Unilateral adrenalectomy as a treatment option in a patient with recurrent Cushing's disease.

In recurrent Cushing's disease (CD), therapeutic management options may pose challenges related to risk-benefit profile of available pharmacological agents or bilateral adrenalectomy. Here, we describe a patient with recurrent CD who in context of progressive worsening of diabetes control and new diagnosis of coronary artery disease was offered a unilateral adrenalectomy (UA) to help alleviate the metabolic burden of hypercortisolemia. Within 6 months following UA she was able to stop her blood pressure medications; her anti-diabetes medications were significantly titrated down and she experienced significant weight loss. Currently, 18 months after the UA, the patient has not experienced new clinical events, her weight is stable and diabetes control is consistently optimal, and she remains off anti-hypertensive medications. This report adds to currently scarce body of literature that patients with difficult to manage CD can be considered as candidates for UA to potentially alleviate the metabolic burden of hypercortisolemia.

Hemochromatosis Gene Mutation in Persons Developing Erythrocytosis on Combined Testosterone and SGLT-2 Inhibitor Therapy.

In clinical trials, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) use alone in persons with type 2 diabetes (T2D) or testosterone replacement therapy (TRT) prescription alone in men with hypogonadism was shown to lead to a modest but significant increase in red blood cell mass. Recent evidence indicates that combined use of TRT and SGLT-2i in persons with T2D may be associated with risk of erythrocytosis. However, factor(s) that may lead to the development of erythrocytosis in these patients is unknown. We describe here 5 consecutive patients with hypogonadism on chronic TRT who developed erythrocytosis following addition of SGLT-2i empagliflozin for optimization of T2D management. In addition to the careful review of medical history, all patients underwent genetic screening for hereditary hemochromatosis. We have found that none of the patients had C282Y mutation in the HFE (Homeostatic Iron Regulator) gene and 4 out of 5 patients had heterozygosity in the H63D allele. Upon TRT discontinuation or its dose reduction or referral for scheduled phlebotomy, patients showed resolution of erythrocytosis. Our study reaffirms that practitioners should monitor for changes in hematocrit following the initiation of SGLT-2i in persons with T2D and hypogonadism on chronic TRT. Also, for the first time, we showed that in some of the patients receiving combined TRT and SGLT-2i H63D heterozygosity in the HFE gene may mediate the development of new-onset erythrocytosis.

American Association of Clinical Endocrinology Disease State Clinical Review: Evaluation and Management of Immune Checkpoint Inhibitor-Mediated Endocrinopathies: A Practical Case-Based Clinical Approach.

OBJECTIVE: The aim of this case-based clinical review was to provide a practical approach for clinicians regarding the management of patients with immune checkpoint inhibitor (ICI)-mediated endocrinopathies. METHODS: A literature search of PubMed, Embase, and Scopus was conducted using appropriate keywords. The discussions and strategies for the diagnosis and management of ICI-mediated endocrinopathies are based on evidence available from prospective, randomized clinical studies; cohort studies; cross-sectional studies; case-based studies; and an expert consensus. RESULTS: Immunotherapy with ICIs has transformed the treatment landscape of diverse types of cancers but frequently results in immune-mediated endocrinopathies that can cause acute and persistent morbidity and, rarely, death. The patterns of endocrinopathies differ between the inhibitors of the cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 or programmed cell death protein 1 ligand pathways but most often involve the thyroid and pituitary glands. The less common but important presentations include insulin-deficient diabetes mellitus, primary adrenal insufficiency, primary hypoparathyroidism, central diabetes insipidus, primary hypogonadism, and pancreatitis, with or without subsequent progression to diabetes mellitus or exocrine insufficiency. CONCLUSION: In recent years, with increasing numbers of patients with cancer being treated with ICIs, more clinicians in a variety of specialties have been called upon to diagnose and treat ICI-mediated endocrinopathies. Herein, we reviewed case scenarios of various clinical manifestations and emphasized the need for a high index of clinical suspicion by all clinicians caring for these patients, including endocrinologists, oncologists, primary care providers, and emergency department physicians. We also provided diagnostic and therapeutic approaches for ICI-induced endocrinopathies and proposed that patients on ICI therapy be evaluated and treated by a multidisciplinary team in collaboration with endocrinologists.

Cardiovascular and renal disease manifestation and healthcare resource utilization in patients on first-line oral therapy for type 2 diabetes: A claims-based observational cohort study.

