Use of Electronic Health Records to Characterize a Rare Disease in The U.S.: Treatment,Comorbidities, and Follow-Up Trends Among Patients With a Confirmed Diagnosis of Acromegaly

Objective: Understanding of acromegaly disease management is hampered in the U.S. by the lack of a national registry. We describe medical management in a population with confirmed acromegaly.Methods: Inpatient and outpatient electronic health records (EHRs) were used to create a database of de-identified patients assigned the Acromegaly and Gigantism International Classification of Diseases, 9^th revision (ICD-9) code and/or an appropriate pituitary procedure code at 1 of 4 regional hospital systems over a 6- to 11-year period. Information regarding demographics, medical history, labs, procedures, and medications was collected and supplemented with a chart review to validate the diagnosis of acromegaly.Results: Of 367 patients with validated acromegaly, available records showed that during the years studied, pituitary surgery was performed on 31%, 4% received radiosurgery, and 22% were prescribed a drug indicated for acromegaly. Insulin-like growth factor-1 (IGF-1) levels were measured in 62% of patients, 83% of whom had at least 1 normal value. Coded comorbidities reflect those reported previously in patients with acromegaly, with the exception of esophageal reflux in 20% of patient records. Fewer data regarding acromegaly-specific medications and testing were available for patients aged 65 and older.Conclusion: AcroMEDIC is a U.S. multisite retrospective study of acromegaly that captured medical management in the majority of patients included in the cohort. Chart review highlighted the importance of verification of coded diagnoses. Most of the acromegaly-related comorbidities identified here are known to increase with age and obesity. Patients ≥65 appeared to have less active management/monitoring of their disease. Medical attention should be directed to this population to address evolving needs over time.Abbreviations: AcroMEDIC = Acromegaly Multisite Electronic Data Innovative Consortium; BMI = body mass index; CCI = Charlson Comorbidity Index; EHR = electronic health record; GH = growth hormone; GHRA = growth hormone receptor antagonist; ICD-9 = International Classification of Diseases, 9^th revision; IGF-1 = insulin-like growth factor-1; SSA = somatostatin analogue     

No Benefit of Dedicated Thyroid Nodule Screening in Patients with Acromegaly

Objective: Acromegaly results from the excessive production of growth hormone and insulin-like growth factor-1. While there is up to a 2-fold increased prevalence of thyroid nodules in patients with acromegaly, the incidence of thyroid cancer in this population varies from 1.6 to 10.6% in several European studies. The goal of our study was to determine the prevalence of thyroid nodules and thyroid cancer among patients with acromegaly at a large urban academic medical center in the United States (U.S.).Methods: A retrospective chart review was performed of all patients with acromegaly between 2006–2015 within the University of California, Los Angeles health system. Data were collected regarding patient demographics, thyroid ultrasounds, thyroid nodule fine needle aspiration (FNA) biopsy cytology, and thyroid surgical pathology.Results: In this cohort (n = 221, 49.3% women, mean age 53.8 ± 15.2 [SD] years, 55.2% Caucasian), 102 patients (46.2%) underwent a thyroid ultrasound, from which 71 patients (52.1% women, mean age 52.9 ± 15.2 [SD] years, 56.3% Caucasian) were found to have a thyroid nodule. Seventeen patients underwent a thyroid nodule FNA biopsy and the results revealed 12 benign biopsies, 1 follicular neoplasm, 3 suspicious for malignancy, and 1 papillary thyroid cancer (PTC), from which 6 underwent thyroidectomy; PTC was confirmed by surgical pathology for all cases (8.5% of all nodules observed).Conclusion: In this sample, the prevalence of thyroid cancer in patients with acromegaly and coexisting thyroid nodules is similar to that reported in the general U.S. population with thyroid nodules (7 to 15%). These findings suggest that there is no benefit of dedicated thyroid nodule screening in patients newly diagnosed with acromegaly.Abbreviations: AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; DTC = differentiated thyroid cancer; FNA = fine needle aspiration; GH = growth hormone; IGF-1 = insulin-like growth factor-1; PTC = papillary thyroid cancer; U.S. = United States     

Reduced Impact of Diabetes Clinic Referral on High-Frequency Emergency Department Users

