Current Understanding of Sodium N-(8-[2-Hydroxylbenzoyl] Amino) Caprylate (SNAC) as an Absorption Enhancer: The Oral Semaglutide Experience.

Oral administration of peptide therapeutics faces challenges because of the distinct environment of the gastrointestinal tract. An oral formulation of semaglutide, a glucagon-like peptide 1 receptor agonist, was approved by the U.S. Food and Drug Administration in 2019 as a peptide therapy for the treatment of type 2 diabetes. Oral semaglutide uses sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) technology to enhance the absorption of semaglutide in the stomach and protect it from degradation by gastric enzymes. This article presents a summary of studies investigating SNAC technology as an absorption enhancer for a number of molecules and, in particular, explores how SNAC, once coformulated with oral semaglutide, facilitates increased absorption and bioavailability. Practical advice and dispensing information for pharmacists is also provided.

Measurement of free fraction, total concentration and protein binding for testosterone, triiodothyronine and thyroxine.

Aims: Measuring the total and free concentrations of hormones is useful, but the technology to do this simultaneously is lacking. Methods: A new method offers the ability to measure these parameters concurrently for testosterone, thyroxine and triiodothyronine. Results: The free concentrations showed significant correlations with patients' vital statistics. Overall, 67% of correlations for total concentration showed that the new and classical methods had equal accuracy, or that comprehensive ultrafiltration was more accurate. The protein binding term was found to correlate significantly with the patients' luteinizing hormone, prostate-specific antigen and height. Conclusion: Comprehensive ultrafiltration for measuring the total concentration, free concentration and protein binding term uses less sample and is much faster than measuring these parameters with three separate methods.

A phase Ib study of interleukin-2 plus pembrolizumab for patients with advanced melanoma.

Introduction: High-dose interleukin-2 (HD IL-2) and pembrolizumab are each approved as single agents by the U.S. F.D.A. for the treatment of metastatic melanoma. There is limited data using the agents concurrently. The objectives of this study were to characterize the safety profile of IL-2 in combination with pembrolizumab in patients with unresectable or metastatic melanoma. Methods: In this Phase Ib study, patients received pembrolizumab (200 mg IV every 3 weeks) and escalating doses of IL-2 (6,000 or 60,000 or 600,000 IU/kg IV bolus every 8 hours up to 14 doses per cycle) in cohorts of 3 patients. Prior treatment with a PD-1 blocking antibody was allowed. The primary endpoint was the maximum tolerated dose (MTD) of IL-2 when co-administered with pembrolizumab. Results: Ten participants were enrolled, and 9 participants were evaluable for safety and efficacy. The majority of the evaluable participants (8/9) had been treated with PD-1 blocking antibody prior to enrollment. Patients received a median of 42, 22, and 9 doses of IL-2 in the low, intermediate, and high dose cohorts, respectively. Adverse events were more frequent with increasing doses of IL-2. No dose limiting toxicities were observed. The MTD of IL-2 was not reached. One partial response occurred in 9 patients (11%). The responding patient, who had received treatment with an anti-PD-1 prior to study entry, was treated in the HD IL-2 cohort. Discussion: Although the sample size was small, HD IL-2 therapy in combination with pembrolizumab appears feasible and tolerable. Clinical trial registration: ClinicalTrials.gov, identifier NCT02748564.

Comparison of liquid-liquid extraction, microextraction and ultrafiltration for measuring free concentrations of testosterone and phenytoin.

Aim: The purpose of the study was to find methods suitable for measuring the free concentrations of testosterone and phenytoin. Materials & methods: Sample solutions of the compounds in buffer and human albumin were processed using liquid-liquid extraction, microextraction and ultrafiltration and analyzed by LC-MS/MS. Results: Liquid-liquid extraction with dibutyl phthalate provided complete extraction from buffer solutions and partial extraction from albumin samples. Spintip C18 devices provided exhaustive extraction from buffer and albumin samples. Spintip C8 devices offered complete extraction from buffer and approximately 50% recovery from albumin samples. Centrifree ultrafiltration devices showed high recovery of free concentrations from all the samples, while Amicon and Nanosep devices provided partial recovery. Conclusion: Spintip C8 and Centrifree devices proved useful for measuring free concentrations.

A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies.

