CLINICAL STATEMENTS AND GUIDELINES T he comorbidities of hypertension, diabetes mellitus, obesity, hyperlipidemia, and metabolic syndrome are common in patients with heart failure (HF) and affect clinical outcomes.1 3 Interestingly, although these comorbidities are associated with the development of incident HF in the general population, in pa- tients with established HF, their contributory roles to clinical outcomes are not pre- dictable, and their management is quite challenging. Recent American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines have addressed the role of lifestyle modification,4 treatment of blood cholesterol,5 and management of overweight and obesity6 in the general population and in patients with increased cardiovascular risk, and a recent report from the Eighth Joint Na- tional Committee addressed the management of hypertension.7 However, these guidelines did not specifically address the management of such comorbidities in patients with HF. Similarly, the most recent ACCF/AHA HF practice guidelines8 in 2013 addressed the overall management of comorbidities in patients with HF in broad terms, but again, specific and detailed recommendations on how to man- age hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syn- drome are lacking. The intent of this AHA scientific statement is to summarize data relevant to contributory risk and to provide guidance on the management of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in the development and prognosis of HF to provide recommendations (Table 1) and to foster communication between physicians and other healthcare professionals and patients on the management of these comorbidities. Recommendations in this document are based on published studies and the multidisciplinary expertise of the writing group and harmonized with published practice guidelines from the and other organizations.7,13 15 Hypertension and HF Hypertension is a worldwide epidemic; in many countries, 50% of the population >60 years of age has hypertension. Hypertension is defined as a repeatedly elevated blood pressure (BP) exceeding 140/90 mmHg. The prevalence of hypertension is steadily increasing, even with the expanded use of antihypertensive medications.16 It is widely recognized that hypertension is associated with increased cardiovascular and all-cause mortality independently of other risk factors.14,17 Specific HF mortality attributable to hypertension is probably underreported because of the competing adjudication for stroke or myocardial infarction (MI) at the end of the spectrum of hypertensive cardiovascular death. Biykem Bozkurt, MD, PhD, FAHA, Chair David Aguilar, MD, FAHA Anita Deswal, MD, MPH, FAHA Sandra B. Dunbar, RN, PhD, FAHA Gary S. Francis, MD, FAHA Tamara Horwich, MD, MS, FAHA Mariell Jessup, MD, FAHA Mikhail Kosiborod, MD, FAHA Allison M. Pritchett, MD Kumudha Ramasubbu, MD Clive Rosendorff, MD, PhD, DScMed, FAHA Clyde Yancy, MD, MSc, FAHA On behalf of the American Heart Association Heart Failure and Transplan- tation Committee of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; and Council on Quality and Outcomes Research Contributory Risk and Management of Comorbidities of Hypertension, Obesity, Diabetes Mellitus, Hyperlipidemia, and Metabolic Syndrome in Chronic Heart Failure A Scientific Statement From the American Heart Association 2016 American Heart Association, Inc. Key Words: AHA Scientific Statements cardiovascular diseases comorbidity diabetes mellitus heart failure hyperlipidemia hypertension obesity risk factors AHA Scientific Statement Bozkurt et al Hypertension Plays a Significant Role in the Development of HF Elevated levels of diastolic BP and especially systolic BP (SBP) are major risk factors for the development of One of the most impactful observations from the Framingham cohort was that the cumulative incidence of HF was significantly higher in patients with hyperten- (Figure 1) Among 5143 patients, 91% of the patients with HF had hypertension antedating the devel- opment of HF, underlining that in the majority of patients with HF, hypertension was a contributing cause. The haz- ard ratios (HRs) for developing HF in hypertensives com- pared with normotensives were 2-fold higher in men and It should be noted that the risk associated with hypertension may be accentuated through its confounding effect on ischemic heart disease and other cardiovascular outcomes such as stroke. Fur- thermore, these studies predate current HF management strategies and guidelines and may no longer reflect the risk in the current population treated for hypertension. However, they underscore the importance of hyperten- sion as a cause of HF when left untreated. The residual lifetime risk for hypertension for middle-aged and elderly Table 1. Applying Classification of Recommendations and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES individuals in the United States is 90%, indicating a huge public health burden20 and defining the importance of strategies to control hypertension to prevent HF. Treatment of Hypertension Prevents the Development of HF Long-term treatment of both systolic and diastolic hyper- tension has been shown to reduce the risk of HF.21,22 With treatment of hypertension, the risk of developing HF is reduced by 30% in younger populations,23 by 50% in the and by almost 80% among the elderly with history of MI.22 A meta-analysis of long-term hyperten- sion treatment trials25 and a number of large, controlled have uniformly demonstrated that optimal BP control decreases the risk of new HF by 50%. In pla- cebo-controlled trials, although the relative risks of total major cardiovascular events were reduced by regimens based on angiotensin-converting enzyme (ACE) inhibitors (22%) or calcium antagonists (18%), the risk for develop- ing HF was reduced significantly by ACE inhibitors but not calcium antagonists.27 Greater risk reductions were produced by treatment regimens that targeted lower BP goals than those targeting relatively higher BP goals.28 Treatment Treatment of Hypertension in Patients at Risk for Developing HF Goals of Treatment of Hypertension to Prevent HF Patients with hypertension are at high risk for develop- ing HF (stage A), and their BP should be controlled in accordance with contemporary guidelines to lower the risk of HF (Level of Evidence A8 ; Table 2). According to the recently published 2014 evidence-based guidelines for the management of high BP in adults,7 the goal for treatment of BP has been identified as <140/90 mmHg for patients who are <60 years of age or for adult pa- tients with chronic kidney disease or diabetes mellitus and as <150/90 mmHg for patients 60 years of age in the general population. It should be noted that this last recommendation of a higher target for patients 60 years of age has been controversial and debated in the There is evidence that the initiation of an- tihypertensive treatment for the above thresholds is as- sociated with a reduction of HF and other cardiovascular events and overall mortality among hypertensive adults 30 years of age in the general population or in hyper- tensive patients 18 years of age with chronic kidney disease or diabetes mellitus.7 Similar targets were quot- ed in the 2002 AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke, which identified a general goal of <140/90 mmHg for the treatment of Figure 1. Cumulative incidence of heart failure, adjusted for death as a competing risk, by baseline systolic blood pressure (SBP) categories of <120, 120 to 139, 140 to 159, and 160 mmHg for women (top), men (middle), and the overall population (bottom). Reprinted from Butler et al19 with permission with permission from BMJ Publishing Group Ltd. Copyright 2011, BMJ Pub- lishing Group Ltd and the British Cardiovascular Society. Table 2. Recommendation for the Treatment of Hypertension in Stage A HF: Asymptomatic Patients at Risk for HF Recommendation COR LOE Referenced Guideline References Hypertension should be controlled in accordance with contemporary