Managing Multiple Cardiovascular Risk Factors: State of the Science

Abstract

Cardiovascular risk comprises genetic, lifestyle, and metabolic factors. Risk factors frequently occur simultaneously, compounding the risk for a cardiovascular event. The most commonly occurring metabolic clustering includes elevated blood pressure, dyslipidemia (high triglyceride levels and low levels of high‐density lipoprotein cholesterol), and impaired glucose tolerance or type 2 diabetes mellitus. Together with visceral obesity, this clustering of risk factors is known as the metabolic syndrome. Although the definition of the metabolic syndrome and its relevance in clinical practice are the subject of discussion, there is emerging consensus about the importance of treating all risk factors early and aggressively. Recent evidence suggests that new‐onset diabetes mellitus and microalbuminuria are independent risk factors that should be considered when assessing composite cardiovascular risk. Treatment should be tailored to a patient's risk profile, with consideration of the varying effects that agents of different therapeutic classes have on cardiovascular and metabolic parameters.

About 80% of patients with hypertension have multiple cardiovascular (CV) risk factors, ¹ including age older than 55 years for men and 65 years for women, family history of premature CV disease, cigarette smoking, and physical inactivity. Microalbuminuria, estimated glomerular filtration rate <60 mL/min, obesity (body mass index ≥30 kg/m²), dyslipidemia, and diabetes mellitus (DM) also increase CV risk.

The presence of multiple risk factors in a patient, known as risk‐factor clustering, compounds the patient's overall CV risk. ¹ While a systolic blood pressure (SBP) of 150–160 mm Hg in a 45‐year‐old man significantly increases CV risk compared with normotensive BP levels, hypertension in the presence of elevated total cholesterol and reduced high‐density lipoprotein (HDL) cholesterol increases risk to a much greater degree. If hypertension, elevated total cholesterol, low HDL cholesterol, and DM occur in the same patient, the risk increases still further (Figure 1). ¹

MANAGING PATIENTS WITH MULTIPLE CV RISK FACTORS

Identifying a patient's global CV risk and aggressively treating risk factors can reduce all major CV events. ² Data from the Multiple Risk Factor Intervention Trial (MRFIT) Research Group ³ showed that death rates for coronary heart disease (CHD) increased with higher serum cholesterol levels for smokers and nonsmokers in each SBP quintile. Similarly, death rates increased with higher SBP in each serum cholesterol quintile. For example, with 2 elevated risk factors such as SBP of 142 mm Hg and serum cholesterol of 203 mg/dL, the death rate per 10,000 patient years was approximately 17%. The combined effect of SBP ≥142 mm Hg and total serum cholesterol ≥245 mg/dL was associated with a death rate of 33.7%. ³

The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ⁴ offers guidelines for the use of individual therapeutic classes of antihypertensive agents for specific indications (Table I). Since JNC 7, several studies have investigated the use of agents from different therapeutic classes in patients with compelling or specific indications. The Valsartan in Acute Myocardial Infarction Trial (VALIANT), ⁵ for example, established that treatment with an angiotensin receptor blocker (ARB) was equivalent to an angiotensin‐converting enzyme inhibitor (ACEI) post‐myocardial infarction (MI). ⁵ Other studies have suggested that the use of an agent that blocks the renin‐angiotensin system may result in a better outcome in patients with diabetic nephropathy when compared with other therapies.

Table I.