Objective: The patterns of emergency department (ED) visits in patients with diabetes are not well understood. The Emergency Department Diabetes Rapid-referral Program (EDRP) allows direct booking of ED patients presenting with urgent diabetes needs into a diabetes specialty clinic within 1 day of ED discharge. The objective of this secondary analysis was to examine characteristics of patients with diabetes who have frequent ED visits and determine reasons for revisits.Methods: A single-center analysis was conducted comparing patients referred to the EDRP (n = 420) to historical unexposed controls (n = 791). The primary outcome was the proportion of patients in each frequency group of ED revisits (none, 1 to 3 [infrequent], 4 to 10 [frequent], or >10 [superfrequent]) in the year after the ED index visit. Secondary outcomes were hospitalization rates and International Classification of Diseases–Ninth Revision (ICD-9) diagnoses at ED revisits.Results: Superfrequent users, responsible for >20% of total ED visits, made up small but not significantly different proportions of EDRP and control populations, 3.6% and 5.2%, respectively. Superfrequent groups had lower hospital admission rates at ED revisits compared to frequent groups. Mental health disorders (including substance abuse) were the primary, secondary, or tertiary ICD-9 codes in 30.6% (95% confidence interval [CI], 27.7% to 33.5%) and 6.6% (95% CI, 5.1% to 8.2%) in the superfrequent and infrequent groups, respectively.Conclusion: Direct access to diabetes specialty care from the ED is effective in reducing ED recidivism but not amongst a small subgroup of superfrequent ED users. This group was more likely to have mental health disorders recorded at ED revisits, suggesting that more comprehensive approaches are needed for this population.Abbreviations: EDRP = Emergency Department Diabetes Rapid-referral Program; ED = emergency department; HbA1c = hemoglobin A1c; ICD-9 = International Classification of Diseases–Ninth Revision     

Does Clinical Inertia Vary By Personalized A1C Goal? A Study Of Predictors And Prevalence Of Clinical Inertia In A U.S. Managed Care Setting

Objective: Clinical inertia is defined as failure to initiate or intensify therapy despite an inadequate treatment response. We assessed the prevalence and identified the predictors of clinical inertia among patients with type 2 diabetes (T2DM) based on personalized goals.Methods: Three hemoglobin A_1c (A1C) targets (American Diabetes Association A1C <7.0%; modified Ismail-Beigi et al; and Healthcare Effectiveness Data and Information Set) were used when identifying adult patients with T2DM who experienced above-target A1C values during the index period (July 1, 2008 to June 30, 2012) in a U.S. managed-care claims database (IMPACT™). Clinical inertia was defined as no intensification of treatment during the response period. Demographic and clinical characteristics were analyzed to identify predictors of treatment intensification.Results: Irrespective of A1C target, the majority of patients with T2DM (70.4 to 72.8%) experienced clinical inertia in the 6 months following the index event, with 5.3 to 6.2% of patients intensifying treatment with insulin. Patients with a lower likelihood of intensification were older, used >1 oral antidiabetes drug during the baseline period, and had an above-target A1C more recently. Treatment intensification was associated with patients who had point-of-service insurance, mental illness, an endocrinologist visit in the baseline period, or higher index A1C.Conclusion: The prevalence of clinical inertia among patients with T2DM in a U.S. managed-care setting is high and has increased over more recent years. Factors predicting increased risk of clinical inertia may help identify “at-risk” populations and assist in developing strategies to improve their management.Abbreviations:A1C = hemoglobin A_1cADA = American Diabetes AssociationCCI = Charlson Comorbidity IndexGLP-1 = glucagon-like peptide 1HEDIS = Healthcare Effectiveness Data and Information SetICD-9-CM = International Classification of Diseases, 9th Revision, Clinical ModificationOAD = oral antidiabetes drugPCPs = primary care physiciansT2DM = type 2 diabetes mellitus     

Identification of Potential Markers for Cushing Disease

Objective: Cushing disease (CD) causes a wide variety of nonspecific symptoms, which may result in delayed diagnosis. It may be possible to uncover unusual combinations of otherwise common symptoms using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Our aim was to identify and evaluate dyads of clinical symptoms or conditions associated with CD.Methods: We conducted a matched case-control study using a commercial healthcare insurance claims database designed to compare the relative risk (RR) of individual conditions and dyad combinations of conditions among patients with CD versus matched non-CD controls.Results: With expert endocrinologist input, we isolated 10 key conditions (localized adiposity, hirsutism, facial plethora, polycystic ovary syndrome, abnormal weight gain, hypokalemia, deep venous thrombosis, muscle weakness, female balding, osteoporosis) with RRs varying from 5.3 for osteoporosis to 61.0 for hirsutism (and infinite RR for localized adiposity). The RRs of dyads of these conditions ranged from 4.1 for psychiatric disorders/serious infections to 128.0 for hirsutism/fatigue in patients with versus without CD. Construction of uncommon dyads resulted in further increases in RRs beyond single condition analyses; for example, osteoporosis alone had an RR of 5.3, which increased to 8.3 with serious infections and to 52.0 with obesity.Conclusion: This study demonstrated that RR of any one of 10 key conditions selected by expert opinion was ≥5 times greater in CD compared to non-CD, and nearly all dyads had RR≥5. An uncommon dyad of osteoporosis and obesity had an RR of 52.0. If clinicians consider the diagnosis of CD when the highest-risk conditions are seen, identification of this rare disease may improve.Abbreviations:CD = Cushing diseaseCPT = Current Procedural TerminologyCS = Cushing syndromeEMR = electronic medical recordICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical ModificationID = identificationRR = relative risk     