guidelines to lower the risk of development of HF. I A 7 9 COR indicates Class of Recommendation; HF, heart failure; and LOE, Level of Evidence. Bozkurt et al hypertension in HF.9 Ongoing trials are intended to spe- cifically address the question of goal BP reduction, and a new ACCF/AHA Guideline Writing Committee has been convened to address the management of hypertension. Medication Choices for the Treatment of Hypertension to Prevent HF For antihypertensive regimens in patients without estab- lished HF, optimal control of BP should remain the prima- ry goal. The most recent 2014 evidence-based guideline for the management of high BP in adults recommends that in the general nonblack population, including those with diabetes mellitus, the initial antihypertensive treat- ment should include a thiazide-type diuretic, a calcium channel blocker, an ACE inhibitor, or an angiotensin recep- tor blocker (ARB).7 Each of these 4 drug classes recom- mended by the writing group yielded comparable effects on overall mortality, cardiovascular (excluding HF), cere- brovascular, and kidney outcomes. However, the effects of these drug classes on HF differ. Treatment with a thiazide-type diuretic or an ACE in- hibitor has been shown to be more effective than treat- ment with a calcium channel blocker in improving HF Although the writing committee recognized that improved HF outcome was an important finding that should be considered in the selection of a drug for initial therapy for hypertension, the panel did not conclude that it was compelling enough to preclude the use of the other drug classes for initial therapy. The panel also acknowl- edged that the evidence supported BP control, rather than a specific agent used to achieve that control, as the most relevant consideration for their recommendation.7 Supporting this, historically, most antihypertensive drugs have demonstrated comparable cardiovascular efficacy Specifically, diuretic-based antihyperten- sive therapies have been shown to prevent HF in a wide range of target populations as first-line therapy.27,35 39 Additionally, low-dose diuretics have been shown to be more effective as a first-line treatment for preventing the development of HF compared with ACE inhibitors, -blockers, or calcium channel blockers by meta-analy- It should also be noted that most of the original tri- als used the longer-acting chlorthalidone rather than hy- drochlorothiazide. ACE inhibitors have also been shown to be very effective in the prevention of HF,14,27,35,40 even more significantly in patients with left ventricular (LV) sys- tolic dysfunction or patients after MI.41,42 Likewise, ARBs have been shown to reduce the incidence of HF, espe- cially in patients with hypertension and type 2 diabetes mellitus and nephropathy.43,44 However, calcium channel blockers appear to be somewhat less efficacious than the above agents for preventing HF.8,27 There are inad- equate data to determine whether this is true only for dihydropyridine calcium channel blockers or whether it is true of the entire class of drugs.26 Regarding -blockers, in the ALLHAT trial (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial), doxazosin was inferior to chlorthalidone for the prevention of HF and was associated with the doubling of HF risk compared The 2013 ACCF/AHA Guideline for the Management of Heart Failure indicated that the role of calcium antagonists or -blockers is less clear for reducing the risk for incident HF, and the choice of antihypertensive therapy should follow the contempo- In addition to medications, patients with hypertension should be advised on healthy lifestyle modi- fication; weight reduction; reduction of sodium intake; increased consumption of fruits, vegetables, and low-fat dairy products; and moderation of alcohol intake.7,9,14 In patients with stage B HF with structural heart disease or LV dysfunction but without HF symptoms, there is benefit with ACE inhibitors, ARBs, or -blockers (Table 3). Thus, in patients with a recent or remote history of MI or acute coronary syndrome and reduced ejection fraction (EF), ACE inhibitors49 51 (or ARBs if the patient is ACE inhibitor intolerant30,52 ) prevent symptomatic HF and reduce mortality. Similarly, in patients with a recent or remote history of MI or acute coronary syndrome and reduced EF, -blockers reduce mortality.53 55 In patients with a reduced EF but without any history of MI or symp- toms of HF, ACE inhibitors prevent symptomatic HF,51,56 and - blockers can improve symptoms, ameliorate LV Table 3. Recommendations for the Treatment of Hypertension in Stage B HF: Patients With Cardiac Structural Abnormalities or Remodeling Who Have Not Developed HF Symptoms Recommendations COR LOE Referenced Guideline References In patients with structural cardiac abnormalities, including LV hypertrophy, BP should be controlled in accordance with clinical practice guidelines for hypertension to prevent symptomatic HF. Nondihydropyridine calcium channel blockers with negative inotropic effects may be harmful in asymptomatic patients with low LVEF. - Adrenergic blockers such as doxazosin should be avoided and might be used only if other drugs for the management of hypertension and HF are inadequate to achieve BP control at maximum tolerated doses. ACE indicates angiotensin-converting enzyme; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; BP, blood pressure; COR, Class of Recommendation; HF, heart failure; LOE, Level of Evidence; LV, left ventricular; LVEF, left ventricular ejection fraction; and MI, myocardial infarction. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES remodeling, and improve LV function.57,58 Although these beneficial effects of ACE inhibitors, ARBs, and -blockers are not specific for patients with hypertension or for treatment of BP, a significant proportion of patients in these trials (40% 60%) had a history of hypertension, and the beneficial effects could be generalized to the hypertensive population. Treatment of Hypertension in Patients With Established HF How Aggressively to Treat BP in Patients With HF? There have not been compelling data to justify a single BP target in treating hypertension in patients with es- tablished HF. Former guidelines and position papers differ significantly in such threshold definitions and lack strong evidence for treatment targets of hypertension in Therefore, the optimal BP target for the treat- ment of hypertension in patients with HF is not firmly established. The 2007 AHA scientific statement on the treatment of hypertension in the prevention and manage- ment of ischemic heart disease recommended a target BP of <130/80 mmHg in patients with HF.48 Similarly, the 2002 AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke 9 identified the BP treatment goal as <130/85 mmHg if HF was present. However, these recommendations were empirical, not supported by trial evidence.9,48 Furthermore, there is con- cern about potential adverse outcomes with BP lowering that is too aggressive, which was further supported by the change to a higher BP threshold of 140/90 mmHg in patients <60 years of age and <150/90 mmHg in patients 60 years of age in the 2014 evidence-based guideline for the management of high BP in adults.7 It should be noted, however, that the writing committee did not address BP treatment targets in patients with es- tablished HF. The lack of definitive BP targets in patients with existing HF notwithstanding, treatment of HF is usu- Table 4. Recommendations for the Treatment of Hypertension in Stage C HF: Patients With Cardiac Structural Abnormalities or Remodeling With Prior or Current Symptoms of HF Recommendations COR LOE Referenced Guideline References Patients with previous or current symptoms of HFrEF should be treated with GDMT, including diuretics, ACE inhibitors (or ARBs if ACE inhibitor intolerant), -blockers, and aldosterone receptor antagonists, which have been proven to improve outcomes for patients with HF and can lower BP in hypertensive patients with HFrEF. I