Prevention of Heart Failure in People With Diabetes

INTRODUCTION

Chronic heart failure (HF) is increasing in prevalence affecting over 6.9 million patients in the United States, and it is estimated that over 20 million individuals have HF globally. An aging population, improved survival after myocardial infarction, and a rising burden of cardio-kidney-metabolic conditions such as hypertension, chronic kidney disease, and diabetes in developing economies have all contributed to the increased disease burden worldwide. Furthermore, while optimal control of traditional risk factors in patients with diabetes has been shown to reduce the risk of atherothrombotic adverse events, the risk of HF persists. Although studies show progress in evidence-based treatment for HF with systolic dysfunction, it often remains a progressive condition and is associated with high mortality risk. These treatments are often instituted late in the disease course when patients are symptomatic with significant LV dysfunction, and its impact on overall survival may be modest on a population basis. Given the irreversible nature of late-stage HF syndromes, prevention and early detection of HF should be a priority. Broadly, the prevention of HF is targeted at risk stratification and the implementation of effective therapeutic approaches to lower the risk of HF. These approaches range from lifestyle modification to intensive management of coexisting cardiovascular risk factors and, more recently, the implementation of novel, effective therapies such as Sodium-Glucose Transport Protein 2/1 inhibitors (SGLT2/1-i) and Glucagon-like peptide-1 receptor agonists (GLP-1RA) for the prevention of HF.

Diabetes has long been associated with an increased risk of incident HF (see also Chapter 23 ). Longitudinal epidemiological studies, such as the Framingham Heart Study, have shown that diabetes increases the lifetime risk of developing symptomatic HF by 2.4-fold in men and a 5.0-fold increase in women, independent of coexisting hypertension or coronary artery disease. The increased risk of HF associated with diabetes is comparable for the two HF subtypes—HF with reduced ejection fraction and HF with preserved ejection fraction. In addition to diabetes, dysglycemia and higher hemoglobin A1c levels, even below the threshold for diabetes, are associated with incrementally greater risk for HF. Therefore patients with dysglycemia represent a critical target population for risk stratification and prevention of HF. Considering the high burden of HF in patients with diabetes and associated worse outcomes, HF prevention should be taken equally as preventing other atherosclerotic cardiovascular complications in patients with diabetes. This is particularly relevant as the burden of ischemic heart disease has declined by up to two-thirds in the past two decades, while the decline in HF hospitalization rates has been more gradual and plateaued in the past decade. In this chapter, we address the strategies and challenges of preventing and screening for HF among patients with diabetes, including consideration of diabetes management in patients at risk of developing HF.

STRATEGIES FOR PREVENTION OF HEART FAILURE

The fundamental principle of effective preventive strategies is to reliably detect individuals either at risk of developing a disease or exhibit evidence of pathological processes capable of causing progression to a clinical disease state. Effective interventions should reduce the risk of progression to disease, significantly delay the clinical onset, or alter the trajectory of disease progression. In addition, the condition targeted by preventive strategies should carry significant morbidity and mortality risks that must be balanced against the resources required and potential risks associated with the screening process or any preemptive treatment. To achieve these goals, a thorough understanding of the prevalence and natural history of the risk factors and the disease state is crucial.

IDENTIFYING PRECURSORS OF SYMPTOMATIC HEART FAILURE

HF is a progressive disorder. Despite the heterogeneity of HF etiology, structural or ventricular dysfunction begins in individuals with risk factors contributing to insults to or persistent stress on the myocardium, which may remain asymptomatic in many individuals. The resultant maladaptive changes in the ventricular geometry (remodeling), hypertrophy, stiffness, and neurohormonal activation culminate in a failing heart with patients experiencing dyspnea, congestion, and decreased exercise tolerance, requiring repeated hospitalizations and having increased mortality risk. Recognizing the importance of prevention in addressing the rising prevalence of HF, international professional guidelines and scientific statements have highlighted the need for aggressive risk modification among individuals at risk of developing HF. The American College of Cardiology and the American Heart Association introduced an HF classification based on stages of risk, development, and progression of HF. This ranges from individuals with risk factors associated with increased risk of developing clinical HF without evidence of structural heart disease (Stage A), patients with structural heart disease but without overt clinical symptoms (Stage B), clinical HF syndromes with either current or past HF symptoms (Stage C), or end-stage refractory HF (Stage D) ( Fig. 15.1 ). By incorporating those who are at increased risk for HF but do not exhibit HF symptoms (Stages A and B) but are nevertheless at significant risk of progressing to irreversible cardiac dysfunction, the American College of Cardiology/American Heart Association (ACC/AHA) classification highlighted the need to target these “pre-HF” patients for preventive measures to alter the natural history progression.

A staged schematic presents four stages of heart failure with patient categories and therapy steps shown from risk without symptoms to advanced refractory symptoms. — FIG. 15.1

Stage A HF: Among patients with diabetes, coexisting risk factors for HF such as hyperglycemia, hypertension, hyperlipidemia, and obesity increase the risk of developing subsequent ventricular dysfunction. These risk factors are highly prevalent among patients with diabetes, are often suboptimally controlled, and represent an important clustering of modifiable cardiometabolic risk factors to consider for population-targeted intensive risk factor intervention for HF prevention ( Fig. 15.2 ). From population studies, the prevalence of Stage A HF among individuals aged 45 years or older is approximately 20%. The underlying assumption is that aggressively treating these modifiable risk factors underpinning the hazard of HF could mitigate the risk of progression to overt ventricular dysfunction. However, recent studies have questioned this paradigm and highlighted the need for novel approaches to HF prevention. These approaches may include more targeted lifestyle modifications and pharmacological therapies such as SGLT2i that may lower the risk of HF in diabetes.