Decrease in Acromegaly-Associated Thyroid Enlargement after Normalization of IGF-1 Levels: A Prospective Observation and in Vitro Study

Objective: Goiter occurs at high frequency in acromegaly patients. Whether normalization of insulin-like growth factor 1 (IGF-1) levels could decrease goiter and thyroid volume remains unclear.Methods: Thyroid hormone levels and ultrasound measurements were assessed in 101 acromegaly patients, compared with 108 patients with nonfunctioning pituitary adenoma (NFPA) and 55 healthy controls. Thirty-four acromegaly patients underwent repeat evaluation 1 year post–transsphenoidal surgery. The effect of IGF-1 on thyroid cell proliferation, cell cycle, and apoptosis was evaluated in vitro.Results: Acromegaly patients showed larger thyroid volume than those with NFPAs (18.32 mL vs. 9.91 mL; P<.001) and healthy controls (18.32 mL vs. 9.63 mL; P<.001). Duration of acromegaly was shown to be independently associated with thyroid volume enlargement (B = 0.259; 95% confidence interval, 0.162 to 0.357) in multivariate analysis. At follow-up, the median thyroid volume decreased from 22.74 to 17.87 mL in the cured group (n = 20; P = .003), but the number of nodular goiters showed no significant change. Serum free thyroxine levels decreased from 13.76 to 10.08 pmol/L in the cured group (P = .006) but increased from 9.28 to 12.09 pmol/L in the active group (P = .013). Change in thyroid volume was significantly correlated with IGF-1 level (r = 0.37; P = .029). In vitro, IGF-1 time- and dose-dependently promoted proliferation and secretory function of thyroid cells by enhancing cell cycle shift from the G1/S to G2/M phase and suppressing apoptosis.Conclusion: Acromegaly-associated thyroid volume increase, but not nodular goiter, could be reversed in cured acromegaly. IGF-1 time- and dose-dependently promoted the proliferation and secretory function of thyroid cells.Abbreviations: CCK-8 = Cell Counting Kit-8; fT3 = free triiodothyronine; fT4 = free thyroxine; GH = growth hormone; IGF-1 = insulin-like growth factor 1; MRI = magnetic resonance imaging; NFPA = nonfunctioning pituitary adenoma; qRT-PCR = quantitative real-time–polymerase chain reaction; TSH = thyroid-stimulating hormone     

Trends in the Care and Outcomes of Medicare Beneficiaries with Type 2 Diabetes, 2002–2011

Objective: To summarize characteristics of Medicare beneficiaries with type 2 diabetes and to describe changing trends in care and outcomes.Methods: We conducted a retrospective cohort study of a nationally representative 5% sample of fee-for-service Medicare beneficiaries 65 years and older with prevalent type 2 diabetes, between January 1, 2002, and December 31, 2011. The main outcome measures were diabetes-related screening tests, mortality, hospital admissions, dialysis, and lower extremity amputation.Results: The average age of Medicare beneficiaries with diabetes was 76.5 years, 56% were women, and 83% were white. Screening practices in beneficiaries with diabetes improved from 2002 to 2011, with rising rates of foot exams, renal screening, hemoglobin A1c tests, and lipid profile tests. The prevalence of nephropathy and neuropathy increased. Although inpatient admissions declined from 2002 to 2011, diabetes-related emergency department visits increased. Amputation and end-stage renal disease remained static, while 1-year mortality declined over the study period.Conclusion: In this medically complex group of patients with high comorbidity, we observed improvements in screening practices and room for further improvement. Although the mortality rate decreased, other outcomes did not improve consistently. Health care resource has changed over time, with decreased hospital admissions and increased emergency department visits.Abbreviations:CCW = Chronic Conditions Data WarehouseESRD = end-stage renal diseaseHbA1c = hemoglobin A1cHEDIS = Healthcare Effectiveness Data and Information SetICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification     

Burden of Illness,Annual Healthcare Utilization,and Costs Associated with Commercially Insured Patients with Cushing Disease in The United States

