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Cardiometabolic Outcomes PDF
Cardiometabolic Outcomes PDF
11, 3320–3330
https://doi.org/10.1210/clinem/dgab468
Clinical Research Article
Received: 14 April 2021; Editorial Decision: 20 June 2021; First Published Online: 29 June 2021; Corrected and Typeset:
21 July 2021.
Abstract
Context: While adrenal adenomas have been linked with cardiovascular morbidity in
convenience samples of patients from specialized referral centers, large-scale population-
based data are lacking.
Objective: To determine the prevalence and incidence of cardiometabolic disease and
assess mortality in a population-based cohort of patients with adrenal adenomas.
Design: Population-based cohort study.
Setting: Olmsted County, Minnesota, USA.
Patients: Patients diagnosed with adrenal adenomas without overt hormone excess and
age- and sex-matched referent subjects without adrenal adenomas.
Main outcome measure: Prevalence, incidence of cardiometabolic outcomes, mortality.
Results: (Adrenal adenomas were diagnosed in 1004 patients (58% women, median
age 63 years) from 1/01/1995 to 12/31/2017. At baseline, patients with adrenal adenomas
were more likely to have hypertension [adjusted odds ratio (aOR) 1.96, 95% CI 1.58-2.44],
dysglycemia (aOR 1.63, 95% CI 1.33-2.00), peripheral vascular disease (aOR 1.59, 95% CI
1.32-2.06), heart failure (aOR 1.64, 95% CI 1.15-2.33), and myocardial infarction (aOR 1.50,
95% CI 1.02-2.22) compared to referent subjects. During median follow-up of 6.8 years,
patients with adrenal adenomas were more likely than referent subjects to develop de
novo chronic kidney disease [adjusted hazard ratio (aHR) 1.46, 95% CI 1.14-1.86], cardiac
arrhythmia (aHR 1.31, 95% CI 1.08-1.58), peripheral vascular disease (aHR 1.28, 95% CI
1.05-1.55), cardiovascular events (aHR 1.33, 95% CI 1.01-1.73), and venous thromboembolic
events (aHR 2.15, 95% CI 1.48-3.13). Adjusted mortality was similar between the 2 groups.
Conclusion: Adrenal adenomas are associated with an increased prevalence and
incidence of adverse cardiometabolic outcomes in a population-based cohort.
Key Words: adrenal incidentaloma, adrenal mass, epidemiology, incidence, prevalence, cardiovascular outcomes,
cardiovascular events
tomography tumor attenuation <10 Hounsfield units, was diagnosed if the postdexamethasone serum cortisol
rapid contrast washout, chemical shift on magnetic reson- concentration was >1.8 mcg/dL, whereas NFAT was diag-
ance imaging, lack of growth on imaging after 6 months), nosed if the postdexamethasone serum cortisol concentra-
clinical follow-up of at least 24 months or histopathology tion was ≤1.8 mcg/dL. Given the historical timeline of the
if surgically removed. The final cohort consisted of 1004 study and the population-based study design, we suspected
patients with adrenal adenomas and no suspected overt that a significant proportion of patients diagnosed with
hormone excess (Fig. 1). an adrenal adenoma would not have been evaluated by
Patients with adrenal adenomas were then 1:1 matched an endocrinologist and would not have undergone a DST.
by age (±1 year) and sex to referent subjects randomly Thus, patients who did not undergo the 1-mg DST and
selected from Olmsted County residents without diagnosis had no features of overt hormonal excess were classified as
codes for adrenal neoplasm. The index date was defined as having adenomas with unknown cortisol secretion.
the date of the earliest adrenal adenoma diagnosis based on
Adrenal tumor diagnosis by ICD-9 and No adrenal tumor diagnosis by ICD-9 and
ICD-10 codes ICD-10 codes
n=1,881
Medical records
missing, n = 22
Figure 1. Flowchart showing the identification of study participants. *Multiple participants (n = 18) met more than 1 exclusion criteria.
