Abstract
Context
Patients with nonfunctioning adenomas (NFAs), adenomas with mild autonomous cortisol secretion (MACS) and Cushing syndrome (CS) demonstrate an increased cardiovascular risk.
Objective
This work aimed to determine the extent of lipoprotein abnormalities in NFA, MACS, and CS.
Methods
We conducted a single-center, cross-sectional study of patients with NFA (n = 167), MACS (n = 213), CS (n = 142), and referent individuals (n = 202) between January 2015 and July 2022. Triglyceride-rich lipoprotein particles (TRLP), low-density lipoprotein particles (LDLP), high-density lipoprotein particles (HDLP), their subclasses and sizes were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, body mass index, smoking, hypertension, diabetes and lipid-lowering drug therapy.
Results
In age- and sex-adjusted analysis, all patients categories demonstrated increased very large TRLP, large TRLP, and greater TRLP size (odds ratio [OR], 1.22-2.08) and total LDLP (OR, 1.22-1.75) and decreased LDL and HDL size compared to referent individuals. In fully adjusted analysis, LDLP concentrations remained elevated in all patient categories (OR, 1.31-1.84). Total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B (ApoB) were also higher in all patient categories in age- and sex-adjusted analysis, with ApoB remaining elevated in all patient categories in fully adjusted analysis. Similar LDLP and ApoB elevations were observed in all patient categories after excluding individuals on lipid-lowering therapy.
Conclusion
Patients with overt, mild, and even absent cortisol excess demonstrate lipoprotein profile abnormalities, in particular, high LDLP and ApoB concentrations, which conceivably contribute to high cardiometabolic risk.
Keywords: MACS, mild autonomous cortisol secretion, cortisol, Cushing syndrome, lipoprotein particle, nuclear magnetic resonance spectroscopy
Adrenal adenoma is a frequent incidental radiological finding in adults, with a prevalence of up to 5% (1-3). Most patients with adrenal adenomas do not present with features of overt hormone excess such as Cushing syndrome (CS) or primary aldosteronism, and are either nonfunctioning (NFA) or demonstrate mild autonomous cortisol secretion (MACS) (1, 4). Despite the absence of overt hormone excess, patients with NFA and MACS demonstrate an increased prevalence and incidence of cardiovascular disease risk factors and mortality (4-15). Dyslipidemia is a known risk factor for developing cardiovascular disease–related morbidity and mortality (16), and may contribute to increased cardiovascular disease risk in patients with NFA and MACS.
Overall, patients with adrenal incidentalomas, that is a mix of patients with NFA and MACS, have been found to have a slightly higher prevalence of dyslipidemia compared to patients with no known adrenal tumors (66% vs 59%) (12). Reported data on the prevalence of dyslipidemia in patients with NFA are discordant. Whereas one study showed no difference in the prevalence of dyslipidemia in patients with NFA when compared to referent individuals at baseline as well as follow-up (8), another study reported a higher prevalence of dyslipidemia, especially total cholesterol (TC) and non–high-density lipoprotein (HDL) cholesterol (73% vs 57%) and greater occurrence of metabolic syndrome (70% vs 31%) in patients with NFA (17). Higher plasma triglycerides and lower HDL cholesterol, without differences in total and low-density lipoprotein (LDL) cholesterol concentrations, has been reported in patients with NFA (18).
A higher prevalence of dyslipidemia has also been reported in MACS, but these studies are limited by small sample sizes, or a lack of referent individuals without adrenal tumors (15, 19). In one meta-analysis of studies comparing patients with MACS vs NFA, both prevalence and incidence of dyslipidemia were similar between the groups, although dyslipidemia was more likely to worsen in patients with MACS (4). However, in another meta-analysis comparing patients with MACS undergoing adrenalectomy vs those followed conservatively, adrenalectomy did not result in significant improvement of dyslipidemia (20). In contrast, a recent meta-analysis reported a higher prevalence of dyslipidemia in patients with MACS as compared to NFA, and a significant postadrenalectomy improvement of dyslipidemia (15).
The objective of this study was to determine the nature and extent of lipid and lipoprotein abnormalities in patients with NFA and MACS as compared to referent subjects. To this end, in addition to a traditional lipid profile, we used advanced nuclear magnetic resonance (NMR) spectroscopy-based lipoprotein analysis, which allows for the determination of the concentrations and sizes of different lipoprotein particles including very low-density lipoprotein (VLDL), triglyceride- rich lipoprotein particle (TRLP), low-density lipoprotein particle (LDLP), high-density lipoprotein particle (HDLP), and their subfractions (21).
Materials and Methods
Study Design and Participants
The study was conducted at Mayo Clinic, Rochester, Minnesota, USA, between January 2015 and May 2022. Patients and referent populations for this study are described later. This study was conducted under two protocols (“Effects of abnormal steroid metabolome on bone in patients with MACS,” initiated in 2019, IRB ID 18-009787 and “Prospective biobank and registry,” IRB ID 13-005838 initiated in 2014), both approved by the institutional review board of Mayo Clinic, Rochester. Both protocols used the same approach to biomaterial collection. The study was conducted under the principles of the Declaration of Helsinki, and all participants gave written informed consent.
Patients
Patients with adrenal adenomas evaluated at Mayo Clinic were prospectively and consecutively enrolled during the study period. As a part of the protocol, a fasting blood sample was collected and stored at −80 °C in the Mayo Clinic biobank (Fig. 1). MACS was diagnosed in the absence of overt features of CS in a patient with benign adrenal adenoma or macronodular adrenal hyperplasia when serum cortisol following the overnight 1-mg dexamethasone suppression test (DST) was greater than 1.8 µg/dL (49.66 nmol/L) (22). NFA was diagnosed when DST was less than 1.8 µg/dL (49.66 nmol/L). Diagnosis of CS was made per established guidelines (23). Patients with incomplete workup or exogenous glucocorticoid use within the last 3 months were excluded. Demographic data along with information regarding comorbidities including hypertension, diabetes, body mass index (BMI) as well as lipid-lowering treatment were obtained for each patient. Malignancy was excluded based on imaging characteristics (unenhanced computed tomography <20 Hounsfield units), absence of tumor growth on imaging follow-up of at least 6 months, or histology (for those treated with adrenalectomy).
Figure 1.
Flowchart of study participant inclusion.
Referent Individuals
Referent participants were recruited by the Mayo Clinic via advertisement and letter invitation to the residents of Olmsted County, Minnesota, USA. Individuals were included if they had abdominal imaging performed for any reason within 5 years prior to enrollment that showed no adrenal tumors. Individuals with adrenal disorders, those taking exogenous glucocorticoid therapy within the last 6 months, or with active malignancy were excluded.