JNC 7 Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes

	Recommended Drugs
Compelling Indications*	Diuretic	BB	ACEI	ARB	CCB	Aldo ANT	Clinical Trial Basis†
Heart failure	•	•	•	•		•	ACC/AHA Heart Failure Guideline, MERIT‐HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES, CHARM
Post‐myocardial infarction		•	•			•	ACC/AHA Post‐MI Guideline, BHAT, SAVE, CAPRICORN, EPHESUS
High coronary disease risk	•	•	•		•		ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA, INVEST
Diabetes	•	•	•	•	•		NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK
Chronic kidney disease			•	•			NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK
Recurrent stroke prevention	•		•				PROGRESS
*Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed in parallel with the blood pressure (BP). †Conditions for which clinical trials demonstrate benefit of specific classes of antihypertensive drugs used as part of an antihypertensive regimen to achieve BP goal to test outcomes. BB indicates β‐blocker; ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; Aldo ANT, aldosterone antagonist; ACC/AHA, American College of Cardiology/American Heart Association; MERIT‐HF, Metoprolol CR/XL Randomized Intervention Trial in Heart Failure; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival Study; CIBIS, Cardiac Insufficiency Bisoprolol Study; SOLVD, Studies of Left Ventricular Dysfunction; AIRE, Acute Infarction Ramipril Efficacy; TRACE, Trandolapril Cardiac Evaluation; ValHEFT, Valsartan Heart Failure Trial; RALES, Randomized Aldactone Evaluation Study; MI, myocardial infarction; BHAT, Beta‐Blocker Heart Attack Trial; SAVE, Survival and Ventricular Enlargement; CAPRICORN, Carvedilol Post Infarction Survival Control in Left Ventricular Dysfunction; EPHESUS, Eplerenone Post‐Acute MI Heart Failure Efficacy and Survival Study; HOPE, Heart Outcomes Protection Evaluation; ANBP2, Second Australian National Blood Pressure Study; CONVINCE, Controlled Onset Verapamil Investigation of Cardiovascular Endpoints; EURO PA, European Trial of the Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; IDNT, Irbesartan in Diabetic Nephropathy Trial; REIN, Ramipril Efficacy in Nephropathy; AASK, African American Study of Kidney Disease and Hypertension; and PROGRESS, Perindopril Protection Against Recurrent Stroke Study. Other acronyms are expanded in the text. Adapted with permission from the Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 4

DYSLIPIDEMIA

Several clinical guidelines focus on recommendations for cholesterol‐lowering treatment in persons with established CHD or who are thought to be at high risk in the short term (<10 years). The Third Report of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) ⁶ emphasizes a clinical approach to reducing long‐term risk using both absolute low‐density lipoprotein (LDL) cholesterol levels and presence of risk factors. The guidelines can be used as a component of an integrated CV risk assessment and can provide clinical approaches to preventing acute coronary syndrome from advanced atherosclerosis in the short term and coronary atherosclerosis in the long term.

Managed care data from Kaiser Permanente ⁷ demonstrate that more than half of patients with hypertension or dyslipidemia also have the other condition, indicating that treatment should include agents for both disorders to decrease the risk of CHD. ⁸ In 2002, an estimated 27 million people in the United States (16% of the population) were at risk for CHD from concomitant hypertension and dyslipidemia. ⁹

The Anglo‐Scandinavian Cardiac Outcomes Trial Lipid‐Lowering Arm (ASCOT‐LLA) ⁹ was the first comprehensive study that showed benefits of lowering lipids in patients with hypertension and other risk factors, but who did not have dyslipidemia defined by contemporary guidelines. The trial enrolled 10,305 patients with a serum cholesterol level ≤250 mg/dL (≤6.5 mmol/L) who were randomized to either a statin (atorvastatin 10 mg/d) or placebo. At 1‐year follow‐up, patients receiving the statin significantly reduced their total cholesterol levels by 24% (50 mg/dL [1.3 mmol/L]), LDL cholesterol by 35% (46 mg/dL [1.2 mmol/L]), and triglycerides by 17% (27 mg/dL [0.3 mmol/L]) relative to placebo, while HDL cholesterol was minimally changed. After a median follow‐up of 3.3 years, the study was discontinued when an analysis demonstrated that statin therapy was associated with 36% fewer (P=.0005) nonfatal MIs and fatal strokes—the primary end point of the study—with outcomes benefits already evident in the first year. Total CV and total coronary events also were significantly lowered. ⁸ , ⁹

These and other data suggest the need to treat patients aggressively based on their CV risk. In addition, the data emphasize that lipid‐lowering therapy should not be limited to patients with high cholesterol levels, especially in high‐risk patients. ⁹ The Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound‐Derived Coronary Atheroma Burden (ASTEROID) ¹⁰ demonstrated that high‐intensity statin therapy with rosuvastatin 40 mg/d can reduce LDL cholesterol levels below current guidelines and increase HDL cholesterol, which may result in significant regression of atherosclerosis (Figure 2). ¹⁰

THE METABOLIC SYNDROME

The clustering in some patients of particular CV risk factors—hypertension, obesity, dyslipidemia, insulin resistance/DM—was first documented in the 1950s and 1960s. In 1988, syndrome X was described. Although the syndrome has had several name changes, it is commonly known as the metabolic syndrome in the United States. The presence of the metabolic syndrome is associated with an increased incidence of CV disease ¹¹ and strongly predicts the subsequent development of type 2 DM.

