Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
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.
Genetic predisposition in pediatric cancer (December 2015)
The prevalence and spectrum of mutations predisposing to cancer are not clear in pediatric cancer patients. In a study that used next-generation sequencing to determine the contribution of known germline predisposition mutations in over 1000 children and adolescents with cancer, pathogenic or probably pathogenic mutations were identified in 8.5 percent of cases . Mutations were most common in patients with adrenocortical cancers and osteosarcoma, but were also identified among patients with retinoblastoma, Ewing sarcoma, central nervous system tumors, rhabdomyosarcoma, leukemia, and neuroblastoma. Importantly, family history did not predict an underlying predisposition syndrome in most patients. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Hereditary cancer syndromes' and "Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and histology", section on 'Inherited conditions'.)
Metformin use and reduced kidney function (April 2016)
The use of metformin is contraindicated in patients with factors predisposing to lactic acidosis, including impaired renal function. The precise renal thresholds for the safe use of metformin remain uncertain. Improved clinical outcomes with metformin have been reported in observational studies of patients with diabetes and renal impairment (estimated glomerular filtration rate [eGFR] 45 to 60 mL/min). On the basis of these studies, the US Food and Drug Administration (FDA) revised its labeling of metformin, which previously had identified metformin as contraindicated in women and men with serum creatinine levels ≥1.4 mg/dL (124 micromol/L) and ≥1.5 mg/dL (133 micromol/L), respectively . The use of metformin is contraindicated in patients with an eGFR <30 mL/min, and the initiation of metformin is not recommended in patients with an eGFR between 30 and 45 mL/min. For patients taking metformin whose eGFR falls below 45 mL/min, the benefits and risks of continuing treatment should be assessed, whereas metformin should be discontinued if the eGFR falls below 30 mL/min. For patients with eGFR between 30 and 60 mL/min, we typically reduce the metformin dose by half (no more than 1000 mg per day), although there are no data to support this approach. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Contraindications'.)
Diabetes as a coronary risk equivalent (March 2016)
Diabetes mellitus (DM) is frequently referred to as a "coronary risk equivalent," meaning that the risk of a coronary heart disease (CHD) event is similar between individuals with DM and individuals with known CHD. However, this “equivalency” averages together patients with widely varying CHD risks, and many patients with DM have much lower risks. This was examined in a prospective cohort study that followed more than 1.5 million adults (ages 30 to 90) for a median of 9.9 years . The rate of new CHD events was lower in patients with DM than in those with a prior CHD event (12.2 versus 22.5 events per 1000 person-years); the risk of events was similar only in patients who had DM for more than 10 years. (See "Treatment of lipids (including hypercholesterolemia) in secondary prevention", section on 'Diabetes mellitus and CV risk'.)
DPP-4 inhibitors and heart failure outcomes in type 2 diabetes (February 2016)
Data from several trials in patients with type 2 diabetes are reassuring in that there does not appear to be an increased risk of adverse coronary heart disease outcomes with short-term use of dipeptidyl peptidase 4 (DPP-4) inhibitors, but concern has been raised about an increased risk of heart failure. A meta-analysis of randomized trials examining the association between DPP-4 inhibitors and heart failure outcomes found an increased risk of hospitalization for heart failure in DPP-4 users compared with placebo (five trials, event rate 3.4 versus 3.0 percent) . The patients in these trials, which were specifically designed to assess the cardiovascular safety of DPP-4 inhibitors, had cardiovascular disease (CVD) or multiple risk factors for CVD. In 38 trials not specifically designed to assess cardiovascular safety, but in which heart failure events were reported, there was no difference in the risk of heart failure between DPP-4 treated patients and controls (event rates 0.27 and 0.26). This analysis suggests a small increased risk of hospitalization for heart failure with DPP-4 inhibitor use in patients with type 2 diabetes who have existing CVD or multiple risk factors for CVD. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
Intranasal glucagon for severe hypoglycemia in patients with diabetes (January 2016)
Hypoglycemia is an important problem in patients with diabetes who use insulin, a sulfonylurea, or a meglitinide. The treatment of severe hypoglycemia, when a patient is unconscious or unable to ingest carbohydrate, requires that close contacts be trained to recognize this complication and administer subcutaneous or intramuscular glucagon while awaiting emergency medical services. An intranasal formulation of a glucagon powder that does not require inhalation or other cooperation from a patient is under investigation. In a randomized trial comparing intranasal (3 mg) and intramuscular (1 mg) glucagon in 77 patients with type 1 diabetes and hypoglycemia (induced in a controlled setting by administering insulin), successful reversal of hypoglycemia occurred in 98.7 and 100 percent of intranasal glucagon and intramuscular glucagon visits, respectively . Mean time to success was slightly longer for intranasal than intramuscular administration (16 versus 13 minutes), a delay that will likely be offset by the time required for caregivers to prepare and administer intramuscular glucagon. Intranasal glucagon remains investigational and is not commercially available. (See "Management of hypoglycemia during treatment of diabetes mellitus", section on 'Severe'.)
