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). Antihyperglycemic Medications in Patients With HF and Diabetes Mellitus Metformin Randomized, clinical trials of metformin therapy, includ- ing a subset of the UKPDS 34 study182 and a trial of 390 diabetic patients receiving background insulin ther- have demonstrated metformin-associated reduc- tions in macrovascular events, including MI and all-cause mortality. A potential reduction in macrovascular events in patients with ischemic HF may improve outcomes in a high-risk population. However, no prospective stud- ies assessing the safety and efficacy of metformin in patients with HF have been published. A large number of observational data support its safety and potential benefit, but residual confounding may be present (ie, patients with advanced illness do not receive metfor- min). The American Diabetes Association Standards of Medical Care in Diabetes statement has specified, In patients with stable CHF, metformin may be used if re- nal function is normal but should be avoided in unstable or hospitalized patients with HF. 13 One of the concerns about the use of metformin in patients with HF is the potential risk of developing lactic acidosis, which may be particularly relevant in patients with renal disease. Current US prescribing guidelines state that metformin should not be used in men with a creatinine level 1.5 mg/dL and in women with a creatinine level 1.4 mg/dL because metformin is renally eliminated. The threshold of renal insufficiency at which to restrict metformin is controversial. In the United Kingdom, National Institute for Health and Clinical Excellence guidelines suggest that metformin can be used down to an estimated glo- merular filtration of 30 mL min 1 (with a dose reduction advised at an estimated glomerular filtration Thiazolidinedione Current ACC/AHA guidelines for the management of heart failure recommend that thiazolidinediones be avoided or discontinued in patients with HF (Class III Rec- ommendation: Harm; Level of Evidence B). Similarly, sci- entific advisories caution against the use of rosiglitazone or pioglitazone in all patients with signs and symptoms of HF. Initiation of either agent is contraindicated in pa- tients with class III to IV HF. Other Medications There are inadequate data to make recommendations on other diabetic agents. Bozkurt et al Obesity and HF Obesity and Incident HF Multiple studies have established obesity as a risk fac- tor for the development of HF. Although the concept of cardiomyopathy relating to obesity has been described the strong, independent, incremental re- lationship between obesity as indexed by body mass in- dex (BMI) and HF incidence was only more recently estab- lished. In a study of 5881 participants in the Framingham Heart Study, the increase in the risk of HF per 1-unit BMI increase was 5% for men and 7% for women, even after adjustment for demographics and known risk factors of MI, diabetes mellitus, hypertension, and cholesterol.192 The continuous gradient between higher BMI and risk of HF has been confirmed in larger prospective, cohort stud- In addition to BMI, other anthropometric indexes of obesity, including waist circumference, waist-to-hip ra- tio, and waist-to-height ratio, have been independently as- sociated with incident HF in large, population-based stud- ies; however, indexes such as waist circumference and waist-to-hip ratio have not been shown to perform better than BMI as predictors of HF.194 196 Although the relation- ship between overweight/obesity and incident HF may be associated with hemodynamic and anatomic cardiac changes related to excess body mass,197 recent evidence suggests that the relationship is also mediated by obesity- related metabolic, inflammatory, and hormonal changes. Obesity is highly correlated with insulin resistance, which may in part potentiate the link between obesity and HF. In the Uppsala study, insulin sensitivity, but not anthropo- metric indexes of obesity, was independently predictive of In a cohort study from Greece, individuals with normal BMI and metabolic syndrome were at substantially higher risk of HF at 6 years compared with obese individu- als without metabolic syndrome.198 Analyses from MESA (Multi-Ethnic Study of Atherosclerosis) suggest that inflam- mation may potentiate the link between obesity and the risk of developing HF. Although the risk of HF was 83% higher in obese compared with nonobese subjects after adjustment for traditional risk factors, the relationship be- tween obesity and incident HF was no longer significant after adjustment for the inflammatory biomarkers.199,200 Obesity and Outcomes in Patients With Established HF: The Obesity Paradox Overweight and obesity are exceedingly prevalent in HF, although the prevalence may vary depending on the pop- ulation studied. However, recent studies have shown that 29% to 40% of patients with HF are overweight and 30% to 49% are obese, with a significantly higher prevalence Figure 5. Cumulative incidence curves for all-cause death according to category of body mass index (BMI) at the baseline examination. Vertical bars indicate standard errors of the incidence estimates at 3 years of follow-up. Data shown are truncated at 3.5 years. Reprinted from Kenchaiah et al.201 Copyright 2007, American Heart Association, Inc. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES of obesity in patients with HFpEF compared with patients Although obesity is well established as a risk factor for CVD and incident HF, as described above, obesity, as measured by BMI or other anthropometric indexes, is not a risk factor for adverse outcomes in patients with established HF. This reversal of traditional epidemiology, or the obesity paradox, has now been well documented in numerous studies in the HF medical literature. Given the high prevalence of obesity not only in the general population but also in HF populations, discussion of obe- sity and its treatment is highly relevant. In an initial study of 1203 patients with advanced HF fol- lowed up at a single university HF referral center, obesity, as defined by BMI, was not associated with worsened out- A subsequent analysis of the Digitalis Investiga- tion Group database of 7788 patients with chronic, stable HF also revealed lower risk-adjusted mortality rates in the overweight and obese compared with normal-weight pa- Similarly, in a