Comorbidities
Both for patients and the referent population, hypertension was defined as systolic blood pressure more than 140 mm Hg or diastolic blood pressure of more than 90 mm Hg and/or use of one or more antihypertensives. Diabetes was defined as fasting plasma glucose equal to or greater than 126 mg/dL (7.0 mmol/L) and or glycated hemoglobin A1c greater than 6.5% (24). Physician diagnosis of diabetes and/or use of any glucose-lowering medications was also used to assess for diabetes. BMI was calculated as weight divided by square of height.
Laboratory Methods
Fasting EDTA-anticoagulated venous blood samples from the patients and the referent population were collected and stored at −80 °C within the Mayo Clinic biobank. Samples were sent frozen at −80 °C to Labcorp, Morrisville, North Carolina, USA. Testing was performed on the Vantera Clinical Analyzer, a fully automated, high-throughput, 400-MHz proton (1H) NMR spectroscopy platform. NMR MetaboProfile analysis was performed using an optimized version of the LP4 deconvolution algorithm (25). Lipoprotein classes reported by the aforementioned algorithm include TRLP, LDLP, HDLP, and their subfractions and average sizes. Very large, large, medium, small, and very small TRLP, and large, medium, and small LDLP were quantified using the conventional deconvolution method and the amplitudes of their spectroscopically distinct lipid methyl group NMR signals. Total TRLP was calculated as the sum of the concentrations of very large, large, medium, small, and very small TRLP. Total LDLP were calculated as the sum of the concentrations of large, medium, and small LDLP. Estimated ranges of particle diameter for the TRL and LDL subfractions were as follows: very large TRLP, 90 to 240 nm; large TRLP, 50 to 89 nm; medium TRLP, 37 to 49 nm; small TRLP, 30 to 36 nm; very small TRLP, 24 to 29 nm; large LDLP, 21.5 to 23 nm; medium LDLP, 20.5 to 21.4 nm; and small LDLP, 19 to 20.4 nm. Total HDLP was calculated by the sum of the concentrations of small, medium, and large HDLP. Estimated ranges of particle diameter for the subclasses and subspecies were as follows: small HDLP (H1 plus H2), 7.4 to 8.0 nm; medium HDLP (H3 plus H4), 8.1 to 9.5 nm; and large HDLP (H5, H6 and H7), 9.6 to 13 nm. Mean TRL, LDL, and HDL sizes were calculated using the weighted averages derived from the sum of the diameters of each respective subfraction multiplied by their relative mass percentages. The interassay precisions as reported by the algorithm are 6.4% for TRLP, 1.5% for LDLP, and 2.4% for HDLP (21, 26). Linear regressions of subclass signal areas against independent chemical measures of cholesterol, HDL cholesterol, triglycerides, and apolipoprotein (ApoB) from a large population sample have produced conversion factors enabling the reporting of NMR-derived lipid and ApoB concentrations. LDL cholesterol was calculated by the National Institutes of Health equation (27). In addition, we obtained the Lipoprotein Insulin Resistance (LP-IR) Index and the triglyceride/HDL cholesterol (TGs/HDL-C) ratio, which are each closely associated with insulin resistance as determined by the homeostasis model assessment of insulin resistance (HOMA-IR) and are both regarded to represent a lipoprotein biomarker proxy of insulin resistance (28-30). The LP-IR index is calculated using 6 NMR-measured lipoprotein variables, that is, weighted average sizes of TRL, LDL and HDL, combined with the concentrations of large VLDL, small LDL and large HDL particles. The LP-IR index has no units and varies between 0 and 100; the higher the score, the more insulin resistant the individual (30, 31).
Statistical Analysis
Median and interquartile range (IQR) statistics were used to describe continuous variables, while categorical variables are shown as number (%). Kruskal-Wallis test and chi-square test were used to compare variables. Differences in the association of each biomarker measurement for the three adrenal disorder groups, compared with the referent population, were measured using logistic regression analysis adjusting for 1) age and sex, 2) for age, sex, BMI, smoking, hypertension, type 2 diabetes, smoking, and lipid-lowering drugs; and 3) for age, sex, BMI, type 2 diabetes, and smoking (for individuals not on any lipid-lowering drugs). Prior to fitting the logistic regression models, the lipid biomarker data was log2-transformed, then standardized by subtracting the mean value and dividing by the SD. The logistic regression model results were summarized using odds ratios (ORs) and 95% CIs. The OR represents the odds of being in the case group compared to the referent population compared with the odds of being in the case group given that the log2-transformed lipid biomarker is 1 SD larger. Analyses were conducted using the R software environment, version 4.2.2. Statistical significance was defined as P less than .05.
Results
A total of 522 patients with adrenal cortical adenomas and 202 referent individuals were included. Patients were diagnosed with NFA (167, 32%), MACS (213, 41%), and CS (142, 27.2%). As expected, patients with CS were younger and were more likely to be women compared to patients with NFA, MACS, and referent individuals (Table 1). When compared to referent individuals, patients had a higher BMI, were more likely to be a current or past smoker, had a higher prevalence of hypertension, dysglycemia, and had experienced a cardiovascular event more frequently (see Table 1). Statin therapy was reported in 51 (30.5%) patients with NFA, 83 (39%) patients with MACS, 40 (36.2%) patients with CS, and in 60 (29.7%) referent participants. Nonstatin lipid-lowering drug therapy was reported in 5 (3%) patients with NFA, 25 (11.7%) with MACS, 18 (12.7%) patients with CS, and 1 (.5%) referent individuals. Table 1 also shows the post-DST cortisol values, which were expectedly different in NFA, MACS, and CS.
Table 1.