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11 3323
embolism. Hypertension was defined as an office systolic (BMI), and smoking status (current or former smoker vs
blood pressure of ≥130 mmHg and/or diastolic blood nonsmoker).
pressure of ≥80 mmHg on 2 or more occasions obtained The cumulative incidence of cardiometabolic disease was
3 months apart, consistent with the American Heart estimated using the Aalen-Johansen approach, with death
Association guidelines (12); anti-hypertensive medi- considered as a competing risk event. We used Cox regres-
cation prescription; and/or documented International sion models to test for group differences univariately and
Classification of Diseases, 9th or 10th edition, diagnosis after adjustment for potential confounders (age, sex, BMI,
code. Dyslipidemia was defined by low-density lipo- smoking status, and prevalent cardiometabolic risk factors)
protein cholesterol of ≥130 mg/dL (3.4 mmol/L), lipid- using all events starting at 1 year following the index date.
lowering medication prescription, and/or documented Multiple imputation using the mice package in R was em-
diagnosis code. Prediabetes was defined by hemoglobin ployed to address any missing data for BMI and smoking
A1c of 5.7% to 6.4% on 2 or more separate occasions status (13). A 2-tailed probability value of P < 0.05 was
Table 1. Clinical characteristics of study participants with or without adrenal adenomas at baseline
with adrenal adenomas compared to referent subjects atrial fibrillation [125/871 (16%) vs 93/911 (11%)],
(Table 2). cardiac arrythmia [242/594 (46%) vs 224/730 (33%)],
heart failure [148/849 (20%) vs 125/927 (13%)], and
peripheral vascular disease [226/711 (35%) vs 200/836
Incidence of Cardiometabolic Disease (25%)] (Fig. 2).
Patients with adrenal adenomas were followed for a In a multivariable model adjusted for age, sex, BMI,
median of 6.8 years (range, 0-22) and referent subjects smoking status, and prevalent cardiometabolic risk factors,
for 7.2 years (range, 0-22) after the index date. The adrenal adenomas were independently associated with an
unadjusted 10-year cumulative incidence of new meta- increased risk for chronic kidney disease [adjusted hazard
bolic and cardiovascular disease was higher in patients ratio (aHR) 1.46, 95% CI 1.14-1.86], cardiovascular
with adrenal adenomas compared to referent subjects: events (aHR 1.33, 95% CI 1.01-1.73), cardiac arrhythmia
dysglycemia [119/700 (18%) vs 88/818 (14%)], chronic (aHR 1.31, 95% CI 1.08-1.58), and peripheral vascular
kidney disease [167/891 (19%) vs 112/930 (12%)], car- disease (aHR 1.28, 95% CI 1.05-1.55) (Table 3). In add-
diovascular events [131/793 (19%) vs 200/863 (14%)], ition, patients with adrenal adenomas were more than
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11 3325
Table 2. Associations between adrenal adenomas and cardiometabolic diagnoses at baseline (case-control analyses)
Cardiometabolic conditions Unadjusted ORa (95% CI) Age and Sex-adjusted OR (95% CI) Model 1b OR (95% CI)
twice as likely to develop a new deep venous thrombosis or with MACS compared to NFAT throughout the follow-up
pulmonary embolism (aHR 2.15, 95% CI 1.48-3.13) com- period (3% vs 2% at 5 years, 20% vs 9% at 10 years, and
pared to referent subjects. 37% vs 19% at 15 years) with an age, sex, BMI, smoking,
and prevalent cardiometabolic risk factors adjusted hazard
ratio of 2.01 (95% CI 0.92-4.41).
Mortality
During the study, 259 patients with adrenal adenomas Discussion
and 196 referent subjects died. The unadjusted overall
In a population-based setting, we found that patients with
mortality was higher in patients with adrenal aden-
adrenal adenomas had both a higher prevalence at base-
omas compared to referent subjects throughout the
line and a higher risk of developing de novo cardiovas-
follow-up period (15% vs 10% at 5 years, 28% vs 21%
cular events and comorbid conditions at follow-up than
at 10 years, and 41% vs 35% at 15 years; P < 0.001.)
age- and sex-matched referent subjects. The majority of
(Fig. 2), but there were no significant differences in mor-
patients in our cohort did not undergo standard of care
tality risk after adjusting for age, sex, BMI, and smoking
hormonal workup, reflecting the timeline of the study, the
status (aHR 1.17, 0.96-1.42) and number of preva-
population-based study design, and the knowledge gaps
lent cardiometabolic risk factors (aHR 1.11, 95% CI
regarding the diagnostic workup of adrenal adenomas in
0.92-1.35).
the general medical community. This prevented us from re-
lating the findings to the presence and degree of MACS in
the study participants.