substudy of the CHARM program, including 7599 subjects with symptomatic HF with a wide range of LVEF, higher BMI was incrementally associated with lower mortality. Furthermore, a BMI 35.0 kg/m2 was not associated with excess risk, and the group with the highest mortality rates was the group of patients with (Figure 5). The association between higher BMI and improved outcomes was seen in patients with HFrEF and with HFpEF.201 A meta-analysis of 9 obser- vational studies of BMI and outcomes in HF (n=28209 HF subjects) revealed that overweight (BMI, 25.0 9.9 kg/m2 ) was associated with reduced relative risk of cardiovascu- lar mortality of 0.81 (95% CI, 0.72 0.92) and that obesity ) was associated with an even lower risk Lastly, the pro- tective effect of obesity was also noted in patients with acute decompensated HF; patients in the highest quartile of BMI had the lowest risk of in-hospital mortality in the Acute Decompensated Heart Failure National Registry.207 BMI, because of its general acceptance and ease of use, is the primary tool for assessing obesity or body fatness in clinical practice; however, BMI does not dis- criminate between fat and lean mass and furthermore cannot assess the distribution of body fat.204,208 Waist circumference has been shown to be associated with im- proved outcomes in both men and women with advanced Furthermore, in a study of patients with ad- vanced HF that assessed body fat percentage using the skin-fold technique, patients with HF in the highest body fat quintile (mean, 37.7%) had the lowest rate of death and urgent heart transplantation (5%) compared with an event rate of 22% in the patients in the lowest body fat quintile (mean, 16.4%).211 A study of community HF clinic patients in the United Kingdom assessed multiple measures of body mass, including weight, height, body surface area, BMI, and bioelectrical impedance data, and found that the larger the patient s size was, the lower the risk of mortality was. In a multivariable model, the single best predictor of outcome was body surface area212 Epicardial adipose tissue is a visceral fat depot of variable volume around the heart that is biochemically active in terms of free fatty acid release and the produc- tion of adipokines.213 In the general population, epicar- dial adipose tissue is known to be associated with meta- bolic syndrome and coronary artery disease risk.210,214 However, preliminary studies have demonstrated low epicardial adipose tissue in patients with HF compared with healthy subjects.215 Furthermore, a recent study found low epicardial adipose tissue in HF to be associ- ated with increased HF mortality, possibly representing a novel component of the obesity paradox in HF.212,216 Taken as a whole, these data suggest that higher body mass, whether fat or lean mass, is associated with im- proved outcomes in the syndrome of HF. The underlying explanatory reasons for this counterintuitive relationship between obesity and improved HF outcomes are not fully understood, although several plausible hypotheses have been put forth.213,214,217,218 Importantly, HF is known to be a catabolic state,215,219 and thus, obesity and increased fat or lean mass likely represent a beneficial greater met- abolic reserve in HF. It is also well recognized that cardiac cachexia or unintentional weight loss is associated with advanced HF state and increased mortality.217,220 In trials that included underweight patients, when patients with obesity were compared with nonobese patients, the det- rimental role of underweight status or cachexia may have confounded the analysis of nonobesity toward an adverse outcome. This is supported by the U-shaped association of BMI and mortality in patients with HF, with increased mortality being observed in patients with a BMI <18.5 . In addition to direct effects of cachexia on mortal- ity, this reverse epidemiology may be explained partly by decreased levels of lipoprotein molecules and adipocytes in the setting of cachexia distorting their endotoxin-scav- enging role, predisposing patients with HF with cachexia to inflammatory consequences of endotoxemia.221 It is also interesting to note that brain natriuretic pep- tide levels are significantly lower in overweight and obese patients with HF compared with lean patients.222 224 A potential important explanation includes the increase in the clearance of active natriuretic peptides by means of an increased expression of clearance receptors on adi- Furthermore, obese subjects are frequently treated for hypertension and coronary artery disease. Pharmacological treatment reduces plasma levels of cardiac natriuretic peptides, and this effect may explain, in part, the lower brain natriuretic peptide levels of some asymptomatic subjects with increased BMI values. Di- minished activation of natriuretic peptides, enhanced protection against endotoxin or inflammatory cytokines, and increased nutritional and metabolic reserve may ex- plain some aspects of reverse epidemiology with obesity and mortality in patients with HF. Still, it is important to Bozkurt et al note that although obese patients have lower levels of brain natriuretic peptide than nonobese patients, brain natriuretic peptide levels predict worse symptoms, im- paired hemodynamics, and higher mortality in any BMI category, even in obese patients.222 It has also been proposed that obese patients may simply have less ad- vanced illness, earlier diagnosis, or competing diagno- ses with excess symptoms such as fatigue and dyspnea caused part by their excess body weight. Treatment of Obesity in Patients Without Established HF and Potential Beneficial Effects to Prevent HF There are multiple beneficial effects of weight reduction in obesity on the cardiovascular system, including decreas- ing LV mass, decreased arterial pressure, decreased fill- ing pressures of the left and right sides of the heart, and improvement in indexes of diastolic and systolic cardiac The role of intentional weight loss in obesity as a means of preventing CVD has been the subject of multiple previous studies and reviews218,219,222,226 229 and is beyond the scope of this document. The recent 2013 AHA/ACC/The Obesity Society Guideline for the Manage- ment of Overweight and Obesity in Adults underlines the importance of the prevention and treatment of overweight and obesity on risk factors for CVD and type 2 diabetes mellitus, as