Role of Neurohormonal Antagonists in Management of Patients With Hypertension, Metabolic Syndrome, and Diabetes

Approximately 1.1 million individualswill have a new or recurrent myocardialinfarction (MI), and more than 500 000 willdevelop new-onset heart failure (HF) in theUnited States this year.¹ Diabetes and hypertensionare each independent risk factors forcardiovascular (CV) events and HF. Patientswith hypertension, diabetes, or both have asubstantially higher risk for future CV eventsand HF. More recently, it has been recognizedthat the metabolic syndrome is also associatedwith a significant increased risk of CVevents and HF.

Activation of the sympathetic nervous systemand the renin-angiotensin-aldosterone system(RAAS) has been demonstrated to play akey role in CV injury, CV events, HF, and CVmortality. The adverse CV risks posed byhypertension, metabolic syndrome, and diabetescan be substantially reduced throughthe use of angiotensin-converting enzyme(ACE) inhibitors and beta blockers. This articlewill describe the rationale for and clinical benefitsof targeting neurohormonal activation inpatients with hypertension and the metabolicsyndrome.

CV Risk Factors

Epidemiologic studies have demonstratedthat both CV risk and HF risk rise accordingto the number of risk factors present; theserisk factors are often additive or, in somecases, synergistic for the risk of major CVevents, including HF and mortality.Hypertension is a significant risk factor forMI, and more than two thirds of patients withHF have antecedent hypertension. Diabetes isan independent risk factor for CV events, andits presence with other risk factors more thandoubles the risk for fatal coronary heart disease(CHD).²

In patients screened for the Multiple RiskFactor Intervention Trial (MRFIT), predictors ofCV mortality in 347 978 men aged 35 to 57years were assessed.³ There were 603 CVdeaths among 5163 (11.7%) men with diabetesover 12 years of follow-up compared with 8965deaths among 34 2815 (2.6%) men withoutdiagnosed diabetes. The absolute risk of CV disease—related death was much higher for menwith diabetes at every age stratum, ethnic background,and risk factor level. The CV risk for anindividual with diabetes with only 1 additionalrisk factor exceeded that for a patient withoutdiabetes with 3 risk factors.

In the East-West study, patients with diabeteswho had suffered a prior MI had amarkedly increased risk of mortality over an 8-year follow-up period.⁴ The 8-year incidence ofrecurrent MI was 45% for patients with diabetesand a prior MI compared with 18.8% forpatients with a history of MI but without diabetes.Patients with diabetes who sustain acutecoronary syndromes also have a substantiallyincreased risk of developing new-onset HF.Diabetes is now considered to be a CHD riskequivalent because patients with diabetes butwithout a history of MI have survival rates similarto those individuals without diabetes whohave had a prior MI.⁵ Approximately threequarters of patients with diabetes will die ofCV disease.¹

Metabolic Syndrome

The metabolic syndrome has been morerecently recognized to be associated with a significantincrease in risk for CV events and HFas well as new-onset diabetes.^5,6 The NationalCholesterol Education Program (NCEP) AdultTreatment Panel III (ATP III) guidelines definethe metabolic syndrome as any 3 of the following:abdominal obesity, elevated triglycerides,low high-density lipoprotein (HDL)cholesterol, elevated blood pressure (BP)(>130/85 mm Hg),and elevated fasting glucoseoccurring in the same patients.

By the ATP III criteria, it is estimated that 22%of US adults 20 years of age or older have themetabolic syndrome (Figure 1).⁷ Among menand women > 60 years of age, more than 40%have the metabolic syndrome. In individualswith the metabolic syndrome, CV mortality overtime is substantially elevated compared withindividuals without the metabolic syndrome. Aprospective study by Sattar and associatesshowed that the metabolic syndrome, as definedby the ATP III criteria, predicts both CHD eventsand new-onset diabetes.⁶ The researchers foundthat men with the metabolic syndrome had 1.7times the risk of a CHD event and 3.5 times therisk of developing diabetes over 4.9 years of follow-up compared with men without the syndrome.The risk increased as the number ofmetabolic abnormalities rose. Compared withmen with no metabolic abnormalities, thosewith 4 or 5 had 3.7 times the risk of CHD and24.5 times the risk of diabetes.