A vertical bar graph presents percentages of adults with diabetes meeting targets for hemoglobin A 1 c, blood pressure, low-density lipoprotein, and statin use across five time periods. — FIG. 15.2

Stage B HF: Stage B HF refers to structural and functional cardiac abnormalities without overt clinical manifestations of HF, based predominantly on cardiac imaging results. For practical purposes, it has been narrowly defined as previous myocardial infarction (MI) with regional dysfunction or scar, LV hypertrophy (LVH), LV systolic dysfunction (LVSD; or reduced ejection fraction), or structural valve disease. Based on data from cross-sectional population studies, stage B HF is estimated to affect approximately 1/3 of the population ≥45 years of age. Depending on the age of the population studied and the HF threshold chosen to characterize abnormal LV function, the prevalence of asymptomatic LVSD in predominantly middle-aged and older adults ranges between 2% and 10%, with higher rates reported among men and the older adults. Asymptomatic LVSD is associated with a significantly increased risk of clinical HF, particularly HF with reduced ejection fraction, and death. In the Framingham cohort, 26% of participants with asymptomatic LVSD progressed to symptomatic HF during the 5-year follow-up, representing an approximately fivefold increased risk compared with subjects with normal LV function. This was associated with a 60% higher mortality risk, but more importantly, over half of the deaths occurred before symptomatic HF developed. Although most studies examining the risk of Stage B HF progressing to symptomatic HF have predominantly included older white individuals, in a large cohort of white and Black young adults (18–30 years old at baseline), the presence of asymptomatic LVSD was a strong predictor of incident HF (greater than 30 times the rate compared with individuals with normal EF) before the age of 50 years, independent of other clinical risk factors, including blood pressure. Given the irrefutable evidence suggesting asymptomatic LV dysfunction as a precursor to symptomatic HF, particularly HF with reduced ejection fraction, and its associated risk of mortality, targeting these high-risk individuals with aggressive preventive measures may meaningfully modify the trajectory of the disease progression into symptomatic HF.

More recently, studies have also focused on identifying diabetic cardiomyopathy. This subclinical Stage B HF phenotype precedes the development of clinical HF in the absence of ischemic heart disease or LV systolic dysfunction. The diabetic cardiomyopathy phenotype is considered an intermediate stage in the development of HF with preserved ejection fraction (HFpEF), and its prevalence varies from 67% to 11.7%, based on the definition used. In a recent pooled analysis from three community-based cohorts, the prevalence of diabetic cardiomyopathy was 67% when defined by any echocardiographic abnormality (LVH or diastolic dysfunction) and 16% when defined by the presence of two out of three echocardiographic abnormalities and elevated natriuretic peptide levels. Diabetic cardiomyopathy was associated with a significantly higher risk of HF, even without other cardiometabolic risk factors such as hypertension and obesity. These findings suggest that diabetic cardiomyopathy may identify a unique subclinical or Stage B HF phenotype that may benefit from effective screening approaches for early identification and efficient implementation of preventive interventions. This is also an important subset of high-risk patients to target for clinical trials of early pharmacological intervention for systolic and diastolic dysfunction. To this end, recent trials have evaluated the role of established and novel cardiometabolic therapies in preventing HF among those with diabetic cardiomyopathy. Specifically, the ARISE-HF trial evaluated the efficacy of an aldose reductase inhibitor in patients with diabetic cardiomyopathy and demonstrate no significant effect of the therapy on changes in peak exercise oxygen uptake or HF symptoms.

SCREENING STRATEGIES FOR PREVENTION OF HEART FAILURE

The first step of any HF preventive strategy is identifying the patient population at risk of developing symptomatic HF. Screening may be achieved by using established clinical risk markers, as mentioned above, complemented by biomarker and imaging-based approaches to identify patients with subclinical abnormal cardiac structure or function on a progressive path of developing symptomatic HF. By identifying these at-risk individuals, interventions aimed to modify and reduce the risk of developing clinical HF may be implemented and objectively assessed to determine if a given preventive strategy leads to improved outcomes.

SCREENING WITH CLINICAL RISK FACTORS

As described, several well-established clinical risk factors, including the diagnosis of DM, increase the risk of HF and should be used by clinicians to identify high-risk individuals who will benefit from aggressive risk factor modification and primary prevention. The advantages of this strategy are the broad availability and generalized feasibility to clinicians, even in areas of limited healthcare resources. Nevertheless, despite the well-documented association of individual risk factors for HF, quantifying the magnitude of risk for a particular patient with multiple risk markers may be challenging. Validated HF risk scores for community-dwelling individuals, such as those derived from the Framingham Heart Study, the Health Aging and Body Composition (ABC) study, and the pooled cohorts (PCP-HF risk score), can identify individuals with an increased risk of developing HF. Although these risk scores are not specific for patients with diabetes, the presence of diabetes or elevated fasting blood glucose has been consistently found to be independent predictors for incident HF. More recently, novel risk scores have been developed to predict HF risk among patients with diabetes. One such risk score, the WATCH-DM score, has been developed and validated to predict the risk of new-onset HF among patients with diabetes. Similarly, the Thrombolysis in Myocardial Infarction-HF (TIMI-HF) risk score was recently developed and validated in patients with diabetes to predict the risk of HF hospitalization among diabetes patients with or without prevalent HF. These risk scores use readily available clinical risk factors to identify individuals at the highest risk of HF and can be implemented in electronic medical records for risk stratification.

