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What's new in endocrinology and diabetes mellitus
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2014. | This topic last updated: Apr 15, 2014.

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.


Fatal hepatotoxicity with ketoconazole (October 2013)

Ketoconazole is considered to be the first-line medical therapy to control hypercortisolism in patients with Cushing's syndrome when surgery is delayed, contraindicated, or unsuccessful. However, in 2013, the US Food and Drug Administration issued a warning about the risk of potentially fatal liver toxicity with ketoconazole use; cases have occurred in patients with no pre-existing liver disease or serious underlying medical conditions [1]. Although the warning was primarily issued for the use of ketoconazole in the management of fungal infections, some recommendations are relevant to its use in Cushing’s syndrome. Ketoconazole is contraindicated in patients with acute or chronic liver disease; liver function tests should be performed prior to starting treatment; and serum alanine transferase (ALT) should be monitored closely after starting therapy. (See "Ketoconazole (systemic): Drug information" and "Medical therapy of hypercortisolism (Cushing’s syndrome)", section on 'Ketoconazole'.)


Mediterranean diet and diabetes prevention (February 2014)

The Mediterranean diet has been associated with several health benefits. In an exploratory analysis of a trial designed to compare the cardiovascular outcomes of two different Mediterranean diets with a low fat diet in men and women at high risk for cardiovascular disease, the incidence of new diabetes could be ascertained in a subgroup of 3541 individuals [2]. The risk of developing diabetes at four-year follow-up was decreased in the groups assigned to the Mediterranean diets. The original trial and the exploratory analysis had several limitations, and randomized trials of Mediterranean diets with diabetes as a primary endpoint are needed before they can be recommended for diabetes prevention. (See "Prevention of type 2 diabetes mellitus", section on 'Diet'.)

Eighth Joint National Committee (JNC-8) guidelines for hypertension (December 2013)

The eighth Joint National Committee (JNC-8) has released new guidelines for the treatment of hypertension [3]. The major change compared with the older JNC-7 guidelines is a higher blood pressure goal for older adults (60 years and older) and for patients with diabetes mellitus or chronic kidney disease. These new guidelines are largely consistent with previous UpToDate recommendations. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Goal blood pressure' and "Treatment of hypertension in the elderly patient, particularly isolated systolic hypertension", section on 'Goal blood pressure'.)

Rosiglitazone (December 2013)

The US Food and Drug Administration has reversed restrictions placed in 2010 on the use of rosiglitazone for the treatment of type 2 diabetes [4]. There had been concerns about cardiovascular safety with this drug. However, the RECORD study, published in 2009, and designed as a noninferiority study comparing rosiglitazone with metformin or sulfonylurea with the premise that rosiglitazone would be beneficial for cardiovascular disease, found no difference in cardiovascular hospitalizations or mortality. Reevaluation of the cardiovascular outcomes data by an independent group showed similar results [5]. Sales of rosiglitazone remain suspended in Europe. (See "Thiazolidinediones in the treatment of diabetes mellitus", section on 'RECORD study'.)

Combination ACE inhibitor and ARB therapy in diabetic nephropathy (November 2013)

Combination therapy with an ACE inhibitor plus an ARB should not be used in patients with diabetic nephropathy. The VA NEPHRON-D trial randomly assigned 1448 patients with diabetic nephropathy to lisinopril or placebo; all patients also received losartan [6]. The trial was discontinued early (after a median of 2.2 years) because of safety concerns. The primary event rate (a 50 percent or 30 mL/min/1.73m2 decline in estimated GFR, end-stage renal disease, or death) occurred with similar frequency in both groups, while acute kidney injury requiring hospitalization or occurring during hospitalization was significantly more common with combination therapy (18.0 versus 11.0 percent), as was severe hyperkalemia (9.9 versus 4.4 percent). (See "Treatment of diabetic nephropathy", section on 'Combination ACE inhibitor and ARB therapy'.)