Screening for diabetes mellitus (January 2016)
Although it has not been firmly established that screening for type 2 diabetes improves long-term outcomes, well-established treatments for diabetes can reduce progression to microvascular disease and early identification of diabetes allows interventions to prevent or limit cardiovascular disease. The US Preventive Services Task Force (USPSTF) has issued new recommendations for diabetes screening. Previously, the USPSTF only recommended screening for diabetes in adults with hypertension, but the new guideline recommends screening for diabetes as part of cardiovascular risk assessment in adults aged 40 to 70 years with body mass index (BMI) ≥25 kg/m2 . The USPSTF suggests screening every three years based on limited evidence. We agree with the new USPSTF guideline and also suggest diabetes screening for adults with hypertension or hyperlipidemia. A fasting plasma glucose (FPG) and/or a glycated hemoglobin (A1C) are the preferred screening tests. (See "Screening for type 2 diabetes mellitus", section on 'A suggested approach'.)
Lixisenatide and cardiovascular outcomes (December 2015)
Glucagon-like peptide-1 (GLP-1) receptor agonists improve glycemic control; however, there are few studies assessing clinically important cardiovascular health outcomes. In one such trial, 6068 patients with type 2 diabetes and a recent acute coronary event were randomly assigned to receive the GLP-1 agonist lixisenatide (not yet available in the United States) or placebo, in addition to other diabetes medications (predominantly metformin, insulin, and sulfonylureas) . After a median follow-up of 25 months, the primary endpoint (a composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) occurred in a similar proportion of patients (13.4 and 13.2 percent in the lixisenatide and placebo groups, respectively). There was no significant difference in any of the individual components of the composite endpoint. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
Goal blood pressure in diabetic patients (December 2015)
The Systolic Blood Pressure Intervention Trial (SPRINT) found that more intensive as compared with standard blood pressure control reduced mortality and major cardiovascular events in nondiabetic hypertensive patients at high cardiovascular risk . Despite not enrolling patients with diabetes, SPRINT findings are indirectly applicable to diabetic patients, who also have a high cardiovascular risk. Based upon data from SPRINT, plus information from previous goal blood pressure trials performed in patients with diabetes, UpToDate now suggests a goal blood pressure of 120-125/<90 mmHg in diabetic patients (if automated oscillometric blood pressure readings are used to measure blood pressure), or a goal blood pressure of 125-130/<90 mmHg (if manual ausculatory measurements are used), rather than a goal blood pressure of <140/<90 mmHg (using manual ausculatory measurements). (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Conclusions about goal blood pressure'.)
Effects of hormonal contraceptives on libido (March 2016)
Available data on the effect of hormonal contraceptives on female sexuality are inconsistent. In the largest study to address this issue, a prospective cohort study found that women who used the copper intrauterine device (IUD) reported lower rates of lack of interest in sex than women using depot medroxyprogesterone, the progestin implant, and the estrogen-progestin vaginal ring, but rates similar to users of the progestin IUD, estrogen-progestin oral contraceptive, and estrogen-progestin patch . In a subset of participants who were using no contraceptive method or withdrawal at baseline, lack of interest in sex at six months was less than at baseline (24 versus 42 percent). Further study is needed to understand whether and how hormonal contraceptives impact sexual function. (See "Sexual dysfunction in women: Epidemiology, risk factors, and evaluation", section on 'Hormonal contraceptives'.)
Zika virus and tissue/gamete donation (March 2016)
Zika virus has been detected in a number of tissues and body fluids. To avoid possible transmission of Zika virus infection, the US Food and Drug Administration (FDA) has issued donor deferral recommendations for hematopoietic stem cells, tissues, and donor sperm or eggs; the recommendations do not apply to solid organs . Living donors with Zika virus infection or relevant epidemiologic exposure (residence in or travel to an area where mosquito-borne transmission of Zika virus infection has been reported, or unprotected sexual contact with a person who meets these criteria) should be considered ineligible for donation for six months. Deceased donors with Zika virus infection in the preceding six months should also be considered ineligible. The deferral period recommended by the FDA for blood donors with risk factors for Zika virus infection remains at four weeks. (See "Zika virus infection: An overview", section on 'Blood/tissue donation'.)