Several limitations exist concerning using risk prediction scores based on clinical risk factors as a screening strategy. First, while easy to use, their integration with the routine clinical workflow for real-world implementation remains untested. Therefore there remains an unmet need to effectively translate risk prediction model results into a clinical tool to further advance efforts in the prevention of HF through aggressive management of these risk factors. One potential direction is to capitalize on the evolution of integrated health systems and the increasing use of electronic health data, whereby an automated analysis and summary of documented risk elements yielding an estimation of risk could be included in the patient care fields to allow for continuous screening for risk and assessment of the efficacy of relevant interventions. Such a process could also generate clinical alerts to inform screening and therapeutic modifications (see also Chapter 31). Second, it remains unclear if using risk scores may modify the uptake of evidence-based HF prevention therapies in patients with diabetes. This is particularly relevant considering the low uptake of these therapies in contemporary clinical practice. Furthermore, whether providing risk information to the provider may modify their behavior in clinical settings remains untested. Third, while developed in a cohort of patients with diabetes, these risk scores only incorporate a few diabetes-specific risk factors and do not utilize time-updated risk factors. Considering the availability of multiple measures of risk factors over time, novel risk prediction models that use time-updated covariates may have better risk prediction abilities. Finally, these risk scores do not include cardiac biomarkers of myocardial injury or stress, which are well-established predictors of HF risk in patients with and without diabetes.

ROLE OF CARDIAC BIOMARKERS IN HEART FAILURE RISK PREDICTION AND SCREENING

In theory, biomarkers are biological variables that can provide information about the presence, severity, and prognosis of a condition of interest. In practice, the term biomarker in HF is limited to circulating serum and plasma analytes that reflect various aspects of the pathophysiology of HF beyond routine hematology and biochemistry panels. To be clinically useful, a particular biomarker must be shown to provide additional information that may alter clinical decision-making or guide interventions, above and beyond careful clinical assessment.

Natriuretic peptides : Circulating levels of biologically active brain natriuretic peptide (BNP) and its biologically inert precursor N-terminal peptide (NT-ProBNP) are elevated in response to high ventricular filling pressure and have been well established as important diagnostic and prognostic biomarkers among patients with signs and symptoms of overt HF. The success observed demonstrating their value in the clinical context of symptomatic HF has prompted interest in evaluating these biomarkers as screening tools for HF risk. In population studies and cohorts with Stage A/B HF, the addition of either NT-ProBNP or BNP measurements helps refine the predictive capability of traditional clinical risk factors in predicting risk for incident HF hospitalization and mortality, especially in patients with diabetes. Furthermore, population studies that included cardiac imaging, a high clinical risk score, and an elevated BNP or NT-ProBNP had the ideal predictive characteristics to detect subclinical LVSD, LV hypertrophy, and diastolic dysfunction. Whether the improved risk prediction and stratification may alter management strategies and improve patient outcomes remains uncertain. Data suggest that a refined HF risk assessment using NT-ProBNP and clinical risk factors in conjunction with multifaceted collaborative clinical care may reduce the incidence of clinical HF. The St Vincent’s Screening to Prevent Heart Failure (STOP-HF) study was designed as a pragmatic, prospective randomized trial to examine the efficacy of a screening program using BNP and collaborative care in an at-risk population in reducing newly diagnosed HF and the prevalence of Stage B HF. The study found that patients randomized to the intervention arm (BNP screening and collaborative care) had a lower incidence of LV dysfunction with or without overt HF (odds ratio [OR], 0.55; 95% CI, 0.37–0.82; P = 0.003). This may be mediated by better-coordinated care, increased emphasis on adherence to guideline-recommended treatments and healthy lifestyle behaviors, a higher rate of screening echocardiography, and significantly more prescriptions of renin-angiotensin-aldosterone system (RAAS)-based therapy. Nevertheless, the proportion of patients with diabetes in the study was relatively low (less than 20%). Furthermore, the event rate in the STOP-HF study was relatively low, and whether the lower rate of HF diagnosis will indeed translate to improved clinical outcomes long term compared with standard care practice remains to be determined.

Cardiac troponin : Cardiac troponins are key sarcomeric proteins responsible for the contractile function of cardiac myocytes. Detectable circulating levels, a marker of myocyte necrosis, have long been used in the diagnosis and prognostication of acute coronary syndromes, myocarditis, and HF. The specificity of cardiac troponin as a biomarker for myocardial necrosis underpins its demonstrated adjunctive utility when added to clinical risk factors for risk stratifying apparent healthy individuals to discriminate those at the highest risk of developing HF. Moreover, newer generations of cardiac troponin assays with markedly improved detection sensitivity have resulted in much larger proportions of cohorts tested having detectable levels, allowing analysis of their association with subclinical cardiovascular pathology and subsequent cardiovascular risk across the spectrum of circulating concentrations. For example, in the multiethnic, population-based Dallas Heart Study, detectable levels of high sensitivity troponin T (hs-cTnT; lower detection limit 0.003 ng/mL) were associated with increased LV hypertrophy and LV end-diastolic volume (LVEDV) and modestly reduced LV ejection fraction identified by cardiac magnetic resonance imaging. Higher levels of hs-cTnT were also associated with increased risk of subsequent all-cause mortality from 1.9% (95% CI, 1.5%–2.6%) to 28.4% (95% CI, 21.0%–37.8%) across incrementally higher quartiles of hs-cTnT levels ( P < 0.001) during a median follow-up of 6.4 years. A separate population-based study focused on older individuals (65 years or older) showed higher baseline hs-cTnT levels, and changes in cTnT levels were significantly associated with incident HF and cardiovascular death ( Fig. 15.3 ). Although the overall predictive value of troponins is independent of the presence of diabetes, the magnitude of the incremental value of troponins in predicting incident HF among patients with diabetes is less defined.

