Disclosures: Kathryn A Martin, MD Nothing to disclose. Jean E Mulder, MD Nothing to disclose.
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.
DPP-4 inhibitors for diabetes and cardiovascular safety (June 2015)
A number of trials have evaluated the cardiovascular effects of DPP-4 inhibitors. In a recent large trial, 14,735 patients with type 2 diabetes and established cardiovascular disease were randomly assigned to sitagliptin or placebo, in addition to other diabetes medications (predominantly metformin, sulfonylurea, insulin) . After a median follow-up of three years, there was no difference in the primary composite cardiovascular outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina), individual components of the composite, or hospitalization rate for heart failure (3.1 percent in each group). Although these data are reassuring, longer-term clinical trials are needed to definitively assess the cardiovascular safety of DPP-4 inhibitors in patients with heart disease. In addition, there are no data on cardiovascular safety in lower-risk patients. With only modest glucose-lowering effectiveness and relative expense, we do not consider DPP-4 inhibitors as options for initial therapy in the majority of patients with type 2 diabetes. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
Combination renin-angiotensin system inhibition in diabetic patients (June 2015)
Several randomized trials that directly compared dual versus single renin-angiotensin system inhibition in diabetic patients found that dual therapy produced no benefit and an increase in adverse effects. Findings are similar in a subsequent network meta-analysis . In this analysis in patients with diabetes and hypertension, dual therapy with an angiotensin-converting enzyme (ACE) inhibitor plus an angiotensin II receptor blocker (ARB) was superior to placebo in preventing end-stage renal disease, but monotherapy with either an ACE inhibitor or an ARB, also compared with placebo, produced similar benefits while dual therapy produced more adverse effects. Combination renin-angiotensin system inhibition with an ACE inhibitor and ARB or direct renin inhibitor is not recommended in diabetic patients. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Avoid combination renin-angiotensin system inhibition'.)
Vorapaxar particularly beneficial in patients with recent MI and diabetes (April 2015)
Patients with diabetes and myocardial infarction (MI) are at high risk of subsequent cardiovascular events. The impact of vorapaxar, an antiplatelet agent, on these high-risk individuals was evaluated in a subgroup analysis of the TRA 2P-TIMI 50 trial, which had previously shown benefit with this agent in a broad group of patients with atherosclerotic cardiovascular disease treated with at least one other antiplatelet drug (aspirin or clopidogrel) . Vorapaxar lowered the risk of cardiovascular events to a greater extent in patients with diabetes and a history of MI than those without diabetes. For patients with diabetes and a recent MI who cannot receive either ticagrelor or prasugrel (our preferred P2Y12 receptor blockers; used in combination with aspirin), and who are at low risk for bleeding, we suggest that vorapaxar be added to clopidogrel and aspirin. (See "Secondary prevention of cardiovascular disease", section on 'Vorapaxar'.)
VEGF inhibitors for diabetic macular edema (March 2015)
Vascular endothelial growth factor (VEGF) inhibitors (bevacizumab, ranibizumab, aflibercept) have been widely studied as a treatment for diabetic macular edema. In the only comparison trial, all three drugs had similar efficacy when visual acuity was better than 20/50, but when the baseline visual acuity was 20/50 or worse, aflibercept significantly improved visual acuity compared with the other two drugs (+19 letters versus +12 and +14 letters), with no difference in improvement between ranibizumab and bevacizumab . Given the wide disparity in cost between the anti-VEGF agents, retina specialists must consider cost of care, as well as published treatment efficacy and the specific details of a patient’s ophthalmic history and retinal examination, in making the choice between drugs for a given patient. It is important to note that, at any level of visual acuity, an individual patient may see an improved response with a second or third drug after failing to respond to initial treatment with any of the three drugs. (See "Diabetic retinopathy: Prevention and treatment", section on 'VEGF inhibitors for ME'.)
Long-term effect of antihypertensive therapy in diabetic patients (October 2014, MODIFIED March 2015)
A randomized trial and a meta-analysis have evaluated the treatment of hypertension in patients with diabetes.
●The ADVANCE trial randomly assigned 11,000 diabetic patients to a fixed combination of perindopril-indapamide or placebo for approximately four years. Patients in the perindopril-indapamide group had lower rates of cardiovascular mortality (3.8 versus 4.6 percent) and all-cause mortality (7.3 versus 8.5 percent). A post-trial, open-label cohort (8500 patients) were followed for an additional six years . Blood pressures between the treatment and placebo groups, which were different during the trial (135/74 versus 140/76 mmHg), became similar within six months of the trial completion and remained similar throughout the cohort phase. Compared with those originally assigned placebo, those who had received perindopril-indapamide had a lower death rate during the cohort phase (15.3 versus 16.7 percent), as well as a lower incidence of major cardiovascular events (13.3 versus 14.2 percent). Combining both the trial and cohort phases together (approximately 10 years of follow-up), all-cause mortality was lower among those in the treatment group. Thus, blood pressure lowering is associated with long-term benefits on mortality and cardiovascular disease in diabetic patients. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'ADVANCE trial'.)