Many medical and public health organizations have defined the metabolic syndrome using differing criteria, resulting in a lack of consensus about the condition. The most widely accepted criteria (Table II) are those of the NCEP ATP III and American Heart Association (AHA)/National Heart, Lung, and Blood Institute (NHLBI), ¹² the World Health Organization (WHO), ¹³ and the American Association of Clinical Endocrinologists (AACE). ¹⁴

Table II.

Definitions of the Metabolic Syndrome

Metabolic Factor	NCEP ATP III AHA/NHLBI 12 Any 3 of 5 Factors	WHO 13 Insulin Resistance (Type 2 DM, IFG, IGT) + Any 2	AACE 14 Diagnosis Depends on Clinical Judgment Based on Risk Factors
Waist circumference, in	M, ≥40; F, ≥35
BMI, kg/m2, and/or		>30 and/or	≥25
waist/hip ratio		M, >0.9; F, >0.85
Triglycerides, mg/dL	≥150	≥150	≥150
HDL cholesterol, mg/dL	M, <40; F, <50	M, <35; F, <40	M, <40; F, <50
Blood pressure, mm Hg	≥130/85	≥140/90*	≥130/85
Glucose, mg/dL	≥100		110–126;
			>140 2 h after glucose challenge
Urinary albumin, mg/min		>20
Albumin/creatinine ratio, mg/g		>30
NCEP ATP III indicates National Cholesterol Education Program Adult Treatment Panel III; AHA, American Heart Association; NHLBI, National Heart, Lung, and Blood Institute; WHO, World Health Organization; DM, diabetes mellitus; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; AACE, American Association of Clinical Endocrinologists; BMI, body mass index; HDL, high‐density lipoprotein; M, male; and F, female. *Or on drug therapy.

For a diagnosis of the metabolic syndrome, the NCEP ATP III and AHA/NHLBI12 require that a patient meet specified criteria for 3 or more of 5 commonly measured parameters: waist circumference, triglycerides, HDL cholesterol, blood pressure (BP), and glucose. ATP III also considers a patient who is receiving treatment for elevated triglycerides, hypertension, DM, or reduced HDL cholesterol as having the risk factor for each such condition.

The WHO criteria ¹³ include insulin resistance (defined as type 2 DM, impaired fasting glucose, or impaired glucose tolerance) and 2 of the following: elevated body mass index and/or waist/hip ratio, triglycerides, BP, urinary albumin, and albumin/creatinine ratio, and low HDL cholesterol.

A diagnosis of the metabolic syndrome according to the AACE criteria ¹⁴ depends on clinical judgment based on the following risk factors: body mass index, BP, elevated triglycerides, low HDL, and elevated glucose levels. The AACE definition also considers other risk factors in making a diagnosis: family history of type 2 DM, hypertension, CV disease, polycystic ovary syndrome, sedentary lifestyle, advancing age, or having an ethnic background associated with a high risk for type 2 DM. ¹² , ¹³ , ¹⁴ , ¹⁵

The AHA and NHLBI agree that the metabolic syndrome is a constellation of interrelated metabolic risk factors that contribute to a prothrombotic, proinflammatory state. ¹⁵ As shown in Figure 3, the presence of such cardiometabolic risk factors has been shown to significantly increase CV morbidity and mortality rates and the prevalence of CHD. ¹⁶ , ¹⁷ , ¹⁸ Isomaa and colleagues ¹⁷ demonstrated the relationship between the metabolic syndrome (defined by WHO) and CV outcomes in 3606 participants in the Botnia Family Study of type 2 DM in Finland and Sweden. With a median follow‐up of 6.9 years, the study reported that a history of CHD, MI, or stroke was significantly more common in individuals with the metabolic syndrome risk factors than those who had no risk factors (P<.001). Of the 360 individuals who died during the observation period, 58% (n=209) died of CV disease. Both total and CV mortality were significantly more prevalent in subjects with the metabolic syndrome than those without the metabolic syndrome (P<.001). ¹⁷