A line graph presents five curves for the proportion of adults free of heart failure across 18 years based on cardiac troponin T categories, from lowest in category 1 to highest in category 5. — FIG. 15.3

As different biomarkers may reflect specific and different pathophysiological pathways contributing to myocardial damage, incorporating multiple such biomarkers in risk prediction models may further improve risk prediction beyond that obtained using individual biomarker predictors. Before such strategies can easily be incorporated into practice, more data on the cost-effectiveness and the impact of biomarker-based screening strategies on clinical outcomes will be needed.

Multimarker approach to risk prediction: Studies have evaluated a multimarker approach to predict HF risk among individuals with type 2 DM. The presence of elevated cardiac biomarkers of hs-TnT or NT-ProBNP with LV hypertrophy, a phenotype referred to as malignant LV hypertrophy, identifies a very high-risk subgroup for HF. In a pooled analysis from multiple community-based cohort studies, an integer-based biomarker score was developed combining hs-TnT, natriuretic peptides, CRP, and LV hypertrophy. The abnormal elevation in two or more biomarkers identified high-risk individuals with an elevated risk of HF on follow-up. Furthermore, the performance of the biomarker-based risk score was comparable to that of clinical risk factors. More recently, in the CANVAS trial in persons with type 2 DM, a panel of three biomarkers, hs-TnT, sST2, and IGFBP-7, also identified individuals with an elevated risk of adverse CV outcomes, including HF. Furthermore, recent studies have also demonstrated the usefulness of combining biomarkers with clinical risk scores to optimize risk prediction performance. Specifically, the addition of biomarker testing, specifically natriuretic peptides, to individuals with low/intermediate risk based on clinical risk scores has been shown to improve risk prediction performance. Future studies are needed to determine whether such approaches to risk prediction combining multiple biomarkers or biomarkers with clinical risk scores may be feasible and effective in allocating evidence-based therapies to high-risk individuals with type 2 DM.

STRATEGIES FOR RISK MODIFICATION

The goal of the primary prevention of HF in patients with diabetes is to minimize adverse cardiac remodeling by reducing the risk of myocardial necrosis or stressors. This can be achieved by directly addressing prevalent risk factors among patients with diabetes, such as coronary heart disease, hypertension, dyslipidemia, and obesity. Specific pharmacological agents indicated for other diabetes micro- and macrovascular complications might offer a parallel reduction in the risk of incident HF, in addition to their primary indications. Direct evidence on the efficacy of HF preventive measures are now emerging for SGLT2i and GLP-1RA. Besides these therapies, most of other recommendations are based on either (1) observational data on associations of certain risk factors with the risk of HF or (2) secondary endpoints of randomized controlled trials where incident HF has been inconsistently measured and often lacks adequate statistical power to detect true efficacy. Lastly, special considerations on the diabetes treatment regimens among patients at risk of developing HF are warranted and will be briefly reviewed here.

OPTIMAL MANAGEMENT OF CARDIOVASCULAR RISK FACTORS TO MITIGATE HEART FAILURE RISK IN DIABETES MELLITUS

The conventional approach to preventing HF in diabetes focused on aggressive modification of traditional HF risk factors such as ischemic heart disease, hypertension, and glycemic control. Recently, there have been advances in the preventive approach to HF, with studies evaluating the role of aggressive lifestyle intervention, weight loss surgeries, and specific pharmacotherapies for HF prevention.

Ischemic hear t disease : In addition to the initial ischemic insult caused by an episode of acute MI, patients with diabetes are at risk of recurrent ischemic events, which may lead to HF. Therapies aimed at reducing post-MI adverse remodeling and future MIs will likely lead to a lower risk of HF development.