●A meta-analysis of 40 trials examined the effect of antihypertensive therapy in 100,354 diabetic patients . Follow-up ranged from six months to more than eight years, with most trials following patients for two years or longer. Compared with placebo, antihypertensive therapy reduced the rates of mortality, total cardiovascular disease, myocardial infarction, and stroke. For most outcomes, the benefit of antihypertensive therapy was limited to those whose initial systolic pressures were greater than 140 mmHg. The risk of stroke, but not other outcomes, was reduced by antihypertensive therapy in patients with lower initial systolic pressures. Some trials compared one antihypertensive drug with another. For most outcomes, no class of drugs was superior or inferior to the others. However, beta-blockers increased the risk of stroke compared with other agents. In general, the results of this meta-analysis support recommendations by UpToDate regarding the treatment of hypertension in diabetic patients. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Meta-analysis'.)
Oral anti-hyperglycemic drugs for treatment of gestational diabetes mellitus (February 2015)
Prevention of macrosomia is a major goal of treatment of gestational diabetes mellitus (GDM), but the best approach is controversial. In a 2015 systematic review and meta-analysis of randomized trials comparing neonatal outcomes in women with GDM treated with glyburide, metformin, or insulin therapy, women assigned to glyburide had a higher rate of macrosomia than those assigned to metformin or insulin therapy . Metformin therapy and insulin therapy resulted in similar rates of macrosomia. We prefer insulin therapy for women with GDM who fail nutritional therapy because it is effective and safe, while there is no information about the long-term effects of transplacental passage of oral anti-hyperglycemic drugs. However, oral anti-hyperglycemic agents are a reasonable alternative for women who refuse to take, or are unable to comply with, insulin therapy. (See "Gestational diabetes mellitus: Glycemic control and maternal prognosis", section on 'Glyburide'.)
Characterizing treatment-induced neuropathy of diabetes (January 2015)
Treatment-induced neuropathy of diabetes (TIND) is a small fiber neuropathy that can occur in patients with chronic hyperglycemia who experience rapid improvement in glycemic control. The main clinical manifestations are severe pain and autonomic dysfunction. Although historically considered rare, data from a study of 954 patients referred to a tertiary care center for diabetic neuropathy evaluation suggest that TIND is more common than previously suspected . Defined by the acute onset of neuropathic pain or autonomic dysfunction within eight weeks of a large improvement in glycemic control (ie, a decrease in glycosylated hemoglobin A1C of ≥2 percentage points over three months), TIND was present in 104 patients (11 percent). The risk of developing TIND and the severity of neuropathic pain and autonomic dysfunction correlated with the magnitude of decrease in hemoglobin A1C. (See "Epidemiology and classification of diabetic neuropathy", section on 'Treatment-induced neuropathy of diabetes'.)
Lower HMG CoA reductase activity increases risk of diabetes (January 2015)
A Mendelian randomization study found that decreased genetic HMG CoA reductase activity is associated with a higher risk of type 2 diabetes, such that at least some of the risk of diabetes seen with statin therapy appears to be due to its inhibition of HMG CoA reductase . Since this inhibition is thought responsible for the primary efficacy of statin therapy, this finding means that any effective statin will probably increase the risk of diabetes . (See "Statins: Actions, side effects, and administration", section on 'Diabetes mellitus'.)
Glycemic control and mortality in type 1 diabetes mellitus (January 2015)
In a report from the Diabetes Control and Complications Trial (DCCT) and follow-up Epidemiology of Diabetes Interventions and Complications Study (EDIC), representing a mean follow-up period of 27 years (1429 patients), there was a modest reduction in all-cause mortality in patients with type 1 diabetes initially assigned to intensive insulin therapy (43 deaths in the intensive therapy group versus 64 in the conventional group) . The median A1C values for the intensive therapy and conventional therapy groups during the 6.5 year DCCT were 7.2 and 9.1 percent, respectively. However, the A1C levels equalized during the subsequent EDIC study. Thus, compared with conventional therapy, intensive insulin therapy for 6.5 years during the DCCT reduced the risk of mortality over at least the next 20 years, despite an absence of a difference in A1C values during the post-DCCT period. (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Mortality'.)