well as CVD morbidity and mortality, but did not have specific comments on the prevention of HF or treatment of obesity in patients with HF.6 Given the strong association between obesity and incident HF discussed above, it is plausible that intentional weight loss via di- etary intervention, physical activity, approved pharma- cotherapy, or surgery may reduce the incidence of HF, although there are no prospective studies of weight loss specifically studying clinical HF as an outcome (Table 8). Treatment of Obesity in Patients With Established HF Although obesity is not associated with impaired sur- vival in HF, patients with obesity and HF may wish to lose weight for a variety of reasons, including but not limited to improving their quality of life (QOL), improv- ing other medical conditions such as diabetes mellitus or sleep apnea, or in those with advanced disease, im- proving their candidacy for aggressive therapies such as heart transplantation or ventricular assist device place- ment (Table 9). The long-term effect of intentional weight loss in obese patients with HF has not been well studied prospectively. However, a few notable, small, short-term studies of interventions to achieve weight loss, including dietary intervention, physical activity, pharmacotherapy, and surgery, have been performed in populations of obese patients with HF. Dietary Intervention Pilot studies have assessed the safety and feasibility of dietary intervention to achieve weight loss in HF. Evan- gelista et al239 randomized 14 symptomatic patients with HFrEF (NYHA class II III) with type 2 diabetes mel- litus and BMI 27 kg/m2 to 12 weeks of a high-protein diet, standard-protein diet, or control. Although patients in both intervention groups achieved weight loss, more weight loss with greater decreases in waist circumfer- ence and percentage body fat was seen with the high- Furthermore, there was a significant improvement in HF symptoms and QOL associated with weight loss. There was, however, no change in cardiac structure or function.226,239 Recently, Pritchett et al240 studied 20 obese patients with HFrEF randomized for 3 months to standard therapy (control) versus lifestyle modification, including a portion-controlled diet with meal replacements and an unsupervised walking program. In this study, the intervention group did not have weight loss, and there was no significant difference between the intervention and control groups in terms of metabolic, biomarker, or functional parameters.227,240 In both stud- ies, the intervention groups had a mean BMI >35 kg/m2 . Neither study reported adverse events, however, sug- gesting that monitored, healthy dietary intervention pro- grams aiming to achieve weight loss are safe in obese patients with HF. These small studies highlight the need to further investigate the effects of various dietary com- positions on body composition, metabolic risk factors, and long-term outcomes in patients with HF. Physical Activity The major study of exercise intervention in HF, HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), demonstrated that aerobic exercise training in patients with HFrEF (n=2331) was associated with a nonsignificant trend toward a reduction in mortality or hospitalization and a substantial improvement in health In a subanalysis of HF-ACTION, obese ) patients had a slightly greater degree of weight loss with exercise intervention compared with the control groups, although the changes in weight were minimal, with a median weight change <1 kg. Further- more, nonsignificant reductions in the composite end Table 8. Recommendation for Obesity in Stage A HF: Asymptomatic Patients at Risk for HF Recommendation COR LOE Referenced Guideline References Obesity should be controlled or avoided to prevent the development of HF along with other CVDs. I C 6 COR indicates Class of Recommendation; CVD cardiovascular disease; HF, heart failure; and LOE, Level of Evidence. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES point of all-cause mortality/hospitalization across a broad range of BMI categories were seen.39 Improvement in QOL was also seen in all the BMI ranges. Thus, data from HF-ACTION suggest that physical activity as part of an exercise program is safe in obese patients with HF and may improve QOL, although its effectiveness at inducing weight loss has not been shown (Table 9). The section on the metabolic syndrome gives further information on exercise as part of lifestyle modification. Medications Currently, only 3 weight-loss medications are approved by the US Food and Drug Administration for the long-term treatment of overweight and obesity (BMI 27 kg/m2 ) in the US general population: orlistat, the recently approved and the combination pill of phenter- mine and topiramate.245 Orlistat, a lipase inhibitor, has been tested in a small population of obese patients with Twenty-one patients with HF with a BMI 30 kg/ and LVEF <40% were randomized to orlistat plus di- etary counseling versus dietary counseling alone. Those randomized to orlistat for 12 weeks had significantly more weight loss ( 4.65 9.8 kg) compared with the control group (4.39 7.4 kg; P=0.04). Furthermore, the orlistat group had more improvement in 6-minute walk distance and in NYHA class compared with the control group. The safety of lorcaserin, an agonist of the 5-hydroxytrypta- mine (serotonin) receptor 2C, in patients with HF is un- known, and the initial US Food and Drug Administration approval includes a provision mandating postmarketing studies to assess for adverse cardiovascular effects. The combination of phentermine and topiramate has been ap- proved for use in adults with a BMI >30 kg/m2 and at least 1 weight-related condition such as hypertension, type 2 diabetes mellitus, or dyslipidemia, but there are no data on patients with HF. The US Food and Drug Administra- tion s statement also includes a notation that the drug can increase heart rate and should not be used in those with unstable heart disease,245 and the sponsor is required to perform a long-term postmarketing study of cardiovascu- lar outcomes associated with the drug. Ephedra, which has been used for the purposes of athletic performance enhancement and weight loss, has been linked to a high rate of serious adverse outcomes, including LV systolic dysfunction, the development of and cardiac deaths, ultimately resulting in ban of this agent