The RAAS is activated immediately post-MI. Angiotensin II plays a key role in the early remodeling of the infarct area and mediates fibrosis via aldosterone and fibrotic pathways such as transforming growth factor β (TGF-β), connective tissue growth factor, and tissue inhibitor of matrix metalloproteinase (MMP) 1. One of the first studies to demonstrate the cardiac protection effect of angiotensin-converting enzymes (ACE) inhibitors in post-MI patients with LVSD was the SAVE (the Survival and Ventricular Enlargement) trial. This study showed that long-term administration of captopril among post-MI patients with LV ejection fraction (LVEF) < 40% was associated with a significant reduction in all-cause mortality, risk of recurrent MI, and incidence of severe HF (relative risk reduction of 34%). In a subgroup analysis, the point estimate of risk reduction among patients with diabetes was consistent with the main study. However, due to the relatively smaller sample size and the lack of statistical power, the treatment difference within the diabetes subset was not statistically significant. This finding was confirmed by the SOLVD (Studies of Left Ventricular Dysfunction) prevention trial, which enrolled 4228 patients with an LVEF of less than 35%, of whom 83% had an MI more than 30 days from entry. The study showed that treatment with enalapril (up to 20 mg once per day) significantly reduced the incidence of progression to overt HF and the rate of related hospitalizations. In the echocardiography substudy of the SOLVD-prevention trial, enalapril was associated with less LV dilatation and hypertrophy in patients with Stage B HF. Similarly, subgroup analysis of the SOLVD-prevention study showed that the presence of diabetes was associated with an adverse prognosis. However, the treatment effect of enalapril and its impact on incident HF was similar across the patient’s risk profile, including the history of diabetes. In congruence with other studies, the TRACE study showed that treatment with trandolopril in the subset of enrolled patients with diabetes (237/1749 patients; 14%) was associated with a lower risk of progression to severe HF (RR, 0.38; 95% CI, 0.21–0.67), but no significant reduction of this endpoint was seen in the nondiabetic group. Similarly, in the GISSI-3 trial, treatment with lisinopril versus a placebo was evaluated in patients with acute MI, and the magnitude of relative risk reduction for all-cause mortality at 6 weeks favoring lisinopril was greatest in the subset of patients with versus without diabetes ( Fig. 15.4 ). In contrast, treatment with lisinopril versus a placebo was not statistically different in either subgroup stratified by diabetes status for the combined endpoint of mortality and LV dysfunction morbidity [defined as (1) clinical HF, (2) asymptomatic LVEF of ≤35%, or (3) LVEF > 35% but with ≥45% injured myocardial segments evaluated by 2D echocardiography] with diabetes: 21.6% versus 24.5% (OR, 0.85; 95% CI, 0.71–1.01); and without diabetes: 14.3% versus 15.5% (OR, 0.91; 95% CI, 0.83–1.00) ( Fig. 15.5 ). The apparent paradox compared to the primary endpoint of mortality could be explained by the lower mortality during the acute phase in patients treated with lisinopril, which consequently leads to a remnant burden of morbidity for post-MI LVSD among survivors.

A pair of line graphs presents mortality over 45 days in nondiabetic and diabetic patients, comparing the Lisinopril and no Lisinopril groups, with a significant difference in diabetic patients. — FIG. 15.4

A stacked bar graph presents endpoint event percentages at 6 months in diabetic and nondiabetic patients with or without Lisinopril across four categories, including deaths and heart failure. — FIG. 15.5

Hypertension : Hypertension often coexists with diabetes and visceral adiposity and represents a major risk factor for both macro- and microvascular complications, including an increased risk of incident HF among patients with diabetes (see also Chapter 18 ). Untreated hypertension accelerates the progression of atherosclerosis, and chronic pressure overload leads to maladaptive LV hypertrophy, diastolic dysfunction, subendocardial ischemia due to impaired microvascular perfusion, and in some cases LV systolic dysfunction ensues. As such, appropriate hypertension management is a key treatment goal in improving the overall clinical outcomes of patients with diabetes and specifically preventing progression to HF.

The United Kingdom Prospective Diabetes Study Group (UKPDS) compared more intensive blood pressure control (<150/85 mm Hg) with lesser control of blood pressure (<180/105 mm Hg) in 1148 patients with newly diagnosed type 2 diabetes and hypertension. Over a median follow-up period of approximately 10 years, more intensive blood pressure (BP) control decreased the risk of developing HF (hazard ratio 0.44; 95% CI 0.2–0.94, P = 0.0043).

Despite the benefits associated with the treatment of hypertension among patients with diabetes, the ideal target BP remains debatable. In the ACCORD-Blood pressure trial, intensive control of BP (systolic BP < 120 mm Hg) was not associated with a lower risk of HF compared with standard control (systolic BP < 140 mm Hg) in patients with diabetes and high cardiovascular risk. In an individual-level metanalysis of 24,444 patients with diabetes, intensive BP lowering was associated with a lower risk of all-cause death, MI, and stroke, but not HF. More recently, in the CHINA trial that included patients with and without diabetes, intensive BP control was associated with a significant reduction in risk of MACE and HF in the overall cohort with comparable treatment effects across the diabetes strata. Similarly, in the recently published BPROAD (Intensive Blood Pressure Control in Patients with Type-2 Diabetes) trial of 12,821 participants with type 2 DM intensive BP control (vs. standard control: target systolic BP < 120 mm Hg systolic vs. <140 mm Hg) was associated with clinically meaningful 19% reduction in the risk of composite endpint of nonfatal stroke, nonfatal-MI, HF hospitalization, or cardiovascular death (HR 0.79; 95% CI, 0.69–0.90, P < 0.001). The American Diabetes Association and ACC/AHA recommend a risk-based approach to BP reduction in patients with diabetes. For individuals with a 10-year estimated ASCVD risk of <15%, a blood pressure target of <140/90 mm Hg is recommended. In contrast, for individuals with diabetes and prevalent cardiovascular disease or a 10-year estimated risk of atherosclerotic cardiovascular disease ≥15%, the recommended BP target is <130/90.

The role of specific anti-HTN therapies in preventing HF among individuals with type 2 DM has been studied previously. The UKPDS demonstrated that captopril and atenolol were comparably efficacious in reducing the risk of HF and other diabetes-related complications. The role of angiotensin receptor blocker (ARB), losartan, in reducing the risk of incident HF hospitalization among patients with diabetes was reported from analyses of the patients with diabetes enrolled in two randomized trials: (i) the LIFE (Losartan Intervention For Endpoint reduction in hypertension) trial enrolling patients with hypertension and LV hypertrophy and (ii) the RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) trial of patients with diabetic nephropathy. Although the RENAAL trial enrolled patients with nephropathy and not hypertension, the baseline mean systolic BP was 153 mm Hg. In both trials, losartan was associated with a significantly lower risk of HF hospitalization (RENAAL trial [vs. placebo]: 39.3% vs. 53.5%; HR, 0.74; P = 0.037) and versus atenolol in the LIFE trial (LIFE Trial [vs. atenolol]: 10.6% vs. 18.7%; HR, 0.57; P = 0.019) ( Fig. 15.6 ). In the ALLHAT trial, among participants with type 2 DM, Chlorthalidone, a diuretic-based antihypertensive therapy, was significantly associated with a lower risk of HF than amlodipine or lisinopril.

