Outcomes analysis of surgical and medical treatments for patients with primary aldosteronism.

Patients with aldosterone-producing adenomas are treated using surgery, and patients with idiopathic hyperaldosteronism receive medical treatment using mineralocorticoid receptor antagonists (MRAs). However, the outcomes of surgical and medical treatment for primary aldosteronism (PA) remain unclear. Therefore, we compared the outcomes of surgical and medical treatment for PA and aimed to identify a specific subgroup that might benefit from medical treatment. We identified 269 patients who were treated for PA (unilateral excess: 221 cases; bilateral excess: 48 cases) during 2000-2015 at the Seoul National University Hospital and two other tertiary centers. The main outcomes were the amelioration of hypertension and hypokalemia. Treatment improved hypertension in the surgical treatment group (78.2%) and the medical treatment group (55.6%) (p = 0.001). At the last follow-up, hypokalemia was normalized in the surgical treatment group (97.1%) and the medical treatment group (93.7%, p = 0.046). Among patients with unilateral aldosterone excess, surgery provided advantages in resolving hypertension without worsening renal function. Among patients who were >60 years old or had impaired renal function, surgical and medical treatment provided similar amelioration of hypokalemia and hypertension. Three patients developed hyperkalemia after surgery, and no patients developed hyperkalemia after initiating medical treatment. The surgical treatment group exhibited a lower postoperative estimated glomerular filtration rate (eGFR) and higher serum potassium levels, compared to the medical treatment group. Surgical treatment provided better hypertension and hypokalemia outcomes among patients with PA, compared to medical treatment. However, MRAs may be appropriate for elderly patients with impaired renal function.

Clinical characteristics of the responders to dipeptidyl peptidase-4 inhibitors in Korean subjects with type 2 diabetes.

We investigated characteristics associated with the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4i) in Korean patients with type 2 diabetes. We reviewed medical records of 477 patients who had taken sitagliptin or vildagliptin longer than 40 weeks. Response to DPP4i was evaluated with HbA1c change after therapy (ΔHbA1c). The Student's t-test between good responders (GR: ΔHbA1c > 1.0%) and poor responders (PR: ΔHbA1c < 0.5%), a correlation analysis among clinical parameters, and a linear multivariate regression analysis were performed. The mean age was 60 yr, duration of diabetes 11 yr and HbA1c was 8.1%. Baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and creatinine were significantly higher in the GR compared to the PR. Duration of diabetes, FPG, HbA1c, C-peptide and creatinine were significantly correlated with ΔHbA1c. In the multivariate analysis, age (r(2) = 0.006), duration of diabetes (r(2) = 0.019), HbA1c (r(2) = 0.296), and creatinine levels (r(2) = 0.024) were independent predictors for the response to DPP4i. Body mass index and insulin resistance were not associated with the response to DPP4i. In conclusion, better response to DPP4i would be expected in Korean patients with type 2 diabetes who have higher baseline HbA1c and creatinine levels with shorter duration of diabetes.

Stimulated Salivary Cortisol as a Noninvasive Diagnostic Tool for Adrenal Insufficiency.

BACKGROUND: Salivary cortisol is routinely used as a diagnostic test for Cushing syndrome. The diagnostic use of salivary cortisol for adrenal insufficiency (AI), however, is less established. We aimed to investigate the utility of morning basal and adrenocorticotropic hormone-stimulated salivary cortisol in diagnosing AI in Korean adults. METHODS: We prospectively included 120 subjects (female, n=70) from Seoul National University Hospital. AI was defined as a stimulated serum cortisol level of <496.8 nmol/L during the short Synacthen test (SST). Serum and saliva samples were drawn between 8:00 AM and 10:00 AM. Salivary cortisol levels were measured using an enzyme immunoassay kit. RESULTS: Thirty-four patients were diagnosed with AI according to the SST results. Age, sex, body mass index, serum albumin levels, and serum creatinine levels did not significantly differ between the normal and AI groups. Basal and stimulated salivary cortisol levels were positively correlated with basal (r=0.538) and stimulated serum cortisol levels (r=0.750), respectively (all P<0.001). Receiver operating characteristic curve analysis yielded a cutoff level of morning basal salivary cortisol of 3.2 nmol/L (sensitivity, 84.9%; specificity, 73.5%; area under the curve [AUC]=0.822). The optimal cutoff value of stimulated salivary cortisol was 13.2 nmol/L (sensitivity, 90.7%; specificity, 94.1%; AUC=0.959). Subjects with a stimulated salivary cortisol level above 13.2 nmol/L but a stimulated serum cortisol level below 496.8 nmol/L (n=2) had lower serum albumin levels than those showing a concordant response. CONCLUSION: The diagnostic performance of stimulated salivary cortisol measurements after the SST was comparable to serum cortisol measurements for diagnosing AI.