Metformin use in nondiabetic obese pregnant women does not improve neonatal outcome (February 2016)
It has been hypothesized that administering metformin to nondiabetic obese pregnant women might reduce gestational weight gain and, in turn, pregnancy complications associated with obesity. In the Metformin in Obese Nondiabetic Pregnant Women randomized trial, metformin use in the second and third trimesters reduced gestational weight gain compared with placebo (4.6 versus 6.3 kg) and the rate of preeclampsia (3 versus 11.3 percent), but did not reduce the frequency of large for gestational age neonates or adverse neonatal outcomes . Based on these and other recent data , we believe use of metformin in pregnancy should be limited to management of hyperglycemia. (See "Weight gain and loss in pregnancy", section on 'Metformin'.)
Novel genetic mutations identified as cause of female infertility (January 2016)
The genetic events that disrupt normal human oocyte maturation are unknown. In a recent study, seven novel mutations in the gene TUBB8 were identified in women with primary infertility . TUBB8 mutations impact only oocytes and result in oocyte meiosis I arrest, which leads to fertilization failure. Although a clinical test is not available, identification of these gene mutations opens new pathways for fertility research and diagnosis for women with primary infertility. (See "Causes of female infertility", section on 'Genetic causes'.)
Vaginal progesterone does not reduce recurrent pregnancy loss (December 2015)
Progesterone produced by the corpus luteum is essential to achieve and maintain pregnancy during most of the first trimester. Vaginal progesterone supplements have been prescribed for women with unexplained recurrent pregnancy loss (RPL) in an attempt to improve outcome, but the benefit has been unclear. In a recent trial that randomly assigned over 800 women with unexplained RPL (defined as three or more consecutive or non-consecutive unexplained first trimester miscarriages) to vaginal progesterone or placebo therapy from diagnosis of pregnancy through 12 weeks of gestation, approximately two-thirds of women in both groups delivered a live infant after 24 weeks of gestation . This trial provides the best evidence to date that vaginal progesterone therapy does not improve live birth rates once a pregnancy has been established. We recommend not using supplemental vaginal progesterone for women with unexplained RPL. (See "Management of couples with recurrent pregnancy loss", section on 'Progesterone'.)
Cardiovascular effects of early versus late menopausal hormone therapy (April 2016)
The Women's Health Initiative reported that menopausal hormone therapy is associated with an excess risk of coronary heart disease, but accumulating data suggest that estrogen therapy started soon after menopause does not increase risk. In The Early versus Late Intervention Trial with Estradiol (ELITE), 643 postmenopausal women, stratified according to time since menopause (<6 or >10 years; early versus late, respectively), received oral estradiol (with progesterone for women with a uterus) or placebo for a median of five years . Progression of subclinical atherosclerosis (measured as carotid intima-medial thickness) was slower with hormone therapy than with placebo in the early intervention group, while rates of progression were similar to placebo in the late intervention group. Estradiol had no effect on computed tomography measures of coronary artery calcium in either the early or late intervention group. (See "Menopausal hormone therapy: Benefits and risks", section on 'Younger postmenopausal women'.)
Endocrine Society Statement: Bioidentical hormone therapy (April 2016)
The Endocrine Society has issued a Scientific Statement warning against the use of custom compounded "bioidentical hormone therapy" for managing menopausal symptoms . This term refers to the use of custom-compounded, multi-hormone regimens (pills, gels, sublingual tablets, or suppositories) with dose adjustments based upon serial hormone monitoring. Compounded preparations typically include estradiol, estrone, estriol, progesterone, testosterone, and dehydroepiandrosterone (DHEA). Included among the key points were the absence of randomized trials demonstrating either efficacy or safety of compounded bioidentical hormone therapy for treating menopausal symptoms and the absence of regulatory oversight. When tested, potencies and patterns of absorption of compounded estrogens have been highly variable. Women who choose to take menopausal hormone therapy should be encouraged to use approved and regulated preparations of bioidentical hormones (for example, 17-beta estradiol and micronized progesterone). (See "Treatment of menopausal symptoms with hormone therapy", section on 'Bioidentical hormone therapy'.)
Acupuncture ineffective for menopausal hot flashes (January 2016)
It is estimated that up to 75 percent of postmenopausal women use complementary therapies to treat their menopausal symptoms, despite little evidence of efficacy. Acupuncture is among the most frequently used, but results from clinical trials have been conflicting. The best evidence to date that acupuncture is no more effective than placebo (sham-acupuncture) comes from a trial in 327 peri- or postmenopausal women with moderate to severe hot flashes who were randomly assigned to 10 traditional Chinese acupuncture or noninsertive sham acupuncture treatments over eight weeks . Hot flash (HF) scores, a calculated score based upon HF frequency and severity, were no different between the groups at the end of treatment (both showed approximately 40 percent improvement). Thus, like other nonhormonal and complementary therapies for hot flashes, acupuncture has an important placebo effect, but it has no additional benefit over sham acupuncture. (See "Menopausal hot flashes", section on 'Inconsistent evidence of efficacy'.)