A for clinical outcomes, B for BP control Addition of hydralazine/isosorbide dinitrate to the background treatment with ACE inhibitor or ARB and -blocker in self-described black patients with HFrEF and persistent NYHA class III or IV HF symptoms is beneficial to reduce morbidity and mortality and can lower BP in hypertensive patients with HFrEF. I A for reduction in morbidity and mortality in HF, B for BP control The treatment of hypertension in patients with HF should include behavioral modification such as sodium restriction and a closely monitored exercise program. Weight reduction in overweight or obese, an appropriate diet, and moderation of alcohol intake are recommended in patients with hypertension. Thiazide or thiazide-like diuretics can be useful for BP control and to reverse mild volume overload and associated symptoms in symptomatic patients with HF with volume overload. Loop diuretics, which are the preferred agents for treatment of congestion in symptomatic patients with HF, are less effective than thiazide or thiazide-like diuretics in lowering BP. Addition of hydralazine isosorbide to the background therapy with ACE inhibitor or ARB and -blocker may be beneficial for BP control in nonblack patients with HFrEF and hypertension. Drugs to avoid in patients with HF and hypertension include nondihydropyridine calcium channel blockers (eg, verapamil and diltiazem) and moxonidine. An attempt should be made to avoid -adrenergic blockers such as doxazosin; they might be used only if other drugs for the management of hypertension and HF are inadequate to achieve BP control at maximum tolerated doses. ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; COR, Class of Recommendation; GDMT, guideline- directed medical therapy; HF,heart failure; HFrEF,heart failure with reduced ejection fraction; LOE,Level of Evidence; and NYHA,NewYork HeartAssociation. Bozkurt et al ally the main focus of the initial treatment of patients with established HF, and the standard treatment of HF usually lowers BP. This is supported by the observation that SBP has usually been lowered to a normal range of 110 to 130 mmHg in most successful HF treatment trials with After optimization of HF treatment, if BP is not controlled, further treatment strategies target- ing both BP and HF can be used. It should also be noted that the BP-lowering effects of HF medications may re- late to the baseline BP; that is, there may be a greater BP-lowering effect in patients with a higher baseline BP. However, the beneficial effects of the HF medications are usually independent of the baseline BP or changes in BP and do not vary according to baseline BP or reduc- tions in SBP levels.60 62 Medication Choices for the Treatment of Hypertension in Patients With HF Currently, there are no randomized, large-scale trials comparing the effectiveness of different antihyperten- sive medications targeting optimal treatment of BP solely in patients with hypertension and established HF. Thus, most evidence comes from hypertension clinical trials that have not excluded patients with a history of HF. In patients with established HF, drugs that have been shown to improve outcomes for patients with HF gen- erally also lower BP. Thus, the emphasis should be on initiating and optimizing guideline-directed medical treat- ment of HF, which will likely help control BP at target doses. Therefore, patients with hypertension and HF with reduced EF (HFrEF) are treated with diuretics, ACE in- hibitors (or ARBs if ACE inhibitor intolerant), -blockers, and aldosterone antagonists unless contraindicated8 (Table 4). Although thiazide or thiazide-like diuretics are usually recommended for the treatment of hypertension,7 in pa- tients with current or prior symptoms of HF who have evi- dence of fluid retention, loop diuretics are usually used8 (Table 4). It should be noted, however, that loop diuret- ics are usually less effective than thiazide or thiazide-like diuretics in lowering BP8 and thus should be used for the management of hypertension in patients with symp- tomatic HF with congestion. For patients with stage C HFrEF, ACE inhibitors (or ARBs in ACE inhibitor intolerant patients), -blockers, and aldosterone antagonists are titrated to target doses as tolerated. BP is frequently within the target range or lower after careful titration of these agents. In those for whom BP remains in the hy- pertensive range, further increases of the recommend- ed agents may be considered. Reasonable next steps would be the addition of other medications with proven benefit in HF populations such as ARBs or aldosterone antagonists or the addition of nitrates or hydralazine. Treatment of Refractory Hypertension in HF Most patients with advanced stage C or D HF do not manifest hypertension and may actually develop hy- potension resulting from pump failure and an inability to raise the BP. However, if a patient with HFrEF has refractory hypertension, there are no definitive studies to provide guidance on the efficacy and safety of addi- tional antihypertensive approaches when recommended HF therapies are inadequate to treat BP. Nondihydro- pyridine calcium channel blockers (diltiazem, verapamil) are used to treat hypertension, but they are not recom- mended as routine treatment for patients with HFrEF.8 Amlodipine and felodipine neither improve nor worsen the survival of patients with HF72,73 ; therefore, a dihy- dropyridine group of calcium channel blockers could be used to control hypertension only after other medica- tions have failed. There are few data assessing the ef- ficacy and safety of other medications or of specific combinations of 3 drugs for hypertension in the HF Accordingly, the recommendation of spe- cific multidrug combinations is largely empirical or anec- dotal. Intuitively, it seems most appropriate to continue to combine agents of different mechanisms of action. In that regard, a triple-drug regimen of an ACE inhibitor or ARB, a calcium channel blocker, and a thiazide diuretic is effective and can be well tolerated.74 It should be kept in mind that carvedilol, 1 of the 3 -blockers proven to reduce mortality in HF, is more effective in reducing BP than metoprolol succinate or bisoprolol because of its combined 1 -blocking properties and may be the -blocker of choice among -blockers in patients with HFrEF with refractory hypertension. Evidence with other -blockers with vasodilatory properties such as is very limited, and they are not the -blocker of choice for the treatment of HFrEF according to HF guidelines.8 Experience with older-gen- eration antihypertensive medications such as prazosin, an -receptor blocker,77 or clonidine, a centrally acting is again very limited and precedes the evi- dence with standard HF therapies. Furthermore, studies suggest potential adverse outcomes with these classes of agents that are elaborated below in the Drugs to Avoid in Patients With HF section. In addition to medication choices, the evaluation of patients with resistant hypertension should be directed toward confirming true treatment resistance, accurate assessment of treatment adherence and use of good BP measurement techniques to exclude pseudo-resistance, and identification of causes contributing to treatment re- sistance, including secondary causes of hypertension. In most cases, treatment resistance is multifactorial in origin, with obesity, excessive dietary sodium intake, ob- structive sleep apnea (OSA), and chronic kidney disease being particularly common factors in patients with HF. New antihypertension treatment strategies such as renin inhibition with aliskiren failed to improve clinical outcomes in patients with HF,80 and catheter-based renal artery denervation (SYMPLICITY HTN-3 trial [A Controlled Trial of Renal Denervation for Resistant Hypertension]) Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES failed to show a significant reduction of SBP in patients with resistant hypertension.81 Other strategies such as targeting excessive sympathetic nerve activity by carotid