AIM: To examine incident cardiovascular disease (CVD) and chronic kidney disease (CKD) diagnosis and associated healthcare resource utilization (HCRU) in a real-world population of patients with type 2 diabetes (T2D) initiating first-line oral antidiabetes drug (OAD) therapy. MATERIALS AND METHODS: Adults with T2D without CVD/CKD initiating first-line OAD therapy from 2008 to 2018 IBM MarketScan claims data were included. Incident CVD/CKD diagnoses following OAD initiation and first diagnosis type were assessed. Risk of incident diagnosis of heart failure (HF) among patients with CKD and of CKD among patients with HF was evaluated. HCRU and costs were compared for the 12 months before and after the first CVD/CKD diagnosis. RESULTS: Of 12 286 016 patients, 1 286 287 met all the inclusion criteria. During follow-up (mean 752 days), 205 865 (16.0%) patients had CVD/CKD diagnoses; the most common first diagnosis was the composite cardiorenal outcome of HF and/or CKD (64.6%). Most first diagnoses were within 2 years of OAD initiation. For HF and CKD, diagnosis of one was associated with increased risk of subsequent diagnosis of the other (both P < .001). Average annualized visits per patient increased by 31% after the first CVD/CKD diagnosis and annualized payer and patient costs increased by 75% and 26%, respectively, compared with the 12 months prediagnosis. Costs increased for all diagnosis types. CONCLUSIONS: Most first CVD/CKD diagnoses occurred within 2 years after OAD initiation and were associated with increased HCRU and costs. Reducing CVD/CKD risk with T2D treatments that improve both cardiovascular and renal outcomes may attenuate the burden of illness.

Efficacy of metformin monotherapy in US veterans with type 2 diabetes and preexisting chronic kidney disease stage 3.

AIM: To evaluate the glycaemic efficacy of metformin in people with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD3). PARTICIPANTS AND METHODS: This was a retrospective study including 145980 US veterans with T2D and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 who initiated metformin monotherapy between November 1999 and July 2017. Propensity-score-matched cohorts were generated based on baseline variables associated with CKD3 (eGFR 30-59 mL/min/1.73 m2 ) to evaluate the independent association between CKD3 and metformin discontinuation, the addition of a second hypoglycaemic agent, and changes in glycated haemoglobin (HbA1c) from baseline in those with and without CKD3. Associations were examined using the Kaplan-Meier method and multivariable regression models, adjusted for baseline and 12-month average metformin dose. RESULTS: The mean age of the entire cohort was 60.7 years, and 95% of the cohort were men, 21% were African American and 9% had CKD3. In the adjusted analyses, patients with CKD3 had a higher risk of metformin discontinuation or addition of a second hypoglycaemic agent, as compared with patients without CKD (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.19-1.26, and HR 1.26, 95% CI 1.13-1.40, respectively). Among metformin monotherapy users, there were no differences in the average HbA1c reduction from baseline to 12 or 24 months between patients with and without CKD3. CONCLUSIONS: Individuals with CKD3 and T2D were at increased risk of metformin monotherapy failure. However, the HbA1c-lowering efficacy of metformin was similar in patients with and without CKD3, highlighting that metformin is a valuable treatment option for newly treated individuals with T2D and CKD3.

Challenges and Strategies for Inpatient Diabetes Management in Older Adults.

Adults older than 65 years of age are the fastest growing segment of the U.S. population. Aging is also one of the most important risk factors for diabetes, and about one-third of all individuals with diabetes are in this age-group. Older people with diabetes are more likely to have comorbidities such as hypertension, ischemic heart disease, chronic kidney disease, and cognitive impairment, which lead to higher rates of hospital admissions compared with individuals without diabetes. Professional organizations have recommended patient-centric individualized glycemic reduction approaches, with an emphasis on potential harms of intensive glycemic control and overtreatment in older adults. Insulin therapy remains a mainstay of diabetes management in the inpatient setting regardless of patients' age; however, there is uncertainty about optimal glycemic targets during the hospital stay. Increasing evidence supports selective use of dipeptidyl peptidase-4 inhibitors, alone or in combination with low-dose basal insulin, in older noncritically ill patients with mild to moderate hyperglycemia. This article reviews the prevalence, diagnosis, and monitoring of, and the available treatment strategies for, diabetes among elderly patients in the inpatient setting.

Cinacalcet-Associated Resolution of Primary Hyperparathyroidism in a Patient With Normal Kidney Function.