A line graph presents five year heart failure hospitalization rates in four groups from the Life and R E N A A L trials comparing atenolol, losartan, and placebo. — FIG. 15.6

Promoting physical activity and fitness for HF prevention: Higher physical activity levels are associated with a lower risk of HF (see also Chapters 3 and 17 ). In a pooled analysis from 12 large cohort studies that included 370,460 participants with over 20,203 events, a graded dose-response relationship was observed between higher levels of PA and lower risk of HF. The benefits of higher levels of PA in preventing HF are greater among older individuals with diabetes versus without diabetes. In the ARIC cohort study, guideline-recommended levels of PA were more strongly associated with a lower risk of HF among those with versus without DM (28% vs. 17% lower risk, respectively). Furthermore, the physical inactivity-associated risk of HF among patients with DM appears to be modifiable. In a cohort study of 294,528 Korean individuals with new-onset diabetes, improvement in physical activity after the diagnosis of diabetes was associated with a significantly lower risk of HF. Among HF subtypes, higher levels of PA appear to be more strongly associated with a lower risk of HFpEF than HF with reduced ejection fraction.

Similar to physical activity, higher levels of cardiorespiratory fitness, an objective measure of habitual physical activity, are associated with a lower risk of HF, particularly HFpEF, in the general population and among those with type 2 DM. Despite these observations, intensive lifestyle interventions to improve cardiorespiratory fitness and weight loss have not been associated with a lower risk of HF. In the Look AHEAD trial, a randomized controlled trial that evaluated the effect of an intensive lifestyle intervention focused on weight loss on cardiovascular outcomes among adults with diabetes and overweight or obesity, intensive lifestyle intervention did not significantly lower the risk of HF. However, this lack of therapeutic benefit may be related to the lack of sustained improvements in cardiorespiratory fitness and weight loss in the intensive lifestyle intervention arm participants during the study period. In the Look AHEAD trial, sustained improvements in cardiorespiratory fitness and weight loss were associated with a significantly lower risk of HF. Taken together, these observations suggest that maintaining a healthy lifestyle aimed at sustained improvements in cardiorespiratory fitness may help lower the risk of HF in individuals with diabetes.

Intentional weight loss to lower the risk of HF : Higher BMI and obesity are strongly associated with HF, particularly HFpEF (see also Chapters 3 , 4 , and 17 ). In addition to BMI, other measures of central adiposity and overall fat mass are also strongly related to HF development. The obesity-associated risk of HF seems to be higher among individuals with versus without DM, particularly in older age. Among patients with diabetes, obesity represents a potentially modifiable target for the prevention of HFpEF. In the Look AHEAD trial, while intensive lifestyle intervention did not significantly reduce the risk of HF among individuals with diabetes, weight loss and reduction in waist circumference over a 4-year follow-up were associated with a lower risk of HF, particularly HFpEF. Randomized controlled trials of weight loss drugs, such as Liraglutide and lorcaserin, have also failed to demonstrate a significant reduction in HF risk. Future trials with agents that achieve a higher degree of weight loss are awaited.

Bariatric surgery : Observational studies have demonstrated that bariatric surgery is associated with lower risk of HF, particularly HFpEF. In a matched analysis of patients who underwent metabolic surgery in the Cleveland Clinic Health System, metabolic surgery was associated with a 39% reduced risk of major adverse cardiovascular events. Similarly, in the Swedish nationwide registry, patients who underwent surgery had greater weight loss compared to lifestyle intervention alone and had a 23% lower risk of HF. More recently, retrospective analysis from the claims-based database demonstrated that patients with diabetes have lower risk of MACE with Roux-En-Y gastric bypass (RYGB) surgery compared with sleeve gastrectomy suggests that the type of bariatric surgery influences HF risk reduction. Moreover, observational studies comparing RYGB to medical weight loss with GLP-1 therapy demonstrated that RYGB was associated with lower risk of HF (HR, 0.43; 95% CI, 0.27–0.68). Together, these data suggest that bariatric surgery may be an effective therapeutic option for reducing HF risk in selected patients with diabetes and obesity.

Glucose lowering and prevention of HF : Hyperglycemia is the hallmark of diabetes mellitus and is the primary treatment goal in managing patients with diabetes (see also Chapters 10 , 12 , and 13 ). Glycated hemoglobin, measured as HbA1c, reflects glycemic control over several months, is routinely used to monitor treatment response clinically and is a marker commonly used to evaluate treatment efficacy in research studies. Although a reduction in HbA1c has been shown to reduce microvascular complications in diabetes, the utility of HbA1c as a surrogate marker for cardiovascular complications, including HF, remains questionable. Furthermore, the impact of intensive glycemic control and glucose-lowering drugs on the prevention of HF remains unknown.

