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.

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.

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.

Evaluation and management of diabetic and non-diabetic hypoglycemia in end-stage renal disease.

Patients with end-stage renal disease (ESRD) regardless of diabetes status are at increased risk of hypoglycemia with a resultant array of adverse clinical outcomes. Therefore, hypoglycemia should be thoroughly evaluated in ESRD patients. In diabetic dialysis patients, hypoglycemic agents and nutritional alterations can trigger hypoglycemia in the background of diminished gluconeogenesis, reduced insulin clearance by the kidney and improved insulin sensitivity following initiation of renal replacement therapy. Detailed evaluation of antidiabetic regimen and nutritional patterns, patient education on self-monitoring of blood glucose and/or referral to a diabetes specialist may reduce risk of subsequent hypoglycemia. In certain situations, it is important to recognize the possibility of non-diabetic causes of hypoglycemia in patients with diabetes and to avoid treating pseudo-hyperglycemia caused by glucose- non-specific glucometers in patients utilizing icodextrin-based solutions for peritoneal dialysis. Adrenal insufficiency, certain medications, malnutrition and/or infection are among the most common causes of hypoglycemia in non-diabetic ESRD patients, and they should be suspected after exclusion of inadvertent use of hypoglycemic agents. The goal of this review article is to summarize approaches and recommendations for the work up and treatment of hypoglycemia in ESRD.

LEVOTHYROXINE REPLACEMENT IN OBESE HYPOTHYROID FEMALES AFTER TOTAL THYROIDECTOMY.

OBJECTIVE: Levothyroxine (LT4) replacement in hypothyroid obese patients is poorly understood. We assessed whether the LT4 regimen required to achieve euthyroidism differs between nonobese and obese hypothyroid females. METHODS: We retrospectively identified nonobese and obese females who received LT4 starting with a standard dose of 1.6 µg/kg after total thyroidectomy for preoperative diagnosis of benign goiter. We examined the association between LT4 dosage required to achieve euthyroid state (thyroid-stimulating hormone [TSH] 0.4-2.5 mIU/L) and patient characteristics using linear regression models with and without adjustment for age, ethnicity, medication use, and postoperative hypoparathyroidism. RESULTS: We identified 32 females (15 nonobese/17 obese) who achieved euthyroid state. Obese patients weighed more (104.1 ± 22.5 vs. 64.9 ± 10.0 kg, P<.0001) and required a higher final LT4 than nonobese (146 ± 38 vs. 102 ± 12 µg, P = .0002) but LT4 requirements per kg total body weight (TBW) were similar (1.60 ± 0.29 vs. 1.42 ± 0.38 µg/kg, P = .15). LT4 dose per kg ideal body weight (IBW) was higher in obese than in nonobese females (2.62 ± 0.67 vs. 1.88 ± 0.28 µg/kg, P = .0004) and this difference persisted after adjustments (P<.05). During LT4 titration, 47% and 20% of obese and nonobese patients had subnormal TSH episodes, respectively (P = .11). After taking LT4 compliance, malabsorption, and competing medication use into consideration, we found marked LT4 dose variability in obese patients. Patients who needed a mean daily LT4 dose ≤150 mg (124 ± 16 µg/day) compared with >150 µg (198 ± 4 µg/day) demonstrated lower LT4 per TBW (1.25 ± 0.18 vs. 1.84 ± 0.43 µg/kg, P = .03) and IBW (2.28 ± 0.47 vs. 3.44 ± 0.18 µg/kg, P<.0001), respectively. CONCLUSION: The standard approach to LT4 replacement in obese and nonobese females after thyroidectomy is imprecise. Mean daily LT4 doses in obese and nonobese patients were similar if expressed per kg TBW, though there was variability in the final LT4 among obese patients. We suggest initiating LT4 at a dose lower than that routinely recommended in obese females.

Management of hyperglycemia during enteral and parenteral nutrition therapy.

Hyperglycemia is a frequent complication of enteral and parenteral nutrition in hospitalized patients. Extensive evidence from observational studies indicates that the development of hyperglycemia during parenteral and enteral nutrition is associated with an increased risk of death and infectious complications. There are no specific guidelines recommending glycemic targets and effective strategies for the management of hyperglycemia during specialized nutritional support. Managing hyperglycemia in these patients should include optimization of carbohydrate content and administration of intravenous or subcutaneous insulin therapy. The administration of continuous insulin infusion and insulin addition to nutrition bag are efficient approaches to control hyperglycemia during parenteral nutrition. Subcutaneous administration of long-acting insulin with scheduled or corrective doses of short-acting insulin is superior to the sliding scale insulin strategy in patients receiving enteral feedings. Randomized controlled studies are needed to evaluate safe and effective therapeutic strategies for the management of hyperglycemia in patients receiving nutritional support.

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.

Medical nutrition therapy in hospitalized patients with diabetes.

Medical nutrition therapy (MNT) plays an important role in management of hyperglycemia in hospitalized patients with diabetes mellitus. The goals of inpatient MNT are to optimize glycemic control, to provide adequate calories to meet metabolic demands, and to create a discharge plan for follow-up care. All patients with and without diabetes should undergo nutrition assessment on admission with subsequent implementation of physiologically sound caloric support. The use of a consistent carbohydrate diabetes meal-planning system has been shown to be effective in facilitating glycemic control in hospitalized patients with diabetes. This system is based on the total amount of carbohydrate offered rather than on specific calorie content at each meal, which facilitates matching the prandial insulin dose to the amount of carbohydrate consumed. In this article, we discuss general guidelines for the implementation of appropriate MNT in hospitalized patients with diabetes.

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.

Effects of oral and intravenous fat load on blood pressure, endothelial function, sympathetic activity, and oxidative stress in obese healthy subjects.

We compared the effects of high and low oral and intravenous (iv) fat load on blood pressure (BP), endothelial function, autonomic nervous system, and oxidative stress in obese healthy subjects. Thirteen obese subjects randomly received five 8-h infusions of iv saline, 20 (32 g, low iv fat) or 40 ml/h intralipid (64 g, high iv fat), and oral fat load at 32 (low oral) or 64 g (high oral). Systolic BP increased by 14 ± 10 (P = 0.007) and 12 ± 9 mmHg (P = 0.007) after low and high iv lipid infusions and by 13 ± 17 (P = 0.045) and 11 ± 11 mmHg (P = 0.040) after low and high oral fat loads, respectively. The baseline flow-mediated dilation was 9.4%, and it decreased by 3.8 ± 2.1 (P = 0.002) and 4.1 ± 3.1% (P < 0.001) after low and high iv lipid infusion and by 3.8 ± 1.8 (P = 0.002) and 5.0 ± 2.5% (P < 0.001) after low and high oral fat load, respectively. Oral and iv fat load stimulated oxidative stress, increased heart rate, and decreased R-R interval variability. Acute iv fat load decreased blood glucose by 6-10 mg/dl (P < 0.05) without changes in insulin concentration, whereas oral fat increased plasma insulin by 3.7-4.0 µU/ml (P < 0.01) without glycemic variations. Intravenous saline and both oral and iv fat load reduced leptin concentration from baseline (P < 0.01). In conclusion, acute fat load administered orally or intravenously significantly increased blood pressure, altered endothelial function, and activated sympathetic nervous system by mechanisms not likely depending on changes in leptin, glucose, and insulin levels in obese healthy subjects. Thus, fat load, independent of its source, has deleterious hemodynamic effects in obese subjects.

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.

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.

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.

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.