Safety and Efficacy of Exenatide Once Weekly in Participants with Type 2 Diabetes and Stage 2/3 Chronic Kidney Disease.

INTRODUCTION: The safety and efficacy of exenatide once weekly (EQW) is overall well established. EQW is primarily renally eliminated. In this study, the efficacy and renal and gastrointestinal tolerability of EQW were summarised in participants with type 2 diabetes and chronic kidney disease stage 3 (CKD3; moderate renal impairment; estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) or CKD stage 2 (CKD2; mild renal impairment; eGFR ≥ 60 to < 90 mL/min/1.73 m2). METHODS: Data on participants with type 2 diabetes and baseline CKD3 or CKD2 from eight phase 3, double-blind or open-label studies with 26- or 28-week controlled treatment periods were pooled. Participants received EQW or a placebo/non-glucagon-like peptide-1 receptor agonist comparator (sitagliptin, metformin, pioglitazone, dapagliflozin and insulin). RESULTS: Participants with baseline CKD3 (N = 182) or CKD2 (N = 772) receiving EQW differed in a number of baseline characteristics, such as age < 65 years, race, mean body mass index and mean type 2 diabetes duration, whereas mean blood pressure and glycated haemoglobin (HbA1c) were similar. Mean reductions in HbA1c, body weight and systolic blood pressure from baseline to week 26/28 in participants receiving EQW were similar between the CKD subgroups. The proportions of participants (CKD3 and CKD2) with any adverse event (AE) were 81% and 72%, respectively, for EQW and 74% and 68%, respectively, for all comparators; those for serious AEs were 2.7% and 3.4%, respectively, for EQW and 6% and 5%, respectively, for all comparators. Gastrointestinal AE rates were higher in the EQW CKD3 subgroup (42.2% of participants) than in the CKD2 (32.8%) subgroup, although rates for nausea and vomiting were similar. There were no dehydration events; one participant in each treatment group had a serious AE of acute kidney injury (EQW with CKD3, n = 1; pioglitazone with CKD2, n = 1). CONCLUSION: Exenatide once weekly was well tolerated and demonstrated similar efficacy in participants with type 2 diabetes with mild and moderate renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00637273, NCT00676338, NCT02229383, NCT02229396, NCT00641056, NCT01652729, NCT00935532, NCT01003184.

Musculoskeletal manifestations of primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) can be associated with a variety of musculoskeletal complaints, which occasionally can be the leading or presenting manifestation. In this paper, we describe the musculoskeletal manifestations observed in patients with primary hyperparathyroidism. Medical record reviews of a select population of 74 patients with primary hyperparathyroidism are seen in a rheumatology practice. Bone manifestations included back pain in 11 patients (15.2 %), generalized bone pain in 7 patients (9.7 %), rib cage/chest pain in 6 (8.3 %), pseudoclubbing in 3, and a giant cell tumor of the mandible in 2 (2.3 %) patients. Articular manifestations such as chondrocalcinosis with or without apatite deposition disease were seen in 13 (17.7 %), arthralgias in 11 (15.2 %), and non-specific synovitis in 7 (9.7 %). Muscle weakness was observed in six patients (8.3 %) and myalgias in three (4.6 %). Less common manifestations such as Achilles tendon rupture, Jaccoud-like arthropathy, sacral insufficiency fracture, arthritis associated with fever of unknown origin (FUO), meningitis, cervical cord compression, and persistent headache were observed in single patients. Musculoskeletal findings are still a frequent and important presentation in patients with primary hyperparathyroidism seen in rheumatology practice. Some of these manifestations can be quite unusual and may represent diagnostic dilemmas to the practicing rheumatologist and/or endocrinologist.

Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce glycaemia and weight, and improve cardiovascular risk factors via different mechanisms. We aimed to compare the efficacy and safety of co-initiation of the GLP-1 receptor agonist exenatide and the SGLT2 inhibitor dapagliflozin with exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled by metformin. METHODS: DURATION-8 was a 28 week, multicentre, double-blind, randomised, active-controlled phase 3 trial done at 109 sites in six countries. Adults (aged ≥18 years) with type 2 diabetes and inadequate glycaemic control (HbA1c 8-12% [64-108 mmol/mol]) despite stable metformin monotherapy (≥1500 mg/day) were randomly assigned (1:1:1), via an interactive voice and web-response system, to receive once-weekly exenatide 2 mg by subcutaneous injection plus once-daily dapagliflozin 10 mg oral tablets, exenatide with dapagliflozin-matched oral placebo, or dapagliflozin with exenatide-matched placebo injections. Randomisation was stratified by baseline HbA1c (<9·0% vs ≥9·0% [<75 mmol/mol vs ≥75 mmol/mol]). The primary endpoint was change in HbA1c from baseline to week 28. Secondary endpoints were the change from baseline in fasting plasma glucose at week 2 and week 28, and 2 h postprandial glucose at week 28; the proportion of patients with an HbA1c less than 7·0% (<53 mmol/mol) at week 28; change in weight at week 28; the proportion of patients with weight loss of 5% or more at week 28; and change in systolic blood pressure at week 28. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02229396. FINDINGS: Between Sept 4, 2014, and Oct 15, 2015, we randomly assigned 695 patients to receive exenatide plus dapagliflozin (n=231), exenatide alone (n=231; n=1 untreated), or dapagliflozin alone (n=233). The intention-to-treat population comprised 685 participants (mean HbA1c 9·3% [SD 1·1]; 78 mmol/mol [12]), of whom 611 (88%) completed the study. After 28 weeks, the change in baseline HbA1c was -2·0% (95% CI -2·1 to -1·8) in the exenatide plus dapagliflozin group, -1·6% (-1·8 to -1·4) in the exenatide group, and -1·4% (-1·6 to -1·2) in the dapagliflozin group. Exenatide plus dapagliflozin significantly reduced HbA1c from baseline to week 28 compared with exenatide alone (-0·4% [95% CI -0·6 to -0·1]; p=0·004) or dapagliflozin alone (-0·6% [-0·8 to -0·3]; p<0·001). Exenatide plus dapagliflozin was significantly superior to either drug alone for all secondary efficacy endpoints, with greater reductions in fasting plasma and postprandial glucose, more patients with an HbA1c less than 7·0% (<53 mmol/mol), greater weight loss, a greater proportion of patients with weight loss of 5% or more, and greater reductions in systolic blood pressure (all p≤0·025). Adverse events were recorded in 131 (57%) of 231 patients in the exenatide plus dapagliflozin group, 124 (54%) of 230 patients in the exenatide group, and 121 (52%) of 233 patients in the dapagliflozin group. The most common adverse events (≥5% of patients in any group) were diarrhoea, injection-site nodules, nausea, and urinary tract infections. No episodes of major hypoglycaemia or minor hypoglycaemia were reported. INTERPRETATION: Co-initiation of exenatide and dapagliflozin improved various glycaemic measures and cardiovascular risk factors in patients with type 2 diabetes inadequately controlled by metformin monotherapy. The dual treatment regimen was well tolerated, with the expected safety profile for this combination. Additional data from an ongoing study (eg, AWARD-10; NCT02597049) will further inform the use of these drug classes in combination. FUNDING: AstraZeneca.

Incidence and severity of pancreatogenic diabetes after pancreatic resection.

BACKGROUND: While many patients experience prolonged survival after pancreatic resection for benign or malignant disease, the long-term risk of pancreatogenic diabetes mellitus (DM) remains poorly characterized. METHODS: One thousand one hundred seven patients underwent pancreatectomy at Thomas Jefferson University between 2006 and 2013. Attempts were made to contact all living patients by telephone and a DM-focused questionnaire was administered. RESULTS: Two hundred fifty-nine of 691 (37 %) surviving patients completed the survey, including 179 pancreaticoduodenectomies (PD), 78 distal pancreatectomies (DP), and 2 total pancreatectomies. In the PD group, 44 (25 %) patients reported having DM prior to resection. Of these, 5 (12 %) had improved glucose control after resection and 21 (48 %) reported escalated DM medication requirements post-resection. Of 135 PD patients without preoperative DM, 24 (18 %) had new-onset DM postoperatively. In the DP group, 23 patients (29 %) had DM preoperatively. None had improved glucose control after resection, while six (26 %) had worse control after resection. Seventeen of 55 DP patients (31 %) without preoperative DM developed new-onset DM postoperatively (p = 0.04 vs. PD). Preoperative HgbA1C >6.0 %, glucose >124 mg/dL, and insulin use >2 units per day were associated with an increased risk of new-onset postoperative DM. CONCLUSIONS: The development or worsening of DM after pancreatic resection is extremely common, with different types of resections conveying different risks for disease progression. DP places patients at a greater risk for the development of new-onset postoperative diabetes when compared to PD. In contrast, patients with preoperative diabetes are more likely to experience worsening of their disease after PD as compared to DP. Patients should be screened prospectively, particularly those at highest risk, and informed of and educated about the potential for post-resection DM.

Ovarian leydig cell hyperplasia: an unusual case of virilization in a postmenopausal woman.