Cinacalcet use is associated with risk of hypocalcemia; however, this risk has been mostly demonstrated in patients with chronic kidney disease. In this article, we describe a case of a 59-year-old male with primary hyperparathyroidism (PHPT), hypercalciuria, osteopenia, and normal kidney function who was started on cinacalcet for the management of recurrent hypercalcemia following prior unsuccessful parathyroidectomy. Within 6 months following cinacalcet commencement, he developed symptomatic and biochemical hypocalcemia requiring discontinuation of the medication and initiation of calcium supplementation. Over more than 3 years of follow-up, his calcium supplementation was gradually tapered off and then discontinued. He is presently eucalcemic and euparathyroid off calcium supplements while also demonstrating normalization of hypercalciuria and bone mineral density. These data indicate that our patient has experienced resolution of PHPT after brief exposure to cinacalcet. We recommend that low starting cinacalcet doses should be considered for treatment of hypercalcemia in patients with PHPT who underwent unsuccessful parathyroidectomy along with close clinical and biochemical follow-up.

Effect of Blueberry Consumption on Cardiometabolic Health Parameters in Men with Type 2 Diabetes: An 8-Week, Double-Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: Blueberries are dietary sources of polyphenols, specifically anthocyanins. Anthocyanins have been identified as having a strong association with type 2 diabetes risk reduction; however, to date few human clinical trials have evaluated the potential beneficial health effects of blueberries in populations with type 2 diabetes. OBJECTIVES: We investigated the effects of blueberry consumption for 8 wk on cardiometabolic parameters in men with type 2 diabetes. METHODS: In a double-blind, parallel-arm, randomized controlled trial, 52 men who are US veterans [mean baseline characteristics: age, 67 y (range: 51-75 y); weight, 102 kg (range: 80-130 kg); BMI (in kg/m2), 34 (range: 26-45)] were randomly assigned to 1 of 2 intervention groups. The interventions were either 22 g freeze-dried blueberries or 22 g placebo. The study participants were asked to consume 11 g freeze-dried blueberries or placebo with each of their morning and evening meals along with their typical diet. RESULTS: Mean ± SE hemoglobin A1c (7.1% ± 0.1% compared with 7.5% ± 0.2%; P = 0.03), fructosamine (275.5 ± 4.1 compared with 292.4 ± 7.9 µmol/L; P = 0.04), triglycerides (179.6 ± 10.1 compared with 199.6 ± 19.9 mg/dL; P = 0.03), aspartate transaminase (23.2 ± 1.4 compared with 30.5 ± 2.7 units/L; P = 0.02), and alanine transaminase (35.6 ± 1.5 compared with 48.3 ± 2.9 units/L; P = 0.0003) were significantly lower for those consuming blueberries for 8 wk than for those consuming the placebo. Fasting plasma glucose concentrations; serum insulin, total cholesterol, LDL-cholesterol, HDL-cholesterol, and C-reactive protein concentrations; blood pressure; and body weight were not significantly different after 8 wk consumption of blueberries compared with the placebo. CONCLUSIONS: Consumption of 22 g freeze-dried blueberries for 8 wk may beneficially affect cardiometabolic health parameters in men with type 2 diabetes.This trial was registered at clinicaltrials.gov as NCT02972996.

Metformin is associated with increase in lactate level in elderly patients with type 2 diabetes and CKD stage 3: A case-control study.

The FDA has recently endorsed metformin use in patients with T2D and stage 3 CKD (CKD3). However, metformin safety in elderly individuals is unknown. The aim of this study was to identify frequency and risk factors of lactic acid (LA) elevation in ambulatory elderly male US veterans with stable diabetic CKD3 treated with metformin. We studied 92 patients with non-diabetic CKD3 (Group1), diabetic CKD3 not on metformin (Group2) and diabetic CKD3 on metformin (Group 3). Mean LA levels were similar at 1.3 ±â€¯0.3 and 1.3 ±â€¯0.4 mmol/L in Groups 1 and 2, respectively; while, LA was significantly higher in Group 3 (2.1 ±â€¯1.0 mmol/L, P < .001). Only 1 patient in each Groups 1 (4%) and 2 (4%) had hyperlactatemia (LA > 2.0 mmol/L), as compared with 17 (42.5%) patients in Group 3 (P < .05). No differences in age, BMI, eGFR, metformin dosage, and HbA1c were seen in Group 3 patients with and without hyperlactatemia. In the multivariate logistic regression analyses, metformin use was the only factor significantly associated with hyperlactatemia (adjusted OR 25.48, P < .005). In conclusion, metformin therapy is associated with increased risk of hyperlactatemia in elderly men with diabetic CKD3.