DPP-4 inhibitors and cardiovascular safety (October 2013)

There are a growing number of trials evaluating the cardiovascular safety of DPP-4 inhibitors. In two different trials, patients with type 2 diabetes and either a history of cardiovascular disease or multiple risk factors for vascular disease were randomly assigned to one of the DPP-4 inhibitors (saxagliptin, alogliptin) or placebo, in addition to other diabetes medications (predominantly metformin, sulfonylureas, insulin) [7,8]. The primary endpoint (a composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke) occurred in a similar proportion of patients in both groups. Although heart failure was infrequent in both groups, significantly more patients in the saxagliptin group were hospitalized for heart failure. Although these data are reassuring in that there does not appear to be an increased risk of adverse cardiovascular outcomes with short-term (two-year) treatment with DPP-4 inhibitors used in combination with other agents, longer-term clinical trials are needed to definitively assess the cardiovascular safety of DPP-4 inhibitors. (See "Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)


Oral emergency contraception in overweight women (February 2014)

In Europe, product labeling for levonorgestrel-based emergency contraception (NorLevo) was recently updated to indicate that it may be less effective in women ≥75 kg (165 pounds) and not effective in women >80 kg (176 pounds) [9,10]. We counsel overweight and obese women about potentially reduced or absent efficacy of levonorgestrel emergency contraception as body mass index increases above the normal range (25) or at weights ≥75 kg (165 pounds). (See "Emergency contraception", section on 'Overweight and obese women'.)

Obesity and outcomes of IVF with donor oocytes (January 2014)

Obesity is associated with infertility, an increased risk of miscarriage, and a decreased conception rate when undergoing in vitro fertilization (IVF) with autologous oocytes. However, a meta-analysis of six studies that included 4758 women undergoing IVF with donor oocytes suggests that obesity may not have a negative impact on outcomes of this procedure [11]. Similar rates of pregnancy, miscarriage, and live birth were observed for obese (BMI >30 kg/m2) and normal weight (BMI 20 to 24.9 kg/m2) women. Since the vast majority of studies report adverse reproductive outcomes in obese women compared to normal weight women, however, women should be counseled about the benefits of weight loss prior to pursuing fertility. (See "Oocyte donation for assisted reproduction", section on 'Obese women'.)

Diagnosis of polycystic ovary syndrome in postmenopausal women (December 2013)

The diagnosis of polycystic ovary syndrome (PCOS) is almost always made during adolescence or early adulthood based upon two out of three of the following criteria: oligomenorrhea, hyperandrogenism, and polycystic ovaries on ultrasound. However, occasional women do not seek intervention during their reproductive years and first present after menopause with longstanding hirsutism and/or alopecia. There currently are no established criteria for making the diagnosis of PCOS in postmenopausal women. The 2013 practice guidelines from the Endocrine Society state that a presumptive diagnosis of PCOS in a postmenopausal woman can be based upon a “well-documented long-term history of oligomenorrhea and hyperandrogenism during the reproductive years” [12]. Finding polycystic ovary morphology on pelvic ultrasound would provide additional support, although ovarian volume and follicle number decrease with age in women with or without PCOS. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Postmenopausal women'.)

In vitro fertilization with donor oocytes: US trends (November 2013)

Analysis of US data for in vitro fertilization with donor oocytes from 2000 to 2010, reported by the Centers for Disease Control (CDC) and the National Assisted Reproductive Technology (ART) Surveillance System (NASS), found an increase in the annual number of donor oocyte cycles from 10,801 to 18,306, and an increase in good perinatal outcomes, defined as a singleton live-born infant delivered at 37 weeks or later and weighing 2500 g or more (18.5 to 24.4 percent) [13]. Use of frozen rather than fresh embryos, and transfer of single rather than multiple embryo transfers, are increasing. (See "Oocyte donation for assisted reproduction", section on 'Current trends'.)


Extra-long acting injectable testosterone preparation approved in US (March 2014)

Testosterone undecanoate is an extra-long acting parenteral testosterone ester developed for the treatment of male hypogonadism; it has been available in several countries outside the United States, but is now approved in the US as well [14]. Unlike other testosterone esters (enanthate and cypionate) that require injection every one to two weeks, testosterone undecanoate is administered every 10 to 14 weeks. However, this preparation has been associated with rare, but important adverse events: pulmonary oil microembolism (POME) and anaphylaxis (1.5 and 0.4 cases per 10,000 injections, respectively) [15]. In the United States, the drug will only be available through a restricted program called the AVEED Risk Evaluation and Mitigation Strategy (REMS) Program. All injections must be administered in an office or hospital setting and monitored for 30 minutes afterwards for adverse reactions. (See "Testosterone treatment of male hypogonadism", section on 'Extra-long-acting injections'.)

Testosterone and cardiovascular safety (March 2014)

The US Food and Drug Administration (FDA) is investigating data about a possible increase in cardiovascular events in men taking testosterone replacement therapy [16]. Earlier studies did not find evidence of excess cardiovascular risk in hypogonadal men receiving testosterone, but a 2010 trial in men aged 65 and older was stopped early because of adverse cardiovascular events. Two more recent retrospective cohort studies also suggest there might be a higher rate of cardiovascular events in some men who take testosterone [17,18]. However, all three studies have important methodological limitations. Given the uncertainty of these data, we continue to recommend that testosterone be administered only to men who are hypogonadal, as evidenced by clinical symptoms and signs consistent with androgen deficiency and a subnormal morning serum total testosterone concentration on three occasions. (See "Testosterone treatment of male hypogonadism", section on 'Cardiovascular risks'.)