Vildagliptin reduces plasma stromal cell-derived factor-1α in patients with type 2 diabetes compared with glimepiride.

AIMS/INTRODUCTION: Dipeptidyl peptidase-4 inhibitors might have pleiotropic protective effects on cardiovascular disease (CVD), in contrast to sulfonylureas. Therefore, we compared various CVD risk factors between vildagliptin and glimepiride. MATERIALS AND METHODS: We carried out a randomized, prospective and crossover trial. A total of 16 patients with type 2 diabetes whose glycated hemoglobin was >7% were randomized to add vildagliptin or glimepiride. After 12-week treatment, each drug was replaced with the other for another 12 weeks. Before and after each treatment, glucose homeostasis and CVD risk factors were assessed, and the continuous glucose monitoring system was applied to calculate glycemic variability. RESULTS: The mean age of the participants was 60 years, 31% were men, body mass index 25.5 kg/m2 and HbA1c 8.41%. Both vildagliptin and glimepiride significantly decreased glycated hemoglobin and glycemic variability indices. Despite the improved glucose homeostasis, favorable change of CVD markers was not prominent in both the arms, along with significant weight gain. Only plasma stromal cell-derived factor (SDF)-1α decreased by 30% in the vildagliptin arm. According to regression analyses, the reduction of SDF-1α was independently associated with vildagliptin usage and serum interleukin-6 changes, but white blood cells were not related with the SDF-1α changes. CONCLUSION: Compared with glimepiride, vildagliptin arrestingly decreased plasma SDF-1α, and its clinical implications should be further investigated.

Optimal follow-up strategies for adrenal incidentalomas: reappraisal of the 2016 ESE-ENSAT guidelines in real clinical practice.

OBJECTIVE: Recently, the European Society of Endocrinology (ESE), in collaboration with the European Network for the Study of Adrenal Tumors (ENSAT), asserted that adrenal incidentalomas (AIs) <4 cm and ≤10 Hounsfield units (HU) do not require further follow-up imaging. To validate the clinical application of the follow-up strategies suggested by the 2016 ESE-ENSAT guidelines, we explored the clinical characteristics and natural course of AIs in a single center over 13 years. DESIGN AND METHODS: This retrospective cohort study included a total of 1149 patients diagnosed with AIs between 2000 and 2013 in a single tertiary center. Hormonal examination and radiological evaluations were performed at the initial diagnosis of AI and during the follow-up according to the appropriate guidelines. RESULTS: The mean age at diagnosis was 54.2 years, and the majority of AIs (68.0%) were nonfunctional lesions. Receiver operating curve analysis was used to discriminate malignant from benign lesions; the optimal cut-off value for mass size was 3.4 cm (sensitivity: 100%; specificity: 95.0%), and that for the pre-contrast HU was 19.9 (sensitivity: 100%; specificity: 67.4%). The majority of nonfunctional lesions did not change in size during the 4-year follow-up period. Applying a cut-off value of 1.8 µg/dL after a 1-mg overnight dexamethasone suppression test, 28.0% of all nonfunctional AIs progressed to autonomous cortisol secretion during the follow-up period. However, we observed no development of overt Cushing's syndrome in the study. CONCLUSIONS: We advocate that no follow-up imaging is required if the detected adrenal mass is <4 cm and has clear benign features. However, prospective studies with longer follow-up are needed to confirm the appropriate follow-up strategies.

Diagnostic Role of Captopril Challenge Test in Korean Subjects with High Aldosterone-to-Renin Ratios.

BACKGROUND: Diagnosis of primary aldosteronism (PA) begins with aldosterone-to-renin ratio (ARR) measurement followed by confirmative tests. However, the ARR has high false positive rates which led to unnecessary confirmatory tests. Captopril challenge test (CCT) has been used as one of confirmatory tests, but the accuracy of it in the diagnosis of PA is still controversial. We aimed to examine the clinical efficacy of CCT as a post-screening test in PA. METHODS: In a prospective study, we enrolled subjects with suspected PA who had hypertension and ARR >20 (ng/dL)/(ng/mL/hr). Sixty-four patients who underwent both the saline infusion test and the CCT were included. RESULTS: The diagnostic performance of plasma aldosterone concentration (PAC) post-CCT was greater than that of ARR post-CCT and ARR pre-CCT in PA (area under the curve=0.956, 0.797, and 0.748, respectively; P=0.001). A cut-off value of 13 ng/dL showed the highest diagnostic odds ratio considering PAC post-CCT at 60 and 90 minutes. A PAC post-CCT of 19 ng/dL had a specificity of 100%, which can be used as a cut-off value for the confirmative test. Determining the diagnostic performance of PAC post-CCT at 90 minutes was sufficient for PA diagnosis. Subjects with PAC post-CCT at 90 minutes <13 ng/dL are less likely to have PA, and those with PAC post-CCT at 90 minutes ≥13 but <19 ng/dL should undergo secondary confirmatory tests. CONCLUSION: The CCT test may be a reliable post-screening test to avoid the hospitalization in the setting of falsely elevated ARR screening tests.