Comparison of PATIENTS with NFAT vs MACS This is the first study to assess the association of adrenal
We examined cardiometabolic outcomes in patients with adenomas with cardiometabolic outcomes in a population-
NFAT (n = 141) vs MACS (n = 81) for participants who based cohort. We found that patients with adrenal aden-
underwent biochemical screening for cortisol excess [see omas without overt hormone excess had a high baseline
Supplementary Tables 4 and 5 in (10)]. There were no prevalence of hypertension, dyslipidemia, dysglycemia,
notable differences in the prevalence and incidence of myocardial infarction, peripheral vascular disease, and
cardiometabolic disease between the two groups; however, heart failure, beyond that observed in age- and sex-matched
the number of incident events in the analyses was small. referent subjects without adrenal tumors, even after adjust-
The unadjusted overall mortality was higher in patients ment for known confounders. These findings are consistent
3326 The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11
60 60
CKD (%)
40 40
20 20
0 0
1 5 10 15 20 1 5 10 15 20
Years Following Index Date Years Following Index Date
AA 642 416 206 53 5 AA 888 582 292 78 7
60 60
Arrhythmia (%)
PVD (%)
40 40
20 20
0 0
1 5 10 15 20 1 5 10 15 20
Years Following Index Date Years Following Index Date
AA 568 347 153 34 3 AA 696 451 209 48 5
Ref 730 479 209 59 4 Ref 836 553 269 81 7
60 60
CV Event (%)
MI or CI (%)
40 40
20 20
0 0
1 5 10 15 20 1 5 10 15 20
Years Following Index Date Years Following Index Date
AA 840 552 282 86 5 AA 791 513 255 76 5
Ref 911 648 318 104 8 Ref 863 604 295 95 8
60 60
Mortality (%)
PE/DVT (%)
40 40
20 20
0 0
1 5 10 15 20 1 5 10 15 20
Years Following Index Date Years Following Index Date
AA 898 613 304 86 4 AA 963 677 352 106 7
Ref 963 693 351 112 10 Ref 990 717 366 117 10
Figure 2. Cumulative incidence of cardiometabolic outcomes and mortality during follow-up, starting at 1 year after the index date. Study partici-
pants with the outcome of interest at baseline or prior to the 1-year mark were excluded. (A) Dysglycemia (composite of prediabetes or diabetes
mellitus); (B) chronic kidney disease; (C) cardiac arrhythmia; (D) peripheral vascular disease; (E) myocardial infarction or coronary intervention; (F)
cardiovascular events (composite of myocardial infarction, coronary intervention, or ischemic stroke); (G) venous thromboembolic events (com-
posite of deep venous thrombosis or pulmonary embolism); and (H) overall mortality. Abbreviations: AA, adrenal adenoma group; CI, coronary
intervention; CKD, chronic kidney disease; CV event, cardiovascular event; DVT, deep venous thrombosis; MI, myocardial infarction; PE, pulmonary
embolism; PVD, peripheral vascular disease; Ref, referent group.
Table 3. Adrenal adenomas and the risk for incident cardiometabolic outcomes
Outcome Adrenal adenoma No adrenal adenoma Model 1a HRb (95% CI) Model 2c HR (95% CI)
At risk, n Events, n 10-year cumulative incidence At risk, n Events 10-year cumulative incidence
Hypertension 109 50 0.86 271 137 0.76 0.81 (0.58-1.13) 0.81 (0.58-1.13)
Dyslipidemia 291 123 0.57 276 148 0.49 1.06 (0.82-1.37) 1.04 (0.80-1.35)
Dysglycemiad 700 119 0.18 818 88 0.14 1.41 (1.06-1.87) 1.32 (0.99-1.76)
Chronic kidney disease 891 167 0.19 930 112 0.12 1.57 (1.23-2.01) 1.46 (1.14-1.86)
Myocardial infarction 884 72 0.09 940 50 0.06 1.53 (1.06-2.22) 1.45 (1.02-2.13)
Coronary intervention 873 69 0.09 928 51 0.07 1.47 (1.02-2.13) 1.37 (0.94-1.98)
Ischemic stroke 890 83 0.10 930 63 0.08 1.28 (0.91-1.78) 1.18 (0.84-1.64)
Cardiovascular eventse 793 131 0.19 863 200 0.14 1.45 (1.11-1.89) 1.33 (1.01-1.73)
Atrial fibrillation 871 125 0.16 911 93 0.11 1.37 (1.04-1.79) 1.29 (0.98-1.69)
Cardiac arrhythmia 594 242 0.46 730 224 0.33 1.35 (1.12-1.63) 1.31 (1.08-1.58)
Heart failure 849 148 0.20 927 125 0.13 1.34 (1.05-1.70) 1.23 (0.96-1.58)
Peripheral vascular disease 711 226 0.35 836 200 0.25 1.35 (1.11-1.65) 1.28 (1.05-1.55)
DVT 921 74 0.09 970 35 0.04 2.10 (1.39-3.16) 2.07 (1.37-3.14)
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11
Abbreviations: DVT, deep venous thrombosis; HR, hazard ratio; PE, pulmonary embolism.