body denervation are awaiting clinical validation in the hypertension and HF populations. Drugs to Avoid in Patients With HF Several classes of drugs should be avoided in patients with HFrEF with a history of hypertension. Because of their negative inotropic properties and the increased likelihood of worsening HF symptoms, the nondihydropyridine cal- cium channel blockers such as diltiazem and verapamil should be avoided.8 The dihydropyridine calcium channel blocker amlodipine appeared to be safe in patients with severe HFrEF in the PRAISE trial (Prospective Randomized Amlodipine Survival Evaluation),82 as was felodipine.73 In the current 2013 HF guidelines, most calcium channel blocking drugs except amlodipine are not recommended.8 Although clonidine is an effective antihypertensive agent, a similar centrally acting drug, moxonidine, was associat- ed with increased mortality in patients with HF; thus, cen- trally acting norepinephrine-depleting agents may need to be avoided or used with caution in patients with HFrEF.83 In the ALLHAT trial, the -blocker doxazosin arm of the trial was discontinued because of a 2-fold increase in the risk of developing HF compared with chlorthalidone treat- Although the ALLHAT study excluded patients with established HF and there are caveats about extrapolating these data to the management of hypertension in patients with established HF, the safety and efficacy of -blockers in the management of patients with HF with hypertension are currently unclear. Potent direct-acting vasodilators such as minoxidil should also be avoided because of their renin-related salt and fluid-retaining effects. Nonsteroidal anti-inflammatory agents should be used with caution in these patients, given their effects on BP, volume status, and renal function. Treatment of Hypertension in Patients With HF With Preserved LVEF Most patients with HF and preserved LVEF (HFpEF), es- pecially elderly women, have hypertension. A significant proportion of these patients also have evidence of LV hy- pertrophy, and some may have atrial dilatation, cardiac enlargement, and wall motion abnormalities without LV systolic dysfunction. Patients with HFpEF may respond particularly well to the treatment of hypertension with regression of hypertrophy84 and improvement in filling Most patients with HFpEF require treat- ment with cardiac medications for the comorbidities of hypertension, diabetes mellitus, coronary artery dis- ease, and atrial fibrillation. The 2013 HF guidelines sug- gest that the use of -blocking agents, ACE inhibitors, and ARBs in patients with hypertension is reasonable to control BP in patients with HFpEF.8 The use of ARBs might also be considered to decrease hospitalizations for patients with HFpEF.8 Recommendations Harmonized With Existing Guidelines for the Recognition and Treatment of Patients With HF With Hypertension See Tables 2 through 4 for a summary of these recom- mendations. Stage A HF For patients with hypertension who are at high risk for developing HF in the future but with no functional or structural cardiac disorder at present time, the following is recommended: 1. Hypertension should be controlled in accor- dance with contemporary guidelines to lower the risk of developing HF (Class I; Level of Stage B HF For patients with hypertension, with cardiac structural abnormalities or remodeling who have not developed HF symptoms, the following is recommended: 1. In patients with structural cardiac abnormali- ties, including LV hypertrophy, BP should be controlled in accordance with clinical prac- tice guidelines for hypertension to prevent symptomatic HF (Class I; Level of Evidence Stage C HF For patients with hypertension and previous or current symptoms of HF in the context of an underlying struc- tural heart problem, the following are recommended: 1. Patients with HFrEF should be treated with guideline-directed medical therapy, includ- ing diuretics, ACE inhibitors or ARBs if ACE inhibitor intolerant, -blockers, and aldoste- rone receptor antagonists, which have been proven to improve outcomes for patients with HF (Class I; Level of Evidence A) and can lower BP in hypertensive patients with HFrEF (Class I; Level of Evidence B).8,29,50,63 68 2. The addition of hydralazine/isosorbide dinitrate to the background regimen of a diuretic, an ACE inhibitor or ARB, and a -blocker treatment in self-described black patients with HFrEF and with persistent New York Heart Association (NYHA) class III or IV HF symptoms is beneficial to reduce morbid- ity and mortality (Class I; Level of Evidence A) and can lower BP in hypertensive patients with HFrEF (Class I; Level of Evidence B).8,69,70 3. The treatment of hypertension in patients with HF should include behavioral modifica- tion such as sodium restriction and a closely monitored exercise program.48 Weight reduc- tion in obese or overweight, a heart-healthy diet, and moderation of alcohol intake in Bozkurt et al individuals with 140 mmHg SBP or 90 mmHg diastolic BP are recommended (Class I; Level of Evidence C).7,9,14,48 4. Thiazide or thiazide-like diuretics can be use- ful for BP control and to reverse mild volume overload and associated symptoms in symp- tomatic patients with HF with volume over- load. Loop diuretics, which are the preferred agents for treatment of congestion in symp- tomatic patients with HF, are less effective than thiazide or thiazide-like diuretics in low- ering BP (Class IIa; Level of Evidence C).7,8,48 5. The addition of hydralazine/isosorbide dini- trate to the background treatment with an ACE inhibitor or ARB and a -blocker may be benefi- cial in nonblack patients with HFrEF and hyper- tension (Class IIa; Level of Evidence C).8,71 6. Drugs to avoid in patients with HF and hyper- tension are nondihydropyridine calcium chan- nel blockers (eg, verapamil and diltiazem) and moxonidine (Class III: Harm; Level of Evidence C). -Adrenergic blockers such as doxazosin should be avoided and might be used only if other drugs for the management of hyper- tension and HF are inadequate to achieve BP control at maximum tolerated doses (Class III: Harm; Level of Evidence C).8,14,29,48 Paradox: Once HFrEF Is Manifest, Higher BP Is Associated With Better Prognosis An epidemiological paradox exists in the HF-hyperten- sion relationship. Although hypertension results in the development of HF, once advanced HFrEF is manifest, lower BP is associated with a worse prognosis, and simi- larly, a higher BP is associated with a better prognosis. This is attributable to a loss of myocardial contractility in advanced HF, which suggests a poor prognosis. In these patients, the higher SBP may be a marker of the abil- ity of the ventricle to generate a SBP or better cardiac output. However, it should be noted that the BP ranges demonstrated to have an association with mortality in retrospective analyses were not defined or validated as targets in prospective, controlled trials and should not be accepted as a target for BP control in patients with HF. In the Digitalis Investigation Group trial database, mor- tality was significantly higher for patients in the lowest SBP group (<100 mmHg) than in the reference group of patients with an SBP of 130 to 139 mmHg (HR, 1.65; Similar results were reported by the Valsartan Heart Failure Trial (Val-HeFT), in which patients in the lowest quartile of SBP (SBP 110 mmHg) had more severe HF and a significantly increased mortality (HR, 1.21; 95% CI, 1.03 1.43; P=0.02) and hospitalization for HF (HR, the upper 3 quartiles of baseline SBP (mean SBP, 130 ; Figure 2). Similar findings are noted in patients with acute decompensated HF.87 90 In a meta-analysis of 10 studies of a total population of 8088 subjects, higher SBP resulted in better out- comes in patients with established HF.91 Studies included in this analysis had a maximum SBP of 158 mmHg. The decrease in mortality rates associated with a 10 mmHg higher SBP was 13.0% in the HF population. In a recent study by Ather et al92 incorporating data from 2 large cohorts of