ObjectiveTo describe the burden of illness, healthcare utilization, and costs associated with Cushing disease (CD), a rare disorder resulting from adrenocorticotropic hormone-secreting pituitary tumors, in commercially insured patients in the U.S.MethodsPatients with CD were identified in 2010 in the IMS Health PharMetrics and Truven Health Analytics MarketScan claims databases. Because there is no diagnosis code for CD, patients were identified with a claim for Cushing syndrome and either benign pituitary adenoma or hypophysectomy. We estimated total sand CD-related utilization and costs using pharmacy and medical claims.ResultsWe identified 685 CD patients (81% female; mean age, 41.7 years; mean Charlson comorbidity index, 1.6; mean number of chronic conditions, 4.2); 30.5% of the patients had diabetes, 22.5% had psychiatric disturbances, 21% had infections, 8.6% had osteoporosis, 8% had cardiovascular disease/stroke, 5.5% had kidney stones, and 0.7% had compression fracture of a vertebra. Patients had a mean of 19.8 office visits per year; 38.4% had inpatient hospitalizations and 34.2% visited the emergency department (ED). Patients had a mean of 3.2 CD-related office visits per year; 26.9% had CD-related hospitalizations, 0.9% had CD-related ED visits, and 36.8% had CD treatments. Mean annual total costs were $34,992 (pharmacy, $3,597; medical costs, $31,395). CD-related costs accounted for $14,310 of total costs (CD treatment costs, $9,353; other CD-related costs, $4,957).ConclusionCD patients have a high burden of illness. Among CD patients in this study, 30.5% had diabetes, 22.5% had psychiatric disturbances, 21% had infections, 8.6% had osteoporosis, 8% had cardiovascular disease/ stroke, and 5.5% had kidney stones. Patients had 19.8 office visits per year, and > 34% of patients were hospitalized. Mean total cost of care was approximately $35,000 per year. (Endocr Pract. 2015;21:77-86)     

Ideglira is Associated With Improved Short-Term Clinical Outcomes and Cost Savings Compared With Insulin Glargine U100 Plus Insulin Aspart in the U.S.

Objective: In the DUAL (Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes) VII trial, IDegLira (a combination of insulin degludec and liraglutide) was compared with insulin glargine U100 plus insulin aspart. Both treatment approaches achieved similar glycemic control, but there were differences in hypoglycemia, changes in body weight, and injection frequency. The aim of the present analysis was to assess the short-term cost effectiveness of IDegLira versus insulin glargine U100 plus insulin aspart for treatment of patients with type 2 diabetes mellitus not meeting glycemic targets on basal insulin in the U.S. setting.Methods: A cost-utility model was developed to evaluate the clinical and economic outcomes associated with the 2 treatments over a 1-year time horizon, capturing the impact on quality of life of hypoglycemic events, body mass index, and injection frequency. Costs were captured from a healthcare payer perspective in 2017 U.S. dollars ($).Results: IDegLira was associated with improved quality of life by 0.12 quality-adjusted life years compared with insulin glargine U100 plus insulin aspart. The key drivers of this difference were reduced injection frequency and hypoglycemic events avoided. IDegLira was associated with increased annual drug costs, but this was entirely offset by reduced needle costs and reduced costs of self-monitoring of blood glucose testing. IDegLira was associated with total annual cost savings of $743 per patient.Conclusion: IDegLira was found to improve quality-adjusted life expectancy and reduce costs when compared with insulin glargine U100 plus insulin aspart for treatment of patients with type 2 diabetes not achieving glycemic control on basal insulin in the U.S. setting.Abbreviations: ADA = American Diabetes Association; BMI = body mass index; CI = confidence interval; DUAL = Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes; GLP-1 = glucagon-like peptide-1; HbA1c = glycated hemoglobin; ICER = incremental cost-effectiveness ratio; IU = international units; QALY = quality-adjusted life year; SMBG = self-monitoring of blood glucose     

Increasing Prevalence Of Addison Disease: Results From A Nationwide Study

Objective: Primary adrenal insufficiency is a life-threatening endocrine disease unless properly treated. However, few studies on the prevalence, concomitances of the disease, and prescribing of drugs have been published. The goal of the study was to establish the prevalence of primary adrenal insufficiency in Iceland and additionally, to study the most common concomitant diseases in patients with primary adrenal insufficiency, as well as the mode of glucocorticoid replacement therapies.Methods: To achieve this, the medical records of all patients in Iceland who had received the International Classification of Diseases and Related Health Problems, 10th Revision, diagnosis code E27, were evaluated for true primary adrenal insufficiency. Additionally, these records were evaluated for concomitant diseases, as well as the mode of glucocorticoid replacement therapy. The study covered the whole population of Iceland over 18 years of age. It was thus a nationwide study. The records were retrieved from large hospitals and clinics and every practicing specialist in endocrinology.Results: Primary adrenal insufficiency was found in 53 individuals, 26 women and 27 men, yielding a prevalence of 22.1 per 100,000 population. Hypothyroidism was by far the most common concomitant disease. Most patients had their glucocorticoid deficiency replaced with shortacting glucocorticoids.Conclusion: The prevalence of primary adrenal insufficiency in Iceland is higher than in earlier reports, with comorbidities being in line with recent studies. Treatment is according to the latest protocols.Abbreviations:CAH = congenital adrenal hyperplasiaCVD = cardiovascular diseaseDM = diabetes mellitusGC = glucocorticoidLSH = Landspitali National University HospitalPAI = primary adrenal insufficiencyPAS = polyendocrine autoimmune syndrome     