In contrast, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) state that not all clinical trials have shown that the metabolic syndrome is a reliable indicator of CV risk. ¹⁹ While various definitions of the metabolic syndrome give all risk factors equivalent significance, ADA and EASD believe that the degree of hypertension and hypercholesterolemia should be considered when assessing CV risk. In addition, there are conflicting data regarding the extent to which the metabolic syndrome as a whole, rather than its individual components, predicts CV disease risk. ¹⁸

As a result, ADA and EASD question the validity of the term metabolic syndrome and believe that research does not suggest it is a separate, treatable disorder. ¹⁹ They argue that each risk factor of the syndrome is already known to increase the risk for heart disease, and they question whether the presence of the metabolic syndrome, by any definition, shows a greater risk for heart disease than risks posed by individual factors. ¹⁹ Instead, they recommend aggressive treatment for individual risk factors for heart disease (eg, DM, insulin resistance, dyslipidemia, hypertension, and microalbuminuria/proteinuria) to target optimal CV outcomes. Many of these arguments may be irrelevant in clinical medicine—risk factors, alone or together, should be treated.

Several groups insist that physicians avoid labeling patients with the term metabolic syndrome and not prescribe specific treatment for the syndrome until new scientific evidence demonstrates its existence and a uniform diagnosis emerges. ¹⁹

Some clinicians, on the other hand, believe that the metabolic syndrome is a useful concept in assessing patient risk. If a patient presents with one or more risk factors included in most definitions of the metabolic syndrome, then clinicians may be alerted to the possible presence of other factors such as microalbuminuria or DM and can include tests for these disorders in the patient workup. ¹⁷ At present, many people believe that the value of the term metabolic syndrome is important, and it appears as though the current definition will persist with modifications made as new findings emerge.

DIABETES MELLITUS

It is widely accepted that there is a link between DM and CV events. Most studies have reported that diabetic patients have as high a risk of experiencing a first MI as nondiabetic patients who already have had an MI. ²⁰ A study in Finland ²⁰ compared the 7‐year incidence of MI (fatal and nonfatal) in 1373 nondiabetic subjects with the incidence of MI in 1059 diabetic patients. They found that the incidence of MI was 18.8% in nondiabetic individuals who had a previous MI at baseline and 3.5% for those who had no previous MI (P<.001). Diabetic patients who had a previous MI had a 45% incidence of another MI and those without a previous MI had a 20.2% incidence of experiencing an MI (P<.001). The hazard ratio (HR) for death from CHD for diabetic patients without prior MI did not differ significantly from that of nondiabetic subjects with prior MI (HR, 1.4; 95% confidence interval [CI], 0.7–2.6) after adjusting for age and sex. After further adjustment for total cholesterol, hypertension, and smoking, the HR remained close to 1.0 (HR, 1.2; 95% CI, 0.6–2.4).20

CONCURRENT DM AND HYPERTENSION

The likelihood of CV events increases when people have concomitant DM and hypertension. In the MRFIT trial, ²¹ the risk of CV death increased 3‐fold when both comorbidities were present.

MRFIT enrolled 347,978 men aged 35–57 years; a total of 5625 were being treated for DM and the rest did not have DM. The study did not classify DM as insulin‐dependent or non‐insulin‐dependent, but >90% were assumed to have non‐insulin‐dependent DM (now referred to as type 2 DM) because of their age. The study showed that men with DM had an absolute risk of CV death greater than men without DM, regardless of age, ethnicity, and level of other risk factors (P<.0001). As the severity of each risk factor increased, the CV risk increased and was progressively greater in diabetic men compared with nondiabetic men. In particular, the absolute excess CV disease mortality risk for diabetic men with the highest levels of BP was almost twice that of nondiabetic men with the same BP. Concurrent DM was associated with a CV risk equivalent to adding 40 mm Hg to the SBP of nondiabetic people with SBP between 120 and 139 mm Hg. ²¹

