive patient with dyslipidemia and diabetes, would aggressive treatment of BP to the “normal” level of <120/80 mm Hg with the additional antihypertensive drugs that would be required result in a further benefit in absolute risk over and above reducing the BP to <130/80 mm Hg with fewer drugs? What about decreasing LDL‐C by 30–40 mg with a statin as compared to the added cost from the additional drugs often required to achieve the “therapeutic option” of an LDL‐C level <70 mg/dL? What about reducing the glycosylated hemoglobin to <7%, currently recommended by the ADA, as compared to a recent proposal to get it as close to the “nondiabetic range” as possible (≤6.1%). ²¹ Can the patient afford all of these therapies? If not, which are most important and to what level of reduction should we target? Clearly in the STENO‐2 trial it appeared that reducing cholesterol and systolic BP <130 mm Hg had the most impact; only 15% were able to reduce glycosylated hemoglobin to <6.5%.

With the cost of health care exploding, we need to incorporate this type of thought process into routine clinical care. It is time to merge all the guidelines for hypertension, dyslipidemia, and diabetes into one coherent document that addresses global CV risk and incremental risk‐factor reduction in a cost‐effective, evidence‐based treatment program. While we await the results of the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which is evaluating the effects on CV outcomes of therapy directed at lower glycemic and BP targets than currently recommended, ²² we should prescribe statin therapy and achieve BP control to the currently recommended levels in all at‐risk patients with hypertension. It is time to distance ourselves from a silo approach to risk‐factor reduction for optimal CV benefit.