Development and Validation of a Novel Tool to Predict Hospital Readmission Risk Among Patients with Diabetes

Objective: To develop and validate a tool to predict the risk of all-cause readmission within 30 days (30-d readmission) among hospitalized patients with diabetes.Methods: A cohort of 44,203 discharges was retrospectively selected from the electronic records of adult patients with diabetes hospitalized at an urban academic medical center. Discharges of 60% of the patients (n = 26,402) were randomly selected as a training sample to develop the index. The remaining 40% (n = 17,801) were selected as a validation sample. Multivariable logistic regression with generalized estimating equations was used to develop the Diabetes Early Readmission Risk Indicator (DERRI™).Results: Ten statistically significant predictors were identified: employment status; living within 5 miles of the hospital; preadmission insulin use; burden of macrovascular diabetes complications; admission serum hematocrit, creatinine, and sodium; having a hospital discharge within 90 days before admission; most recent discharge status up to 1 year before admission; and a diagnosis of anemia. Discrimination of the model was acceptable (C statistic 0.70), and calibration was good. Characteristics of the validation and training samples were similar. Performance of the DERRI™ in the validation sample was essentially unchanged (C statistic 0.69). Mean predicted 30-d readmission risks were also similar between the training and validation samples (39.3% and 38.7% in the highest quintiles).Conclusion: The DERRI™ was found to be a valid tool to predict all-cause 30-d readmission risk of individual patients with diabetes. The identification of high-risk patients may encourage the use of interventions targeting those at greatest risk, potentially leading to better outcomes and lower healthcare costs.Abbreviations:DERRI™ = Diabetes Early Readmission Risk IndicatorICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical ModificationGEE = generalized estimating equationsROC = receiver operating characteristic     

The Diabetes Epidemic in China: An Integrated Review of National Surveys

Objective: To review trends in the prevalence and incidence of diabetes mellitus (DM) and related risk factors in China.Methods: We searched the literature using PubMed, China Knowledge Resource Integrated Database, and China Wanfang Digital Database for large epidemiologic studies and national surveys.Results: During the past 30 years (1980–2010), 7 national diabetes mellitus surveys were conducted in China mainland, indicating that the prevalence of DM has increased 17-fold, from 0.67 to 11.6% of the population. The prevalence of impaired glucose regulation (IGR, including impaired fasting glucose and impaired glucose tolerance) also increased, from 2.09 in 1994 to 27.2% in 2010. There was no national representative study of the incidence of diabetes to date; the reported incidence of type 2 diabetes during past 25 years in several cohort studies varied (2.7 to 15.8 per 1,000 person-years). Potential risk factors which could have contributed to the increasing prevalence and incidence of DM and IGR in the Chinese population include social and economic development, urbanization, dietary pattern, and Westernized lifestyle. Further, genetic studies have suggested that unique inheritable risk factors in the Chinese population may increase the risk for DM when compared to Caucasians.Conclusion: DM and IGR have become epidemic in China. Public health strategies should focus on modifying lifestyle and dietary factors, particularly among those with a susceptible genetic background.Abbreviations:BMI = body mass indexDM = diabetes mellitusFBG = fasting blood glucoseGWAS = genome-wide association studyIGR = impaired glucose regulationIGT = impaired glucose toleranceOGTT = oral glucose tolerance testT2D = type 2 diabetesWC = waist circumferenceWHR = waist-hip ratio     

Hba1C Control And Cost-Effectiveness in Patients With Type 2 Diabetes Mellitus Initiated On Canagliflozin or A Glucagon-Like Peptide 1 Receptor Agonist in A Real-World Setting