PURPOSE: Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS: Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1-4 plus C 450 to 750 mg/m2 Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. RESULTS: Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. CONCLUSION: V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.

The Occurrence and Burden of Hypophosphatasia in an Ambulatory Care Endocrinology Practice.

OBJECTIVE: Hypophosphatasia (HPP) is an inherited disease resulting from loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase. The presentation and severity of the disease are highly variable, ranging from perinatal onset with high mortality rates to adult identification with low mortality rates and symptoms ranging from minimal to severe. Moderate forms of HPP typically manifest during middle age and are often undiagnosed. The objective of this study was to determine the occurrence and burden of HPP in an ambulatory care endocrinology practice. METHODS: Potential subjects were identified with a computerized text search of patient electronic medical records. Search terms included serum alkaline phosphatase (ALP) levels of ≤40 U/L. Records of patients with at least 2 low ALP levels were reviewed manually to identify potential patients with a history consistent with hypophosphatasia. RESULTS: In total, 315 patients with ALP levels ≤40 U/L were identified from an estimated 20 000 patient records. Fifty-six patients with a single low level were excluded from further review. The remaining 259 patients were reviewed, 10 of whom had histories consistent with HPP. None of the identified 10 patients was currently being treated or had previously been treated for HPP. Information about these patients was shared with their respective providers, along with the recommendation to proceed with further evaluation to confirm the diagnosis of HPP. CONCLUSION: Hypophosphatasia is an uncommon condition with variable presentation, often resulting in a missed diagnosis. Surveillance of practices by identifying patients with low ALP levels is a rational screening approach to identifying potential patients with HPP.

Management of type 2 diabetes with oral semaglutide: Practical guidance for pharmacists.

PURPOSE: To provide pharmacists with information on counseling patients with type 2 diabetes (T2D) receiving oral semaglutide. SUMMARY: Oral semaglutide, the first oral glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA), was approved for the treatment of adults with T2D by the US Food and Drug Administration in September 2019. Semaglutide has been coformulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate to improve bioavailability of semaglutide following oral administration. Oral semaglutide has been shown to have efficacy and safety profiles similar to those of other GLP-1RAs. Many patients with T2D have a complex oral medication regimen to manage their T2D and concomitant chronic comorbid conditions. Therefore, it is important that patients follow the dose administration instructions closely: oral semaglutide should be taken on an empty stomach upon waking with a sip (≤120 mL) of plain water and at least 30 minutes before the first food, beverage, or other oral medications of the day. The most common adverse effects of oral semaglutide are gastrointestinal (typically nausea, diarrhea, and vomiting). It is important for pharmacists to counsel patients prescribed oral semaglutide about optimal oral dosing, why correct dosing conditions are necessary, expected therapeutic response, and effective strategies to mitigate potential gastrointestinal adverse events. CONCLUSION: Information and practical strategies provided by pharmacists may facilitate initiation and maintenance of oral semaglutide therapy and ensure that each patient achieves an optimal therapeutic response.

Method for Simultaneous Determination of Free Concentration, Total Concentration, and Plasma Binding Capacity in Clinical Samples.

Most quantitative research methods are based on measuring either the total or the free concentration of an analyte in a sample. However, this is often insufficient for the study of complex biological systems. The main objective of this research was to develop new methods for providing more information from samples: the free concentration (Cf), the total concentration (Ct), and the plasma binding capacity (PBC). Samples were processed using microextraction and ultrafiltration. For each of these techniques, two quantification procedures were used: addition of isotopically labeled standard and repeated analysis of the same sample. The new methods were validated by analyzing clinical samples and samples with known concentrations. Methods based on addition of labeled compound were found to be the fastest, and most reproducible. For analysis of clinical samples, methods based on microextraction were more sensitive and more accurate than those based on ultrafiltration. For analysis of pooled plasma samples, the overall accuracy of all approaches to determine PBC, testosterone Cf, and testosterone Ct was between 94 and 109%, 87-113%, and 94-122% respectively. The new approach goes beyond a simple concentration measurement, giving more information from clinical samples, with great potential for personalizing drug dosage and therapy to the needs of individual patients.

Programmed Cell Death-1 Monoclonal Antibody Therapy and Type 1 Diabetes Mellitus: A Review of the Literature.

