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Diabetes and Progression of Heart Failure: The Atherosclerosis Risk In Communities (ARIC) StudyFree Access

Original Investigation

J Am Coll Cardiol, 79 (23) 2285–2293
Sections

Central Illustration

Abstract

Background

The influence of diabetes on progression from preclinical heart failure (HF) stages to overt HF is poorly understood.

Objectives

The purpose of this study was to characterize the influence of diabetes on the progression from preclinical HF stages (A or B based on the 2021 Universal Definition) to overt HF.

Methods

We included 4,774 adults with preclinical HF (stage A [n = 1,551] or B [n = 3,223]) who attended the ARIC (Atherosclerosis Risk In Communities) study Visit 5 (2011-2013). Within each stage (A or B), we assessed the associations of diabetes and glycemic control (hemoglobin A1C [HbA1C] <7% vs ≥7%) with progression to HF, and of cross-categories of HF stages (A vs B), diabetes, and glycemic control with incident HF.

Results

Among the participants (mean age 75.4 years, 58% women, 20% Black), there were 470 HF events during 8.6 years of follow-up. Stage B participants with HbA1C ≥7% experienced clinical HF at a younger age than those with controlled diabetes or without diabetes (mean age 80 years vs 83 years vs 82 years; P < 0.001). HbA1C ≥7% was more strongly associated with HF in stage B (HR: 1.83; 95% CI: 1.33-2.51) compared with stage A (HR: 1.52; 95% CI: 0.53-4.38). In cross-categories of preclinical HF stage and HbA1C, participants with stage B and HbA1C ≥7% had increased risk of HF progression compared with stage A without diabetes (HR: 7.56; 95% CI: 4.68-12.20).

Conclusions

Among older adults with preclinical HF stages, uncontrolled diabetes was associated with substantial risk of HF progression. Our results suggest that targeting diabetes early in the HF process is critical.

Introduction

Diabetes and heart failure (HF) are highly prevalent1,2 and strongly interrelated.3,4 A total of 1 in 3 HF patients has diabetes,5 and diabetes raises the risk of HF by 2- to 5-fold.3,4 Clinical trials of sodium-glucose cotransporter-2 (SGLT-2) inhibitors have demonstrated a significant reduction of HF-related hospitalizations among individuals with diabetes and HF.6-8 This has led to the incorporation of these therapies in treatment guidelines9-11 and has reinforced the need for a better understanding of the link between diabetes and HF.

Diabetes is an important target for preventive efforts in HF,12 but the natural history of diabetes-related cardiac dysfunction is poorly characterized. Prior studies have established cross-sectional associations of diabetes with echocardiographic parameters13-17 and prospective associations of diabetes with the development of clinically overt HF.3,4 There is growing focus in HF guidelines on halting progression from preclinical stages (A and B) to the clinical stages (C and D), as defined by the American College of Cardiology (ACC) and the American Heart Association (AHA).18 In 2021, the Heart Failure Society of America, the Heart Failure Association of the European Society of Cardiology, and the Japanese Heart Failure Society proposed a universal definition and classification of HF, in which elevated N-terminal pro–B-type natriuretic peptide (NT-proBNP) (≥125 pg/mL) or elevated high sensitivity cardiac troponin are used to define early nonsymptomatic stage B HF as an alternative approach to echocardiographic imaging.19

The influence of diabetes and glycemic control on the progression across HF stages has not been rigorously examined in the general population.20 This question is particularly important as there are 3-4 times more individuals in the preclinical stages of the HF disease process than those with clinical HF (stages C and D).21,22

We conducted a prospective cohort analysis of data from the ARIC (Atherosclerosis Risk In Communities) study to characterize the influence of diabetes on the progression from preclinical stages of HF (stages A or B) to overt HF.