Objective: To compare glycated hemoglobin (HbA1c) control and medication costs between patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin 300 mg (CANA) or a glucagon-like peptide 1 receptor agonist (GLP-1 RA) in a real-world setting.Methods: Adults with T2DM newly initiated on CANA or a GLP-1 RA (index date) were identified from IQVIA™ Real-World Data Electronic Medical Records U.S. database (March 29, 2012–April 30, 2016). Inverse probability of treatment weighting accounted for differences in baseline characteristics. HbA1c levels at 3-month intervals were compared using generalized estimating equations. Medication costs used wholesale acquisition costs.Results: For both cohorts (CANA: n = 11,435; GLP-1 RA: n = 11,582), HbA1c levels decreased at 3 months postindex and remained lower through 30 months. Absolute changes in mean HbA1c from index to 3 months postindex for CANA and GLP-1 RA were -1.16% and -1.21% (patients with baseline HbA1c ≥7% &lsqb;53 mmol/mol]); -1.54% and -1.51% (patients with baseline HbA1c ≥8% &lsqb;64 mmol/mol]); and -2.13% and -1.99% (patients with baseline HbA1c ≥9% &lsqb;75 mmol/mol]), respectively. Postindex, CANA patients with baseline HbA1c ≥7% had similar HbA1c levels at each interval versus GLP-1 RA patients, except 9 months (mean HbA1c, 7.75% &lsqb;61 mmol/mol] vs. 7.86% &lsqb;62 mmol/mol]; P = .0305). CANA patients with baseline HbA1c ≥8% and ≥9% had consistently lower HbA1c numerically versus GLP-1 RA patients and statistically lower HbA1c at 9 (baseline HbA1c ≥8% or ≥9%), 27, and 30 months (baseline HbA1c ≥9%). Continuous 12-month medication cost $3,326 less for CANA versus GLP-1 RA.Conclusion: This retrospective study demonstrated a similar evolution of HbA1c levels among CANA and GLP-1 RA patients in a real-world setting. Lower medication costs suggest CANA is economically dominant over GLP-1 RA (similar effectiveness, lower cost).Abbreviations:AHA = antihyperglycemic agentBMI = body mass indexCANA = canagliflozin 300 mgDCSI = diabetes complications severity indexeGFR = estimated glomerular filtration rateEMR = electronic medical recordGLP-1 RA = glucagon-like peptide 1 receptor agonistHbA1c = glycated hemoglobinICD-9-CM = International Classification of Diseases–Ninth Revision–Clinical ModificationICD-10-CM = International Classification of Diseases–Tenth Revision–Clinical ModificationIPTW = inverse probability of treatment weightingITT = intent-to-treatMPR = medication possession ratioPDC = proportion of days coveredPS = propensity scorePSM = propensity score matchingQuan-CCI = Quan-Charlson comorbidity indexSGLT2 = sodium-glucose cotransporter 2T2DM = type 2 diabetes mellitusWAC = wholesale acquisition cost     

Limitations of Current Approaches For The Treatment of Acromegaly

Objective: Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH), typically from a benign pituitary somatotroph adenoma, that leads to subsequent hypersecretion of insulin-like growth factor 1 (IGF-1). Patients with acromegaly have an increased risk of mortality and progressive worsening of comorbidities. Surgery, medical therapy, and radiotherapy are currently available treatment approaches for patients with acromegaly, with overall therapeutic goals of lowering GH levels and achieving normal IGF-1 levels, reducing tumor size, improving comorbidities, and minimizing mortality risk. Although surgery can lead to biochemical remission in some patients with acromegaly, many patients will continue to have uncontrolled disease and require additional treatment.Methods: We reviewed recently published reports and present a summary of the safety and efficacy of current treatment modalities for patients with acromegaly.Results: A substantial proportion of patients who receive medical therapy or radiotherapy will have persistently elevated GH and/or IGF-1. Because of the serious health consequences of continued elevation of GH and IGF-1, there is a need to improve therapeutic approaches to optimize biochemical control, particularly in high-need patient populations for whom current treatment options provide limited benefit.Conclusion: This review discusses current treatment options for patients with acromegaly, limitations associated with each treatment approach, and areas within the current treatment algorithm, as well as patient populations for which improved therapeutic options are needed. Novel agents in development were also highlighted, which have the potential to improve management of patients with uncontrolled or persistent acromegaly.Abbreviations:AACE = American Association of Clinical EndocrinologistsAE = adverse eventATG = AutogelCFRT = conventional fractionated radiotherapyDA = dopamine agonistENDO = Endocrine SocietyGH = growth hormoneGHRA = growth hormone receptor antagonistIGF-1 = insulin-like growth factor 1LAR = long-acting releaseLFT = liver function testSC = subcutaneousSRS = stereotactic radiosurgerySSA = somatostatin analoguesst = somatostatin receptorsst₂ = somatostatin receptor subtype 2sst₅ = somatostatin receptor subtype 5TSS = transsphenoidal surgery     

Association Between Hypoglycemia And Fall-Related Fractures And Health Care Utilization In Older Veterans With Type 2 Diabetes