by the US Food and Drug Administration. There has also been concern about the use of sibutra- mine in HF because of reports of the development of cardiomyopathy, and this medication is contraindicated in patients with HF238 (Table 9). Bariatric Surgery in HF Obesity surgery, or bariatric surgery, is recommended for class 2 obesity or above (BMI 35 kg/m2 ) and possibly in individuals with a BMI of 30 to 34.9 kg/m2 when associ- ated with comorbid conditions such as diabetes mellitus, sleep apnea, and systemic hypertension, but the safety and efficacy of bariatric surgery in patients with HF have not been ascertained. Bariatric surgery has been shown to improve cardiovascular risk factors, including sustain- able weight loss, reversal of diabetes mellitus, improve- ments in lipid profiles and inflammation, and a reduction in the frequency of apnea in those with OSA.228,247 In the Utah Obesity Study, a large retrospective cohort of 423 severely obese patients who underwent gastric bypass surgery compared with a control group of 733 severely obese subjects who did not have surgery, gastric bypass surgery was associated with a large reduction in BMI ; P<0.0001) and improved LV systolic function, as assessed by fractional midwall shortening, and improved diastolic function, as assessed by E/E ratio.230,232 Furthermore, in a long-term follow-up of the SOS study (Swedish Obesity Surgery), pa- tients in the surgery group compared with obese patients without surgery were more likely to have normal diastolic function and improved systolic function as defined by a slightly improved systolic myocardial velocity. In both studies, the LVEFs of the surgery and control groups were normal at baseline and similar at follow-up.231,248 Although severe HF or systolic dysfunction is considered a general contraindication to bariatric surgery,228,249 a few notable studies have investigated its safety and efficacy in obese patients with HF.232,243,244,250 In a retrospective study of 14 patients with HFrEF who underwent bariatric surgery (10 with laparoscopic Roux-en-Y gastric bypass) and had a Table 9. Recommendations for the Treatment of Obesity in Stages B and C HF: Patients With Cardiac Structural Abnormalities or Remodeling With or Without HF Symptoms Recommendations COR LOE Referenced Guideline References Purposeful weight loss via healthy dietary intervention and physical activity for the purposes of improving health-related QOL or managing comorbidities such as diabetes mellitus, hypertension, or sleep apnea may be reasonable in obese patients with HF. Sibutramine and ephedra weight loss preparations may contribute to the development of HF and should be avoided. COR indicates Class of Recommendation; HF, heart failure; LOE, Level of Evidence; and QOL, quality of life. Bozkurt et al decrease in mean BMI from 50.8 2.04 to 36.8 1.72 , significant improvement in LVEF from 23 2% to Similarly, in another retrospective report, 12 obese patients with HFrEF who underwent bariatric surgery had improvement in LVEF In both of these reports, patients also had improvements in NYHA functional class. Clearly, further prospective studies are needed to better define which patients can be safely re- ferred for bariatric surgery, the optimal surgical techniques, and the effects on long-term outcomes. QOL and Obesity in Patients With HF Recent studies have suggested that health-related QOL is lower in obese patients with HF.230,251 Evangelista et al251 evaluated the effect of obesity on QOL (measured by the Minnesota Living With Heart Failure Questionnaire) in an ambulatory cohort of 358 patients followed up at an HF clinic. Obesity was associated with decreasing QOL, in- cluding both physical health and emotional well-being. In addition, of note, overweight women reported more im- paired QOL than men, consistent with other studies that obese women have more impaired health-related QOL than obese men.252 High body weight is a modifiable risk factor, and proper weight management could potentially improve the low QOL of obese patients with HF. Our understanding of changes in QOL with exercise in obese and overweight patients with HF was enhanced by a secondary analysis of the HF-ACTION program.202 HF-ACTION enrolled patients with NYHA class II to IV HFrEF who were able to exercise.230 At baseline, QOL as measured by the Kansas City Cardiomyopathy Ques- tionnaire was lower in the obese (not overweight) cate- gories. Aerobic exercise training was associated with a significant improvement in QOL across all BMI catego- ries, with a slightly greater degree of improvement in QOL with exercise in the more obese patients (BMI 35 Thus, exercise therapy may be a strategy to improve the QOL of obese patients with HF. Because adherence to exercise programs has been shown to be difficult in patients with HF and home-based exercise programs may be more practical and less expensive to implement, adherence to the programs may need to be monitored with heartrate monitors, exercise diaries, Obesity is even more prevalent in patients with HFpEF. Although no study has specifically examined exercise training and QOL in obese patients with HFpEF, >50% of patients enrolled in studies of exercise training in HFpEF are obese (mean BMI >30 kg/m2 A meta-analysis of 228 individuals with HFpEF enrolled in studies that examined exercise training demonstrated a significantly greater improvement in exercise capacity and QOL in patients in the exercise training arm compared with the control arms with no serious adverse events related to Taken together, the above data suggest that exercise therapy may be safe in obese patients with HFrEF and HFpEF and may be associated with improvement in both QOL and exercise capacity. Sleep Apnea, Obesity, and HF OSA, obesity, and HF have a complex interaction.259 In the Sleep Heart Health Study, OSA was detected in 37% of patients with HF, with a higher prevalence of OSA in men than in women.260 In men, the main risk factor for OSA was obesity, whereas in women, it was older age. Studies have reported a prevalence of OSA of 11% to 26% in patients with HFrEF and 40% to 50% in patients The greater associations of HFpEF with obesity and of hypertension with both OSA and obesity may be factors in the higher prevalence of OSA in this patient population. Although no randomized trials have been performed to evaluate the effect of treatment of OSA on