Insulin Resistance, Neurohormones,and CV Risk

The pathophysiology of both the metabolicsyndrome and type 2 diabetes is related toinsulin resistance. Insulin resistance states havebeen strongly associated with an increase in therisk for CV events and HF. Is there a link betweeninsulin resistance, all the conditions that characterizethe metabolic syndrome, and CV risk?

Reaven et al⁸ proposed an interrelationshipbetween angiotensin II, norepinephrine, andinsulin resistance. Insulin resistance leads tohyperinsulinemia, which leads to activation ofthe sympathetic nervous system and theRAAS. Likewise, activation of these neuroendocrinesystems leads to hyperinsulinemia.This contributes not only to the hemodynamiceffect of elevated BP but also to an increasein atherogenesis, progressive CV disease, andprothrombotic and proinflammatory CV riskfactors. The interrelationships between thecomponents of this deadly triad lead to progressionof CV disease and put patients withthe metabolic syndrome at high risk for fataland nonfatal CV events.

Metabolic Syndrome, Diabetes, and Hypertension

For a patient with the metabolic syndrome,the ATP III guidelines⁵ recommend that first anattempt be made to reduce underlying causesvia nonpharmacologic measures—weightreduction through dietary measures and exerciseand smoking cessation. In most cases,however, it is necessary to use pharmacologicmeasures to treat the associated lipid and non-lipidrisk factors, including hypertension. Howis this best achieved? By targeting insulin resistance?By targeting activation of the sympatheticnervous system and RAAS?

According to recent guideline recommendations,⁹ patients with diabetes should be managedas if they have known CHD, which meansthat their CV risk factors (BP and lipids) shouldbe treated to the same targets as patients withknown CHD.

SeventhReport of the Joint National Committee onPrevention, Detection, Evaluation, and Treatmentof High Blood Pressure

According to the National Kidney Foundation,¹⁰ the BP goal for patients with diabetesand hypertension is systolic BP of <130 mm Hgand diastolic BP of 80 mm Hg. This goal is alsoendorsed by the recently released (JNC 7).¹¹ BP-loweringmedications for patients withcompelling indications, such as diabetes,should reduce BP and other risk factors. In thecase of diabetes, this includes reducing proteinuria.Such agents include ACE inhibitors,beta blockers, combined alpha and beta blockers,low-dose diuretics, nondihydropyridinecalcium channel blockers, and angiotensinreceptor blockers. Compelling conditionsmore often than not will require > 1 antihypertensiveagent and likely as many as 3 to 4agents to achieve the desired BP levels.

The American College of Cardiology (ACC)/American Heart Association (AHA) practiceguidelines for patients at high risk for HF¹² nowinclude a staging process that has at its initialstage, or Stage A, patients with hypertension orother conditions strongly associated withdevelopment of HF, in recognition of the factthat early identification and management ofthese patients can delay or halt the progressionto more severe stages. The recommendation isto control systolic and diastolic BP in concordancewith the guidelines. These guidelinesacknowledge that the appropriate antihypertensiveregimen frequently consists of severalmedications used in combination, and recommendmedications that are useful for the treatmentof both hypertension and HF, such asdiuretics, ACE inhibitors, and beta blockers.

The guidelines are less consistent as towhether all BP-lowering agents reduce CV riskto the same extent and whether the goal is merelyto lower BP. Although there is compelling clinicaltrial evidence that various antihypertensivemedications with different modes of action havevaried effects on CV risk, the guidelines differ inhow to interpret these results. Beyond their antihypertensiveeffects, beta blockers and ACEinhibitors favorably affect the metabolic syndromeconstellation of risk factors by preservingkidney function, arresting the atheroscleroticprocess, and preventing or reversing CV or renovascularend-organ damage.