Cardiovascular safety of bupropion-naltrexone remains unknown (March 2016)
Bupropion-naltrexone is available as an adjunct to diet and exercise in patients with body mass index ≥30 kg/m2 or ≥27 kg/m2 in the presence of at least one weight-related comorbidity. There has been uncertainty about its cardiovascular (CV) safety because it can raise blood pressure and heart rate. A randomized trial designed to assess CV outcomes of bupropion-naltrexone compared with placebo in 8910 overweight or obese patients at increased CV risk was terminated early due to public release of confidential interim data by the sponsor . Interim analyses were performed after 25 and 50 percent of planned events, and the final analysis after 64 percent of originally planned end points. Although in the final analysis the primary outcome (time to first major adverse CV event) occurred in a similar proportion of patients in each group, the data should be interpreted with caution. As more data were accumulated after the first interim analysis, the active treatment group experienced more adverse CV events, as evidenced by increasing point estimates (hazard ratios 0.59, 0.88, and 0.95, respectively). Because the trial was terminated early, it is unclear how to interpret these data, and the cardiovascular safety remains unknown. (See "Obesity in adults: Drug therapy", section on 'Cardiovascular effects'.)
Normal-weight central obesity and mortality (December 2015)
Overall obesity, as defined by body mass index (BMI), has been thought to play the major role in the obesity-associated excess risk of cardiovascular morbidity and mortality, with abdominal or central obesity (as defined by an increased waist-to-hip ratio [WHR]) playing an independent but lesser role. However, data from the Third National Health and Nutrition Examination Survey suggest that normal-weight central obesity (normal BMI with increased WHR) is associated with higher mortality than BMI-defined obesity, particularly when compared with individuals without central obesity . In a cross-sectional survey of over 15,000 individuals, men with a normal BMI but central obesity (WHR ≥0.90) had the highest total mortality risk when compared with men without central obesity who were normal weight, overweight, or obese (hazard ratio [HR] 1.87, 2.24, 2.42, respectively). A similar pattern was seen in normal weight women with central obesity, but the excess risk was not as great. A limitation of the study is that central obesity was determined by WHR only; no quantitative imaging studies of adipose tissue were performed. These data suggest that normal weight individuals with central obesity appear to have an increased mortality risk, and should be targeted for lifestyle modification strategies. (See "Obesity in adults: Health hazards", section on 'Normal weight central obesity'.)
High-dose vitamin D may increase risk of falls (February 2016)
Evidence conflicts on the effectiveness of vitamin D for fall prevention in older adults, with emerging evidence that high-dose vitamin D administered monthly may increase fall risk. A randomized trial compared monthly high-dose vitamin D (60,000 international units of vitamin D3 in one group; 24,000 international units vitamin D3 plus 300 microg calcifediol in another) with a lower dose (24,000 units vitamin D3) in community-dwelling men and women age 70 and older who had a history of a prior fall . Lower extremity function at 12 months did not differ among the groups, but there was a higher incidence of falls and mean number of falls in both groups that received high-dose vitamin D. Of note, there was no placebo group in this trial. (See "Falls: Prevention in community-dwelling older persons", section on 'Vitamin D supplementation' and "Vitamin D and extraskeletal health", section on 'Muscle function'.)
Enzyme replacement therapy for hypophosphatasia (November 2015)
Hypophosphatasia is a rare, autosomal disease that is associated with low levels of alkaline phosphatase in serum and bone and the development of osteomalacia and severe periodontal disease. It may present in the perinatal period, when it is lethal; in infancy, where rachitic deformities develop by age six months; in childhood, with premature loss of deciduous teeth, delayed walking, and waddling gait; or in adulthood, where it is characterized by the presence of recurrent metatarsal stress fractures and bone pain, and an increased incidence of chondrocalcinosis. Historically, there have been few treatment options. However, enzyme replacement therapy (asfotase alfa) for perinatal, infantile, and juvenile-onset hypophosphatasia became available in October 2015, based upon the results of open-label prospective studies in 99 patients with perinatal, infantile, or juvenile-onset hypophosphatasia, in whom enzyme replacement therapy was associated with improved overall survival, ventilator-free survival, growth, and bone mineralization compared with a historic cohort . (See "Clinical manifestations, diagnosis, and treatment of osteomalacia", section on 'Other causes'.)
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