Methods

Study population

The ARIC study originally recruited 15,792 participants from 4 U.S. communities (Forsyth County, North Carolina; Jackson, Mississippi; suburbs of Minneapolis, Minnesota; and Washington County, Maryland) in 1987-1989.23 Since then, participants have returned for subsequent study visits and received telephone calls annually and semiannually (since 2012). The baseline for the present study was the fifth visit (Visit 5), which took place from 2011 to 2013 and was attended by 6,538 individuals who had echocardiograms performed to assess indices of cardiac function and structure.

In the current investigation, participants were excluded if they had one of the following: prevalent heart failure (n = 1,040); HF stage 0 or stage C (n = 355); or missing data on HF stage (n = 268), HF status by 2019 (n = 8), hemoglobin A1C (HbA1C), or covariates (n = 456). We also excluded participants with ethnicity/race other than Black or White and Black participants from Minneapolis and Washington County because of small numbers (n = 45). Our final sample included 4,774 participants.

All study protocols received Institutional Review Board approval at each study site, and all participants provided written informed consent.

Definition of diabetes and measurement of glucose and HbA1C

Diabetes was defined by a self-reported physician diagnosis, self-reported use of diabetes medications, a nonfasting blood glucose level ≥200 mg/dL, a fasting blood glucose (FBG) ≥126 mg/dL, or HbA1C ≥6.5%. We categorized persons with diabetes as having controlled (HbA1C <7%) or uncontrolled diabetes (HbA1C ≥7%) based on treatment goals recommended by the American Diabetes Association (ADA) for most adults.24 HbA1C was measured using high-performance liquid chromatography (Tosoh G7 analyzer, Tosoh Biosciences) standardized to the Diabetes Control and Complications Trial assay.25

HF stages

Our primary definition of the HF stages was based on the 2021 universal definition of HF.19

Stage A of the of the HF risk continuum was defined as the presence of at least 1 of the following clinical HF risk factors in the absence of structural heart disease or symptoms of HF: prevalent atherosclerotic cardiovascular disease (coronary artery disease, stroke, or peripheral artery disease), hypertension (blood pressure ≥140/90 mm Hg or blood pressure-lowering medication use), diabetes mellitus, obesity, metabolic syndrome (ATP III criteria26), or chronic kidney disease.19,22

Stage B of the HF risk continuum was defined as the presence of structural heart disease or elevated cardiac biomarkers (N-terminal pro–B-type natriuretic peptide [NT-proBNP] ≥125 pg/mL) and/or high-sensitivity cardiac troponin T >14 ng/L in women and >22 ng/L in men), but without signs or symptoms of HF.19 Structural heart disease was defined as the presence of at least 1 of the following cardiac structural or functional abnormalities by echocardiography at Visit 5: abnormal left ventricular ejection fraction (LVEF), regional wall motion abnormality, left ventricular (LV) enlargement based on left ventricular end-diastolic volume (LVEDV) indexed to body surface, LV hypertrophy based on LV mass indexed to height,27 moderate or greater aortic stenosis, aortic regurgitation, mitral regurgitation, or mitral stenosis.22 The echocardiographic assessment at Visit 5 was performed using a standardized protocol across all field centers.27

Incident HF events

Our primary outcome was a new diagnosis of definite or probable acute decompensated HF (clear evidence from symptoms, signs, imaging, or treatment of an acute exacerbation; worsening or new onset of symptoms; or other decompensated circulatory state) or chronic stable HF (evidence of compensated HF signs and symptoms controlled by therapy with no evidence of therapy augmentation or symptom worsening during the hospitalization).28 We also examined a secondary outcome based on a more restrictive definition of definite or probable acute decompensated HF only.28

The ascertainment of incident HF was done through a 2-stage process including International Classification of Disease codes from hospital records and an adjudication by an expert panel.23,28 Incident HF was based on HF hospitalization or HF death according to International Classification of Disease-9th Revision or -10th Revision codes (code 428 or I50 in any position) obtained by active surveillance of all hospitalizations and deaths (Supplemental Table 1).29 For those with data on cardiac function at the time of hospitalization, HF was further classified as heart failure with preserved ejection fraction (HFpEF) or with heart failure with reduced ejection fraction (HFrEF) based on LVEF ascertained at the time of HF hospitalization. An LVEF ≥50% was used to define HFpEF and <50% was used to define HFrEF. Follow-up was available through December 31, 2019 (except for the Jackson center, where the information for events is only available through December 31, 2017).