ambulatory patients with chronic HF, it was noted that the relationship of BP and mortality is differ- ent in patients with mild and those with severe LV sys- tolic dysfunction. In patients with mild to moderate LV systolic dysfunction, SBP was found to have a nonlinear U-shaped association with increased all-cause mortality at both the lower and upper ranges of SBP (Figure 3A). It should be noted, however, that these numbers were defined to have an association with mortality in a retro- spective analyses, were not defined or validated targets in a prospective, controlled trial, and thus should not be accepted as a target for BP control in patients with HF. In the same study, in patients with severe LV systolic dys- function with LVEF <30%, SBP was found to have a linear association, with lower SBP being associated with worse mortality (Figure 3B), similar to what has been described in other HF studies. Nu ez et al93 also noted a differen- tial prognostic effect of SBP on mortality according to LV function in patients with acute decompensated HF. These results suggest that the association of SBP with mortality may vary with LV function severity. In patients with HF with preserved or mildly depressed LV function, SBP appears to have a nonlinear U-shaped relationship, with increased mortality at both ends of low or high BP. In patients with HF with severe LV systolic dysfunction Figure 2. Effect of baseline systolic blood pressure (SBP) in all-cause mortality in the Valsartan Heart Failure Trial. Reprinted from Anand et al.60 Copyright 2008, American Heart Association, Inc. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES (EF <30%), SBP has a linear association with mortality, with higher SBP being associated with better survival and lower SBP being associated with worse mortality. Diabetes Mellitus and HF Association of Diabetes Mellitus With the Development of Incident HF Multiple observational studies have demonstrated that diabetes mellitus is associated with an increased risk for the development of HF.94 98 In the Framingham Heart Study, diabetes mellitus was associated with a nearly 2-fold greater risk of HF in men and a nearly 4-fold in- creased risk of HF in women independently of the pres- ence of hypertension, coronary artery disease, LV hy- pertrophy, and valvular heart disease.95 In the NHANES (National Health and Nutrition Examination Survey) Epide- miologic Follow-Up Study, diabetes mellitus was indepen- dently associated with an 80% increased risk of HF.94 In the Framingham Heart Study, the population-attributable risk for HF associated with diabetes mellitus was 6% in men and 12% in women.18,19 Studies have also demonstrated that milder eleva- tions in glucose and abnormalities in insulin resistance, even in the absence of overt diabetes mellitus, are as- sociated with an increased risk for HF.99,100 In individuals without known diabetes mellitus or HF at baseline in the ARIC study (Atherosclerosis Risk in Communities), the risk of incident HF was higher in individuals with hemo- CI, 0.98 1.37) compared with those with an HbA1c of (Table 5). The mechanisms contributing to the greater degree of HF in individuals with diabetes mellitus are likely mul- tifactorial and include the commonly shared HF risk factors of hypertension, coronary artery disease, renal Figure 3. Restricted cubic spline analysis for Cox proportional hazards model. A, In patients with heart failure (HF) with mild to moderate left ventricular systolic dysfunction (left ventricular ejection fraction 30% and <50%) showing a nonlinear U-shaped association of systolic blood pressure (SBP) with increased all-cause mortal- ity at both the lower and upper ranges of SBP. The red line represents the estimated logarithmic hazard ratio (HR) of all-cause mortality; the blue lines represent the 95% pointwise confidence bands. B, In patients with HF with severe left ventricular systolic dysfunction (left ventricular ejection fraction <30%) showing a relatively linear association of SBP with all-cause mortality. The red line represents the estimated logarithmic HR of all-cause mortality; the blue lines represent the 95% pointwise confidence bands. HFrEF indicates heart failure with reduced ejection fraction; and EPRP, Veterans Affairs External Peer Review Program. Reprinted from Ather et al92 with permission from Elsevier. Copyright 2011, Mosby, Inc. Table 5. Recommendations for the Treatment of Diabetes Mellitus in Stage A HF: Asymptomatic Patients at Risk for HF Recommendations COR LOE Referenced Guideline References For patients with diabetes mellitus (who are all at high risk for developing HF), blood sugar should be controlled in accordance with contemporary guidelines. ACE inhibitors or ARBs can be useful to prevent HF in patients at high risk for developing HF who have a history of atherosclerotic vascular disease, diabetes mellitus, or hypertension with associated cardiovascular risk factors. IIa A for ACE inhibitor, B for ARBs for prevention of HF ACE indicates angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; COR, Class of Recommendation; HF, heart failure; and LOE, Level of Evidence. Bozkurt et al dysfunction, and obesity. In addition, diabetes mellitus may independently contribute to cardiac dysfunction in the absence of these risk factors (ie, diabetic car- diomyopathy). Potential pathogenic factors contribut- ing to cardiac dysfunction in patients with diabetes mellitus include the direct and indirect effects of hy- perglycemia and advanced glycation end products, autonomic dysfunction, microangiopathy, subclinical macrovessel (coronary) disease, mitochondrial dysfunction, lipotoxicity, and potential Association of Diabetes Mellitus With Outcomes in Patients With Established HF Diabetes mellitus is commonly present in patients with HF. It is estimated that 12% to 30% of patients with symptomatic HF have previously diagnosed diabetes Between 1995 and 1999 in Olmsted County, Minnesota, the prevalence of diabetes mellitus in pa- tients with incident HF was 25%.106 The prevalence of diabetes mellitus appears to be even greater in patients hospitalized with acute decompensated HF, with regis- tries demonstrating a prevalence of 40% to 44%.107,108 Similarly, in a registry of individuals with HFpEF, diabetes mellitus was present in 46% of patients.109 Systematic assessment with oral glucose tolerance testing in pa- tients with HF without a previous diagnosis of diabetes mellitus may also identify a large proportion (18%) of patients with newly diagnosed diabetes mellitus.110 The presence of diabetes mellitus in patients with HF is associated with increased morbidity and mortal- In the CHARM Program (Candesartan Heart Failure Assessment of Reduction), rates of HF hospitaliza- tion in patients with diabetes mellitus were approximately twice the rates of those without diabetes mellitus.113 In SOLVD (Studies of Left Ventricular Dysfunction), the ad- justed relative risk of HF hospitalization for subjects with in the treatment and prevention trials, respectively.116 The association of increased mortality with diabetes mel- litus in patients with HF appears to be limited to or more apparent in patients with an ischemic than in those with a nonischemic pathogenesis.112,117 Diabetes mellitus has also been independently associated with increased mor- tality in patients with HF in multiple observational studies and clinical trials.104,106,111,113,114 Treatment: Current Evidence of HF Risk Reduction With the Treatment of Diabetes Mellitus in Patients With HF Given the increased morbidity and mortality associated with diabetes mellitus and HF, efforts for preventing HF are increasingly important. These efforts include the treatment and prevention of coronary artery disease and adequate treatment of hypertension in patients with dia- betes mellitus. An important risk factor for the development of HF in patients with diabetes mellitus is abnormal glucose con- In a large cohort study of nearly 50000 dia- betic patients without HF at