Baseline clinical and laboratory characteristics of patients and referent individuals
| Variables | NFA | MACS | CS | Referent individuals | P |
|---|---|---|---|---|---|
| n | 167 | 213 | 142 | 202 | |
| Women, n (%) | 106 (63.5%) | 140 (65.7%) | 125 (88.0%) | 111(55%) | <.001a |
|
Age, y
median (IQR) |
60.1 (53.0-66.4) |
61.0 (51.1-69.5) |
46.3 (34.7-58.4) |
63.9 (55.3-73.8) |
<.001b |
| White race, n (%) | 160 (95.8%) | 204 (95.8%) | 135 (95.1%) | 188 (93.1%) | .567a |
|
BMI, median (IQR) |
32.0 (27.8-37.6) |
31.1 (26.3-36.0) |
32.5 (28.1-39.3) |
26.9 (24.7-31.7) |
<.001b |
|
SBP, mm Hg
median (IQR) |
130 (121-140) |
132 (122-143) |
134 (123-146) |
122 (114-132) |
<.001b |
|
DBP, mm Hg
median (IQR) |
78 (71-86) |
80 (74-86) |
84 (79-91) |
74 (68-81) |
<.001b |
| Hypertension, n (%) | 106 (63.5%) | 174 (81.7%) | 107 (75.4%) | 81 (40.1%) | <.001a |
| Type 2 diabetes, n (%) | 35 (21.0%) | 63 (29.6%) | 47 (33.1%) | 18 (8.9%) | <.001a |
| Dyslipidemia pharmacotherapy | <.001a | ||||
| No therapy, n(%) | 111 (66.5%) | 105 (49.3%) | 84 (59.2%) | 141 (69.8%) | |
| Nonstatin, n (%) | 5 (3.0%) | 25 (11.7%) | 18 (12.7%) | 1 (.5%) | |
| Statin, n (%) | 51 (30.9%) | 83 (39%) | 40 (28.2%) | 60 (29.7%) | |
| Cardiovascular events, n (%) | 32 (19.2%) | 48 (22.5%) | 13 (19.2%) | 33 (16.3%) | .011a |
|
eGFR, mL/min/1.73 m2
median (IQR) |
80 (65-94) |
80 (66-95) |
90 (72-104) |
78 (68-88) |
<.001b |
| Smoking status | <.001a | ||||
| Never, n (%) | 78 (46.7%) | 95 (44.6%) | 104 (73.2%) | 120 (59.4%) | |
| Past smoker, n (%) | 62 (37.1%) | 76 (35.7%) | 21 (14.8%) | 72 (35.6%) | |
| Current smoker, n (%) | 27 (16.2%) | 42 (19.7%) | 17 (12.0%) | 10 (5.0%) | |
|
Postdexamethasone cortisol, µg/dL
median (IQR) |
1.2 (1.0-1.5) |
3.1 (2.3-5.2) |
13.0 (6.8-19.3) |
— | — |
Abbreviations: BMI, body mass index; CS, Cushing syndrome; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; IQR, interquartile range; MACS, mild autonomous cortisol secretion; NFA, nonfunctioning adenoma; SBP, systolic blood pressure.
a Pearson chi-square test.
b Kruskal-Wallis rank sum test.
Table 2 shows the median (IQR) concentrations of plasma TRLP, LDLP, HDLP, their subfractions and sizes, as well as conventional lipid profile measures in patients with NFA, MACS, and CS. After adjusting for age and sex, very large and large TRLP were higher and TRL size was greater in all patient groups, as compared to the referent individuals (Table 3, Fig. 2; differences vs referent participants are expressed in ORs with 95% CIs). After additional adjustment for BMI, presence of hypertension, diabetes, smoking status, and lipid-lowering drug therapy, most of the differences compared to the referent individuals were not statistically significant (Table 4, Fig. 3). In age- and sex-adjusted analysis, the LDLP concentration was also higher in all patient groups, which was attributable to increases in small-sized LDL; this resulted in a smaller average LDL size (see Table 3, Fig. 2). Notably, the increases in LDLP in all patient groups remained significant in fully adjusted analysis, whereas the concentration of small-sized LDL was still higher in patients with NFA and CS compared to the referent participants (see Table 4, Fig. 3). In age-and sex-adjusted analysis, the HDLP concentration was not different in NFA and MACS but was higher in patients with CS (see Table 3, Fig. 2). In addition, there was a shift in HDLP distribution resulting in a smaller HDL size in all patient categories (see Table 4, Fig. 3). In fully adjusted analysis, there was only an increase in small-sized HDL in patients with CS (see Table 4, Fig. 3). Both the LP-IR index and the TGs/HDL-C ratio were higher in the 3 patient groups compared to referent participants in age- and sex-adjusted analysis (see Table 3); these differences were no longer present in fully adjusted analysis (see Table 4).
Table 2.
Distribution of lipoproteins in patients and referent individuals
| Lipoprotein | NFA | MACS | CS | Referent individuals |
|---|---|---|---|---|
| TRLP particle concentrations, nmol/L | ||||
| Total TRLP | 141 (101-193) | 129 (91-176) | 146 (96-209) | 126 (88-174) |
| TRLP subclasses, nmol/L | ||||
| Very large TRLP | 0.17 (0.06-0.60) | 0.09 (0.04-0.25) | 0.17 (0.06-0.53) | 0.06 (0.03-0.14) |
| Large TRLP | 3.69 (1.07-7.49) | 2.04 (0.54-6.18) | 3.79 (1.37-8.23) | 1.28 (0.23-4.80) |
| Medium TRLP | 16 (8-28) | 16 (8-28) | 18 (10-35) | 14 (8-24) |
| Small TRLP | 47 (25-71) | 35 (17-60) | 37 (17-64) | 38 (15-64) |
| Very small TRLP | 64 (30-116) | 63 (28-109) | 69 (29-119) | 60 (34-96) |
| LDLP concentrations, nmol/L | ||||
| Total LDLP | 1422 (1210-1725) | 1333 (1096-1615) | 1581 (1279-1977) | 1220 (990-1505) |
| LDLP subclasses, nmol/L | ||||
| Large LDLP | 252 (146-433) | 229 (105-390) | 249 (121-445) | 264 (133-399) |
| Medium LDLP | 506 (272-774) | 456 (271-695) | 547 (330-826) | 490 (315-649) |
| Small LDLP | 562 (372-818) | 518 (303-862) | 657 (365-995) | 392 (236-596) |
| HDLP concentrations, µmol/L | ||||
| Total HDLP | 20 (19-23) | 20 (18-22) | 22 (19-24) | 20 (18-22) |
| Large HDLP | 1.46 (1.00-2.65) | 1.53 (0.77-2.97) | 1.47 (0.90-2.31) | 2.00 (1.21-3.25) |
| Medium HDLP | 3.51 (2.43-4.97) | 3.38 (2.29-4.81) | 4.02 (2.64-5.54) | 3.61 (2.51-5.11) |
| Small HDLP | 15 (13-17) | 15 (12-17) | 15 (13-18) | 14 (12-16) |
| Lipoprotein sizes, nm | ||||
| TRL size | 45 (41-54) | 45 (40-52) | 49 (43-55) | 44 (39-49) |
| LDL size | 20.9 (20.6-21.3) | 20.9 (20.6-21.3) | 20.9 (20.5-21.3) | 21.1 (20.7-21.4) |
| HDL size | 8.92 (8.71-9.19) | 8.92 (8.63-9.32) | 8.91 (8.68-9.29) | 9.07 (8.82-9.40) |
| Conventional lipoprotein cholesterol and ApoB measurements | ||||
| TC, mg/dL | 195 (170-220) | 182 (157-210) | 210 (169-237) | 184 (159-207) |
| LDL-C, mg/dL | 118 (98-139) | 104 (84-130) | 122 (92-146) | 107 (84-126) |
| HDL-C, mg/dL | 50 (44-61) | 50 (42-63) | 56 (45-63) | 56 (46-66) |
| TGs, mg/dL | 122 (88-184) | 111 (82-161) | 140 (102-192) | 92 (65-129) |
| ApoB, mg/dL | 103 (92-118) | 100 (87-113) | 112 (94-132) | 94 (80-107) |
| Other biomarkers | ||||
| Lipoprotein Insulin Resistance Index | 51 (38-62) |
46 (32-67) |
52 (39-65) |
40 (25-57) |
| TGs/HDL-C ratio | 2.5 (1.6-3.9) |
2.1 (1.4-3.5) |
2.5 (1.6-4.2) |
1.7 (1-2.6) |
Data presented as median (IQR). The Lipoprotein Insulin Resistance Index has no units and varies between 0 and 100; the higher the score, the more insulin resistant the individual.