longer-term outcomes of mortality and morbid- ity in patients with HF, smaller short-term studies have suggested that treatment of OSA with continuous posi- tive airway pressure is associated with an improvement in EF, dyspnea, and QOL in patients with HFrEF233,234 and in BP, diastolic function, and cardiac remodeling in patients Whether weight loss in obese patients with HF will result in improvements in OSA and associ- ated cardiovascular abnormalities and, more important, in longer-term outcomes in patients with OSA and HF (in HFpEF and HFrEF) remains an area for future research. Recommendations Harmonized With Existing Guidelines There are no specific recommendations for weight loss in the 2013 ACCF/AHA focused update guidelines on but the guidelines acknowledge that obesity and in- sulin resistance are important risk factors for the devel- opment of HF and that there are no large-scale studies on the safety or efficacy of weight loss with diet, exer- cise, or bariatric surgery in obese patients with HF. In addition, the writing committee cautions against the use of ephedra, sibutramine, and other weight-loss prepara- tions because they may contribute to the development of HF and should be avoided.8 Currently, given the above concerns and the lack of evidence on intentional weight loss in HF, the 2009 AHA scientific statement on promoting self-care in individu- als with HF suggests weight loss only if the BMI is >40 If the BMI is <30 kg/m2 , weight loss is not encouraged. In the 2010 Heart Failure Society of America guide- lines, for both obesity cardiomyopathy and obesity-hy- poventilation syndromes, weight loss is recommended to improve symptoms and prognosis. Realizing that there is a paucity of data, the guidelines authors suggest that Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES caloric restriction may be reasonable in severely obese patients with the goal of weight stabilization or reduc- The authors also acknowledge that for patients with HF with a BMI >35 kg/m2 , gastrointestinal surgery may be an option. Additionally, in patients with diabetes mellitus, dyslipidemia, or severe obesity, specific dietary instructions are recommended (Level of Evidence B). Recommendations for the Recognition and Treatment of Obesity in Patients at Risk for or With Established HF See Tables 8 and 9 for a summary of these recommen- dations. Stage A HF 1. Obesity should be controlled or avoided to prevent the development of HF along with other CVDs (Class I; Level of Evidence C). Stages B and C HF 1. Purposeful weight loss via healthy dietary intervention or physical activity for the pur- poses of improving health-related QOL or managing comorbidities such as diabetes mellitus, hypertension, or sleep apnea may be reasonable in obese patients with HF (Class IIb; Level of Evidence C). 2. Sibutramine or ephedra weight loss prepara- tions are contraindicated in HF. Use of ephedra weight-loss preparations may contribute to the development of HF and should be avoided (Class III: Harm; Level of Evidence C). No Data Weight reduction, including with bariatric surgery or weight-loss drugs such as orlistat, has not been proven to reduce the incidence or severity of HF or mortality in HF. Hyperlipidemia and HF Hyperlipidemia and Its Paradoxical Association With Clinical Outcomes in HF In the general population and in patients with atheroscle- rotic CVD, hypercholesterolemia has consistently been shown to be associated with worse outcomes, including mortality, cardiovascular events, and the development In contrast, in patients with established HF, several analyses have now demonstrated an inverse relationship between cholesterol levels and outcome. That is, low cholesterol levels have been shown to be independently associated with increased mortality and higher cholesterol levels with improved survival. In pa- tients with chronic HF, this inverse relationship has been demonstrated in patients with HF of ischemic and non- ischemic origin with a cutoff for total cholesterol at 190 This inverse relationship also held true in a large cohort of patients admitted with acute It is currently unclear whether low cholesterol levels play a causative role in the worse out- come of patients with HF or whether low cholesterol lev- els merely reflect an advanced disease state. Moreover, the question of whether there is a difference between intrinsically low cholesterol and low cholesterol as a re- sult of treatment remains unanswered. Treatment of Hyperlipidemia in HF for the Indication of HF Alone Numerous retrospective analyses and small, prospec- tive trials have demonstrated the beneficial effects of statins in patients with HF with respect to mortality and Furthermore, retrospective analy- ses of trials in patients with coronary artery disease but without a history of HF demonstrated a reduction in the risk of development of HF and HF hospitalizations in patients taking statins.272 However, 2 large, prospec- tive, randomized trials failed to confirm these beneficial effects of statins in patients with established HF. CORO- NA (Controlled Rosuvastatin Multinational Trial in Heart Failure) randomized 5011 patients (age 60 years) with NYHA class II to IV ischemic HF to 10 mg rosuvastatin versus placebo. In this trial, treatment with rosuvastatin did not confer a significant benefit with respect to the primary end point, a composite of death resulting from cardiovascular causes, nonfatal MI, or nonfatal stroke, or several secondary end points, including all-cause mortality, coronary events, and worsening HF, despite a significant decrease in low-density lipoprotein choles- terol and C-reactive protein. Interestingly, rosuvastatin reduced the total number of hospitalizations for cardio- vascular causes and hospitalizations for HF, raising the possibility that the drug could have prevented the de- velopment of acute coronary disease that would have contributed to such episodes.273 The second trial, GISSI- HF (Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico Heart Failure), randomized 4574 patients with NYHA class II to IV chronic HF regardless of pathogenesis to rosuvastatin 10 mg or placebo; 40% of the patients had ischemic cardiomyopathy. The 2 copri- mary end points, time to death and time to death or admission to hospital for cardiovascular reasons, were not significantly different between the rosuvastatin- and placebo-treated