Objective. To report an unusual case of ovarian Leydig cell hyperplasia resulting in virilization in a postmenopausal woman. Methods. Patient's medical history and pertinent literature were reviewed. Results. A 64-year-old woman presented with virilization with worsening hirsutism, deepening of her voice, male musculature, and male pattern alopecia. Her pertinent past medical history included type 1 diabetes, hyperlipidemia, and hypertension. Her pertinent past surgical history included hysterectomy due to fibroids. On further work-up, her serum total testosterone was 506 ng/dL (nl range: 2-45) and free testosterone was 40 pg/mL (nl range: 0.1-6.4). After ruling out adrenal causes, the patient underwent an empiric bilateral oophorectomy that showed Leydig cell hyperplasia on pathology. Six weeks postoperatively, serum testosterone was undetectable with significant clinical improvement. Conclusion. Postmenopausal hyperandrogenism can be the result of numerous etiologies ranging from normal physiologic changes to ovarian or rarely adrenal tumors. Our patient was found to have Leydig cell hyperplasia of her ovaries, a rarely reported cause of virilization.

Skin manifestations of hormone-secreting tumors.

Endocrine and metabolic diseases, besides affecting other organs, can result in changes in cutaneous function and morphology and can lead to a complex symptomatology. Dermatologists may see some of these skin lesions first, either before the endocrinologist, or even after the internist or specialist has missed the right diagnosis. Because some skin lesions might reflect a life-threatening endocrine or metabolic disorder, identifying the underlying disorder is very important, so that patients can receive corrective rather than symptomatic treatment. In this issue, we will review various hormone-secreting tumors, including pituitary disorders (Cushing's syndrome and acromegaly), hyperthyroidism, glucagonoma, carcinoid syndrome, mastocytosis, and hyperandrogenism. We will focus on clinical manifestations, mainly cutaneous, followed by a brief discussion on how to make the diagnosis of each condition in addition to treatment options.

Diabetes knowledge: are resident physicians and nurses adequately prepared to manage diabetes?

OBJECTIVE: To assess and compare the diabetes knowledge of nurses and residents in surgery, internal medicine, and family practice. METHODS: A 21-question survey based on current diabetes standards of care was developed and administered. The results were stratified by type of participant and analyzed statistically. RESULTS: A total of 52 internal medicine residents (IMR), 21 family practice residents (FPR), 42 surgery residents (SR), and 48 registered nurses (RN) participated. The survey had good overall internal consistency (Cronbach a of 0.78) and test-retest reliability (Pearson correlation coefficient of 0.71). The total mean percent correct for all participants was 61%. The total scores of IMR, FPR, and RN groups were similar (69%, 64%, and 66%) and significantly greater (P<0.001) than the SR score (44%). Collectively, all survey participants averaged less than 50% correct on several items. The IMR scored higher than the SR and FPR on several items. The nurses outscored the physicians on items regarding insulin preparations, treatment of hypoglycemia, and perioperative insulin management. A subgroup of 13 RN with additional diabetes training earned the highest total score (82%). CONCLUSION: Our novel survey was shown to be a statistically valid tool for assessment of diabetes knowledge. IMR, FPR, and inpatient RN have similar but insufficient levels of knowledge about diabetes. SR may have a more profound deficit of diabetes knowledge. Previous additional diabetes training among nurses was associated with greater diabetes knowledge. Most nurses and residents require additional education in order to provide optimal care to patients with diabetes.

Rare syndromes.

Dermatologists may also encounter patients presenting with skin lesions that reflect an underlying endocrine disorder not commonly seen in daily practice. Some of these endocrine disorders include glucagonoma, neurofibromatosis type 1, McCune-Albright syndrome, multiple endocrine neoplasia, the Carney complex, carcinoid tumors, and mastocytosis. The clinical syndrome classically associated with glucagonoma includes necrolytic migratory erythema, weight loss, diabetes mellitus, anemia, cheilitis, venous thrombosis, and neuropsychiatric symptoms. The hallmarks of neurofibromatosis type 1 are the multiple café-au-lait spots and associated cutaneous neurofibromas. Other presenting features include freckling, peripheral neurofibromas, Lisch nodules, bone abnormalities, tumors, neurologic abnormalities and hypertension. McCune-Albright syndrome is characterized by café-au-lait spots, polyostotic fibrous dysplasia, sexual precocity, and hyperfunction of multiple endocrine glands. Multiple endocrine neoplasia type 2A is characterized by medullary thyroid cancer, pheochromocytoma, and primary parathyroid hyperplasia. In some patients with multiple endocrine neoplasia type 2A, cutaneous lichen amyloidosis may also be present. Multiple endocrine neoplasia type 2B is characterized by medullary thyroid cancer and pheochromocytoma but not hyperparathyroidism. The syndrome also includes mucosal neuromas, typically involving the lips and tongue, intestinal ganglioneuromas and a marfanoid habitus. Multiple endocrine neoplasia type 1 is an autosomal dominant predisposition to tumors of the parathyroid glands (four-gland hyperplasia), anterior pituitary, and pancreatic islet cells; hence, the mnemonic device of the "3 Ps"; multiple cutaneous lesions (angiofibromas and collagenomas) are frequent in patients with multiple endocrine neoplasia type 1. Carney complex may be viewed as a form of multiple endocrine neoplasia because affected patients often have tumors of two or more endocrine glands, including primary pigmented nodular adrenocortical disease (some with Cushing's syndrome), pituitary adenoma, testicular neoplasms, thyroid adenoma or carcinoma, and ovarian cysts. Additional unusual manifestations include psammomatous melanotic schwannoma, breast ductal adenoma, and a rare bone tumor, osteochondromyxoma. Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various humoral factors elaborated by some carcinoid tumors; the major manifestations are diarrhea, flushing, bronchospasm, and cardiac valvular lesions. Mast cell diseases include all disorders of mast cell proliferation. These diseases can be limited to the skin, referred to as "cutaneous mastocytosis," or involve extracutaneous tissues, called "systemic mastocytosis." Patients present with urticaria pigmentosa, mastocytoma, or diffuse cutaneous mastocytosis. Systemic involvement may be gastronintestinal, hematologic, neurologic, and skeletal.