In general, there is consensus that clinicians should make every effort to control hyperglycemia. Still, evidence remains lacking regarding the effects (if any) of glucose control on the risk of HF. Several studies have examined the impact of intensive glycemic control on vascular complications in diabetes, but unfortunately, incident HF events were not uniformly collected nor independently adjudicated. The best data regarding the role of intensive glycemic control in reducing the risk of HF comes from a meta-analysis including the UKPDS, Action to Control Cardiovascular Risk in Diabetes (ACCORD) , ADVANCE, and Veterans Affairs Diabetes Trial. In a meta-analysis of these trials, intensive glucose control was associated with a modestly lower risk of major cardiovascular events (HR, 0.91; 95% CI, 0.84–0.99), driven by a 15% reduction in risk of myocardial infarction (HR, 0.85, 95% CI, 0.76–0.94). However, there was no difference for hospitalized or fatal HF events (HR, 1.00; 95% CI, 0.86–1.16).

The lack of benefit of intensive glycemic control on the risk of HF should be interpreted in the context of recent analysis from the ACCORD trial demonstrating a significant association between large fluctuations in A1c, greater variability in A1c, and increased risk of HF. This is particularly relevant for individuals with only modestly elevated A1c, as noted among participants of the ACCORD trial (mean A1c = 8%). Furthermore, a higher burden of hypoglycemic events, often associated with intensive glucose control, is also associated with an increased risk of HF. Future studies are needed to determine if optimal glycemic control achieved using glucose-lowering therapies that do not increase the risk of hypoglycemia and cause significant fluctuations in A1c levels may reduce the risk of HF.

Antihyperglycemic agents for prevention of HF — SGLT2 inhibitors : SGLT2 inhibitors were initially developed as glucose-regulating therapies but are now established as effective therapies for managing HF (see also Chapter 12 ). The EMPA-REG OUTCOME trial that evaluated the cardiovascular safety of empagliflozin, an SGLT2i, was the first antihyperglycemic therapy demonstrating a significant reduction in the risk of major adverse cardiovascular events, HF, and all-cause mortality risk among patients with diabetes. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of a composite of cardiovascular death, nonfatal MI, or nonfatal stroke by 14%, HF hospitalization by 35%, and all-cause death by 32%. Other SGLTi such as canagliflozin, dapagliflozin, ertugliflozin, and sotagliflozin have also demonstrated a significant reduction in HF hospitalization in large RCTs, establishing the SGLT inhibitor class of medications as an effective therapy to prevent HF in diabetes. While the mechanism of action through which SGLTi may lower the risk of HF is not entirely understood, it has been shown to reduce the burden of myocardial injury and neurohormonal stress, improve kidney function, increase hemoconcentration, and lower BP. These favorable physiologic changes may reduce HF risk. The current ACC, AHA, European Society of Cardiology, and American Diabetes Association guidelines recommend the use of SGLT2i for the prevention of HF.

GLP-1 receptor agonists —GLP-1 receptor agonists, another class of drugs, have significantly reduced the risk of atherosclerotic cardiovascular disease among patients with DM. (See also Chapter 13. ) However, reduction in HF risk has been less consistently observed with GLP-1 receptor agonists. In the Liraglutide and Cardiovascular Outcomes Trial in Type 2 Diabetes (LEADER) trial, liraglutide, a GLP-1 receptor agonist, was associated with a significant 17% reduction in the risk of stroke, MI, or cardiovascular death (HR [95%CI] Liraglutide vs. Placebo: 0.87 [0.78–097]). In contrast, the rates of HF hospitalization were not significantly different between the liraglutide and the placebo arm (4.7 vs. 5.3% HR [95% CI]: 0.87 [0.73–1.05]). A similar pattern of results was observed with semaglutide, a once-weekly injectable GLP-1 agonist, in the SUSTAIN-6 trial, with a significant reduction in risk of major atherosclerotic events but not HF. However, recent trials with newer GLP-1 receptor agonists (albiglutide and efpglenatide) have demonstrated a significant reduction in HF risk. Specifically, in the Harmony Outcomes trial, participants randomized to albiglutide (vs. placebo) had a 29% lower risk of HF hospitalization. Similarly, in the AMPLITUDE-O trial, efpeglenatide was associated with a 39% reduction in the risk of HF hospitalization. In a pooled meta-analysis of eight cardiovascular outcome trials, GLP-1 receptor agonists were associated with an 11% reduction in the risk of HF hospitalization.

ANTIHYPERGLYCEMIC AGENTS THAT MAY INCREASE THE RISK OF HEART FAILURE

Thiazolidinediones : In a meta-analysis of these trials, Thiazolidinediones (TZDs), namely rosiglitazone and pioglitazone, improve insulin sensitivity by activating peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and reduce blood glucose levels. Because of the efficacy in glycemic control, both as monotherapy and in combination with sulfonylureas, metformin, and insulin, the use of TZDs expanded rapidly following their clinical introduction in 1997. However, results from subsequent postmarketing observational studies, meta-analyses, and clinical trials raised the concern of increased risk for HF associated with TZDs use.