Is it necessary to treat all CV risk factors simultaneously? The Steno‐2 study ²² compared CV risk in patients with type 2 DM who were conventionally or intensively treated. The study randomized 80 diabetic patients to receive intensive therapy consisting of a combination of behavioral therapy, pharmacotherapy (for hyperglycemia, hypertension, dyslipidemia, and microalbuminuria), and aspirin (for preventing thrombosis) from a team of experienced DM clinicians; another 80 patients received the conventional approach to multiple risk‐factor management from their primary care physician. At the end of the trial, the intensely treated patients had better glucose control, lower BP, and better lipid profiles than the conventionally managed group. The composite primary end point was CV death, nonfatal MI, nonfatal stroke, revascularization, and amputation. Mean follow‐up was 7.8 years. Over the course of the study, patients who were intensively treated had a 53% reduction in CV risk (Figure 4). ²²

The United Kingdom Prospective Diabetes Study (UKPDS) ²³ demonstrated the importance of lowering BP levels in patients with DM. UKPDS 35 evaluated the relationship between glycemia over time and the relative risk of macrovascular and microvascular complications in adults with type 2 DM. The study population included 3642 white, Asian, Indian, and Afro‐Caribbean patients. Although tight glucose and BP control reduced the risk of CV events (eg, stroke, DM‐related death) in patients with DM, tight BP control was significantly more beneficial in reducing macrovascular disease. There was no difference in outcome in patients treated with an ACEI compared with a β‐blocker‐based regimen. It should be noted that the tight BP control that was achieved in the study was a BP of 144/82 mm Hg (compared with BP of 154/87 mm Hg in the less vigorously treated group). Under current recommendations, this would be inadequate control, suggesting that further BP reduction might have achieved greater CV benefits. ²³

The benefit of intensive glucose control was also evident in the UKPDS 38 study, which showed a direct relationship between the risk of diabetic complications and the degree of glycemia over time. Patients allocated to a regimen of intensive blood glucose control had a 0.9% lower hemoglobin A_1c and a 16% risk reduction (P=.052) for MI compared with patients on conventional therapy. An observational analysis of patients with newly diagnosed type 2 DM showed significant (P<.0001) reductions in events, including MI, for each 1% reduction in hemoglobin A_1c. ²⁴

NEW‐ONSET OR NEWLY DIAGNOSED DM

New‐onset or, more appropriately, newly diagnosed DM has emerged as an independent predictor of all‐cause mortality, as shown by MRFIT, ²⁵ a primary prevention trial conducted from 1973 to 1982. Participants were free of CV disease at baseline. Data obtained during an 18‐year posttrial follow‐up involved 11,645 of the original 12,866 men randomized. Incident DM was retrospectively diagnosed according to current criteria (fasting glucose ≥126 mg/dL) or use of insulin or oral hypoglycemic agents. Incident CV disease was defined as nonfatal clinical MI or silent MI on electrocardiogram, revascularization, and nonfatal stroke. Mortality rates over an 18‐year follow‐up were compared among 4 groups: (1) patients without new‐onset DM or CV disease, (2) patients with new‐onset DM but no CV disease, (3) patients with CV disease but no DM, and (4) patients with new‐onset DM and CV disease. The group with DM and CV disease had the highest mortality (HR, 2.75 vs no DM or CV disease; P<.0001), followed by the group with CV disease but no DM (HR, 1.92; P<.0001). The group with new‐onset DM but no CV disease had an HR of 1.49 compared with the group with neither disease (P<.0001). Marked differences in survival rates have long‐term prognostic implications for patients with type 2 DM. ²⁵

Clinicians should be attempting to lower BP while avoiding medications that may increase new‐onset DM, if possible. Trials including the Valsartan Antihypertensive Long‐Term Use Evaluation (VALUE), ²⁶ Losartan Intervention for Endpoint Reduction in Hypertension (LIFE), ²⁷ International Verapamil‐Trandolapril Study (INVEST) ²⁸ and Captopril Prevention Project (CAPPP), ²⁹ have shown a higher risk of developing new‐onset DM in association with antihypertensive regimens that include a thiazide or thiazide‐like (chlorthalidone) diuretic or β‐blocker. In the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), ³⁰ new‐onset DM was also more frequent in the diuretic compared with the ACEI group, but outcome was not affected by this finding. The mechanisms by which diuretics and β‐blockers affect insulin sensitivity are not well understood; however, β‐blockers with a vasodilating effect, such as carvedilol, do not reduce insulin sensitivity. ³⁰ This suggests that an increase in peripheral vascular resistance caused by other β‐blockers may play a role in the effect on insulin sensitivity, possibly in conjunction with effects on insulin clearance and secretion, and a reduction in enzyme activities. ³⁰