a
Model 1: adjusted for age, sex, body mass index, and cigarette smoking (ever/never).
b
Hazard ratios were calculated to assess the risk of incident outcomes in patients with adrenal adenomas vs referent subjects, starting at 1 year after the index date. Participants with the outcome of interest at baseline or prior
to the one-year mark were excluded from the analysis for the particular condition.
c
Model 2: adjusted for Model 1 variables plus number of prevalent cardiovascular risk factors (hypertension, dyslipidemia, dysglycemia, chronic kidney disease, peripheral vascular disease, heart failure, atrial fibrillation, and
cardiovascular events).
d
Dysgylcemia: composite of prediabetes or diabetes mellitus.
e
Cardiovascular events: composite of myocardial infarction, coronary intervention, or ischemic stroke.
3327
with the high cardiometabolic disease burden reported in study) in 198 patients with adrenal adenomas and MACS
convenience samples of patients with NFAT and MACS (14) and of incident atrial fibrillation in 102 patients with
derived from university hospitals or specialized endocrin- adrenal adenomas and MACS (15) compared to patients
ology clinics (2,6,14-18). with NFAT.
The prevalence of cardiometabolic conditions in our In our cohort of 1004 patients, we found that patients
cohort was higher than the pooled prevalence reported in with adrenal adenomas had a higher incidence of de novo
the recent systematic review and meta-analysis on the nat- chronic kidney disease, cardiovascular events, cardiac ar-
ural history of adrenal incidentalomas (6). This difference rhythmia, and peripheral vascular disease than referent
may be due to several reasons. We used comprehensive subjects without adrenal tumors, even after adjustment for
definitions for the classification of hypertension, diabetes known confounders. The risk for incident dysglycemia was
mellitus, and dyslipidemia that incorporated laboratory lower than the 2-fold excess risk reported by Lopez et al
results, medication prescription, and blood pressure meas- in patients with NFAT compared to patients without ad-
did not differ after adjusting for smoking and cardiovas- study participants who had the outcome of interest at base-
cular morbidity, suggesting that these factors are potential line or prior to the 1-year mark. In addition, we examined
contributors to the excess mortality risk in patients with the frequency of cross-sectional imaging in cases and refer-
adrenal adenomas. One previous study from an academic ents in the 5 years preceding the index date and found no
medical center found an increased all-cause mortality risk major differences. Second, because Olmsted County resi-
(aHR 1.14, 95% CI 1.003-1.29) in 969 patients with ad- dents are predominately Caucasian (94%), our findings
renal incidentalomas compared to controls without adrenal may not apply to populations with different ethnic and
tumors (23). However, several important covariates, such socioeconomic characteristics. Third, while the 1-mg DST
as smoking status, were not considered in their analyses. is the guideline recommended test to screen for cortisol ex-
A few studies have also reported increased mortality in cess, additional data may be needed to verify the diagnosis
patients with adrenal adenomas based on post-DST cor- of autonomous cortisol secretion. In particular, the DST
tisol concentrations (14,17,24), but a systematic review may have false-positive results due to noncompliance,
Disclosures: I.B. reports advisory board participation and/or con- Management of High Blood Pressure in Adults: A Report of the
sulting with Corcept Therapeutics, Strongbridge, Sparrow Pharma- American College of Cardiology/American Heart Association
ceutics, and HRA Pharma outside the submitted work. All other au- Task Force on Clinical Practice Guidelines. Hypertension.
thors have nothing to disclose. 2018;71(6):e13-e115.
Data Availability: Some or all data sets generated during and/ 13. van Buuren S, Groothuis-Oudshoorn K. mice: multivariate im-
or analyzed during the current study are not publicly available but putation by chained equations in R. J Stat Softw. 2011;45(3):67.
are available from the corresponding author on reasonable request. 14. Di Dalmazi G, Vicennati V, Garelli S, et al. Cardiovascular events
and mortality in patients with adrenal incidentalomas that are
either non-secreting or associated with intermediate phenotype
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