The main side effects of TZDs indicating potential HF were signs of fluid retention, such as pedal edema and weight gain. In the initial randomized trials, pedal edema was reported in 4.8% receiving pioglitazone as monotherapy and 6% to 7.5% when used in combination with either metformin or sulfonylureas, compared with 1.2% to 2.5% in patients receiving either a placebo or active comparators. The incidence of edema is significantly higher in patients receiving concomitant insulin, with 15.3% of patients assigned to pioglitazone compared with 7.0% for insulin alone. However, the incidence of investigator-reported edema was dramatically higher in the cardiovascular outcome trial of pioglitazone, the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) study, which enrolled patients with a long duration of diabetes and prevalent cardiovascular disease. In this high-risk population, edema was observed in 27.4% of pioglitazone-treated patients compared with 15.9% of the placebo-treated patients ( P < 0.001). Similar trends were also observed with rosiglitazone, with edema observed in 4.8% of patients treated with rosiglitazone alone compared with 1.3% on a placebo in randomized trials with rosiglitazone. A higher incidence of edema has been observed with rosiglitazone use in combination with metformin or sulfonylurea (3%–4%) than with either comparator drug alone (1.1%–2.2%). Similarly, concomitant use of insulin was associated with higher rates of edema, with 13.1% and 16.2% rosiglitazone 4 or 8 mg per day, respectively, compared with 4.7% in those taking insulin alone.

Pioglitazone and rosiglitazone also increase the risk of HF, as has been observed in patients with diabetes participating in major outcome trials designed to assess the cardiovascular safety of TZDs. In the PROACTIVE trial, a significantly higher proportion of patients in the pioglitazone versus placebo arm had an HF event (11% vs. 8%; P < 0.0001). Of these HF events, more pioglitazone than placebo patients (5.7% vs. 4.1%) had serious HF, defined by a requirement for hospitalization or prolonged hospital stay; was fatal or life threatening; or resulted in persistent, significant disability or incapacity ( P = 0.007). It is important to highlight that HF events were not prespecified endpoints in the PROACTIVE study but were detected as part of standard adverse event reporting. Subsequently, the HF risk was confirmed through adjudication of these safety events. Similarly, in the RECORD study, rosiglitazone use was associated with an increased risk of HF hospitalization. HF-related hospitalization or mortality occurred in 61 people in the rosiglitazone group and 29 in the active control group (HR, 2.10; 1.35–3.27; risk difference per 1000 person-years 2.6; 1.1–4.1) ( Fig. 15.7 ).

A line graph presents cumulative heart failure incidence over six years in patients treated with rosiglitazone or metformin and sulfonylurea in the Record study. — FIG. 15.7

The mechanistic and causal relationship between TZDs and incident HF remains unclear. However, it is generally accepted that this is predominantly mediated by the effect of TZDs on increased fluid retention; hence, unmasking underlying LV dysfunction (either diastolic or systolic), rather than direct cardiotoxicity. Nonetheless, clinicians should not discount the clinical significance of such events, as patients who developed HF events experienced high mortality rates (approximately 30%) during the follow-up period.

Earlier observations and findings from the PROACTIVE and RECORD trials support the recommendations from the AHA and American Diabetes Association advising clinicians to assess individual patient’s risks prior to commencing TZDs (see Table 15.1 ) and to discontinue TZDs use in patients with symptomatic HF. More importantly, the experiences from TZDs highlighted the pitfall of relying on intermediate markers, such as HbA1c, in assessing the clinical effectiveness of glucose-lowering agents in the risk of macrovascular complications.

Table 15.1

Risk Factors Associated With Increased Risk of Heart Failure in Diabetic Patients Treated With Thiazolidinediones ( TZDs )

From Nesto RW, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation . 2003;108(23):2941–2948.

RISK FACTORS FOR HEART FAILURE IN PATIENTS TREATED WITH TZDS
History of heart failure (either systolic or diastolic)
History of prior myocardial infarction or symptomatic coronary artery disease
Hypertension
Left ventricular hypertrophy
Significant aortic or mitral valve heart disease
Advanced age (>70 years)
Long-standing diabetes (>10 years)
Preexisting edema or current treatment with loop diuretics
Development of edema or weight gain on TZD therapy
Insulin coadministration
Chronic renal failure (creatinine > 2.0 mg/dL)

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Thoracic Key

Fastest Thoracic Insight Engine

Prevention of Heart Failure in People With Diabetes

INTRODUCTION

STRATEGIES FOR PREVENTION OF HEART FAILURE

IDENTIFYING PRECURSORS OF SYMPTOMATIC HEART FAILURE

SCREENING STRATEGIES FOR PREVENTION OF HEART FAILURE

SCREENING WITH CLINICAL RISK FACTORS

ROLE OF CARDIAC BIOMARKERS IN HEART FAILURE RISK PREDICTION AND SCREENING

STRATEGIES FOR RISK MODIFICATION

OPTIMAL MANAGEMENT OF CARDIOVASCULAR RISK FACTORS TO MITIGATE HEART FAILURE RISK IN DIABETES MELLITUS

ANTIHYPERGLYCEMIC AGENTS THAT MAY INCREASE THE RISK OF HEART FAILURE

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Thoracic Key

Fastest Thoracic Insight Engine

Prevention of Heart Failure in People With Diabetes

INTRODUCTION

STRATEGIES FOR PREVENTION OF HEART FAILURE

IDENTIFYING PRECURSORS OF SYMPTOMATIC HEART FAILURE

SCREENING STRATEGIES FOR PREVENTION OF HEART FAILURE

SCREENING WITH CLINICAL RISK FACTORS

ROLE OF CARDIAC BIOMARKERS IN HEART FAILURE RISK PREDICTION AND SCREENING

STRATEGIES FOR RISK MODIFICATION

OPTIMAL MANAGEMENT OF CARDIOVASCULAR RISK FACTORS TO MITIGATE HEART FAILURE RISK IN DIABETES MELLITUS

ANTIHYPERGLYCEMIC AGENTS THAT MAY INCREASE THE RISK OF HEART FAILURE

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