Neurohormonal Antagonists and CVProtection

A more direct and clinical trial—supportedapproach would be to recommend that allpatients with diabetes or the metabolic syndromebe treated with CV protective medicationsthat have been demonstrated to lower CVevents and HF: aspirin, beta blockers, ACEinhibitors, and statins. Clinical trial evidencedemonstrates major benefits from ACEinhibitor and beta-blocker therapy in patientswith diabetes.

Antagonism of the RAAS with ACE inhibitorshas been shown to provide substantial clinicalbenefits to diabetic patients with prior CVevents, HF, or both. The Heart OutcomesPrevention Evaluation (HOPE) study demonstratedthe significant benefits of ACE inhibitionin patients with documented coronary,cerebral, or peripheral vascular disease.¹³

This study assessed the effects of treatmentwith the ACE inhibitor ramipril versus placeboin 9297 patients who had evidence of vasculardisease or diabetes plus 1 additional CV riskfactor and who did not have left ventriculardysfunction or HF. Treatment with ramiprilresulted in reduced rates of death from CVcauses, MI, stroke, death from any cause, revascularizationprocedures, cardiac arrest, HF, andcomplications related to diabetes. Ramipriltreatment also reduced the risk of new-onsetHF by 23%.¹³

A substudy of the HOPE trial, theMicroalbuminuria, Cardiovascular, and RenalOutcomes Prevention Evaluation (MICROHOPE)study, examined whether ramiprilcould lower the risks of CV disease and renaldisease in patients with diabetes.¹⁴ The analysisincluded 3577 patients with diabetes who hadbeen included in the HOPE study. Ramiprilreduced the risk of total mortality by 24%, MIby 22%, stroke by 33%, CV death by 37%, andrevascularization by 17% in patients with diabetes.The HOPE and MICRO-HOPE studiesprovide compelling evidence that ACE inhibitioncan benefit patients with diabetes, themetabolic syndrome, and prior CV events.

The United Kingdom Prospective DiabetesStudy (UKPDS)¹⁵ demonstrated that treatmentwith either an ACE inhibitor or a beta blockerin patients with type 2 diabetes improved clinicaloutcomes and reduced risk: MI wasreduced by 21%, diabetes-related death by32%, renal failure by 42%, stroke by 44%, andnew incidence of HF by 56%.The CV benefitswith beta blockers were similar in magnitudeto that achieved with ACE inhibitors.

The Bezafibrate Infarction Prevention (BIP)trial,¹⁶ a study of patients with diabetes andcoronary artery disease, compared patientstreated with beta blockers with those whowere not. After 3 years, a 43% reduction in CVevents and a 42% reduction in CV mortalitywas seen in the patients with diabetes treatedwith beta blockers.

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In the Carvedilol Post Infarct SurvivalControl in LV Dysfunction (CAPRICORN) trial,post-MI patients with left ventricular dysfunction(ejection fraction, &#8804; 40%) were randomlyassigned to treatment with carvedilol or placebo.¹⁷ Patients selected for this trial werealready treated with aspirin and ACE inhibitionand frequently had undergone revascularization.Treatment with carvedilol, which combinesnonselective beta blockade with alphablockade, substantially reduced all-cause mortality(23% relative risk reduction, = .031),CVmortality (25% relative risk reduction, =.049), and fatal or nonfatal MI (40% relative riskreduction, = .010) compared with placebo inpatients with diabetes and those with hypertensionas well as the overall population.

Further analysis of results from CAPRICORNindicated that the benefits of carvedilol werenot diminished in patients with either diabetesor hypertension. The reduction in risk for all-causemortality or nonfatal MI for the entirepopulation in this trial was 29% versus 26% forpatients with diabetes and 23% for those withhypertension (Figure 2).Thus, even in patientsalready treated with ACE inhibitors, the additionof carvedilol to the post-MI patient loweredrisk even further.