Two Food and Drug Administration-approved programmed cell death-1 (PD-1) inhibitors, nivolumab (Opdivo®), and pembrolizumab (Keytruda®), are indicated for treatment-resistant malignancies. Inhibition of PD-1 also inhibits T-cell peripheral tolerance, enhancing autoimmunity. Various autoimmune conditions have been reported with the use of these agents, including type 1 diabetes mellitus (T1DM). This article reviews literature regarding the development of T1DM in patients treated with PD-1 inhibitors and identifies strategies for the appropriate identification, monitoring, and follow-up of these patients. Published cases of T1DM related to PD-1 inhibitor therapy were identified using PubMed. Eighty-three identified publications were reviewed, of which 37 publications involving 42 cases of anti-PD-1 therapy-induced T1DM were identified. The average age of patients at presentation was 62 years and 59.5% were male. The mean number of PD-1 inhibitor doses received was 5, with a mean time to presentation of 11 weeks. Initial presentation of diabetic ketoacidosis was reported in 69% of cases, with an average blood glucose of 660 mg/dL and an average HbA1c of 8.7%. The exact mechanism PD-1 inhibitor therapy-induced T1DM is unknown. Blood glucose monitoring is recommended for all patients receiving anti-PD-1 therapy. Further research is needed to delineate the frequency of this adverse effect, as well as to evaluate potential risk factors and ideal management strategies.

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.

Pomalidomide desensitization for hypersensitivity: A case report.

INTRODUCTION: Pomalidomide is an immunomodulating agent that is used to treat relapsed and/or refractory multiple myeloma. Although the incidence of hypersensitivity with pomalidomide is not well documented, the most common type of hypersensitivity involves a cutaneous reaction. Previous reports have successfully utilized a desensitization protocol in patients who developed hypersensitivity to pomalidomide. Here we describe a case of a patient who developed urticaria on pomalidomide and successfully underwent a desensitization using the previously reported method in a case report. CASE REPORT: A 68-year-old woman with relapsed multiple myeloma and no known drug allergies developed urticaria a day after taking the first dose of pomalidomide. MANAGEMENT AND OUTCOME: The patient underwent a 10-step desensitization process in the medical intensive care unit without any reported adverse events. The following day in the medical intensive care unit, the patient was able to tolerate a full dose of pomalidomide with no further reactions and was discharged with instructions to take a full dose of pomalidomide daily for 21 days out of a 28-day cycle. The patient was followed up in the outpatient clinic and noted no further reactions from pomalidomide at the three-month visit. DISCUSSION: The 10-step desensitization protocol with pomalidomide was well tolerated in the patient with hypersensitivity to pomalidomide. Whether this approach would work in patients with more severe reactions such as anaphylaxis and angioedema is still unknown.

A pharmacist-run anabolic osteoporosis clinic: An abaloparatide descriptive report.

OBJECTIVES: To review the first-year experience of abaloparatide use in a pharmacist-run anabolic osteoporosis clinic. SETTING: This ambulatory-care health system endocrinology practice consists of 10 board-certified endocrinologists and 6 nurse practitioners and physician assistants. Approximately 1200 patients are seen weekly. The practice is affiliated with the Albany College of Pharmacy and Health Sciences and hosts 2 clinical pharmacy faculty members and a PGY-2 endocrinology pharmacy resident. A pharmacist-run teriparatide clinic was implemented in 2002. In 2017, the clinic was expanded to accept referrals for abaloparatide. No description of a pharmacist-run abaloparatide clinic has yet been reported. PRACTICE DESCRIPTION: Patients are referred to a clinical pharmacist for initiation and education of anabolic osteoporosis therapy. The pharmacist is responsible for assessing for contraindications to anabolic therapy, securing managed care coverage of an anabolic agent, and providing medication counseling. This pharmacist is available as a resource to patients throughout their course of anabolic osteoporosis therapy. PRACTICE INNOVATION: This is the first description of a pharmacist-run abaloparatide clinic. EVALUATION: Not applicable. RESULTS: During its first year of availability, 52 patients were referred for abaloparatide therapy. Of these, 31 patients (59.6%) initiated treatment. The population predominately consisted of postmenopausal white women. Approximately two-thirds of patients had a history of an osteoporosis-related fracture, and half of patients had previously received antiresorptive therapy for osteoporosis. Mean baseline T-scores for the lumbar spine and femoral neck were -2.41 and -2.57, respectively. Twenty-one patients did not initiate abaloparatide therapy owing to cost (9), concerns of therapy (8), or contraindication to therapy (4). An additional 5 patients discontinued abaloparatide therapy owing to adverse effects. CONCLUSION: This paper reviews the first-year experience of abaloparatide use in a pharmacist-run anabolic osteoporosis clinic. The fact that only 60% of referred patients initiated therapy indicates that significant barriers (e.g., high patient cost and safety concerns) remain.