Abbreviations: ApoB, apolipoprotein B; CS, Cushing syndrome; HDL-C, high-density lipoprotein cholesterol; HDLP, high-density lipoprotein particle; LDL-C, low-density lipoprotein cholesterol; LDLP, low-density lipoprotein particle; MACS, mild autonomous cortisol secretion; NFA, nonfunctioning adenoma; TC, total cholesterol; TGs, triglycerides; TRLP, triglyceride-rich lipoprotein particles.
Table 3.
Comparison of lipid markers in comparison to referent individuals (age- and sex-adjusted odds ratio with 95% CIs)
| Lipoprotein | NFA | P | MACS | P | CS | P |
|---|---|---|---|---|---|---|
| TRLP particle concentrations | ||||||
| Total TRLP | 1.17(0.98-1.40) | .083 | 1.00 (0.86-1.17) | .967 | 1.20 (0.98-1.47) | .075 |
| TRLP subclasses | ||||||
| Very large TRLP | 1.49 (1.23-1.82)* | <.001 | 1.22 (1.00-1.48)* | .049 | 1.43 (1.15-1.78)* | .001 |
| Large TRLP | 1.68 (1.32-2.13)* | <.001 | 1.31 (1.06-1.62)* | .011 | 2.08 (1.57-2.76)* | <.001 |
| Medium TRLP | 1.13 (.91-1.41) | .260 | 1.04 (.85-1.27) | .697 | 1.41 (1.09-1.83)* | .009 |
| Small TRLP | 1.20 (0.95-1.50) | .123 | 0.89 (0.74-1.06) | .189 | 0.96 (0.78-1.20) | .733 |
| Very small TRLP | 0.93 (0.77-1.13) | .492 | 0.93 (0.78-1.12) | .452 | 0.99 (0.80-1.22) | .912 |
| LDLP concentrations | ||||||
| Total LDLP | 1.52 (1.26-1.85)* | <.001 | 1.22 (1.03-1.44)* | .024 | 1.75 (1.40-2.17)* | <.001 |
| LDL subclasses | ||||||
| Large LDLP | 0.90 (0.70-1.16) | .419 | 0.78 (0.62-0.97)* | .029 | 0.77 (0.60-1.00) | .051 |
| Medium LDLP | 0.78 (0.50-1.23) | .287 | 0.70 (0.46-1.05) | .086 | 0.79 (0.48-1.30) | .353 |
| Small LDLP | 2.03(1.48-2.78)* | <.001 | 1.52 (1.19-1.93)* | .001 | 2.38 (1.69-3.34)* | <.001 |
| HDLP concentrations | ||||||
| Total HDLP | 0.96 (0.80-1.16) | .698 | 0.92 (0.77-1.09) | .325 | 1.44 (1.16-1.80)* | .001 |
| Large HDLP | 0.76 (0.61-0.95)* | .014 | 0.70 (0.57-0.86)* | .001 | 0.71 (0.55-0.90)* | .005 |
| Medium HDLP | 0.89 (0.73-1.08) | .224 | 0.82 (0.69-0.97)* | .024 | 0.85 (0.69-1.06) | .150 |
| Small HDLP | 1.14 (0.94-1.39) | .194 | 1.13 (0.95-1.36) | .176 | 2.20 (1.67-2.90)* | <.001 |
| Lipoprotein sizes | ||||||
| TRL size | 1.40 (1.13-1.74)* | .002 | 1.23 (1.00-1.51)* | .046 | 1.54 (1.22-1.96)* | <.001 |
| LDL size | 0.72 (0.56-0.92)* | .009 | 0.65 (0.52-0.82)* | <.001 | 0.49 (0.37-0.65)* | <.001 |
| HDL size | 0.79 (0.63-0.99)* | .043 | 0.76 (0.62-0.94)* | .013 | 0.65 (0.50-0.85)* | .002 |
| Conventional lipoprotein cholesterol and ApoB measurements | ||||||
| TC | 1.30 (1.06-1.58)* | .010 | 0.94 (0.79-1.13) | .520 | 1.43(1.13-1.79)* | .002 |
| LDL-C | 1.29 (1.06-1.57)* | .011 | 0.94 (0.79-1.12) | .510 | 1.17 (0.91-1.41) | .169 |
| HDL-C | 0.74 (0.59-0.92)* | .007 | 0.72 (0.58-.88)* | .001 | 0.85 (0.66-1.08) | .180 |
| TGs | 1.90(1.51-2.39)* | <.001 | 1.57(1.26-1.94)* | <.001 | 2.41 (1.88-3.09)* | <.001 |
| ApoB | 1.74 (1.38-2.19)* | <.001 | 1.32 (1.07-1.63)* | .011 | 2.27 (1.75-2.94)* | <.001 |
| Lipoprotein biomarkers of insulin resistance | ||||||
| Lipoprotein Insulin Resistance Index | 1.57 (1.25-1.97)* | <.001 | 1.37 (1.12-1.69)* | .003 | 1.88 (1.46-2.41)* | <.001 |
| TGs/HDL-C ratio | 1.79 (1.41-2.27)* | <.001 | 1.60 (1.28-1.99)* | <.001 | 2.05 (1.59-2.66)* | <.001 |
The Lipoprotein Insulin Resistance Index has no units and varies between 0 and 100; the higher the score the more insulin resistant the individual.