These findings suggest that beta blockadeprovides multiple CV benefits to patients withthe metabolic syndrome and diabetes. Betablocker therapy can reverse CV remodeling,prevent sudden death and arrhythmias, anddecrease myocardial wall stress. These agentsare also antiatherogenic, reducing inflammation,shear stress, endothelial dysfunction, andatherosclerotic lesion progression, whichreduces the incidence of new-onset HF and CVdeath in patients with diabetes.¹⁸

In contrast, benefits seen with the use ofinsulin or sulfonylureas for tight glycemic controlpale in comparison with the magnitude ofrisk reduction achieved with antihypertensivetherapy in the UKPDS. For example, there wasa 56% reduction in new-onset HF in thegroups receiving an ACE inhibitor or betablocker, but only a 9% reduction with tightglycemic control. Overall, diabetic mortalitywas reduced 32% with ACE inhibitors and betablockers compared with 8% with glycemiccontrol.¹⁵ Although this clearly does not meanthat glycemic control is not important or cannotreduce macrovascular risk, it does highlightthat glycemic control alone is notsufficient to substantially lower CV risk inpatients with diabetes.

Concerns About Beta-blockerTherapy

Despite these considerable benefits, physicianshave lingering concerns about addingbeta blockade to the treatment of patients withhypertension and diabetes. These concernshave centered on their potential metaboliceffects, such as worsening HDL cholesterol,increasing total or low-density lipoprotein cholesterol,or both, negatively affecting glucosemetabolism and renal blood flow, and maskinghypoglycemia.

The pharmacologic properties of betablockers have been overgeneralized to be classeffects. In reality, the relative selectivity ofthese agents appears to differentiate them, particularlywith respect to their metaboliceffects. The potential benefits of balancedadrenergic blockade, including alpha₁ inhibition,are apparent. Figures 3A and 3B illustratethe differences between a beta-selective agent,atenolol, and a balanced adrenergic agent, carvedilol,with respect to lipid levels andglycemic control.¹⁹ This is true also withrespect to insulin sensitivity. In patients withhypertension, a 20% to 30% worsening ofinsulin sensitivity is seen with atenolol, metoprolol,and propranolol, while beta blockerswith vasodilating properties—dilevalol, celiprolol,and carvedilol—reduce insulin resistance(Figure 4).²⁰

These positive effects of beta blockers onparameters of specific concern in patientswith the metabolic syndrome or diabetes, coupledwith the proven mortality and morbiditybenefits of neurohormonal blockade in allpatients with diabetes, support the use ofcarvedilol in conjunction with ACE inhibitortherapy in patients with the metabolic syndromeor diabetes.

Summary

Hypertension, the metabolic syndrome, anddiabetes account for a substantial proportionof CV events and HF in the United States.Lowering BP, achieving lipid goals, and obtainingmetabolic control is important. However,even patients who have obtained these goalsremain at higher risk.

The benefits of RAAS and sympathetic systemmodulation in reducing CV events in thesehigh-risk patients extend beyond hemodynamiceffects alone. A combination of ACEinhibitors and beta blockers provides benefitsin patients with the metabolic syndrome, diabetes,hypertension, and atherosclerosis; a consistentreduction in CV morbidity and mortalitybeing the ultimate goal. ACE inhibitors and betablockers for the treatment of the metabolic syndrome,diabetes, and hypertension represents amajor therapeutic advance. Every effort shouldbe made to apply these life-saving therapies inall patients with the metabolic syndrome, diabetes,and hypertension in the absence of contraindicationsor intolerance.

Case Report

A 64-year-old African American woman whohas had type 2 diabetes for the past 6 years presentsfor a routine follow-up visit. She deniesany chest pain or other symptoms and reportsthat her blood glucose is well controlled. Bloodpressure (BP) on this visit is 139/88 mm Hgand heart rate is 82 bpm. Her body mass indexis estimated to be 31 kg/m². Her current medicalregimen includes glyburide 6 mg/day,amlodipine 5 mg/day, omeprazole 20 mg/day,and vitamin E.