High-Dose Ipilimumab and High-Dose Interleukin-2 for Patients With Advanced Melanoma.

High-dose ipilimumab (IPI) and high-dose interleukin-2 (IL-2) are approved agents for metastatic melanoma, but the efficacy and safety of the combination are unknown. The objective of this study was to evaluate the feasibility, safety, and efficacy of combination high-dose IPI and high-dose IL-2 in patients with histologically confirmed advanced unresectable stage III and IV melanoma. This Phase II, multicenter, open-label, single-arm trial was conducted in nine patients enrolled between 12/2014 and 12/2015. Subjects were treated with high-dose IPI 10 mg/kg intravenous (IV) every 3 weeks for four doses starting at week 1 and high-dose IL-2 (600,000 IU/kg IV bolus every 8 h for up to 14 doses) concurrently with IPI at weeks 4 and 7. After the first 12 weeks of combination therapy, maintenance IPI (10 mg/kg IV) monotherapy was administered every 12 weeks for up to 1 year. No patient had received prior PD-1 blockade, and only one received prior vemurafenib. Confirmed partial response was achieved in one (11%), stable disease in four (44%), and progressive disease in four (44%) of nine patients. Two patients achieved durable disease control of 44+ and 50+ months at the most recent follow-up without subsequent therapy. The median overall survival was not reached after a minimum 24 months of follow-up time. One-year and 2-year survival rates were 89 and 67%, respectively. Seven patients (78%) experienced grade 3 or 4 adverse events related to the study therapy, three of which were attributed to both agents. One patient discontinued the treatment due to liver and kidney toxicity. While toxicity was significant, all events were reversible, and there was no treatment-related mortality. In peripheral blood of patients with decreasing tumor burden, the ratio of the non-classical MHC-II proteins HLA-DM to HLA-DO increased 2-fold, raising the possibility of the ratio of HLA-DM:HLA-DO as a novel biomarker of response to treatment. Although the sample size was limited, combination therapy with high-dose IPI and high-dose IL-2 was feasible and associated with clinical benefit. IL-2-based compounds in combination with CTLA-4 blockade should be studied in advanced melanoma patients who fail to benefit from first-line PD-1 blockade. Clinical Trial Registration: ClinicalTrials.gov, NCT02203604. Registered 30 July 2014, https://clinicaltrials.gov/ct2/show/NCT02203604.

Phase I trial of selenium plus chemotherapy in gynecologic cancers.

PURPOSE: Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. METHODS: Chemo-naïve patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RESULTS: Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 µg to 5000 µg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. CONCLUSION: Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 µg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.

A real-world, observational study of weekly exenatide added to basal insulin in patients with type 2 diabetes mellitus (NCT02895672).

AIM: This is a pre-post observational study from an endocrinology ambulatory care practice which assessed the effectiveness and safety following the addition of a glucagon-like peptide-1 (GLP-1) agonist, weekly exenatide (Bydureon), to basal insulin therapy in patients with type 2 diabetes mellitus (T2DM). Liraglutide plus basal insulin served as a comparison group. MATERIALS AND METHODS: A data collection form was utilized to collect study-related information. The primary study outcome was change in HbA1c from baseline to 12 months after GLP-1 receptor agonist therapy was added to basal insulin therapy. Secondary outcomes were change in weight, percentage of patients achieving an HbA1c of <7% (53 mmol/mol) or ≤6.5% (48 mmol/mol) and changes in blood pressure and lipid parameters. Safety was assessed by a collection of reported adverse events. RESULTS: One-hundred and fifty patients met inclusion criteria (seventy-five per treatment arm). After 1 year of therapy, HbA1c decreased by 0.7% in the entire cohort (once-weekly exenatide: -0.7%; once-daily liraglutide: -0.8%; no significant between-group difference). More subjects in the weekly exenatide arm achieved an HbA1c < 7% (53 mmol/mol) (P = .03), but a comparable number achieved an HbA1c ≤ 6.5% (48 mmol/mol). Although significantly more patients achieved an HbA1c < 7% (53 mmol/mol) in the once-weekly exenatide arm, the baseline HbA1c was lower (7.9%) than the liraglutide arm (8.4%). No significant differences were observed between groups for other secondary outcomes. A similar number of subjects discontinued therapy, mainly due to gastrointestinal-ill effects, and hypoglycaemia incidence did not increase compared with the previous year. CONCLUSION: The addition of once-weekly exenatide to basal insulin was associated with appreciable reductions in HbA1c and weight without an increase in hypoglycaemia.

Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes.

Among persons with type 2 diabetes (t2d), the development of glucose intolerance involves dysfunction in several organs and tissues, including the muscle, liver, pancreas, kidney, gastrointestinal tract, adipose tissue, and brain. individuals with t2d typically have a number of comorbidities, including hypertension, hyperlipidemia, and being overweight or obese, and are, consequently, at high cardiovascular risk. guidelines recommend a comprehensive care strategy that includes treatment of diabetes-related complications and comorbidities beyond those related to hyperglycemia. use of glucose-lowering therapies with complementary activities that address multiple facets of the disease may improve long-term outcomes for patients with t2d. two recent drug classes developed for use in t2d, glucagon-like peptide-1 receptor agonists (glp-1ras) and sodium glucose cotransporter 2 (sglt2) inhibitors, have been shown in clinical trials to have beneficial effects on glycemic control, body weight, cardiovascular risk factors, and (for liraglutide, semaglutide, and empagliflozin) cardiovascular outcomes, while having an acceptable safety profile. between them, these drug classes directly or indirectly affect many of the organs and tissues involved in the pathogenesis of t2d, and their beneficial effects on glycemic- and cardiovascular-related parameters are likely to be complementary and potentially additive. in the largest clinical trial of a glp-1ra and an sglt2 inhibitor in combination (duration-8), patients with t2d (n = 685) who received exenatide plus dapagliflozin added to their treatment regimen for 28 weeks had significantly greater reductions from baseline in glycated hemoglobin, body weight, and systolic blood pressure compared with patients who received either drug as monotherapy. this review summarizes the complementary aspects of these drug classes and presents the available data among patients receiving dual therapy with a glp-1ra and an sglt2 inhibitor.

Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy.

With the recent regulatory approval of Talimogene laherparepvec (T-VEC) for the treatment of advanced of melanoma in the United States, Europe and Australia, oncolytic virus immunotherapy has earned its place in the clinic. However, the adoption of T-VEC by the U.S. oncology community has been slow, and so far has been largely limited to specialized cancer centers. Limiting factors include the intratumoral route of administration, which is unfamiliar to medical oncologists, biosafety concerns related to the use of a live virus in the clinic, and the explosion of other therapeutic strategies now available for the treatment of advanced melanoma. Herein, we review the development of T-VEC, and suggest how it fits into the in the current clinical treatment paradigm, and provide pearls for drug preparation, administration, and monitoring of response to therapy.

No Postoperative Adrenal Insufficiency in a Patient with Unilateral Cortisol-Secreting Adenomas Treated with Mifepristone Before Surgery.