Objective: To examine the association between hypoglycemia and fall-related outcomes in older patients with type 2 diabetes mellitus (T2DM).Methods: This retrospective cohort study used electronic medical records of T2DM patients (≥65 years) from the Veterans Integrated Service Network 16 (VISN 16) data warehouse (01/01/2004-06/30/2010). Patients in nonhypoglycemia group (non-HG) were 1:1 randomly matched with patients in hypoglycemia group (HG) by age (±5 years), sex, race, and medical center location. Fall-related events (i.e., fractures and head injuries) were identified, with a fall being the external cause within ±2 days. McNemar tests and generalized estimating equation (GEE) models were used to compare fall-related events in the 1-year outcome period after the index date (i.e., date of first hypoglycemic episode). We also examined fall-related healthcare utilization.Results: A total of 4,215 patients in each group were studied, with the mean age of 76.5 years (SD: 5.85). The mean Charlson comorbidity index (CCI) scores were 5.73 (SD: 2.95) in the HG and 4.34 (SD: 2.40) in the non-HG. The HG had significantly higher rates of fall-related events than non-HG, 27 (0.64%) versus 1 (0.02%) and 89 (2.11%) versus 21 (0.50%) events within 30 days and 1 year, respectively. GEE models confirmed the elevated risk of fall-related events after controlling for sociodemographic and clinical characteristics, comorbidities, and medication use (adjusted odds ratio [aOR]: 2.70; 95% confidence interval [CI]: 1.64–4.47). The HG patients were more likely to have emergency department (ED) visits, hospital admissions, and long-term care placement compared to their counterparts.Conclusion: Hypoglycemia is associated with worse fall-related outcomes among the elderly veterans.Abbreviations:aOR = adjusted odds ratioCCI = Charlson comorbidity indexCI = confidence intervalED = emergency departmentGEE = generalized estimating equationHG = hypoglycemia groupICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical ModificationMI = myocardial infarction T2DM = type 2 diabetes mellitusVHA = Veterans Health Affairs     

Necessity of Multimodal Treatment of Acromegaly and Outcomes

Objective: Uncontrolled acromegaly is associated with increased morbidity and mortality. Despite multimodal therapeutic options, adequate control can be challenging and lead to prolonged exposure to growth hormone excess. The aim of this study was to assess treatment patterns and outcomes in patients with acromegaly following surgery at a single institution.Methods: A retrospective analysis of response to treatment modalities for patients with a new diagnosis of acromegaly at the Mayo Clinic in Rochester, Minnesota, from 1995–2015.Results: A total of 245 patients with newly diagnosed acromegaly (mean age at diagnosis, 47 ± 14 years; mean follow-up, 5.5 ± 5 years) were evaluated. Primary surgical intervention was performed in 236 patients; 117 (54%) did not achieve remission. Among those with ≥3 months follow-up, 76/217 (35%) patients required three or more forms of treatment. Mean tumor size at diagnosis was 1.6 ± 0.8 cm (80% macroadenomas), and 35% (75/217) had cavernous sinus invasion on pre-operative imaging. The most common second-line treatment was radiation treatment (RT) (50%, 59/117). Among those with persistent disease following surgery, a normal insulin-like growth factor 1 (IGF-1) was achieved in 52% (61/117), with a median time to acromegaly control of 4.5 years. The rate of IGF-1 normalization was 2.1-fold higher in those who received RT compared to those who did not.Conclusion: In patients with persistent acromegaly following surgery, multiple treatment modalities, including RT, may be required to achieve remission. Treatment outcome uncertainty and the need for multiple interventions add to the disease burden associated with persistent acromegaly.Abbreviations: CI = confidence interval; GH = growth hormone; IGF-1 = insulin like growth factor-1; KM = Kaplan-Meier; RT = radiation treatment     

Comparison of Cabergoline Versus Raloxifene Add-On Therapy to Long-Acting Somatostatin Analogue in Patients With Inadequately Controlled Acromegaly: A Randomized Open Label Clinical Trial

Objective: The present study aimed to evaluate the efficacy of add-on therapy of cabergoline versus raloxifene to long-acting somatostatin analogues (SAs) in patients with inadequately controlled acromegaly.Methods: This was a prospective, randomized open label clinical trial. Forty-four patients (22 per group) completed the study; where participants received either cabergoline (3 mg/week) or raloxifene (60 mg twice daily) add-on therapy for 12 weeks in a parallel manner. The primary outcome was the rate of reduction in serum insulin-like growth factor 1 (IGF-1) from baseline. Secondary outcomes comprised normalization of serum IGF-1 for age and sex.Results: Serum IGF-1 was significantly decreased in both the cabergoline (40.3 ± 25.6%, P<.001) and raloxifene (31.5 ± 24.6%, P<.001) groups, with no significant difference between arms (P>.05). Normalization in serum IGF-1 values occurred in 40.9% of patients who were on cabergoline compared to 45.5% of those receiving raloxifene (P = .76). The subsequent logistic regression analysis highlighted baseline IGF-1 as a significant predictor of IGF-1 normalization (odds ratio, 0.995; 95% confidence interval, 0.990–0.999; P = .02). Using the receiver operating characteristic (ROC) curve analysis for the entire group, the baseline IGF-1 value of 1.47 the upper limit of normal (ULN) was the best cut-off point to identify patients with normal IGF-1 at the end of the study (sensitivity: 52.6%, specificity: 84.0%, Yoden's index: 0.366). Full biochemical control of acromegaly was achieved in 22.7% of patients in the cabergoline group compared to 13.6% of those in the raloxifene group (P = .43).Conclusion: Cabergoline and raloxifene add-on therapy could effectively decrease serum IGF-1 level in patients with inadequately controlled acromegaly. The efficacy profiles of both drugs are comparable.Abbreviations: DA = dopamine agonist; FBG = fasting blood glucose; GH = growth hormone; IGF1 = insulin-like growth factor-1; IQR = interquartile range; OR = odds ratio; ROC = receiver operating characteristic; SA = somatostatin analogue; SERM = selective estrogen modulator receptor; ULN = upper limit of normal     