With this history in mind, the questions oneneeds to consider for this patient are:

• What is her risk of having a cardiovascular(CV) event in the next 5 years?
• Is her BP well controlled and at goal?
• What other diagnostic tests are needed tohelp guide her therapy?

The key risk factors for this patient arehypertension and diabetes (the latter is a coronaryheart disease risk equivalent). Her risk fora major CV event is estimated to be > 2% peryear, which means that over the next 5 years,her risk would be &#8805; 10%. Evaluation of hermedical regimen reveals that her current therapywill not be sufficient to lower that risk.

The BP goal in patients with diabetes islower than the goal for those with hypertensionalone. For a patient with diabetes, the systolicBP goal is < 130 mm Hg, and the diastolicBP goal is < 80 mm Hg. This patient clearly isnot at goal, and, in fact, she may require 3 ormore medications to reach her BP goal. In addition,it would be advisable to use medicationsthat lower her overall incidence of CV eventsand mortality besides just lowering her BP.

Additional tests that would be useful beforeadjusting her therapeutic regimen include anelectrocardiogram (ECG) to identify any evidenceof left ventricular (LV) hypertrophy, anassessment of renal function, a determinationof glycemic control, a lipid panel, and a measureof urinary albumin. Laboratory reportsreveal the following:

• Blood urea nitrogen (BUN): 22 mg/dL
• Creatinine: 1.6 mmol/day
• Glycosylated hemoglobin (HbA_1c): 9.4%
• Lipid panel: total cholesterol: 212 mg/dL
• Low-density lipoprotein (LDL): 128 mg/dL
• High-density lipoprotein (HDL): 36 mg/dL
• Triglycerides: 240 mg/dL
• The ECG shows LV hypertrophy.

Based on these assessments, what medicationsshould be considered to control her BP?

What are the lipid goals for this patient;does she need a lipid-lowering medication orwould diet and exercise alone be adequate?

The medications shown to lower risk forstroke, myocardial infarction (MI), progressionof renal disease, or development of heart failure(HF) include low-dose diuretics, angiotensin-converting enzyme (ACE) inhibitors,and beta blockers. It is likely, however, that acombination of these agents will be requiredto achieve adequate risk reduction in thispatient.

Calcium channel blockers, specifically thedihydropyridines, have not been shown tolower risk for MI or HF or to provide renoprotection,and, therefore, the amlodipine wasdiscontinued. In its place, hydrochlorothiazide12.5 mg/day, an ACE inhibitor(enalapril 5 mg/day), and a beta blocker,specifically, carvedilol, 6.25 mg/day, wereselected. For additional CV risk reduction,aspirin 81 mg/day, as well as a statin (simvastatin20 mg/day) were started along withdiet and exercise counseling.

The lipid goals for this patient are an LDLcholesterol level of < 100 mg/dL, HDL cholesterol> 40 mg/dL, and triglycerides < 150mg/dL. The Heart Protection Study showedthat patients with diabetes with LDL cholesterollevels in the normal range still derivedmajor benefit from treatment with a statineven in the absence of documented vasculardisease. To achieve tighter glycemic control,rosiglitazone 4 mg/day was started with a goalfor an HbA_1c level of < 7%.

On follow-up 6 weeks later, the patientreports feeling well. She is apparently compliantwith her medications, and she hasbegun a walking program covering a mile aday. Her BP reading is now 128/78 mm Hg.Her BUN is 28 mg/dL; creatinine clearance isstill 1.6 mmol/day. Her LDL cholesterol is atgoal at 98 mg/dL, HDL cholesterol is > 40mg/dL, and triglycerides are 120 mg/dL. Withthe additional therapeutic measures, by 6weeks, she has achieved both appropriate BPand lipid goals.

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