As noted, several studies have shown that ACEIs and ARBs reduce the risk of new‐onset DM, while calcium channel blockers (CCBs) are thought to be neutral in this regard. ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ In addition, a recently completed but yet unpublished study (STAR) ³⁸ has investigated the effects of various drug combinations on glucose tolerance in patients with the metabolic syndrome. The results of these studies highlight the importance of considering the impact on glycemic control of various antihypertensive medications, although at present there is no evidence from these trials that CV outcome is affected if BP is controlled.

The European Prospective Investigation into Cancer in Norfolk (EPIC) study ³⁹ has highlighted the need for tight control of glycemia. In this prospective study of 4662 men and 5570 women aged 45–79 years who were followed for an average of 6 years, every 1% increase in hemoglobin A_1c≥7% increased the risk of CV disease (adjusted for age and other risk factors) by 20% and the risk of CHD and all‐cause mortality by 22%. ³⁹ In a separate study, Verdecchia and colleagues ⁴⁰ confirmed that both new‐onset DM and previously diagnosed DM are independent predictors of CV events, with Hrs of 2.92 and 3.57, respectively. In contrast, a follow‐up of the Systolic Hypertension in the Elderly Program ⁴¹ did not indicate a similar prognosis of new‐onset DM and preexisting DM. Although the risk of developing new‐onset DM was not listed as a compelling indication in JNC 7, results from multiple outcome trials subsequently published warrant consideration of such a recommendation.

MICROALBUMINURIA/PROTEINURIA

Microalbuminuria is a marker of endothelial damage indicating increased susceptibility to the atherogenic effect of other established risk factors and is an independent predictor for developing ischemic heart disease (Figure 5). ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ The WHO Multinational Monitoring Trends and Determinants of Cardiovascular Disease (MONICA) study ⁴² included 2085 participants without ischemic heart disease, renal disease, urinary tract infection, or DM. Individuals with microalbuminuria had a 2.3‐fold increased risk of ischemic heart disease compared with individuals who did not have microalbuminuria (95% CI, 1.3–3.9; P=.002). Microalbuminuria was defined as an albumin/creatinine ratio >90th percentile (>0.65 mg/mmol or >5.75 mg/g) of the distribution in the general population. The increased risk equals the risk associated with male sex, older age (10‐year increase; range, 30–60 years), and current smoking status. The presence of microalbuminuria more than doubles the predictive effect of conventional atherosclerotic risk factors for developing ischemic heart disease. ⁴²

Screening and monitoring hypertensive patients for microalbuminuria with a spot urine albumin/creatinine ratio, even in the absence of the metabolic syndrome, chronic kidney disease, or DM can provide important information about the effect of BP control on organs. The National Kidney Foundation (NKF) has defined 3 levels of proteinuria based on spot urine measuring the albumin/creatinine ratio: normal (<30 mg/g), microalbuminuria (30–300 mg/g), and macroalbuminuria (>300 mg/g). ⁴⁴

The National Health and Nutrition Examination Survey (NHANES) ⁴⁷ reports a microalbuminuria prevalence of 5.1% of the US population 6 years and older without adverse health conditions. In hypertensive people, the prevalence increases to 16.0% and, in diagnosed diabetics, to 28.8%. As a result, the NKF recommends testing of at‐risk populations—not just people with DM—particularly those nearing the 30 mg/g albumin/creatinine ratio, the dividing line between normoalbuminuria and microalbuminuria. ⁴⁴ , ⁴⁸ Exercise should be avoided before testing for microalbuminuria, and an initial positive result needs to be confirmed by a subsequent test at least 24 hours later.