Tamoxifen in dietary supplements for athletic performance (March 2014)

Tamoxifen, an antiestrogen, has been identified as an unlabeled ingredient in dietary supplements marketed to enhance athletic performance [19]. Bodybuilders and other athletes who take exogenous testosterone frequently take tamoxifen (10 to 20 mg/day) to prevent gynecomastia. Tamoxifen doses in one supplement, EstoSuppress, were as high as 7.6 mg/day, close to the therapeutic doses (10 to 20 mg/day for painful gynecomastia and male breast cancer) that have been associated with venous thromboembolism (VTE) [20]. In athletes using androgens and tamoxifen, inadvertent use of additional tamoxifen from dietary supplements could add to the already elevated VTE risk. (See "Use of androgens and other hormones to enhance athletic performance", section on 'Antiestrogens'.)


Obesity prevalence in preschool children (March 2014)

In the United States, the overall prevalence of childhood obesity tripled between the early 1980s and 2000, then reached a plateau. Now, a nationwide population study has reported a dramatic decrease in obesity among preschool aged children (two to five years) [21]. In this age group, obesity rates peaked at 13.9 percent in 2004, then fell by 40 percent to 8.4 percent in 2011-2012. In the same study, the rates of obesity among older children and adolescents remained stable. (See "Definition; epidemiology; and etiology of obesity in children and adolescents", section on 'Trends'.)

Obesity usually is established before school entry (February 2014)

Longitudinal studies reveal that a substantial component of adolescent obesity is established before five years of age. In a large study from the United States, children who were overweight at entry into kindergarten were four times as likely to become obese by eighth grade as compared with normal-weight children [22]. Moreover, the severity of obesity was an important predictor of persistence. Among children who had mild obesity at entry into kindergarten (mean age 5.6 years), 47 percent remained obese in eighth grade (mean age 14.1 years). Among those who had severe obesity (BMI 99th percentile) in kindergarten, more than 70 percent remained obese in eighth grade (figure 1). These observations provide support for the concept of interventions early in life to prevent and treat obesity. (See "Definition; epidemiology; and etiology of obesity in children and adolescents", section on 'Persistence into adulthood'.)


Sclerostin inhibitors for osteoporosis (January 2014)

Sclerostin is produced by osteocytes and inhibits bone formation. Inhibition of sclerostin, therefore, should enhance osteoblast function and improve bone mass. In a phase 2 trial in postmenopausal women, the highest monthly dose of a monoclonal anti-sclerostin antibody (romosozumab) led to greater increases in bone density at the lumbar spine, total hip, and femoral neck compared with oral alendronate (dosed weekly), subcutaneous teriparatide (daily) or placebo (monthly or every three months) [23]. Ramosozumab led to a transient increase in bone formation markers and a more sustained decrease in bone resorption markers, a pattern not seen with available osteoporosis therapies. There was an increased frequency of injection site reactions in the romosozumab group. Ongoing trials should provide more information about antifracture efficacy and safety. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Emerging therapies'.)

Bisphosphonates and risk of atypical femur fractures (October 2013)

An international task force appointed by the American Society of Bone and Mineral Research published a report on atypical diaphyseal and subtrochanteric femoral fractures in 2010, which was updated in 2013 [24,25]. Although long-term use (median treatment seven years) of bisphosphonates increases the relative risk of atypical fractures, the absolute risk is low (3.2 to 50 cases per 100,000 person-years). The risk may rise with duration of bisphosphonate exposure. (See "The use of bisphosphonates in postmenopausal women with osteoporosis", section on 'Atypical femur fractures'.)


Familial hyperprolactinemia due to mutation in the prolactin receptor gene (December 2013)

Hyperprolactinemia is most commonly associated with pituitary tumors. A germline loss-of-function mutation in the prolactin receptor gene (PRLR), resulting in prolactin insensitivity, has been identified as a cause of familial hyperprolactinemia [26]. The family included three sisters, two with oligomenorrhea, one with primary infertility, and all with serum prolactin concentrations in the 100 to 180 ng/mL range (4.35 to 7.83 nmol/L) and normal pituitary MRIs. (See "Causes of hyperprolactinemia", section on 'Genetic'.)