Autonomously Functioning Thyroid Nodules In Patients &#x003c;21 Years Of Age: The Rhode Island Hospital Experience From 2003&#x00C2;&#x20AC;&#x201C;2013

Objective: This study evaluates the clinical characteristics, workup, treatment, and outcomes of pediatric patients diagnosed with an autonomously functioning thyroid nodule (AFTN) in a large cohort of patients presenting for evaluation of a thyroid nodule. There are few prior studies on AFTN in pediatrics, with limited data on treatment and outcomes. Rates of malignancy in AFTN are perceived as low, but prior studies have varying reports.Methods: This is a retrospective chart review of patients less than 21 years of age at Rhode Island Hospital over an 11-year period (2003&#x00E2;&#x20AC;&#x201C;2013). We reviewed 354 charts, which yielded 242 patients with a diagnosis of thyroid nodule and 17 patients with AFTN.Results: The prevalence of AFTN in patients presenting with thyroid nodules was 7%. Mean age of patients was 15.8 years at diagnosis, and mean nodule size was 3.3 cm. There was female predominance. Thyroid-stimulating hormone levels were suppressed at diagnosis in 87% of patients. Six patients were treated with surgery, 5 patients with radioactive iodine therapy (RAI), 2 patients with medication, and 1 patient was observed without treatment. Three patients treated with RAI required subsequent treatment for hypothyroidism or continued hyperthyroidism. One patient had papillary thyroid carcinoma based on final surgical pathology.Conclusion: Our study found a higher prevalence of AFTN compared to the reported prevalence in adults. We concur with the new guidelines on management of thyroid nodules in recommending surgery for treatment of AFTN, based on the variability of outcomes after treatment with RAI.Abbreviations:AFTN = autonomously functioning thyroid noduleanti-TG = thyroglobulin antibodiesanti-TPO = thyroid peroxidase antibodiesFNA = fine-needle aspirationICD-9 = International Classification of Diseases, Ninth RevisionPTC = papillary thyroid carcinomaRAI = radioactive iodineT₃ = triiodothyronineT₄ = thyroxineTSH = thyroid-stimulating hormoneTSI = thyroid-stimulating immunoglobulin     

Comparative Efficacy of Medical Treatment for Acromegaly: A Systematic Review and Network Meta-Analysis of Integrated Randomized Trials and Observational Studies

Objective: Comprehensive evidence comparing different medications for acromegaly is scarce. The aim of this study was to perform a network meta-analysis based on evidence from both randomized trials and observational studies of medical treatments for acromegaly.Methods: Electronic databases were searched for both observational studies and randomized trials that enrolled acromegaly patients treated with medications of interest. Simulated trials were generated by a machine learning algorithm and then synthesized with Bayesian random-effects network meta-analyses. The main outcome was the rate of insulin-like growth factor 1 (IGF-1) control after medical treatment.Results: We included 90 studies (100 arms, 4,523 patients) before matching. After matching, 28 simulated trials were generated. Balance of matched arms was checked by spatial distance and correlation matrix. Cotreatment with somatostatin receptor ligands and pegvisomant was the most effective treatment compared with other treatments. In unselected patients, pegvisomant was better than octreotide long-acting release (logOR, 0.85; 95% credible interval [CrI], 0.05 to 1.65) or lanreotide (logOR, 1.09, 95% CrI, 0.05 to 2.14), and the mean absolute IGF-1 control rate ranged from 40 to 60%. In partially responsive patients, cotreatment with somatostatin receptor ligands and pegvisomant was similar to pegvisomant monotherapy, ranking as the most two effective treatments, and the mean absolute IGF-1 control rate was over 60%.Conclusion: Our analysis suggested that the combination of data from observational studies and randomized trials in network meta-analysis was feasible. The findings of this network meta-analysis provided robust evidence supporting the current guidelines in treatment strategy for acromegaly.Abbreviations: CrI = credible interval; DA = dopamine agonist; GH = growth hormone; IGF-1 = insulin-like growth factor 1; ITT = intention-to-treat; LAN = lanreotide; LAN-ATG = lanreotide autogel; OCT = octreotide; OCT-LAR = octreotide long acting repeatable; OR = odds ratio; PEG = pegvisomant; PP = per-protocol; SRL = somatostatin receptor ligand