The goal of early treatment for microalbuminuria, especially for people with type 1 DM, is to prevent progression to macroalbuminuria. To achieve normoalbuminuria levels, 3 other factors must be considered: improvement of hyperglycemia to the greatest extent possible, reduction in BP (even in normotensive individuals), and use of antihypertensive agents that decrease activity of the renin‐angiotensin system.

The Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) ⁴⁹ studied the effects of a nondihydropyridine CCB and ACEI alone or in combination on the prevention of microalbuminuria in 1204 patients with type 2 DM and hypertension. Significantly fewer patients using either the ACEI alone or the combination of ACEI and nondihydropyridine CCB developed persistent microalbuminuria, suggesting that ACEI therapy alone is adequate to prevent microalbuminuria.

To date, no studies have shown that reducing microalbuminuria reduces CV risk, although the Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND‐IT) ⁵⁰ showed a trend in reduced CV events with reduced urinary albumin. It is unclear from the data, however, whether the CV risk reduction was the result of BP lowering, the reduction in microalbuminuria, or both.

The predictive value of microalbuminuria for the subsequent development of kidney disease is uncertain for type 2 DM patients and patients with diabetic renal disease; however, the Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA‐2) study ⁵¹ demonstrated that treatment with an ARB‐based regimen significantly delayed the progression from microalbuminuria to macroalbuminuria and the onset of diabetic nephropathy, independent of its BP‐lower‐ing effects.

In hypertensive patients with nephropathy caused by type 2 DM, Lewis and colleagues ⁴⁵ found that an ARB (irbesartan)‐based regimen reduced proteinuria (macroalbuminuria) on average by 33%, while a dihydropyridine CCB (amlodipine)‐based regimen reduced proteinuria by 6% compared with 10% for placebo. Follow‐up over 2.6 years indicated less progression of nephropathy in the patients with reduced proteinuria. ⁴⁵

In contrast to the neutral effects on proteinuria of dihydropyridine CCBs, several studies have shown that nondihydropyridine CCBs (eg, verapamil) reduce proteinuria. In a systematic review of 28 studies in hypertensive adults who had clinically evident proteinuria with or without DM, the effects of dihydropyridines and nondihydropyridines on proteinuria and SBP were evaluated. ⁴⁶ Nondihydropyridines reduced urinary protein excretion by 30%, whereas dihydropyridines showed no effect (+2%), although SBP changes were similar. ⁴⁶

CHRONIC KIDNEY DISEASE: DEVELOPMENT AND IMPACT

Chronic kidney disease is defined as kidney damage leading to a glomerular filtration rate <60 mL/min/1.73m² for ≥3 months. ⁵² Chronic kidney disease is associated with an increased prevalence and severity of both traditional and nontraditional risk factors (inflammation, malnutrition, anemia, mineral disorders) for CV disease. In addition, CV disease is 10–100 times more common in patients with kidney disease than patients of the same age and sex without kidney disease. Many chronic kidney disease patients die of CV disease complications before their disease progresses to end‐stage renal disease. Those who do progress to end‐stage renal disease usually die as a result of CV, not renal, disease. ⁵³ , ⁵⁴ DM and hypertension are the leading causes of end‐stage renal disease (requiring dialysis) in the United States and, despite the wide availability of preventive treatments, the incidence of end‐stage renal disease has increased approximately 7‐fold for persons with hypertension and 11‐fold for those with DM. ⁵⁵ A part of this increase may be the result of fewer people dying of CV diseases at an earlier age or people undergoing dialysis at an older age. Consequently, therapy for patients with chronic kidney disease should not be directed only at slowing progression of kidney disease, but should focus also on treating comorbidities, such as hypertension, DM, and CHD.

SUMMARY

Numerous clinical trials indicate the need for early and aggressive BP control, often requiring multidrug regimens. In addition, clinical evidence supports aggressive management strategies aimed at halting chronic kidney disease, reducing proteinuria, and avoiding the onset of or controlling type 2 DM. Individual CV risk stratification should translate into a customized drug regimen that effectively weighs the varying effects of agents from different therapeutic classes on metabolic and cardiovascular risk factors. Although the metabolic syndrome was not recognized by JNC 7 as a compelling indication for aggressive antihypertensive therapy, future JNC guidelines will likely include recommendations for treating this cluster of risk factors.