Insulin resistance, diabetes and cardiovascular risk: approaches to treatment.

The prevalence of diabetes is increasing worldwide. Insulin resistance and diabetes mellitus are major predictors of cardiovascular ischaemic disease. Other risk factors for cardiovascular death including hypertension, dyslipidaemia, smoking and visceral obesity are especially lethal in diabetics. C-reactive protein, plasminogen activator inhibitor-1, matrix metalloproteinases and other emerging risk factors and their roles are continually being researched and discovered. Treatment of this syndrome must be aimed at lifestyle modification, glycaemic control and management of concomitant risk factors. Diet and exercise play a vital role in the treatment of diabetes and the metabolic syndrome. Weight reduction and increased physical activity will improve insulin resistance, hyperglycaemia, hypertension and dyslipidaemia. Hypertension management has been shown to be especially important in diabetics to prevent cardiovascular events. Likewise, multiple clinical trials show that reduction of cholesterol is even more vital in diabetics than the general population for risk reduction of coronary disease. There is a great deal of evidence that tight control of glycaemia is essential to treatment of this condition. There are a variety of available pharmacological agents available including metformin, insulin secretagogues, alpha-glucosidase inhibitors, thiazolidinediones and insulin. The mechanisms and side effects of these medications are discussed. As macrovascular disease is the major cause of morbidity and mortality, an early, aggressive, multi-factorial approach to treatment of the metabolic syndrome and diabetes is vital to prevent adverse cardiac outcomes.

Cutaneous manifestations of endocrine disorders: a guide for dermatologists.

Dermatologists may commonly see skin lesions that reflect an underlying endocrine disorder. Identifying the endocrinopathy is very important, so that patients can receive corrective rather than symptomatic treatment. Skin diseases with underlying endocrine pathology include: thyrotoxicosis; hypothyroidism; Cushing syndrome; Addison disease; acromegaly; hyperandrogenism; hypopituitarism; primary hyperparathyroidism; hypoparathyroidism; pseudohypoparathyroidism and manifestations of diabetes mellitus. Thyrotoxicosis may lead to multiple cutaneous manifestations, including hair loss, pretibial myxedema, onycholysis and acropachy. In patients with hypothyroidism, there is hair loss, the skin is cold and pale, with myxedematous changes, mainly in the hands and in the periorbital region. The striking features of Cushing syndrome are centripetal obesity, moon facies, buffalo hump, supraclavicular fat pads, and abdominal striae. In Addison disease, the skin is hyperpigmented, mostly on the face, neck and back of the hands. Virtually all patients with acromegaly have acral and soft tissue overgrowth, with characteristic findings, like macrognathia and enlarged hands and feet. The skin is thickened, and facial features are coarser. Conditions leading to hyperandrogenism in females present as acne, hirsutism and signs of virilization (temporal balding, clitoromegaly).A prominent feature of hypopituitarism is a pallor of the skin with a yellowish tinge. The skin is also thinner, resulting in fine wrinkling around the eyes and mouth, making the patient look older. Primary hyperparathyroidism is rarely associated with pruritus and chronic urticaria. In hypoparathyroidism, the skin is dry, scaly and puffy. Nails become brittle and hair is coarse and sparse. Pseudohypoparathyroidism may have a special somatic phenotype known as Albright osteodystrophy. This consists of short stature, short neck, brachydactyly and subcutaneous calcifications. Some of the cutaneous manifestations of diabetes mellitus include necrobiosis lipoidica diabeticorum, diabetic dermopathy, scleredema adultorum and acanthosis nigricans.