Covariates

Covariates at ARIC Visit 5 (2011–2013) were assessed by standardized questionnaires, physical examination, and laboratory tests. Covariates included age, sex, race-center, smoking status, alcohol use, body mass index, estimated glomerular filtration rate (eGFR), estimated using the Chronic Kidney Disease Epidemiology Collaboration equation,30 systolic blood pressure, diastolic blood pressure, use of hypertension medication (including angiotensin-converting enzyme [ACE] inhibitors, or angiotensin receptor blockers [ARBs]), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, lipid-lowering medication use, urinary albumin-to-creatinine ratio, and incident coronary heart disease (as a time-varying covariate).

Statistical analyses

We classified participants into categories defined by the early preclinical stages A and B of the HF risk continuum and diabetes status, and compared differences in baseline characteristics across groups using Student’s t-test (for continuous variables) or the chi-square test (for categorical variables).

We estimated the crude and adjusted HF incidence rates and respective 95% CIs according to diabetes status and stage (A or B) using Poisson regression.

We used Cox regression to characterize the prospective association of diabetes with incident HF (and its subtypes) within stage (A or B). Persons without diabetes served as the reference group. We plotted heart failure–free survivor curves using the Kaplan-Meier method, and the differences between event-free survivor probability between the different categories of exposure were compared using the log-rank test. We also evaluated risk of HF by cross categories of preclinical stage (A or B) and diabetes status—including further categorization according to glycemic control f (HbA1C <7% vs HbA1C ≥7%), with stage A and no diabetes as the reference. Model 1 included age, sex, race/center, alcohol use, and smoking. Model 2 included variables in Model 1 plus body mass index, eGFR, urinary albumin-to-creatinine ratio, systolic blood pressure, use of hypertension medications, LDL cholesterol, HDL cholesterol, triglycerides, use of cholesterol-lowering medication, and time-varying coronary artery disease. Model 3 included variables in Model 2 plus the current use of beta-blocker, ACE inhibitors, or ARBs.

We conducted additional analyses of the prospective associations of cross categories of preclinical HF stage (A or B) and the duration of diabetes (categorized as <10 years vs ≥10 years)—with incident HF (reference group: stage A and no diabetes). We also conducted separate analyses using each of the HF definitions (definite or probable acute decompensated HF and the more restrictive [secondary] definition of definite or probable acute decompensated HF only).

For analyses of incident HFpEF and HFrEF, we used cause-specific Cox proportional hazards models by censoring for the other HF subtype and mortality.

We conducted sensitivity analyses using an alternative classification of the HF process based on the 2013 ACC/AHA guidelines, whereby stage B was defined solely based on image-based structural and functional alterations.18 All 2-sided P values <0.05 were considered statistically significant. All analyses were performed using Stata version 15 (StataCorp).

Results

Characteristics of the study sample

Among the 4,774 participants in our study (mean age 75.4 ± 5.1 years, 58% women, 20% Black); 1,454 (30%) had diabetes, 1,551 (32.5%) had stage A, and 3,223 (67.5%) had stage B as per the universal definition and classification of HF stages.

In both preclinical HF stages, individuals with diabetes were more likely to be Black, use blood pressure or lipid-lowering medication, have higher levels of LDL cholesterol or triglycerides, and have lower levels of HDL cholesterol (Table 1). In stage A, individuals with diabetes were additionally more likely to be women, to use alcohol, and to have a lower systolic blood pressure compared with those without diabetes. Among individuals in stage B, those with diabetes were also more likely to have a lower eGFR.