baseline, each 1% increase in HbA1c was associated with an 8% increased risk of In a similar study of patients with diabetes mellitus enrolled in the ARIC study, the adjusted HR of HF for for individuals without coronary heart disease at baseline and 1.20 (95% CI, 1.04 1.40) for those with coronary heart disease at baseline.119 The increased risk for the development of HF with increasing HbA1c in ARIC was also present in patients in the absence of incident coro- In the CHS (Cardiovascular Health Study), elevated fasting glucose among older adults with diabetes mellitus was also independently associated with incident HF.121 Despite the epidemiological data linking worse gly- cemic control to greater rates of HF in observational studies and clinical trials, data from randomized, con- trolled, clinical trials of more intensive glucose control have not demonstrated a benefit in HF reduction with intensive glycemic control. In a meta-analysis of 8 ran- domized, controlled trials (that included a total of 37229 patients) comparing more with less intensive glucose- lowering strategies, the risk of HF-related events did not differ significantly between more intensive regimens and standard therapy despite achieving an average HbA1c In subgroup analyses limited to clinical trials specifically designed to compare strategies targeting more intensive and standard glycemic control (VA-CSDM [Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes] Feasibility, UKPDS [United Kingdom Prospective Diabetes Study], ADVANCE [Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation], ACCORD [Action to Control Cardiovascular Risk in Diabetes], and VADT [Vet- erans Affairs Diabetes Trial]), intensive glucose-lowering strategies were not associated with a reduced risk of HF compared with standard regimens (odds ratio, 1.02; Glycemic Control and Outcomes in Patients With Established HF In patients with established HF at baseline, the relation- ship between glycemic control and outcomes has not been clearly defined. Some observational data have demonstrated a potential U-shaped or inverse relation- ship between glycemic levels (HbA1c) and mortality in in- dividuals with established HF and diabetes mellitus.123 125 In a study of 5815 ambulatory patients with HF receiving Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES medical treatment for diabetes mellitus treated at Vet- erans Affairs medical centers, individuals with modest glycemic control (HbA1c >7.1% 7.8%) had lower mor- tality compared with individuals with either higher or low- er HbA1c levels (Figure 4).123 In another cohort of 123 diabetic individuals with advanced HFrEF referred to a single academic medical center, patients with an HbA1c 7.0% had significantly increased mortality compared with those with an HbA1c >7.0% (adjusted HR, 2.3; 95% In a similar study of 358 patients with advanced HFrEF and diabetes mellitus, the relationship between HbA1c levels and 2-year mortality or need for urgent transplantation was assessed with the use of 7.2%; quartile 3, 7.3% 8.5%; and quartile 4, 8.6%). Two-year event-free survival was 61% and 65% in quar- The reasons for this paradoxical re- lationship have not been well established, and given the observational nature of these analyses, these studies do not necessarily imply that glucose lowering causes adverse events. The nature of the association between glucose control and outcomes in patients with HF has also not been consistent in all HF cohorts. In a subset of individuals enrolled in the CHARM trial who had HbA1c available, the relationship between HbA1c and outcomes was assessed in 2412 participants (of whom 907 par- ticipants had known diabetes mellitus).126 In the total CHARM cohort, increasing levels of HbA1c were associ- ated with increased risk of total mortality, HF hospitaliza- tion, and a composite outcome of cardiovascular death or HF hospitalization. Of note, the graded relationship between HbA1c and mortality was more pronounced in the nondiabetic patients enrolled in CHARM and did not reach statistical significance for the outcomes of car- diovascular death (P for heterogeneity=0.04) and total mortality (P for heterogeneity=0.008) in the cohort of HF patient with diabetes mellitus.126 Among patients hospi- talized with HF, hyperglycemia is commonly observed in both patients with and those without recognized diabe- tes mellitus. In a large, nationally representative study of >50000 elderly patients hospitalized with HF, elevated glucose was found in nearly half of patients and was as- sociated with greater HF severity.127 However, in sharp contrast to patients hospitalized with acute coronary syndromes, there was no significant association be- tween glucose values on admission and either short- or long-term mortality, regardless of their diabetes mellitus status. Given these findings and the absence of data from clinical trials of targeted glucose control in this pa- tient population, there is insufficient evidence to recom- mend specific glucose thresholds or glucose treatment targets in patients hospitalized with HF. To date, no randomized, clinical trials of more versus less intensive glucose control have been performed spe- cifically in patients with HF. Until such trials are complet- ed, the ideal glucose targets in patients with established HF remain uncertain. Prospective data from subgroups of clinical trials assessing optimal glycemic targets in pa- tients with HF also are limited. In VADT, which examined an intensive glycemic control strategy compared with standard care, individuals with NYHA class III to IV HF and the outcomes of subsets of dia- betic individuals who may have less advanced HF have not been reported separately.129 In the ACCORD trial, which examined whether a therapeutic strategy targeting normal HbA1c (ie, <6.0%) would reduce the rate of car- diovascular events compared with a strategy targeting HbA1c levels from 7.0% to 7.9% in diabetic patients with established cardiovascular disease (CVD) or high CVD risk, 5% of individuals (n=494) had HF at baseline.130 In ACCORD, there was an unexpected finding of increased mortality in the intensive treatment arm compared with the standard therapy arm.130 This increased hazard was not statistically different in patients with and without HF at baseline (interaction P=0.71).131 Safety and Efficacy of Antihyperglycemic Drugs in Patients With Established HF and Diabetes Mellitus The optimal hyperglycemic therapy in patients with HF with diabetes mellitus has not been well defined, and some antihyperglycemic drugs may pose challenges for patients with HF. In diabetes, metformin is currently recommended as first-line therapy in patients with type 2 diabetes melli- tus in the absence of contraindications.132,133 Metformin Figure 4. The U-shaped association between the proportion of patients who died at the 2-year follow-up according to quintiles (Q) of hemoglobin A1c (HbA1c) in diabetic patients with heart failure, with the lowest risk of death in those patients with modest glucose control (7.1%<HbA1c 7.8%). P=0.001. Error bars indicate 95% confidence intervals. Reprinted from Aguilar et al123 with permission from the American College of Cardiology Foundation. Copyright 2009, American College of Cardiology Foundation. Bozkurt et al was previously contraindicated in individuals with HF because of potential concerns about lactic acidosis.133 Subsequent analyses and reviews have suggested that the risk of lactic acidosis associated with metformin is extremely low in patients with type 2 diabetes mellitus and may not be higher than in diabetic patients not re- ceiving metformin therapy.134 136 In addition, multiple ob- servational studies in patients with diabetes mellitus and established HF have suggested that metformin not only may be safe but also may be associated with improved survival in patients with diabetes mellitus and HF.137 145 Animal studies in HF models have also demonstrated potential cardioprotective effects of metformin therapy on the progression