Comparison between two methods of bioelectrical impedance analyses for accuracy in measuring abdominal visceral fat area.

OBJECTIVES: To compare the accuracy of abdominal visceral fat area (VFA) measurements between abdominal dual bioelectrical impedance analysis (BIA) and whole-body BIA referenced to computed tomography (CT) measures. METHODS: Abdominal VFAs were measured in 102 individuals: 59 men and 43 women with a mean age of 44.2 ± 16.3 years (range 21 - 76), body mass index 23.9 ± 7.8 kg/m(2) (range 18 - 35) using a DUALSCAN HDS-2000 machine (dual abdominal BIA) and an InBody720 machine (whole-body BIA). The VFA values from each machine were compared with those from CT under various conditions. RESULTS: Mean abdominal VFAs were 116 ± 69 cm(2) by CT, 89 ± 47 cm(2) by dual abdominal BIA, and 84 ± 33 cm(2) by whole-body BIA. The former measure showed a higher correlation with the CT measure than the latter (r=0.89 vs. r=0.64, P<0.001). Both BIA methods tended to underestimate abdominal VFAs compared with CT scans when CT VFA was not small. The dual abdominal BIA had less bias than the whole-body BIA in the assessment of VFAs. The whole-body BIA was affected by subcutaneous fat area. CONCLUSIONS: Dual BIA was more accurate in assessing abdominal VFA than whole-body BIA.

Serum bilirubin levels are positively associated with glycemic variability in women with type 2 diabetes.

AIMS/INTRODUCTION: Glycemic variability is known to induce oxidative stress. We investigated the relationships between glycemic variability and serum bilirubin levels, an endogenous anti-oxidant, in patients with diabetes. MATERIALS AND METHODS: A cross-sectional study was carried out with 77 patients with type 2 diabetes who had been recruited to two clinical studies from 2008 to 2014. There were no participants with diseases of the pancreas, liver, biliary tract and chronic renal insufficiency. Glycemic variation was calculated by a continuous glucose monitoring system, and correlation analyses were carried out to evaluate their association with bilirubin levels. Multiple linear regression was carried out to identify independent factors influencing bilirubin levels and glycemic variation. RESULTS: Among the participants, 42.3% were men. The mean (standard deviation) age was 61.5 years (10.4 years), body mass index was 24.2 kg/m2 (2.8 kg/m2 ), diabetes duration was 17.7 years (9.5 years), hemoglobin A1c was 60.7 mmol/mol (7.1 mmol/mol; 7.7 [0.7]%) and bilirubin was 11.8 µmol/L (4.10 µmol/L). Serum bilirubin levels were not different according to age, body mass index and hemoglobin A1c . However, the mean amplitude of glucose excursion was positively associated with bilirubin levels in women (r = 0.588, P < 0.001). After adjustment with duration of diabetes, serum albumin, liver enzymes, and mean glucose, the correlation between bilirubin and mean amplitude of glucose excursion remained significant (r = 0.566, P < 0.001). Multiple linear regression analyses showed that bilirubin was an independent determinant for the mean amplitude of glucose excursion in women. 1,5-Anhydroglucitol was also associated with bilirubin levels in women. CONCLUSIONS: Bilirubin level within the physiological range might be an independent predictor for glycemic variability in women with type 2 diabetes.

Characterization of Patients with Type 2 Diabetes according to Body Mass Index: Korea National Health and Nutrition Examination Survey from 2007 to 2011.