Alemtuzumab and thyroid dysfunction (January 2014)

Alemtuzumab is a monoclonal antibody used as an antineoplastic agent and for the treatment of relapsing-remitting multiple sclerosis. It increases the risk of autoimmune disorders, including thyroid disease. In a trial evaluating alemtuzumab versus interferon–beta-1a in patients with multiple sclerosis, thyroid dysfunction occurred more frequently in patients taking alemtuzumab (34 versus 6.5 percent) [27]. Among patients with alemtuzumab-related thyroid dysfunction, Graves’ hyperthyroidism occurred most commonly (22 percent), followed by hypothyroidism and subacute thyroiditis (7 and 4 percent, respectively). (See "Drug interactions with thyroid hormones", section on 'Other'.)


Vitamin D and mortality (February 2014)

Some observational studies suggest that low serum 25-hydroxyvitamin D levels are associated with higher mortality. In a meta-analysis of 56 randomized trials that compared any type of vitamin D supplementation with placebo or no intervention, vitamin D resulted in a small but significant reduction in all-cause mortality (12.5 versus 12.7 percent) [28]. When different forms of vitamin D were assessed, only vitamin D3 significantly reduced all-cause and cancer mortality. Since mortality has not been reported in all vitamin D trials, there is the possibility of reporting bias where trials showing a mortality effect would be more likely to include results on mortality. (See "Vitamin D and extraskeletal health", section on 'Mortality'.)

Guidelines for vitamin D supplementation from the American Geriatrics Society (February 2014)

The optimal intake of vitamin D and the optimal serum 25-hydroxyvitamin D to prevent falls and fractures are uncertain. The American Geriatrics Society Workgroup on Vitamin D Supplementation recommends at least 1000 international units of vitamin D daily, as well as calcium supplements, for older adults (≥65 years) to reduce the risk of fractures and falls [29]. While some UpToDate authors suggest this dosing, other UpToDate authors suggest a lower dose (600 to 800 international units of vitamin D daily) for most older adults, in whom vitamin D intake and effective sun exposure are often suboptimal. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Calcium and vitamin D supplementation in osteoporosis", section on 'Optimal intake'.)

Vitamin D and muscle strength (January 2014)

Observational studies have shown an association between poor vitamin D status and muscle weakness, but it is not clear if vitamin D supplementation improves muscle strength. Results from previous randomized trials have been conflicting. In a trial from Norway, 251 immigrant adults (from South Asia, Middle East, and Africa, mean age 36 to 39 years) with vitamin D deficiency (mean serum 25(OH)D 10.4 ng/mL [26 nmol/L]) were randomly assigned to vitamin D3 supplementation or placebo [30]. After 16 weeks, there were no differences in measures of proximal leg muscle strength or handgrip strength. (See "Vitamin D and extraskeletal health", section on 'Muscle weakness'.)


Intensive insulin therapy in critically ill children (January 2014)

In critically ill adults, intensive insulin therapy (IIT) has not been shown to improve survival, and hypoglycemic events due to IIT may be associated with increased mortality. The effects of IIT in critically ill children are less well established. A randomized trial of nearly 1400 children in pediatric surgical intensive care units compared the effects of tight (blood glucose target 72 to 126 mg/dL [4 to 7 mmol/L]) and conventional (target 180 to 216 mg/dL [10 to 12 mmol/L]) glycemic control [31]. At 30 days, IIT did not affect mortality or number of ventilator-free days and resulted in more frequent episodes of severe hypoglycemia. However, the achieved target glucose level in the conventional group was lower than expected (114 mg/dL [6.3 mmol/L]), which may have limited the overall analysis. Although the optimal blood glucose level in critically ill children has not been well defined, these results suggest that, similar to adults, IIT is of no benefit and may be harmful when episodes of hypoglycemia are frequent. (See "Glycemic control and intensive insulin therapy in critical illness", section on 'Children'.)

Postmenopausal hormone therapy and primary open-angle glaucoma (February 2014)

Postmenopausal hormone therapy may reduce intraocular pressure and lower the risk of primary open-angle glaucoma (POAG), but the absolute risk reduction is small [32]. In a retrospective analysis of claims data from women over age 50 years, the calculated absolute risks of developing POAG for women taking four years of unopposed estrogen, combined estrogen-progestin, or no hormone therapy were 1.6, 1.7, and 2.1 percent, respectively. We do not consider this small reduction in glaucoma risk to be an important consideration in deciding whether to recommend short-term hormone therapy for menopausal symptoms. (See "Postmenopausal hormone therapy: Benefits and risks", section on 'Eyes'.)

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