Table 1 Baseline Characteristics of Participants by Diabetes Status and Preclinical Heart Failure Stages (A and B)

Preclinical Stage A Heart FailurePreclinical Stage B Heart Failure
No Diabetes (n = 1,083)Diabetes (n = 468)P ValueNo Diabetes (n = 2,237)Diabetes (n = 986)P Value
Age, y73.8 ± 4.573.6 ± 4.50.4976.3 ± 5.275.9 ± 5.00.051
Black246 (22.7)153 (32.7)<0.001331 (14.8)232 (23.5)<0.001
Female598 (55.2)233 (49.8)0.0491,362 (60.9)590 (59.8)0.58
Alcohol use931 (86.0)398 (85.0)0.631,886 (84.3)798 (80.9)0.018
Smoking673 (62.1)291 (62.2)0.991,325 (59.2)596 (60.4)0.52
Body mass index, kg/m227.9 ± 4.629.3 ± 4.8<0.00127.9 ± 5.630.8 ± 5.9<0.001
eGFR, mL/min/1.73 m274.2 ± 14.275.3 ± 15.70.1768.6 ± 16.266.6 ± 18.60.003
Systolic blood pressure, mm Hg128.1 ± 15.5127.6 ± 16.50.57132.6 ± 18.4131.5 ± 18.90.11
HDL cholesterol, mg/dL53.3 ± 13.848.6 ± 12.4<0.00154.5 ± 14.348.0 ± 12.6<0.001
LDL cholesterol, mg/dL112.6 ± 33.895.0 ± 32.6<0.001109.0 ± 33.592.9 ± 31.9<0.001
Triglycerides, mg/dL125.9 ± 60.7130.1 ± 61.60.21119.8 ± 56.0140.8 ± 78.7<0.001
HbA1C, %5.7 ± 0.46.5 ± 0.9<0.0015.6 ± 0.46.6 ± 1.2<0.001
Diabetes duration, y0.0 ± 0.09.4 ± 7.8<0.0010.0 ± 0.011.5 ± 8.6<0.001
Hypertension medications701 (64.7)390 (83.5)<0.0011,622 (72.7)884 (89.7)<0.001
Cholesterol-lowering medication503 (46.7)312 (67.1)<0.0011,101 (49.5)697 (70.8)<0.001
Current use of beta-blockers172 (16.0)100 (21.5)0.009740 (33.3)388 (39.4)<0.001
Current use of ACE inhibitors204 (18.9)150 (32.3)<0.001429 (19.3)310 (31.5)<0.001
Current use of ARBs77 (7.1)64 (13.8)<0.001176 (7.9)150 (15.2)<0.001
Urine albumin creatine ratio, mg/g15.6 ± 30.126.4 ± 77.2<0.00137.2 ± 193.583.0 ± 413.5<0.001
History of coronary heart disease69 (6.4)28 (6.0)0.77263 (11.8)146 (14.8)0.017
History of CVD (CHD and stroke)87 (8.0)45 (9.6)0.31332 (14.8)190 (19.3)0.002

Values are mean ± SD or n (%).

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CHD = coronary heart disease; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

Diabetes, stage A and B of HF risk continuum, and risks of incident clinical HF (HFpEF and HFrEF)

Over a median follow-up of 7.5 years (maximum 8.6 years), there were 470 HF events, of which 223 were HFpEF, 186 were HFrEF, and 61 were unclassified with regards to HF subtype.

There was a gradient in the absolute risk of HF (incidence rate) across preclinical stages and diabetes status, with individuals in stage B having a higher risk irrespective of their diabetes status (Table 2, Supplemental Figure 1) (log-rank P < 0.001). However, individuals with diabetes had a high absolute HF risk, with those with diabetes and stage B HF having at least 4 times the absolute risk of those in stage A without diabetes (Table 2). In stage B, the highest absolute risk was observed among individuals with HbA1C ≥7% (Table 3). Similar patterns were observed for HF subtypes (Supplemental Tables 2 and 3).