BACKGROUND: Glucocorticoid replacement is commonly required to treat secondary adrenal insufficiency after surgical resection of unilateral cortisol-secreting adrenocortical adenomas. Here, we describe a patient with unilateral cortisol-secreting adenomas in which the preoperative use of mifepristone therapy was associated with recovery of the hypothalamic-pituitary-adrenal (HPA) axis, eliminating the need for postoperative glucocorticoid replacement. CASE PRESENTATION: A 66-year-old Caucasian man with type 2 diabetes mellitus, hyperlipidemia, hypertension, and obesity was hospitalized for Fournier's gangrene and methicillin-resistant Staphylococcus aureus sepsis. Abdominal computed tomography scan revealed three left adrenal adenomas measuring 1.4, 2.1, and 1.2 cm and an atrophic right adrenal gland. Twenty-four-hour urinary free cortisol level was elevated (237 µg/24 hours, reference range 0-50 µg/24 hours). Hormonal evaluation after resolution of the infection showed an abnormal 8 mg overnight dexamethasone suppression test (cortisol postdexamethasone 14.5 µg/dL), suppressed adrenocorticotropic hormone (ACTH; <5 pg/mL, reference range 7.2-63.3 pg/mL), and low-normal dehydroepiandrosterone sulfate (50.5 µg/dL, male reference range 30.9-295.6 µg/dL). Because of his poor medical condition and uncontrolled diabetes, his Cushing's syndrome was treated with medical therapy before surgery. Mifepristone therapy was started and, within five months, his diabetes was controlled and insulin discontinued. The previously suppressed ACTH increased to above normal range accompanied by an increase in dehydroepiandrosterone sulfate levels, indicating recovery of the HPA axis and atrophic contralateral adrenal gland. The patient received one precautionary intraoperative dose of hydrocortisone and none thereafter. Two days postoperatively, ACTH (843 pg/mL) and cortisol levels (44.8 µg/dL) were significantly elevated, reflecting an appropriate HPA axis response to the stress of surgery, and two weeks postoperatively, ACTH was within normal range and a repeat dexamethasone suppression test was normal. Six months postoperatively, ACTH was within normal limits and cortisol was approaching normal. The patient has exhibited no postoperative signs or symptoms of adrenal insufficiency in 12 months. CONCLUSION: Preoperative mifepristone therapy was associated with apparent recovery of the HPA axis prior to unilateral adrenalectomy in a patient with unilateral adrenal adenomas. Postoperatively, the patient experienced no signs or symptoms of adrenal insufficiency and no glucocorticoid replacement was required.

SGLT-2 INHIBITOR THERAPY ADDED TO GLP-1 AGONIST THERAPY IN THE MANAGEMENT OF T2DM.

OBJECTIVE: To assess the real-world efficacy and safety of canagliflozin therapy added to type 2 diabetes mellitus (T2DM) patients who have received a minimum 1 year of glucagon-like peptide-1 (GLP-1) agonist therapy. METHODS: This pre-post observational study assessed the efficacy and safety of canagliflozin in a group of T2DM patients from a community endocrinology practice who received GLP-1 agonist therapy for a minimum of 12 months. The primary study outcome was change in mean glycated hemoglobin (HbA1c) level from baseline. Secondary endpoints included changes in average weight, and comparison of the percentage of patients obtaining an HbA1c <7%. RESULTS: A total of 75 patients met all the study criteria. Baseline patient characteristics were as follows: average age, 58 ± 9 years; mean duration of T2DM, 14 ± 6 years; 56% male; 92% Caucasian; baseline body mass index (BMI), 39.4 ± 9.4 kg/m(2); and mean baseline HbA1c, 7.94 ± 0.69%. HbA1c and weight were significantly reduced by 0.39% and 4.6 kg, respectively. Adverse effects were reported by 13 (17.3%) patients, including 4 (5.3%) who discontinued canagliflozin because of adverse reactions. CONCLUSION: Canagliflozin was generally well tolerated and significantly further reduced mean HbA1c levels and body weight in patients with T2DM when added to GLP-1 regimen.

A clinical perspective of canagliflozin in the management of type 2 diabetes mellitus.

OBJECTIVE: To assess the real-world efficacy and safety of the first sodium-glucose cotransporter-2 inhibitor, canagliflozin, in the treatment of patients with type 2 diabetes mellitus (T2DM). METHODS: This observational study assessed the efficacy and tolerability of canagliflozin in T2DM patients. Primary study outcomes were changes in HbA1C and weight, and percentage of patients reporting adverse effects of therapy. RESULTS: The study criteria were met by 111 patient records. Baseline patient characteristics were: average age, 59 ± 9 years; mean duration of T2DM, 11.9 ± 7.3 years; 57.6% of patients were male; 92.8% were Caucasian; baseline BMI, 38.9 ± 11 kg/m(2); and mean baseline HbA1C, 7.53 (58.8 mmol/mol) ± 1.08%. HbA1C and weight were significantly reduced by 0.37% and 4.4 kg, respectively. Adverse effects were reported by 21 patients, and 17 (15.3%) discontinued canagliflozin because of adverse reactions. CONCLUSION: Canagliflozin was generally well tolerated and significantly reduced HbA1C levels and body weight in patients with T2DM when added to a regimen of other anti-hyperglycemic agents.