BACKGROUND: The present study aimed to investigate the clinical characteristics of type 2 diabetes mellitus (T2DM) in Korean adults according to body mass index (BMI) and to analyze the association with cardiovascular disease (CVD). METHODS: We conducted a cross-sectional study of data from the Korea National Health and Nutrition Examination Survey from 2007 to 2011. A total of 3,370 patients with T2DM were divided into categories according to BMI. We conducted a comparison of the T2DM patient population composition by BMI category between different countries. We investigated the prevalence of awareness, treatment, and target control of T2DM according to BMI. RESULTS: Patients with T2DM had a higher BMI, and were more likely to have a history of CVD than healthy controls. For Korean adults with T2DM, 8% had BMI ≥30 kg/m². By contrast, the population of patients with T2DM and BMI ≥30 kg/m² was 72% in patients in the USA and 56% in the UK. The rate of recognition, treatment, and control has worsened in parallel with increasing BMI. Even in patients with BMI 25 to 29.9 kg/m², the prevalence of CVD or high risk factors for CVD was significantly higher than in patients with BMI 18.5 to 22.9 kg/m² (odds ratio, 2.07). CONCLUSION: Korean patients with T2DM had lower BMI than those in Western countries. Higher BMI was associated with lower awareness, treatment, and control of diabetes, and a positive association was observed between CVD or high risk factors for CVD and BMI, even for patients who were overweight but not obese.

Efficacy of a New Medical Information system, Ubiquitous Healthcare Service with Voice Inception Technique in Elderly Diabetic Patients.

We have demonstrated previously that an individualized health management system using advanced medical information technology, named ubiquitous (u)-healthcare, was helpful in achieving better glycemic control than routine care. Recently, we generated a new u-healthcare system using a voice inception technique for elderly diabetic patients to communicate information about their glucose control, physical activity, and diet more easily. In a randomized clinical trial, 70 diabetic patients aged 60-85 years were assigned randomly to a standard care group or u-healthcare group for 6 months. The primary end points were the changes in glycated hemoglobin (HbA1c) and glucose fluctuation assessed by the mean amplitude glycemic excursion (MAGE). Changes in body weight, lifestyle, and knowledge about diabetes were also investigated. After 6 months, the HbA1c levels decreased significantly in the u-healthcare group (from 8.6 ± 1.0% to 7.5 ± 0.6%) compared with the standard care group (from 8.7 ± 0.9% to 8.2 ± 1.1%, P < 0.01). The MAGE decreased more in the u-healthcare group than in the standard care group. Systolic blood pressure and body weight decreased and liver functions improved in the u-healthcare group, but not in the standard care group. The u-healthcare system with voice inception technique was effective in achieving glycemic control without hypoglycemia in elderly diabetic patients (Clinicaltrials.gov: NCT01891474).

Comparison of Abdominal Visceral Adipose Tissue Area Measured by Computed Tomography with That Estimated by Bioelectrical Impedance Analysis Method in Korean Subjects.

We evaluated the concordance between visceral fat area (VFA) estimated by bioelectrical impedance analysis (BIA) or computed tomography (CT) in Korean subjects with a wide range in age and body mass index (BMI). In 1006 individuals (mean age 55.2 ± 11.8 (19-87) years, mean BMI 26.0 ± 3.5 (17-46) kg/m², 48.9% men), VFA quantified by CT was compared with VFA using multifrequency BIA machines within 15 days. Concordance rates were compared by age or BMI using correlation analysis, Bland-Altman plots, and intraclass correlation coefficient (ICC). Using BIA data, we established a regression formula to reflect CT-VFA. The mean VFAs by CT and BIA were 131.9 ± 57.3 cm² and 110.5 ± 33.9 cm², respectively (r = 0.605, p < 0.001). The mean difference was 21.4 ± 45.6 cm², tending to increase with BMI. In women with BMI <25 kg/m² or age <50 years, the VFAs by BIA were similar to those by CT (ICC = 0.496 in BMI <25 kg/m² and ICC = 0.638 in age <50 years). However, the difference was greater in men with BMI ≥25 kg/m² or age ≥50 years. Applying our formula, the difference between estimations decreased to 0.2 ± 38.2cm². VFA estimated by BIA correlated well with that by CT, but a more accurate formula is needed to match CT data, particularly in older men or subjects with a high BMI.