Table 2 Association of Diabetes and Preclinical Stages of Heart Failure With Incident Clinical Heart Failure

Preclinical Stage A Heart FailurePreclinical Stage B Heart Failure
No DiabetesDiabetesNo DiabetesDiabetes
Incidence rate, per 1,000 person-y3.6 (2.5-5.3)5.7 (3.6-9.0)19.0 (16.9-21.4)25.7 (21.9-30.1)
Mean age at the time of heart failure occurrence, y78.2 ± 3.681.9 ± 5.482.9 ± 5.581.1 ± 5.3
Mean time to heart failure event, y5.5 ± 1.96.1 ± 1.54.1 ± 2.14.0 ± 2.0
HRs
 Model 11.00 (Reference)1.60 (0.88-2.91)4.70 (3.16-7.00)6.87 (4.55-10.38)
 Model 21.00 (Reference)1.57 (0.86-2.86)4.26 (2.86-6.37)5.50 (3.60-8.39)
 Model 31.00 (Reference)1.56 (0.86-2.85)4.16 (2.78-6.21)5.32 (3.48-8.13)

Values are mean ± SD or HR (95% CI) unless otherwise indicated. Model 1: age, sex, race/center, alcohol use, and smoking. Model 2: Model 1 + body mass index, estimated glomerular filtration rate, urinary albumin to creatinine ratio, systolic blood pressure, use of hypertension medications, LDL cholesterol, HDL cholesterol, triglycerides, use of cholesterol-lowering medication, urinary albumin-to-creatinine ratio, and time-varying coronary heart disease status. Model 3: Model 2 + use of beta-blocker and use of angiotensin receptor blockers.

Abbreviations as in Table 1.

Table 3 Diabetes, Glycemic Control, and Preclinical Heart Failure Stages With Incident Clinical Heart Failure

Stage AStage B
No Diabetes (n = 1,083)Diabetes and HbA1C <7% (n = 355)Diabetes and HbA1C ≥7% (n = 113)No Diabetes (n = 2,237)Diabetes and HbA1C <7% (n = 703)Diabetes and HbA1C ≥7% (n = 203)
Incidence rate, per 1,000 person-y3.6 (2.5-5.3)5.8 (3.4-9.8)5.4 (2.0-14.5)19.0 (16.9-21.4)21.7 (17.7-26.6)36.4 (28.2-47.1)
Mean age at the time of heart failure occurrence, y78.2 ± 3.683.5 ± 4.976.5 ± 3.582.9 ± 5.582.1 ± 5.279.5 ± 5.1
Mean time to heart failure event, y5.5 ± 1.96.1 ± 1.45.9 ± 2.04.1 ± 2.14.2 ± 1.93.5 ± 2.0
HRs
 Model 11.00 (Reference)1.62 (0.85-3.09)1.53 (0.53-4.39)4.67 (3.14-6.96)5.69 (3.70-8.76)10.16 (6.42-16.07)
 Model 21.00 (Reference)1.58 (0.83-3.03)1.57 (0.55-4.51)4.25 (2.85-6.34)4.72 (3.04-7.33)7.83 (4.86-12.62)
 Model 31.00 (Reference)1.60 (0.84-3.06)1.52 (0.53-4.38)4.13 (2.77-6.18)4.59 (2.96-7.13)7.56 (4.68-12.20)

Values are mean ± SD or HR (95% CI) unless otherwise indicated. Model 1: age, sex, race/center, alcohol use, and smoking. Model 2: Model 1 + body mass index, estimated glomerular filtration rate, urinary albumin to creatinine ratio, systolic blood pressure, use of hypertension medications, LDL cholesterol, HDL cholesterol, triglycerides, use of cholesterol-lowering medication, and time-varying coronary heart disease status. Model 3: Model 2 + use of beta-blocker and use of angiotensin receptor blockers. The primary heart failure outcome was definite or probable acute decompensated heart failure (clear evidence from symptoms, signs, imaging, or treatment of an acute exacerbation, worsening or new onset of symptoms, or other decompensated circulatory state) or chronic stable heart failure (evidence of compensated HF signs and symptoms controlled by therapy with no evidence of therapy augmentation or symptom worsening during the hospitalization).