of HF via activation of AMP-activated protein kinase pathways,146 149 inhibition of cardiac fibro- and modulation of cardiomyocyte autophagy.147 It is important to note that prospective, large outcome trials assessing the safety and efficacy of metformin in patients with established HF have not been performed. Nonetheless, the contraindication to metformin use in patients with HF has been removed.151 Metformin, which is excreted by the kidneys, remains contraindicated in patients with renal insufficiency, a comorbid condition particularly relevant in patients with HF. The package in- sert states that metformin should not be used in men with serum creatinine levels 1.5 mg/dL and in women but the exact level of renal insufficiency precluding metformin use remains contro- In the United Kingdom, National Institute for Health and Clinical Excellence guidelines suggest that metformin can be used to an estimated glomerular fil- (with a dose reduction advised at an estimated glomerular filtration rate <45 Given these concerns, metformin should be used cautiously (or avoided) in patients at risk for worsening renal dysfunction (eg, acute decompen- sated HF). Further prospective human studies are neces- sary to assess the potential benefits and safety of met- formin in patients with diabetes mellitus and HF. Thiazolidinediones have been associated with fluid retention and increased rates of HF in randomized, controlled trials of patients predominantly free of HF at The exact mechanisms contributing to in- creased HF events with thiazolidinediones are not known, but the predominant proposed mechanism relates to thiazolidinedione-associated volume expansion resulting from increased renal sodium reabsorption159 rather than a direct effect on myocardial structure and function.160 Prospective, randomized, controlled studies specifically in patients with established HF and diabetes mellitus have demonstrated increased rates of edema, a need for in- creased HF medications, and increased HF hospitaliza- tion in patients treated with thiazolidinediones compared with patients treated with placebo or sulfonylurea.161,162 Given these findings, caution is urged for the use of thia- zolidinediones in all patients with signs and symptoms of HF, and initiation of either agent is contraindicated in patients with NYHA class III to IV HF155,163 (Table 6). Sulfonylureas are commonly used in diabetic patients with HF. In a study of >16000 Medicare recipients who had been discharged with a diagnosis of HF, approxi- mately half of the patients were treated with sulfonyl- In that observational study, sulfonylurea was not associated with increased mortality (HR, 0.99; 95% Some observation studies have sug- gested improved survival with metformin compared with Prospective, randomized, controlled trials on sulfonylurea use in patients with HF have not been performed. Important adverse effects relevant to patients with HF include the risk of hypoglycemia and weight gain associated with sulfonylurea therapy. The new-generation sulfonylureas (eg, glyburide, gliclazide, glipizide, glimepiride) have largely replaced the first- generation agents (eg, acetohexamide, chlorpropamide, tolazamide, tolbutamide) in routine use because they are more potent, can be administered in lower doses, and can be given on a once-daily basis. A few studies based on older-generation sulfonylureas have led to conflicting results for cardiovascular risk. Some evidence suggests greater risk of mortality with first-generation sulfonyl- compared with more recent ones that have been implicated in marginal cardiovascular benefit.165 These older studies have been criticized for flaws in clinical trial Although no certain cardioprotective effect or beneficial effect in HF can be attributed to sulfonylureas, newer-generation compounds have not been associated with adverse cardiovascular outcomes.165 Mechanistic differences exist between sulfonylureas. Impairment of Table 6. Recommendations for the Treatment of Diabetes Mellitus in Stage C HF: Patients With Cardiac Structural Abnormalities or Remodeling With Prior or Current Symptoms of HF Recommendations COR LOE Referenced Guideline References Physicians should control diabetes mellitus in patients with HF in accordance with recommended guidelines Caution is urged for the use of thiazolidinediones in all patients with signs and symptoms of congestive HF. Initiation of these agents is contraindicated in patients with class III or IV HF. III: Harm for NYHA class III IV HF COR indicates Class of Recommendation; HF, heart failure; LOE, Level of Evidence; and NYHA, New York Heart Association. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES cardiac ischemic preconditioning has been implicated as a reason for the potential detrimental cardiovascular effect of older-generation sulfonylureas on the basis of nonselective effects of these agents on pancreatic and cardiac K-ATPase channels. Impairment of cardiac isch- emic preconditioning does not seem to occur with more selective and newer-generation sulfonylureas.166 The incretin-based therapies (glucagon-like peptide-1 hibitors) have emerged as a new class of hyperglycemic medications. The side-effect profile of these medications when used as monotherapy (less risk of hypoglycemia and association with modest weight loss with GLP-1 ago- nists) represents potential benefits, but the safety and efficacy of DPP-4 inhibitors and GLP-1 agonists have not been studied extensively in patients with established HF. Human studies of DPP-4 inhibitors or GLP-1 based thera- pies have also been limited by HF not being identified as a prospective primary outcome, and these limited studies in patients with HF have yielded mixed results in cardio- vascular versus HF outcomes.167 170 Although there were no significant changes with the use of DPP-4 inhibitors in cardiovascular outcomes in large-scale clinical stud- the SAVOR-TIMI 53 trial (Saxagliptin Assess- ment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Thrombolysis in Myocardial Infarction), reported by Scirica et al,172 showed a 27% increase in hospitalization for HF among patients with diabetes mel- litus who received saxagliptin compared with placebo. In this trial, 12.8% of patients had a history of HF at baseline. The composite risk of cardiovascular events and hospitalization for HF was similar for patients with history of HF compared with patients without a history of HF with the use of saxagliptin.173 A recent meta-anal- ysis of available studies suggests that DPP-4 inhibitor use is associated with an increased risk of HF, without any clear evidence of differences among drugs of that Additional studies are being conducted to as- sess the cardiovascular efficacy of DPP-4 inhibitors and GLP-1 based therapies, with HF being measured as a secondary outcome. These studies may provide insights into the safety and efficacy of incretin-based therapies with primary outcomes of HF, especially in patients with diabetes mellitus and established HF. Many patients with diabetes mellitus and HF will require insulin therapy either as monotherapy or in combination with other agents to achieve adequate glycemic control. Insulin is associated with hypoglycemia and weight gain. Some observational studies have demonstrated that in- sulin use may be associated with a greater risk of devel- oping incident HF in patients with diabetes mellitus.175 In diabetic patients with established HF, observational studies have also demonstrated an association between insulin use and increased mortality,114,176,177 although these findings are potentially limited by unmeasured confounding factors, and not all observational studies have demonstrated this increased hazard.140 Given that individuals who require insulin for type 2 diabetes mel- litus are more likely to have a longer diabetes mellitus duration and severity, the use of insulin may be a marker of more advanced disease and a high-risk group rather than a direct contributor to increased HF events and in- creased