patients. Similarly, the rates of second- ary outcomes, which included cardiovascular death, ischemic end points, and admissions for HF, were not different between the 2 groups.274 However, similar to CORONA, treatment with rosuvastatin was shown to be safe in patients with HF. In summary, low cholesterol levels are associated with increased mortality in patients with chronic HF and in those presenting with acute decompensated Bozkurt et al HF of ischemic and nonischemic origin. Despite retro- spective analyses and small trials demonstrating ben- eficial effects of statins in patients with HF, 2 large, well-executed, prospective, randomized trials revealed that statin treatment does not confer significant clini- cal benefit in patients with HF of either ischemic or nonischemic origin. Thus, the routine use of statins to treat HF of any type is not indicated outside the cur- rent practice guidelines for the primary and secondary prevention of atherosclerotic vascular disease.8,275,276 Similarly, according to the 2013 ACC/AHA Guide- line on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, 5 statin therapy is not routinely recommended for individuals with NYHA class II to IV HF (Table 10). That said, pa- tients with ischemic cardiomyopathy who are already on statins may be continued on them. Moreover, be- cause of the established effect of statins on lowering the rate of ischemic events and improving survival in patients with ischemic heart disease, statins should strongly be considered in patients with HF presenting with acute ischemic events or with evidence of signifi- cant myocardial ischemia (Table 10). In light of the ob- served inverse relationship between cholesterol levels and mortality in patients with HF, it is unknown whether the cholesterol treatment goals recommended for the general population and patients with atherosclerotic CVD apply to patients with HF and remain to be deter- mined. The 2013 ACC/AHA guideline for the treatment of blood cholesterol makes no recommendations for the initiation or discontinuation of statins in patients with NYHA class II to IV ischemic HFrEF.5 Treatment With n-3 Polyunsaturated Fatty Acids in Patients With HF The use of a different type of lipid therapy, n-3 polyun- saturated fatty acids (PUFAs), has also been investigat- ed in the treatment of HF. Use of PUFA gained interest in HF on the premise that primary and secondary pre- vention trials in patients with coronary heart disease demonstrated a 10% to 20% relative risk reduction in fatal and nonfatal cardiovascular events with PUFA sup- Furthermore, in clinical and preclinical studies, PUFA use has been associated with antiar- rhythmic effects, with a beneficial impact on sudden Thus, in the GISSI-HF trial, 6975 patients with NYHA class II to IV chronic HF were ran- domized to therapy with 1 g PUFA daily or placebo.278 Of note, 50% of patients had ischemic cardiomyopa- thy and <10% had HFpEF. Treatment with PUFA was associated with a significant decrease in the primary end points of time to death and time to death or admis- sion to hospital for cardiovascular reasons.277 279 The number needed to treat was 56 patients with chronic HF for a median duration of 3.9 years to avoid 1 death Table 11. Recommendations for the Treatment of Hyperlipidemia in Stage C HF: Patients With Cardiac Structural Abnormalities or Remodeling With Prior or Current Symptoms of HF Recommendations COR LOE Referenced Guideline References PUFA supplementation is reasonable to use as adjunctive therapy in patients with NYHA class II IV symptoms and HFrEF or HFpEF, unless contraindicated, to reduce mortality and cardiovascular hospitalizations. Statins are not beneficial as adjunctive therapy when prescribed solely for the diagnosis of HF in the absence of other indications, and routine use of statins for the treatment of HF is not indicated outside of current practice guidelines for the primary and secondary prevention of atherosclerotic vascular disease. COR indicates Class of Recommendation; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LOE, Level of Evidence; NYHA, New York Heart Association; and PUFA, n-3 polyunsaturated fatty acid. Table 10. Recommendations for the Treatment of Hyperlipidemia in Stages A and B HF: Asymptomatic Patients at Risk for HF or With Structural Heart Disease Recommendations COR LOE Referenced Guideline References In patients with a recent or remote history of MI or ACS, statins should be used to prevent cardiovascular events. I A 282 285 Lipid disorders should be controlled in accordance with contemporary guidelines. ACS indicates acute coronary syndrome; COR, Class of Recommendation; HF, heart failure; LOE, Level of Evidence; and MI, myocardial infarction. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES or 44 to avoid 1 event such as death or admission to hospital for cardiovascular reasons. Although the benefit is statistically modest, it was incremental to background HF therapy. Moreover, use of PUFA was found to be safe in patients with HF. Thus, the use of PUFA is reasonable in patients with HFrEF regardless of type and lipid profile. Recommendations Harmonized With Existing Guidelines for the Treatment of Hyperlipidemia in Patients at Risk for and With Established HF See Tables 10 and 11 for a summary of these recom- mendations. Stage A HF 1. Lipid disorders should be controlled in accor- dance with contemporary guidelines5,52,272,286 (Class IIa; Level of Evidence B). Stage B HF 1. In patients with a recent or remote history of MI or acute coronary syndrome, statins should be used to prevent cardiovascular (Class I; Level of Evidence A). Stages C and D HF 1. PUFA supplementation is reasonable to use as adjunctive therapy in patients with NYHA class II to IV symptoms and HFrEF or HFpEF, unless contraindicated, to reduce mortality and cardiovascular hospitalizations8,277 279 (Class IIa; Level of Evidence B). 