HbA1C = hemoglobin A1C; other abbreviations as in Table 1.

Among individuals in stage A, the mean age at the time of the clinical HF was lowest among individuals with HbA1C ≥7% (77 years), compared with those with HbA1C <7% (84 years) or no diabetes (78 years) (P < 0.001) (Table 3). The time to HF event was shorter for stage A individuals with uncontrolled diabetes, compared with those with diabetes and HbA1C <7% or no diabetes (Table 3). Among persons in stage B, those with uncontrolled diabetes experienced a clinical HF event at a younger age (mean age 80 years) than their counterparts with controlled diabetes (mean age 82 years) or no diabetes (mean age 83 years) (P < 0.001) (Table 3). The mean age of occurrence of a clinical HF event was lowest among individuals in stage B and with uncontrolled diabetes (mean age 80 years [80 years for HFpEF and 82 years for HFrEF] in this group).

Within-stage (A and B) comparisons showed that uncontrolled diabetes (HbA1c ≥7%) was associated with a significantly higher relative risk of a clinical HF event compared with those without diabetes (Supplemental Table 4), but less so in stage A (HR: 1.52; 95% CI: 0.53-4.38) than in stage B (HR: 1.83; 95% CI: 1.33-2.51). The Central Illustration and Supplemental Figure 2 show the association of HbA1C and incident HF within preclinical HF stages (A and B) and by diabetes status. The association of HbA1C and incident HF was steeper among individuals in stage B compared with stage A (P interaction = 0.742). In fully adjusted models combining participants in either stage A or B, the HRs for individuals with uncontrolled diabetes vs no diabetes were 1.15 (95% CI: 0.70-1.88) for HFpEF and 3.02 (95% CI: 1.92-4.76) for HFrEF.

Central Illustration
Central Illustration

Heart Failure Incidence by Hemoglobin A1C, Diabetes, and Preclinical Heart Failure

The black line is the incidence rate and gray shaded areas are the 95% CI. Models were adjusted for age, sex, and race/center. The histograms represent the frequency distribution of hemoglobin A1C in the study sample: the blue bars are adults without diabetes; the red bars are adults with diabetes.

In multivariable adjusted analyses (Table 2), compared with individuals without diabetes and in stage A, those in stage B and with diabetes had a >5-fold higher risk of incident HF (HR: 5.32; 95% CI: 3.48-8.13). The corresponding HRs were 4.16 (95% CI: 2.78-6.21) for those in stage B and without diabetes, and 1.56 (95% CI: 0.86 to −2.85) for those in stage A and with diabetes.

Uncontrolled diabetes (HbA1c <7%) was associated with higher risk of incident HF for individuals in both stage A and B. Compared with individuals without diabetes and in preclinical stage A, those in preclinical stage B and with uncontrolled diabetes had a 7.6-fold higher risk of incident HF (HR: 7.56; 95% CI: 4.68-12.20) (Table 3). The corresponding HRs were 4.59 (95% CI: 2.96-7.13) for those in stage B and controlled diabetes, and 1.52 (95% CI: 0.53-4.38) for those in stage A and with uncontrolled diabetes. Individuals in stage B and with uncontrolled diabetes had a more than 5-fold higher risk of incident HFpEF (HR: 5.70; 95% CI: 3.01-10.78) and 5-fold higher risk of incident HFrEF (HR: 16.13; 95% CI: 7.40-35.15), compared with those without diabetes and in stage A HF (Supplemental Table 3).

A longer duration of diabetes (≥10 years) was associated with a higher risk of incident overt clinical HF, especially in stage B HF (Supplemental Table 5). Indeed, when compared with individuals without diabetes and in preclinical stage A HF, those in preclinical stage B and a diabetes duration ≥10 years had an ∼6-fold higher risk of incident HF (HR: 5.83; 95% CI: 3.71-9.16) (Supplemental Table 5).

Analyses using the more restrictive definition of definite or probable acute decompensated HF only (as a secondary outcome) showed results similar to those obtained with the main HF definition (Supplemental Tables 5 to 7).