Hypertension Management in Diabetes: 2018 Update.

IN BRIEF Several guidelines and position statements are published to help clinicians manage hypertension in patients with diabetes. Although there is an unequivocal call to treat hypertension in diabetes, professional organizations and experts have differing opinions regarding the most optimal blood pressure targets and treatments to lower vascular risks in the diabetes population. The objective of this article is to summarize the most recent hypertension management guidelines with particular attention to the origins and evidence behind these recommendations.

Utility of DXA screening for diagnosis of osteoporosis in US veterans aged 70 years and older.

Dual energy X-ray absorptiometry (DXA) is recommended for osteoporosis screening in men aged 70 years and older but supportive data is limited. The aim of this study was to determine the efficacy of DXA for the diagnosis of increased fragility in this group of subjects. We retrospectively identified men aged 70 years and older without prior history of fracture and/or conditions predisposing to low bone mineral density (BMD) who attended the VA endocrinology clinic and performed DXA for osteoporosis screening. We analyzed the relationship between BMD and demographic, anthropometric data and biochemical parameters using linear regression models. Out of 55 subjects identified, 13 (24%) men had normal BMD, 30 (54%) had osteopenia and 12 (22%) had a diagnosis of osteoporosis based on the femoral neck (FN) T-score. Lumbar spine T-scores were normal in all three groups. Weight and body mass index (BMI) were significantly higher in the normal BMD group compared with the osteopenia and osteoporosis groups (p<0.001). After adjustments for age, weight, BMI, vitamin D concentrations, and diabetes status, differences in the FN BMD among the groups remained significant (p<0.001). Based on the Fracture Risk Assessment Tool (FRAX) score calculations in 43 non-osteoporotic patients, 15 patients with osteopenia had a 10-year hip fracture probability ≥3%. Screening with DXA in male US veterans aged 70 years and older without known osteoporosis risk factors revealed that up to 50% of men may qualify for diagnostic workup to determine the etiology of low BMD and/or to meet criteria to initiate pharmacological therapy to reduce future fracture risk.

Hyperglycemic, high anion-gap metabolic acidosis in patients receiving SGLT-2 inhibitors for diabetes management.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are a class of antidiabetic medications that improve glycemic control via inhibiting the reabsorption of filtered glucose and are approved for use in type 2 diabetes (T2DM). These drugs have recently been associated with euglycemic diabetic ketoacidosis (DKA). An increasing number of cases of SGLT-2i-associated DKA have occurred in patients with T2DM. Herein, we describe five episodes of hyperglycemic DKA in four type 2 diabetes patients receiving SGLT-2i therapy. Risk for ketoacidosis in our case series was mediated predominately by reduction of insulin dose and insulinopenia. None of the patients reported a history of low carbohydrate diet or alcohol use, and all but one patient had negative glutamic acid decarboxylase antibodies. Resolution of DKA in SGLT-2i treated patients took longer than for T1DM patients with DKA based on literature data. The mechanisms by which SGLT-2i are associated with ketoacidosis are not fully understood and likely involve hyperglucagonemia and other factors. Further studies are needed to elucidate the precise mechanism.

Osteoporosis in patients with diabetes after kidney transplantation.

Preexisting diabetes increases risk of fractures after kidney transplantation (KT). However, little is known about mechanisms and prevention of increased fragility in these patients. Pathophysiology of osteoporosis after KT is complex and characterized by high prevalence of adynamic bone disease. Despite high prevalence of preexisting diabetes in KT recipients, diabetes patients were underrepresented in the studies that explored mechanisms and treatments of osteoporosis after KT. Therefore, caution should be exercised before considering conventional fracture prevention strategies in this unique group of patients. Many traditional osteoporosis medications reduce bone turnover and, hence, can be ineffective or even harmful in diabetic patients after KT. Contrary to predictions, evidence from the studies conducted in mostly non-diabetic subjects demonstrated that bisphosphonates failed to reduce fracture rates after KT. Therefore, bisphosphonates use should be limited in diabetic patients until more evidence supporting their post-transplant efficacy is available. We recommend the following strategies that may help reduce fracture risk in diabetes subjects after KT such as adequate management of calcium, parathyroid hormone, and vitamin D levels, optimization of glycemic control, use of steroid-sparing immunosuppressive regimens, and fall prevention.