Abbreviations: ApoB, Apolipoprotein B; CS, Cushing syndrome; HDL-C, high-density lipoprotein cholesterol; HDLP, high-density lipoprotein particle; LDL-C, low-density lipoprotein cholesterol; LDLP, low-density lipoprotein particle; MACS, mild autonomous cortisol secretion; NFA, nonfunctioning adenoma; TC, total cholesterol; TGs, triglycerides; TRLP, triglyceride-rich lipoprotein particles.
Figure 2.
Lipoprotein particles in patient groups as compared to referent individuals. Age- and sex-adjusted odds ratio with 95% CIs. ApoB, apolipoprotein B; CS, Cushing syndrome; HDL-C, high-density lipoprotein cholesterol; HDLP, high-density lipoprotein particle; L, large; LDL-C, low-density lipoprotein cholesterol; LDLP, low-density lipoprotein particle; M, medium; MACS, mild autonomous cortisol secretion; NFA, nonfunctioning adenoma; S, small; TC, total cholesterol; TG, triglcyeride; TRLP, triglyceride-rich lipoprotein particle; VL, very large.
Table 4.
Lipoprotein particles in patients in comparison to referent individuals (age-, sex-, body mass index–, hypertension-, type 2 diabetes mellitus–, smoking-, and lipid-lowering therapy–adjusted odds ratio with 95% CIs)
| Lipoprotein | NFA | P | MACS | P | CS | P |
|---|---|---|---|---|---|---|
| TRLP particle concentrations | ||||||
| Total TRLP | 1.04 (.85-1.27) | .682 | 0.91 (0.76-1.10) | .334 | 1.01 (0.81-1.27) | .933 |
| TRLP subclasses | ||||||
| Very large TRLP | 1.24 (1.00-1.53) | .050 | 0.97 (0.78-1.21) | .809 | 1.03 (0.80-1.33) | .814 |
| Large TRLP | 1.18 (0.90-1.55) | .226 | 0.85 (0.65-1.09) | .202 | 1.18 (0.84-1.65) | .339 |
| Medium TRLP | 1.07 (0.83-1.38) | .590 | 0.89 (0.70-1.12) | .315 | 1.11 (0.83-1.49) | .478 |
| Small TRLP | 1.20 (0.95-1.52) | .126 | 0.96 (0.79-1.17) | .683 | 1.05 (0.82-1.34) | .698 |
| Very small TRLP | 0.81 (0.65-1.02) | .072 | 0.82 (0.66-1.01) | .064 | 0.82 (0.64-1.05) | .112 |
| LDLP concentrations | ||||||
| Total LDLP | 1.58 (1.27-1.96)* | <.001 | 1.37 (1.12-1.67)* | .002 | 1.86 (1.45-2.38)* | <.001 |
| LDLP subclasses | ||||||
| Large LDLP | 1.24 (0.92-1.65) | .153 | 1.22 (0.93-1.59) | .145 | 1.37 (1.01-1.86)* | .044 |
| Medium LDLP | 0.89 (0.56-1.43) | .637 | 0.93 (0.60-1.46) | .766 | 1.20 (0.66-2.17) | .547 |
| Small LDLP | 1.84 (1.32-2.56)* | <.001 | 1.26 (0.98-1.60) | .068 | 1.72 (1.24-2.38)* | .001 |
| HDLP concentrations | ||||||
| Total HDLP | 1.11 (0.90-1.37) | .326 | 1.07 (0.88-1.30) | .522 | 1.71 (1.32-2.22)* | <.001 |
| HDLP subclasses | ||||||
| Large HDLP | 1.08 (0.84-1.40) | .541 | 0.95 (0.75-1.22) | .707 | 1.10 (0.81-1.48) | .545 |
| Medium HDLP | 0.97 (0.79-1.20) | .800 | 0.95 (0.78-1.16) | .610 | 1.06 (0.82-1.37) | .670 |
| Small HDLP | 1.09 (0.88-1.36) | .418 | 1.08 (0.88-1.32) | .476 | 1.85 (1.37-2.52)* | <.001 |
| Mean lipoprotein sizes | ||||||
| TRL size | 0.99 (0.78-1.26) | .920 | 0.77 (0.60-.98)* | .032 | 0.85 (0.64-1.14) | .285 |
| LDL size | 0.95 (0.71-1.27) | .742 | 1.03 (0.78-1.36) | .853 | 0.88 (0.64-1.22) | .456 |
| HDL size | 1.11 (0.84-1.45) | .464 | 1.04 (0.80-1.34) | .791 | 1.04 (0.75-1.45) | .794 |
| Conventional lipoprotein cholesterol and ApoB measurements | ||||||
| TC | 1.58 (1.24-2.01)* | <.001 | 1.25 (1.00-1.56)* | .051 | 1.94 (1.47-2.55)* | <.001 |
| LDL-C | 1.55 (1.22-1.96)* | <.001 | 1.26 (1.01-1.58)* | .038 | 1.62 (1.24-2.11)* | <.001 |
| HDL-C | 1.04 (0.79-1.35) | .786 | 1.03 (0.80-1.32) | .829 | 1.43 (1.05-1.95)* | .023 |
| TGs | 1.42 (1.10-1.84)* | .007 | 1.09 (0.85-1.40) | .498 | 1.54 (1.14-2.06)* | .004 |
| ApoB | 1.82 (1.39-2.37)* | <.001 | 1.51 (1.17-1.94)* | .001 | 2.45 (1.81-3.30)* | <.001 |
| Lipoprotein biomarkers of insulin resistance | ||||||
| Lipoprotein Insulin Resistance Index | 1.06 (0.81-1.37) | .679 | 0.85 (0.66-1.10) | .216 | 1.00 (0.73-1.37) | .992 |
| TGs/HDL-C ratio | 1.29 (0.99-1.70) | .062 | 1.07 (0.83-1.39) | .594 | 1.23 (0.90-1.67) | .188 |
The Lipoprotein Insulin Resistance Index has no units and varies between 0 and 100; the higher the score, the more insulin resistant the individual.