mortality in patients with HF. In a recent large, randomized, controlled trial of 12537 patients with im- paired fasting glucose, impaired glucose tolerance, or early type 2 diabetes mellitus and cardiovascular risk factors, patients were randomized to insulin glargine or In this prospective study, rates of car- diovascular outcomes (including HF events) were similar in the insulin-glargine and standard care groups.178 Sodium-glucose cotransporter 2 inhibitors are a newer class of glucose-lowering medications with sev- eral compounds currently approved for diabetes mellitus Sodium-glucose cotransporter 2 in- hibitors promote the renal excretion of glucose, thereby causing osmotic diuresis. In a recent trial in patients with diabetes and cardiovascular risk, empagliflozin, an inhibitor of sodium glucose cotransporter 2, when added to standard care, was shown to reduce cardio- vascular death, all-cause mortality, and HF hospitaliza- tions. Hospitalization for HF was reduced by 35%; 10% of the patients had pre-existing HF. Consistent effects of empagliflozin were observed across subgroups de- fined by baseline characteristics, including patients with versus without HF. But among patients with HF, improve- ment in clinical outcomes including reductions in mortal- ity, cardiovascular death, or HF hospitalizations did not reach significance. There was no measure of LVEF or natriuretic peptides in the trial. Currently, other ongoing large, cardiovascular outcome trials of several sodium- glucose cotransporter 2 inhibitors (and other novel glucose-lowering medications with potentially favorable cardiovascular effects such as glucagon-like peptide-1 agonists) will provide additional valuable data, especially in patients with established HF, in this regard. Recommendations Harmonized With Existing Guidelines for the Recognition and Treatment of Patients With HF With Diabetes Mellitus See Tables 5 through 7 for summary of these recom- mendations. Stage A HF 1. For patients with diabetes mellitus (who are all at high risk for developing HF), blood sugar should be controlled in accordance with contemporary guidelines (Class I; Level of Evidence C).8 2. ACE inhibitors can be useful to prevent HF in patients at high risk for developing HF who have a history of atherosclerotic vascular Bozkurt et al disease, diabetes mellitus, or hypertension with associated cardiovascular risk factors (Class IIa; Level of Evidence A). 3. ARBs can be useful to prevent HF in patients at high risk for developing HF who have a history of atherosclerotic vascular disease, diabetes mellitus, or hypertension with asso- ciated cardiovascular risk factors (Class IIa; Level of Evidence B). Stages B and C HF Management of Hyperglycemia: Glycemic Goals in Patients With Diabetes Mellitus and HF Current American Diabetes Association (ADA) guide- and the AHA/ACC statement on intensive glycemic control and the prevention of cardiovascular events181 provide the following: The following recommendations are from the ADA Standards of Medical Care (2015)13 : (1) Lowering A1c to approximately 7% has been shown to reduce microvascular complications of diabetes, and if implemented soon after the diagnosis of diabetes, it is associated with long-term reduction in macrovascular dis- ease. Therefore, a reasonable A1c goal for many nonpregnant adults is <7%. (B)13,181 (2) Providers might reasonably suggest more strin- gent A1c goals (such as <6.5%) for selected individual patients, if this can be achieved with- out significant hypoglycemia or other adverse effects of treatment. Appropriate patients might include those with short duration of dia- betes, type 2 diabetes treated with lifestyle or metformin only, long life expectancy, and no significant CVD. (C)13,181 Less-stringent A1c goals (such as <8%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid condi- tions, and those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self-management educa- tion, appropriate glucose monitoring, and effective doses of multiple glucose lowering agents including insulin. (B)13,181 The following recommendations are from Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a Position Statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association 181 : Microvascular disease: lowering A1c to below or approximately 7% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabe- tes. Therefore, the A1c goal for nonpregnant adults in general is <7%. ADA, A-level recom- mendation; ACC/AHA, Class I recommenda- tion (Level of Evidence A). Macrovascular disease: in type 1 and type 2 diabetes, randomized controlled trials of intensive versus standard glycemic control have not shown a significant reduction in CVD Table 7. Glycemic Goals in Patients With Diabetes Mellitus and HF Recommendations COR LOE Referenced Guideline References Lowering HbA1c to <7% or 7% is reasonable for many nonpregnant adults with HF. IIa A to reduce microvascular complications, B to reduce macrovascular complications More stringent HbA1c goals (eg, <6.5%), if can be achieved without significant hypoglycemia or other adverse effects of treatment, might be considered for patients with a short duration of diabetes mellitus, a long life expectancy, and no significant CVD. IIb C 13 Less stringent HbA1c goals (eg, <8%) may be reasonable for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, and extensive comorbid conditions and those with long-standing diabetes mellitus in whom the general goal is difficult to attain despite diabetes mellitus self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents, including insulin. COR indicates Class of Recommendation; CVD, cardiovascular disease; HbA1c, hemoglobin A1c; HF, heart failure; and LOE, Level of Evidence. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES outcomes during the randomized portion of the trials. However, long-term follow-up of the DCCT and UKPDS cohorts suggests that treat- ment to A1c targets below or near 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular disease. Until more evidence becomes available, the general goal of <7% appears reasonable. ADA, B-level recommen- dation; ACC/AHA, Class IIb recommendation (Level of Evidence A). For some patients, individualized glycemic tar- gets other than the above general goal may be appropriate: a. Subgroup analyses of clinical trials such as the DCCT and UKPDS and the micro- vascular evidence from the ADVANCE trial suggest a small but incremental benefit in microvascular outcomes with A1c values closer to normal. Therefore, for selected individual patients, providers might rea- sonably suggest even lower A1c goals than the general goal of <7% if it can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expec- tancy, and no significant CVD. ADA, B-level recommendation; ACC/AHA, Class IIa rec- ommendation (Level of Evidence C). b. Conversely, less stringent A1c goals than the general goal of <7% may be appropri- ate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascu- lar complications, or extensive comorbid conditions or those with long-standing diabetes in whom the general goal is dif- ficult to attain despite diabetes self-man- agement education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents, including insu- lin. ADA, C-level recommendation; ACC/ AHA, Class IIa recommendation (Level of Evidence C). There are no compelling data to suggest that tight glycemic control improves out- comes in patients with HF. Observational studies suggest a potential hazard asso- ciated with lower glycemic HbA1c levels (<7%), but this may be confounded by baseline comorbid conditions. Prospective data are available only from ACCORD. There is not enough evidence to sug- gest that HbA1c targets should be dif- ferent from the targets described above. Particularly relevant to patients with HF is that less stringent goals of HbA1c <7% may be more appropriate, particularly in patients with conditions that are difficult to control (hypoglycemia, adverse effects of medications, variable blood glucose). 