2. Statins are not beneficial as adjunctive therapy when prescribed solely for the diagnosis of HF in the absence of other indications, and routine use of statins for the treatment of HF is not indicated outside of current practice guide- lines for the primary and secondary preven- tion of atherosclerotic vascular disease5,8,273 276 (Class III: No benefit; Level of Evidence A). Metabolic Syndrome and HF: Clustering Risk With Comorbidities The Metabolic Syndrome and Incremental Risk in HF In the earlier sections of this document, the indepen- dent roles of hypertension, diabetes mellitus, and obe- sity in the development of HF and their effect on out- comes in patients with HF are reviewed. In this section, we review whether there is incremental risk when these comorbidities cluster as the metabolic syndrome in patients with HF. The metabolic syndrome constitutes a clustering of risk factors that include elevated glu- cose, hypertension, central obesity, and dyslipidemias, namely hypertriglyceridemia and low high-density lipo- Although the underlying cause of the syn- drome remains poorly understood, insulin resistance and central obesity are thought to play a key role. A variety of organizations have proposed definitions for the metabolic syndrome,288 291 and there are some ca- veats in the application of the various definitions of the metabolic syndrome. The risk factors included in the metabolic syndrome are continuous and may impart varying degrees of risk across the spectrum of values. Instead, the definitions have been used in a dichoto- mous manner with risk assessed as above or below a cut point. In addition, each criterion of the definition is given equal weight toward the diagnosis of the metabol- ic syndrome. Lastly, unmeasured or related conditions such as chronic inflammation, prothrombotic milieu, polycystic ovary syndrome, nonalcoholic steatohepa- titis, cholesterol gallstones, and sleep apnea may be associated with the metabolic syndrome. Impact of the Metabolic Syndrome on Incident HF A number of studies have demonstrated that the pres- ence of the metabolic syndrome translates into an in- creased risk of developing HF. NHANES III (Third National Health and Nutrition Examination Survey; 1988 1994) reported an association between the metabolic syn- drome and HF.292 Participants with the metabolic syn- drome were twice as likely to report HF. The prevalence of HF increased with the number of components of the metabolic syndrome. However, when the homeostasis model assessment was included in the multivariate mod- el, the odds ratio of the metabolic syndrome was no longer significant, suggesting that 90.7% of the associa- tion between the metabolic syndrome and HF was at- tributed to insulin resistance. Interestingly, the strength of this association varied among ethnic groups, with the homeostasis model assessment explaining 85.7% of the association in whites, 95.7% in Mexican Americans, and only 32.7% in blacks. The first prospective study to confirm that the meta- bolic syndrome is a significant predictor of incident HF comes from the Uppsala Longitudinal Study of Adult A cohort of 2314 men (age, 50 years) without HF, MI, or valvular disease at baseline was followed up for 20 years. With the application of a modified ver- sion of the ATP III (Adult Treatment Panel III) criteria (BMI was used instead of waist circumference), the risk of incident HF was 5.3 per 1000 person-years for those with the metabolic syndrome versus 1.7 per 1000 person-years for those without the metabolic syn- drome. The metabolic syndrome increased the risk of developing HF >3-fold and remained significant after adjustment for established risk factors for HF. The inci- dence of HF in those with the metabolic syndrome began Bozkurt et al diverging from those without the syndrome at 10 years of follow-up, suggesting that long-term follow-up may be necessary to truly estimate the impact of the metabolic syndrome. The increased risk of HF with the metabolic syn- drome has consistently been demonstrated in other populations. In assessments of the contribution of the individual metabolic syndrome components to incident HF, the results vary slightly between studies, but over- all, obesity, hypertension, and an increased fasting glucose most strongly predicted incident HF. These risk factors had HRs similar to that of the metabolic syndrome as a whole, suggesting that the metabolic syndrome does not predict HF better than its individual components. Wang et al294 applied the World Health Organization, National Cholesterol Education Program, International Diabetes Federation, and AHA/National Heart, Lung, and Blood Institute definitions to a popu- lation of elderly Finns and found that each of them was predictive of incident HF. Both MESA199 and this study demonstrated that the metabolic syndrome predicts HF independently of MI, suggesting that it is also as- sociated with nonischemic HF. also demonstrate the important contribution of other typically unmeasured components of the metabolic syndrome, including inflammation and microalbuminuria (included in the World Health Organi- zation definition), to the development of HF. In CHS, a C-reactive protein level 3 mg/L and interleukin-6 level 2.21 pg/mL were significant predictors of incident HF and provided additive information when combined with the metabolic syndrome in predicting the development Moreover, in MESA, C-reactive protein, interleu- kin-6, fibrinogen, and microalbuminuria levels were sig- nificantly associated with incident HF. Although obesity ) was also an independent risk factor for the development of HF, its results were attenuated with the addition of interleukin-6 or C-reactive protein to the model, suggesting that the effects of obesity may be partially mediated through inflammatory pathways.199 Role of the Metabolic Syndrome in Patients With Established HF The prevalence and effects of the metabolic syndrome in the established HF population are less well studied. Because the metabolic syndrome is an independent risk factor for the development of HF, it is not surprising that its prevalence in the HF population is higher than in the general adult population. The 2 studies from the United States, 1 study done in a hospitalized HF popula- tion (without restriction of EF with modified ATP III using and the other focused on an outpa- tient population with HFrEF,297 reported a prevalence of 68.3% and 40%, respectively. The prevalence of the metabolic syndrome in a Japanese HF cohort was 37%, which is more than double the prevalence found in the general Japanese population.298 Lastly, a small Turkish study of HFrEF reported a prevalence of 51%.299 These studies uniformly found a higher prevalence of the meta- bolic syndrome in women than in men. Hispanics had the highest prevalence of the metabolic syndrome (78.8%) followed by whites (69.5%) and