Supplementary analyses

Supplementary analyses using an alternative definition of preclinical stage B based on the 2013 ACC/AHA guidelines, whereby stage B was defined solely based on image-based structural and functional alterations without any consideration for high-sensitivity cardiac troponin T or NT-proBNP levels, showed roughly similar results (Supplemental Tables 8 to 14, Supplemental Figures 3 to 5).

Discussion

Using data from the ARIC study, we quantified the association of diabetes with progression from the preclinical stages A and B to symptomatic HF and its subtypes (HFpEF and HFrEF). Diabetes was associated with progression to HF (with a younger age of HF onset and a shorter time to event) and increased HF risk across stages A and B. There were significantly higher absolute and relative risks related to diabetes among individuals in stage B, as compared with persons with diabetes in stage A. Individuals with structural cardiac abnormality (stage B), especially those with HbA1c ≥7%, experienced HF at a younger age and at a higher rate than among those without diabetes.

The observed associations of diabetes and diabetes control with HF progression were independent of other cardiovascular risk factors and the intervening development of incident coronary heart disease. Our results suggest that targeting diabetes early in the HF process is critical. There are likely substantial benefits for HF failure prevention by aggressively treating diabetes as early as possible in the HF disease process, with potentially significant results from an intervention in both stages A and B (in which a structural abnormality is already established).

HF staging emphasizes the continuum of risk and helps providers identify and optimally manage patients who are at particularly high risk before developing signs and symptoms of HF.12 To our knowledge, our study is the first of its kind to assess the impact of diabetes on the incidence of HF among individuals free of overt clinical HF, but categorized according to the presence of other risk factors (stage A) and of structural cardiac disease as assessed by echocardiography (stage B). In addressing the associations of diabetes and clinical overt HF, accounting for preclinical HF stages seems logical, because a significant proportion of individuals in the community have an asymptomatic cardiac structural abnormality (stage B) detectable by echocardiography.21,22 Our observation of a particularly high risk in the presence of a combination of diabetes and structural abnormality is consistent with evidence that asymptomatic ventricular dysfunction is associated with a high absolute and relative risk of progression to overt HF.31 Our study further demonstrates the deleterious role of diabetes in both stages A and B of the HF disease process.

Our prospective study extends prior literature on the link between diabetes and HF.3,4,13-17,32,33 Unique aspects of our study include rigorous characterization of the different stages of the natural history of HF (including preclinical HF stages A and B), assessment of glycemic control, and HF subtypes. A prior study that examined the impact of diabetes on the progression from stage B structural disease to overt HF found that diabetes increases the risk of progression to overt HF,20 consistent with our results. Our study extends the latter findings by examining stage A, expanding the definition of stage B to include imaging parameters other than LVEF and cardiac markers, and evaluating glycemic control.

Several mechanisms potentially explain the effects of diabetes on progression to overt HF. Ischemic and nonischemic pathways may both play a role. Nonischemic pathways involve direct glucose-toxicity, lipotoxicity, increased tissue glycation leading to enhanced fibrosis, altered myocardial insulin signaling related to insulin resistance, mitochondrial dysfunction, and autonomic perturbations.34-37 Other postulated pathways include hyperglycemia-related coronary vasomotor abnormalities, endothelial dysfunction, and impaired angiogenesis.34-37

Our study has implications for both clinical and public health practice. The observed high risk of progression to overt HF among those with HF risk factors only (stage A) or structural cardiac disease (stage B) in persons with diabetes further inform our understanding of the natural history of diabetes-related cardiac dysfunction. Our results suggest that interventions to address diabetes in the early stages of HF will be most effective in preventing progression to overt HF. The greater relative risk of progression to overt HF observed in stage A highlights the importance of addressing diabetes before the occurrence of structural heart disease or stage B HF. The high absolute and relative risks of progression to overt HF associated with diabetes in stage B HF signals the urgent need for intervention in this high-risk group and that prevention of diabetes should be a clinical and public health priority, especially because the observed times to event in our study are consistent with a short preclinical window for intervention. The delivery of HF prevention interventions in the primary care setting may be particularly important.