Abbreviations: ApoB, Apolipoprotein B; CS, Cushing syndrome; HDL-C, high-density lipoprotein cholesterol; HDLP, high-density lipoprotein particle; LDL-C, low-density lipoprotein cholesterol; LDLP, low-density lipoprotein particle; MACS, mild autonomous cortisol secretion; NFA, nonfunctioning adenoma; TC, total cholesterol; TGs, triglycerides; TRLP, Triglyceride rich lipoprotein particles.
Figure 3.
Lipoprotein particles in patient groups as compared to referent individuals. Age-, sex-, BMI-, hypertension-, type 2 diabetes–, smoking-, and lipid-reduction therapy–adjusted odds ratio with 95% CIs. ApoB, apolipoprotein B; BMI, body mass index; CS, Cushing syndrome; HDL-C, high-density lipoprotein cholesterol; HDLP, high-density lipoprotein particle; L, large; LDL-C, low-density lipoprotein cholesterol; LDLP, low-density lipoprotein particle; M, medium; MACS, mild autonomous cortisol secretion; NFA, nonfunctioning adenoma; S, small; TC, total cholesterol; TG, triglycerides; TRLP, triglyceride-rich lipoprotein particle; VL, very large.
In the analysis in which we excluded individuals on statins and other lipid-lowering drug therapy, essentially similar findings were found with respect to increases in LDLP in all patient groups after adjustment for age, sex, BMI, hypertension, diabetes, and smoking (Table 5, Fig. 4). In this analysis, there were also increases in small LDLP in patients with NFA and CS. Again, HDLP was increased in patients with CS, attributable to an increase in small-sized HDL (see Table 5, Fig. 4). In this analysis, the LP-IR index was not different in the 3 groups in the fully adjusted analysis, with the TGs/HDL-C ratio remaining higher in patients with NFA.
Table 5.
Lipoprotein particles in patients not on lipid-lowering therapy in comparison to referent individuals (age-, sex-, body mass index–, hypertension-, type 2 diabetes mellitus– , smoking-adjusted odds ratio with 95% CIs)
| Lipid marker | NFA | P | MACS | P | CS | P |
|---|---|---|---|---|---|---|
| TRLP concentrations | ||||||
| Total TRLP | 0.96 (0.74-1.24) | .749 | 0.88 (0.69-1.13) | .335 | 1.05 (0.77-1.43) | .774 |
| TRLP subclasses | ||||||
| Very large TRLP | 1.37 (1.00-1.89) | .051 | 1.17 (0.84-1.63) | .362 | 1.26 (0.86-1.84) | .230 |
| Large TRLP | 1.40 (1.00-1.97) | .053 | 1.01 (0.72-1.41) | .969 | 1.27 (0.83-1.96) | .270 |
| Medium TRLP | 1.24 (.92-1.67) | .161 | 0.98 (0.74-1.28) | .870 | 1.16 (0.82-1.65) | .391 |
| Small TRLP | 1.12 (0.83-1.50) | .466 | 0.87 (0.68-1.13) | .309 | 1.16 (0.83-1.64) | .388 |
| Very small TRLP | 0.77 (0.59-1.00)* | .048 | 0.79 (0.61-1.02) | .074 | 0.80 (0.59-1.10) | .166 |
| LDLP concentrations | ||||||
| Total LDLP | 1.67 (1.24-2.26)* | .001 | 1.38 (1.03-1.85)* | .030 | 2.18 (1.53-3.11)* | <.001 |
| LDLP subclasses | ||||||
| Large LDLP | 1.36 (0.84-2.21) | .206 | 1.11 (0.70-1.74) | .661 | 2.29 (1.14-4.59)* | .019 |
| Medium LDLP | 0.89 (0.46-1.72) | .738 | 0.89 (0.47-1.69) | .725 | 1.45 (.52-4.01) | .473 |
| Small LDLP | 1.70 (1.18-2.45)* | .005 | 1.21 (0.91-1.61) | .193 | 1.61 (1.11-2.34)* | .011 |
| HDLP concentrations | ||||||
| Total HDLP | 1.28 (0.96-1.69) | .087 | 1.13 (0.86-1.48) | .395 | 2.12 (1.47-3.07)* | <.001 |
| HDLP subclasses | ||||||
| Large HDLP | 0.95 (0.68-1.32) | .744 | 0.88 (0.62-1.23) | .447 | 0.95 (0.63-1.43) | .796 |
| Medium HDLP | 0.90 (0.70-1.17) | .439 | .99 (.76-1.29) | .944 | .99 (.70-1.41) | .969 |
| Small HDLP | 1.37 (1.02-1.84)* | .036 | 1.09 (0.83-1.44) | .522 | 2.75 (1.76-4.31)* | <.001 |
| Mean lipoprotein sizes | ||||||
| TRL size | 1.14 (0.83-1.55) | .421 | 0.98 (0.71-1.34) | .889 | 1.01 (0.69-1.48) | .942 |
| LDL size | 0.75 (0.52-1.10) | .146 | 0.74 (0.50-1.10) | .138 | 0.80 (0.50-1.28) | .353 |
| HDL size | 0.94 (0.67-1.31) | .698 | 0.97 (0.70-1.36) | .877 | 0.93 (0.60-1.43) | .744 |
| Conventional lipoprotein cholesterol and ApoB measurements | ||||||
| TC | 1.58 (1.15-2.17)* | .005 | 1.18 (0.86-1.62) | .296 | 2.40 (1.63-3.55)* | <.001 |
| LDL-C | 1.50 (1.09-2.08)* | .014 | 1.10 (0.80-1.50) | .573 | 1.96 (1.33-2.90)* | .001 |
| HDL-C | 1.00 (0.71-1.41) | .999 | 1.03 (0.73-1.45) | .878 | 1.43 (0.93-2.19) | .101 |
| TGs | 1.71 (1.22-2.40)* | .002 | 1.33 (0.94-1.87) | .107 | 1.97 (1.31-2.96)* | .001 |
| ApoB | 1.93 (1.36-2.75)* | <.001 | 1.52 (1.07-2.16)* | .019 | 2.90 (1.92-4.37)* | <.001 |
| Lipoprotein biomarkers of insulin resistance | ||||||
| Lipoprotein Insulin Resistance Index | 1.29 (0.92-1.80) | .140 | 1.02 (0.72-1.43) | .926 | 1.16 (0.76-1.78) | .482 |
| TGs/HDL-C ratio | 1.55 (1.08-2.22)* | .017 | 1.24 (0.86-1.79) | .243 | 1.52 (0.99-2.33) | .057 |
The Lipoprotein Insulin Resistance Index has no units and varies between 0 and 100; the higher the score the more insulin resistant the individual.