Clinical Characteristics and Metabolic Predictors of Rapid Responders to Dipeptidyl Peptidase-4 Inhibitor as an Add-on Therapy to Sulfonylurea and Metformin.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitor add-on therapy is a new option for patients with inadequately controlled type 2 diabetes who are taking combined metformin and sulfonylurea (SU). We evaluated the efficacy and safety of this triple therapy and the characteristics of rapid responders and hypoglycemia-prone patients. METHODS: We included 807 patients with type 2 diabetes who were prescribed a newly added DPP-4 inhibitor to ongoing metformin and SU in 2009 to 2011. Glycemia and other metabolic parameters at baseline, 12, 24, and 52 weeks, as well as episodes of hypoglycemia were analyzed. Rapid responders were defined as patients with ≥25% reduction in glycosylated hemoglobin (HbA1c) within 12 weeks. RESULTS: At baseline, while on the submaximal metformin and SU combination, the mean HbA1c level was 8.4%. Twelve weeks after initiation of DPP-4 inhibitor add-on, 269 patients (34.4%) achieved an HbA1c level ≤7%. Sixty-six patients (8.2%, 47 men) were rapid responders. The duration of diabetes was shorter in rapid responders, and their baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and homeostasis model assessment of insulin resistance were significantly higher. Patients who experienced hypoglycemia after taking DPP-4 inhibitor add-on were more likely to be female, to have a lower body weight and lower triglyceride and FPG levels, and to have higher homeostasis model assessment of ß-cells. CONCLUSION: An oral hypoglycemic triple agent combination including a DPP-4 inhibitor was effective in patients with uncontrolled diabetes. Proactive dose reduction of SU should be considered when a DPP-4 inhibitor is added for rapid responders and hypoglycemia-prone patients.

Limited Diagnostic Utility of Plasma Adrenocorticotropic Hormone for Differentiation between Adrenal Cushing Syndrome and Cushing Disease.

BACKGROUND: Measurement of the plasma adrenocorticotropic hormone (ACTH) level has been recommended as the first diagnostic test for differentiating between ACTH-independent Cushing syndrome (CS) and ACTH-dependent CS. When plasma ACTH values are inconclusive, a differential diagnosis of CS can be made based upon measurement of the serum dehydroepiandrosterone sulfate (DHEA-S) level and results of the high-dose dexamethasone suppression test (HDST). The aim of this study was to assess the utility of plasma ACTH to differentiate adrenal CS from Cushing' disease (CD) and compare it with that of the HDST results and serum DHEA-S level. METHODS: We performed a retrospective, multicenter study from January 2000 to May 2012 involving 92 patients with endogenous CS. The levels of plasma ACTH, serum cortisol, 24-hour urine free cortisol (UFC) after the HDST, and serum DHEA-S were measured. RESULTS: Fifty-seven patients had adrenal CS and 35 patients had CD. The area under the curve of plasma ACTH, serum DHEA-S, percentage suppression of serum cortisol, and UFC after HDST were 0.954, 0.841, 0.950, and 0.997, respectively (all P<0.001). The cut-off values for plasma ACTH, percentage suppression of serum cortisol, and UFC after HDST were 5.3 pmol/L, 33.3%, and 61.6%, respectively. The sensitivity and specificity of plasma ACTH measurement were 84.2% and 94.3%, those of serum cortisol were 95.8% and 90.6%, and those of UFC after the HDST were 97.9% and 96.7%, respectively. CONCLUSION: Significant overlap in plasma ACTH levels was seen between patients with adrenal CS and those with CD. The HDST may be useful in differentiating between these forms of the disease, especially when the plasma ACTH level alone is not conclusive.

Clinical risk factors of postoperative hyperkalemia after adrenalectomy in patients with aldosterone-producing adenoma.

OBJECTIVE: Unilateral adrenalectomy is the first-line treatment for aldosterone-producing adenomas (APA). Hyperkalemia after adrenalectomy because of contralateral zona glomerulosa insufficiency has been reported. We investigated clinical risk factors to predict postoperative hyperkalemia in patients with APA undergoing adrenalectomy. DESIGN AND METHODS: This study was conducted by retrospectively reviewing medical records from 2000 to 2012 at Seoul National University Hospital and two other tertiary centers. Data from 124 patients who underwent adrenalectomy were included. Hyperkalemia was defined as serum potassium >5.5 mmol/l. Clinical preoperative risk factors included age, blood pressure, plasma renin activity (PRA), plasma aldosterone concentration (PAC), serum potassium, serum creatinine, glomerular filtration rate (GFR), the mass size on pathology, and mineralocorticoid receptor (MR) antagonist use. RESULTS: Out of 124 patients, 13 (10.5%) developed postoperative hyperkalemia. The incidences of transient and persistent hyperkalemia were 3.2 and 7.3% respectively. Preoperative PRA and PAC were not significantly different in postoperative hyperkalemic patients compared with normokalemic patients. Patients with persistent hyperkalemia were older, had a longer duration of hypertension, larger mass size on pathology, and lower GFR (all P<0.05). The incidence of postoperative hyperkalemia was not different between MR antagonist users and non-users. CONCLUSION: Older age (≥53 years), longer duration of hypertension (≥9.5 years), larger mass size on pathology (≥1.95 cm), and impaired preoperative renal function (GFR <58.2 ml/min) were associated with prolonged postoperative hyperkalemia in patients with APA. MR antagonist use did not prevent postoperative hyperkalemia.