Current clinical practice guidelines for HF management focus on individuals with clinical (stage C and D) HF,9-11 with less emphasis on individuals with preclinical stages A and B. Our results demonstrate the importance of glycemic control in preventing progression of HF and highlight the vulnerability of older adults with diabetes and stage A or B of the HF risk continuum who may greatly benefit from pharmacological intervention. No clinical trials of SGLT-2 inhibitors or glucagon-like peptide-1 receptors agonists have specifically included individuals with diabetes and the stage A or B HF phenotype.38,39 However, some of the major trials have shown similar results on the efficacy of SGLT-2 inhibitors at preventing adverse outcomes among individuals with diabetes with and without (likely in stage A or B) overt clinical HF.40,41 Our study highlights the need for clinical trials of early therapy to prevent progression of cardiac remodeling among individuals with diabetes and structural heart disease.

Study limitations and strengths

There are limitations to our study. First, our analyses on HFpEF and HFrEF were limited by the small number of events. Second, our study was limited to older individuals, and thus our results need confirmation in younger adults, although preclinical stages A and B are less common in younger ages and clinical HF is most frequent among older individuals. Last, because our study was observational, we cannot rule out residual confounding.

The strengths of this study include a well-characterized community-based cohort of Black and White older adults with detailed characterization of the early stages of HF using start-of-the-art echocardiography, cardiac biomarkers, rigorous surveillance and adjudication for events, and information on HF subtypes. Our study provides insight into the natural history of diabetes-related cardiac dysfunction. The study also benefited from rigorous adjustment for known risk factors, including the degree of blood glucose control, coronary artery disease (as a time-varying covariate), and the use of medications that can affect cardiac remodeling (beta-blockers, ACE inhibitors, and ARBs).

Conclusions

In a cohort of older Black and White older adults with preclinical HF stages, uncontrolled diabetes was associated with a substantial excess risk of progression to overt HF in both preclinical stages A and B. There was a higher absolute risk in stage B with a more rapid progression to overt HF in persons with diabetes. A significantly higher risk for diabetes with overt HF was observed in stage B. Our findings indicate that preclinical stages of the HF disease process should be a focus of aggressive preventive therapies. There is a need to investigate the novel therapies, such as SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists, among individuals with diabetes and preclinical HF stages to prevent progression to overt HF.

Perspectives

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Diabetes, especially when uncontrolled, is strongly associated with progression to overt HF, and the risk is highest among patients with preclinical stage B HF.

TRANSLATIONAL OUTLOOK: Interventions are needed to prevent and treat diabetes among asymptomatic patients with other risk factors for or early stages of HF, when the preclinical time window is brief.

Funding Support and Author Disclosures

The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). Dr Echouffo-Tcheugui was supported by NIH/NHLBI grant K23 HL153774. Dr Ndumele was supported by NIH grant R01HL146907. Dr Shah was supported by NIH/NHLBI grants R01HL135008, R01HL143224, R01HL150342, R01HL148218, and K24HL152008; has received research support not related to this study from Novartis and Philips Ultrasound; and has received consulting fees from Philips Ultrasound and Edwards Lifesciences. Dr Selvin was supported by NIH/NHLBI grant K24 HL152440 and NIH/NIDDK grant R01DK089174; and has received payments from Wolters Kluwer for chapters and laboratory monographs in UpToDate on measurements of glycemic control and screening tests for type 2 diabetes. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Abbreviations and Acronyms

ACE

angiotensin-converting enzyme

ARB

angiotensin receptor blocker

eGFR

estimated glomerular filtration rate

HbA1C

hemoglobin A1C

HDL

high-density lipoprotein

HF

heart failure

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

LDL

low-density lipoprotein

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Footnotes

Listen to this manuscript's audio summary by Editor-in-Chief Dr Valentin Fuster on www.jacc.org/journal/jacc.

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