Abbreviations: ApoB, apolipoprotein B; CS, Cushing syndrome; HDL-C, high-density lipoprotein cholesterol; HDLP, high-density lipoprotein particle; LDL-C, low-density lipoprotein cholesterol; LDLP, low-density lipoprotein particle; MACS, mild autonomous cortisol secretion; NFA, nonfunctioning adenoma; TC, total cholesterol; TGs, triglycerides; TRLP, triglyceride-rich lipoprotein particles.
Figure 4.
Lipoprotein particles in patient groups not on lipid-lowering therapy as compared to referent individuals. Age, sex, BMI, hypertension, type 2 diabetes, smoking, and lipid-reduction therapy–adjusted odds ratio with 95% CIs. ApoB, apolipoprotein B; BMI, body mass index; CS, Cushing syndrome; HDL-C, high-density lipoprotein cholesterol; HDLP, high-density lipoprotein particle; L, large; LDL-C, low-density lipoprotein cholesterol; LDLP, low-density lipoprotein particle; M, medium; MACS, mild autonomous cortisol secretion; NFA, nonfunctioning adenoma; S, small; TC, total cholesterol; TG, triglycerides; TRLP, triglyceride-rich lipoprotein particle; VL, very large.
Of the conventional (apo)lipoprotein and lipid measurements, plasma TGs and ApoB were increased in all patient groups, whereas TC and LDL-C were higher in patients with NFA and CS in age- and sex-adjusted analysis. HDL-C was decreased in patients with NFA and MACS (see Table 3, Fig. 2). In fully adjusted analysis, ApoB, TC, and LDL-C were significantly elevated in all patient categories, whereas TGs were elevated in patients with NFA and CS (see Table 4, Fig. 3). HDL-C was not different between NFA and MACS patients but was higher in CS vs referent participants in this analysis (see Table 4, Fig. 3). In the analysis excluding individuals on statin and other lipid-lowering drug therapy, ApoB levels and LDLP remained elevated in all 3 patient groups in fully adjusted analysis (see Table 5, Fig. 4). TC and LDL-C levels were higher in patients with NFA and CS in this analysis, whereas HDL-C was similar in all patient categories vs referent participants.
When examining associations between postdexamethasone cortisol concentrations and lipid biomarkers in patients not treated with lipid-lowering therapy, only total HDLP (r = .16; P = .007) and small HDLP (r = .1; P = .049) were statistically significant (supplemental data reference No. 25856245) (32).
Discussion
In the present study we have comprehensively evaluated detailed lipoprotein profiles in a large cohort of patients with nonfunctioning and cortisol-secreting adrenal adenomas compared to referent individuals recruited from the same region of the United States. Here we report increases in LDL-C, LDLP, and ApoB in all 3 patient categories of NFA, MACS, and CS after adjustment for multiple factors. Predominance of small LDLP was also noted irrespective of cortisol secretion, though statistically significant elevations were noted mainly in patients with NFA and CS. Similar atherogenic lipid profile changes consisting of elevated LDLP and ApoB were also noted in all patient groups after excluding individuals on lipid-lowering drug treatment. Combined, our present results demonstrate dyslipidemia not only in patients with mild and overt excess cortisol secretion but also in patients with NFAs, independent of metabolic comorbidities and irrespective of lipid-lowering drug therapy, which may account for an increased prevalence of cardiovascular disease in patients with NFA, MACS, and CS.
In line with other studies, patients with NFA, MACS, and CS were more likely to be obese, to have hypertension and dysglycemia, and to have experienced a cardiovascular event when compared to the referent population (4-15). Notably, the referent population comprised individuals from the United States who had undergone abdominal imaging that did not reveal an adrenal incidentaloma, thus eliminating the imaging bias. We noted elevated plasma TGs with increases in very large and large TRLP in all 3 patient categories in age- and sex-adjusted analysis. This is likely attributable, at least in part, to the higher prevalence of metabolic comorbidities in these patients. It may also contribute to the modulation of LDLP, resulting in an increase in small-dense LDLP. Using similar NMR methodology, we have previously shown that larger TRLP and smaller LDLP concentrations are higher in individuals with preexisting and new-onset diabetes (33, 34). Using more conventional lipoprotein subfraction assays, larger TRLP are known to be elevated in diabetes and abdominal obesity, consequent to enhanced hepatic TG production and impaired clearance (35-38). Concordant with the effect of metabolic comorbidities on TRLP subfraction distribution, larger TRLP concentrations and TRL size were not increased in any of the patient groups when compared to the referent population after further adjustment for BMI and prevalent diabetes, but small LDLP remained elevated in patients with NFA and CS. Higher TGs and LDL-C levels have been reported in overt hypercortisolism (39). Remarkably, the alterations in TRL and LDL subfraction distributions were not exaggerated in CS patients, although the plasma TGs and LDL-C levels tended to be higher than in patients with NFA and MACS. In comparison, a small-scale study showed only modest plasma TG elevations in women with CS compared to age- and body fat distribution–matched control individuals, which was ascribed to enhanced TG production rather than to impaired clearance (40).
The most salient and robust finding of the present study is the increase in the total LDLP concentration in all 3 patient groups in all analyses, coinciding with similarly consistent ApoB elevations. Plasma TC and LDL-C levels were also elevated in patients with NFA and CS but not in patients with MACS in fully adjusted analysis, as well as after excluding participants on lipid-lowering drug treatment. The causal relationship of LDL-C with atherosclerotic cardiovascular disease is well established (41). Small LDLP may outperform LDL-C in predicting myocardial infarction (42), whereas the association of ApoB with new-onset cardiovascular disease is (at least) as strong as that with LDL-C (43-45). Moreover, though not unequivocally reported, the association of incident coronary heart disease with LDLP concentration as compared to conventional lipid measures may result in some improvement in net reclassification (46, 47). In addition, small LDLP and a smaller LDL size are associated with incident diabetes (33, 48). LDLP, in particular small LDLP, may also predict new-onset hypertension (49). Of interest, such LDLP and ApoB elevations were similar in patients with NFA compared to those with MACS and CS. We surmise that higher LDL concentrations may contribute to an increased risk of cardiovascular morbidity (6, 8, 12, 18), as well as higher overall and cardiovascular mortality, as recently demonstrated in a retrospective, large-scale, case-control study from Sweden (14).