blacks (60.9%).296 In the 2 studies that did not restrict EF, the prevalence of HF- pEF was higher in those with the metabolic syndrome. The effect of the metabolic syndrome on mortality in the HF population has been assessed in 2 studies with discrepant results. Hassan et al296 reported a lower mortality in patients with HF with compared with those without the metabolic syndrome (43.8% versus 57.6%) in a retrospective cohort of patients (n=625) admitted with HF. There was a nonlinear decrease in mortality with an increasing number of metabolic syndrome criteria: 68.2% in those with no criteria to 37.0% in those with all 5 criteria. Conversely, a prospective cohort of 865 out- patients with HFrEF (EF <40%) demonstrated a mortality of 24% in those with the metabolic syndrome compared with 16% in those without at 2.6 years of follow-up.297 The Kaplan-Meier curves were similar for up to 4 years of follow-up for both groups and diverged thereafter with higher mortality in the metabolic syndrome group. As described for obesity, hypertension, and dia- betes mellitus, a similar paradoxical effect may ex- ist with respect to the metabolic syndrome: Although obesity, higher BP, and elevated cholesterol are risk factors for the development of HF and mortality in the general adult population, these factors are associated with improved survival in patients with established HF. The metabolic syndrome is associated with higher all- cause and cardiovascular mortality in the general adult but as suggested by Hassan et al,296 the metabolic syndrome may exert an inverse associa- tion with improved survival in the HF population. Further studies are warranted to confirm and better understand this paradox. Treatment of the Metabolic Syndrome Given that overweight and obesity, physical inactivity, and an atherogenic diet contribute to the development of the metabolic syndrome, the institution of lifestyle modification is first-line therapy. Lifestyle modification involves the institution of changes in diet, exercise, and behavior to gradually achieve a modest degree of in- tentional weight loss.289,302 In the general population, a realistic weight loss goal is a 7% to 10% reduction in baseline weight over 6 to 12 months. Even if this degree of weight loss does not achieve a normal BMI, it imparts significant metabolic benefits. In general, the diet should be low in saturated fats, trans fats, cholesterol, and simple sugars and incorporate an increased intake of fruits, vegetables, and whole grains. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES Exercise is an important factor in initiating and maintaining weight loss. A minimum of 30 minutes of moderate-inten- sity physical activity is recommended on most days of the week, with further increases in exercise imparting greater benefits. Implementation of the above lifestyle recommen- dations to achieve a gradual, modest weight loss has sig- nificant benefits in the general population. These include a significant reduction in BP, total cholesterol, triglycerides, and fasting glucose. In addition, there is a 58% reduction in the development of diabetes mellitus.303 A slightly different dietary approach to the metabolic syndrome may be the implementation of a Mediterranean- style diet. In general, the traditional Mediterranean diet consists of a high intake of monounsaturated fatty acids, primarily from olives and olive oil, and PUFAs, particu- larly -linoleic acid from nuts, as well as increased con- sumption of fruits, vegetables, whole grains, legumes, and fish, along with moderation in alcohol intake and lim- ited red meats (Table 12). Kastorini et al305 performed a meta-analysis demonstrating that the Mediterranean diet exerts favorable effects on the components of the meta- bolic syndrome, namely reducing waist circumference, triglycerides, SBP, diastolic BP, glucose, and insulin re- sistance measured by homeostatic model assessment, and increases high-density lipoprotein levels. Lifestyle Modifications and HF Multifactorial Lifestyle Modification Interventions Does Multifactorial Lifestyle Modification Prevent HF? A healthful lifestyle appears to reduce the risk of devel- oping HF. The Physicians Health Study (1982 2008) demonstrated that participants with the healthiest life- styles had the lowest lifetime risk of developing HF.306 Six healthy lifestyle factors were assessed: BMI <25 kg/ , not smoking, regular exercise 5 times/wk, moder- ate drinking (5 14 times/wk), consumption of breakfast cereal, and consumption of fruits and vegetables ( 4 servings/d). During 22.4 years of follow-up in 20900 men, 1200 (5.7%) developed HF. A higher number of healthy lifestyle characteristics was associated with a lower risk of developing HF. The lifetime risk for HF in those without any of the above healthy lifestyle factors was 21.2% compared with only 10.1% in those with 4 lifestyle factors. There are limited data to determine whether the imple- mentation of lifestyle modification in at-risk patients can translate into a reduced risk of HF. The Steno-2 study307 (Intensified Multifactorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria) reported a reduced risk of CVD in patients with type 2 diabetes mellitus who par- ticipated in an intensive, multifactorial intervention that in- cluded quarterly clinic visits; a low-fat diet; 30 minutes of exercise 3 to 5 times/wk; prescription of an ACE inhibitor, a multivitamin, and aspirin; and a step-wise approach to pharmacological therapy for diabetes mellitus, hyperten- sion, and hyperlipidemia. After a mean follow-up of 7.8 years, the intensive therapy group experienced a signifi- cant risk reduction in a combined end point that included cardiovascular mortality, nonfatal MI, coronary artery by- pass surgery, percutaneous coronary intervention, nonfa- tal stroke, amputation, or vascular surgery for peripheral P=0.008). Because the Steno-2 trial used an aggressive lifestyle and pharmacological approach to improving the metabolic risk factors, the study could not assess the contributions of the individual treatment components and specific reduction in HF. In the Look-AHEAD trial (Action in Health in Diabetes), intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes Participants (n=5145) were randomized to conventional therapy or an intensive lifestyle modification program that included a hypocaloric, low-fat diet; use of Table 12. 