HDL-C was decreased with concomitant decreases in large HDLP and a smaller HDL size, but the total HDLP concentration was not decreased in patients with NFA and MACS in age- and sex-adjusted analysis. These differences in HDL variables in patients with NFA and MACS were no longer present in fully adjusted analyses. These findings again point to the effect of metabolic disturbances on HDL metabolism as both diabetes and obesity are associated with lower HDL-C and smaller HDL size (35, 36, 50, 51), whereas lower HDL-C and small HDLP may confer a higher risk of hypertension (50). Variable increases in HDL-C have been reported in CS without much change in lipoprotein lipase and hepatic lipase activity (39, 40). In a randomized study among patients with secondary adrenal insufficiency, we have previously demonstrated that doubling of the glucocorticoid replacement dose increases HDL-C along with an increase in estimated HDL size (52). Since glucocorticoids are able to downregulate cholesteryl ester transfer protein (CETP) expression in vitro, and the increase in estimated HDL size was found to be related to a decrease in plasma CETP activity (52), an inhibitory effect on CETP may confer a plausible mechanism to explain at least in part changes in HDL with cortisol excess. In the present study, increases in HDL-C in patients with CS did not reach statistical significance. Notably, we demonstrated here for the first time that the total HDLP concentration is elevated in patients with CS, which is attributable to an increase in small HDLP, and these findings remained statistically significant in fully adjusted analysis as well as after excluding individuals using lipid-lowering drug treatment. Evidence is accumulating that lower total HDLP concentrations are more consistently associated with the risk of myocardial infarction and ischemic stroke than lower HDL-C (53). Furthermore, a recent meta-analysis making use of the same NMR methodology and LP4 algorithm as used in this report demonstrated that small- and medium-sized HDLP are in particular associated with an attenuated risk of myocardial infarction, outperforming HDL-C (53) (54). On the other hand, increased large HDLP, decreased small HDLP, and a greater HDL size were found to be associated with lower risk of new-onset diabetes (48, 50). As inferred from fully adjusted analysis, this would theoretically raise the possibility that the elevations in total HDLP and small HDLP could attenuate cardiovascular risk while conversely aggravating diabetes risk in patients with CS.
The mechanisms responsible for the higher prevalence of cardiometabolic comorbidities and their coinciding lipoprotein abnormalities, in particular those regarding large TRLP and small LDL, in patients with NFA and MACS are incompletely understood. One overarching hypothesis is that insulin resistance is enhanced not only in CS but also in adenomas with more subtle cortisol secretion (55). HOMA-IR values have been reported to be elevated even in NFA (56). As insulin measurements were not available in the present study, we used lipid biomarker proxies of insulin resistance. The LP-IR index and the TGs/HDL-C ratio were both indeed elevated in all 3 patient categories in age- and sex-analysis in support of an association between adrenal cortical tumors and insulin resistance, likely irrespective of cortisol excess. Adrenal adenomas could elicit insulin resistance via several pathways including glucocorticoid-mediated enhanced fatty acid availability, resulting in mitochondrial/oxidative stress and impaired insulin action via the insulin receptor substrate acting downstream from the insulin tyrosine kinase receptor (55). However, the mechanisms responsible for the increases in LDLP and ApoB in patients with NFA, MACS, and CS remain unclear. Among other possibilities, alterations in the proprotein convertase subtilisin/kexin type (PCSK9) system, a key regulatory pathway in LDL metabolism (57, 58), could play a contributory role.
Our study has several strengths and limitations. As we used NMR spectroscopy to characterize the lipoprotein profile in patients with adrenal adenomas, we were able to detail subtle trends and differences that are not possible to assess using conventional lipid profiles. We included a large cohort of referent participants without adrenal tumors confirmed on available abdominal imaging. As the vast majority of patients with NFA and MACS are found incidentally, it was essential to rule out unknown adrenal incidentalomas in our referent population. With this approach we were able to eliminate any imaging bias. Limitations may include referral and selection bias. A vast majority of our participants were White, thus making it difficult to extrapolate the findings of this study to individuals of other ethnicities. Moreover, the cross-sectional design of our study does not allow us to draw conclusions regarding cause-effect relationships.
In conclusion, this large-scale study demonstrates increases in LDLP and ApoB concentrations not only in patients with overt and mild cortisol excess but also in patients with NFAs. The present study thus broadens the evidence that NFAs are not metabolically benign and are associated with an abnormal lipoprotein profile that increases cardiovascular risk that may warrant LDL-lowering treatment in all groups of patients with adrenal cortical adenomas.
Abbreviations
- ApoB
apolipoprotein B
- CETP
cholesteryl ester transfer protein
- CS
Cushing syndrome
- DST
dexamethasone suppression test
- HDL-C
high-density lipoprotein cholesterol
- HDLP
high-density lipoprotein particle
- HOMA-IR
homeostasis model assessment of insulin resistance
- IQR
interquartile range
- LDL-C
low-density lipoprotein cholesterol
- LDLP
low-density lipoprotein particle
- LP-IR
Lipoprotein Insulin Resistance
- MACS
mild autonomous cortisol secretion
- NFA
nonfunctioning adenoma
- NMR
nuclear magnetic resonance
- OR
odds ratio
- TC
total cholesterol
- TGs
triglycerides
- TRLP
triglyceride-rich lipoprotein particles
Contributor Information
Rashi Sandooja, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.
Jasmine Saini, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.
Annop Kittithaworn, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.
Raul Gregg-Garcia, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA; Department of Internal Medicine, Indiana University, Indianapolis, IN 46202, USA.
Prerna Dogra, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA; Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53705, USA.
Elizabeth Atkinson, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN 55905, USA.
Kai Yu, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA; Division of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Vanessa Fell, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.
Vinaya Simha, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.
Margery A Connelly, Labcorp, Morrisville, NC 27560, USA.
Robin P F Dullaart, Department of Internal Medicine, Division of Endocrinology, University of Groningen and University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, Netherlands.
Irina Bancos, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.
Funding
This work was partly supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) USA (under award Nos. K23DK121888 and R03DK132121 to I.B). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Disclosures
I.B. reports advisory board participation/consulting (fees to institution) with HRA Pharma, Corcept, Recordati, Xeris, Novo Nordisk, AstraZeneca, Sparrow Pharmaceutics, Neurocrine, Spruce, and Diurnal outside the submitted work, and data monitoring and safety board participation for Adrenas. I.B. also reports funding for investigator-initiated research (outside this work) from HRA Pharma and Recordati. M.C. is an employee of Labcorp. The remainder of the authors have nothing to disclose.
Data Availability
Some or all data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding authors on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Citations
- Sandooja R. Supplementary data.docx. 2024, figshare.
Data Availability Statement
Some or all data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding authors on reasonable request.