Fertility among survivors of childhood Hodgkin lymphoma (June 2015)
Counseling regarding infertility risks associated with Hodgkin lymphoma (HL) therapy is important for HL survivors of childbearing age. The impact of regimens used for childhood HL on long-term fertility was evaluated in a prospective study of over 450 female survivors of childhood HL in continuous remission with a median follow-up of 20 years . For those younger than age 40, the likelihood of parenthood was similar to an age-matched German population. Factors associated with a decreased likelihood of successful pregnancy included age over 40 years and receipt of pelvic radiation. These results should be reassuring to HL survivors. (See "Overview of the approach to the adult survivor of classical Hodgkin lymphoma", section on 'Gonadal dysfunction'.)
Empiric progesterone supplementation of no benefit in recurrent pregnancy loss (April 2015)
Recurrent pregnancy loss is an extremely stressful experience for families and clinicians. One proposed mechanism of recurrent pregnancy loss is luteal phase deficiency, or inadequate progesterone production by the corpus luteum. A 2015 Committee Opinion by the American Society of Reproductive Medicine concluded that there is no evidence that empiric treatment of luteal phase deficiency with progesterone supplementation is beneficial to women with recurrent pregnancy loss in natural, unstimulated cycles (ie, no use of fertility therapy) . When abnormal luteal function is the result of an identified medical condition, such as elevated prolactin, the underlying medical problem should be addressed. (See "Management of couples with recurrent pregnancy loss", section on 'Progesterone'.)
Testosterone injectables versus gels and cardiovascular risk (June 2015)
Concerns have been raised that testosterone therapy in men may be associated with an increase in cardiovascular risk. Available data now suggest that the route of testosterone administration may be associated with the excess risk. In a retrospective analysis of three databases of over 544,000 men receiving newly prescribed testosterone therapy, use of injectable testosterone preparations (which result in intermittent supraphysiologic serum testosterone concentrations) was associated with a greater risk of myocardial infarction (MI) and stroke, but not venous thromboembolism, when compared with testosterone gel use . Of note, the absolute risks associated with testosterone injectables were low, and the study did not compare the rate of cardiovascular events in testosterone users versus nonusers. These data do not change our management approach. We typically suggest testosterone gels, but some men prefer injectables because of their lower cost and convenience. (See "Testosterone treatment of male hypogonadism", section on 'Cardiovascular risks'.)
X-linked TEX11 mutations and azoospermia (May 2015)
Y-chromosome defects and a number of autosomal and X-linked gene mutations are increasingly recognized as genetic causes of azoospermia and severe oligospermia. X-linked TEX11 mutations have now been identified as an important cause of meiotic arrest and azoospermia in infertile men . In a report, hemizygous TEX11 mutations on chromosome Xq13.2 were identified in 7 of 289 men with azoospermia (2.4 percent). In testes from normal men, immunohistochemical analysis showed TEX11 expression in late spermatocytes, and in round and elongated spermatids. Testes from patients with azoospermia and TEX11 mutations had meiotic arrest and no TEX11 expression. (See "Causes of male infertility", section on 'Autosomal and X chromosome defects'.)
Testosterone therapy and cardiovascular risk (April 2015)
Testosterone products are approved by the US Food and Drug Administration (FDA) only for use in men who have low serum testosterone levels in conjunction with an associated medical condition. However, there has been a dramatic increase in inappropriate use of testosterone therapy in healthy middle-aged men with nonspecific symptoms, such as decreased energy and sexual interest, and in older men with low testosterone due to normal aging. A number of studies suggest that there may be an increased risk of myocardial infarction and stroke associated with testosterone use. Although data are conflicting, the FDA is now requiring that manufacturers of testosterone products add information to the labeling about this possible increase in cardiovascular risk . Labeling must also be changed to clarify the approved uses of testosterone. (See "Testosterone treatment of male hypogonadism", section on 'Cardiovascular risks'.)
Menopausal hormone therapy and cardiovascular risk: Timing of exposure (June 2015)
Current evidence suggests that the use of menopausal hormone therapy (MHT) in the early menopausal years (<10 years from menopause) may not be associated with excess cardiovascular risk when compared with use in the later menopausal years. This has been referred to as the "timing hypothesis." Additional support for this hypothesis comes from a 2015 meta-analysis of 19 trials of oral (including the Womens Health Initiative), but not transdermal, MHT in over 40,000 postmenopausal women . A subgroup analysis in women who started MHT less than 10 years after menopause showed a lower risk of coronary heart disease (CHD) compared with placebo (RR 0.52; 8 fewer cases of heart disease per 1000 women treated/year) and a lower mortality rate (RR 0.70; 6 fewer deaths per 1000 women treated/year). However, there were important limitations in this analysis; when one methodologically flawed trial was removed, the beneficial effects on CHD and mortality were no longer significant (but no adverse effects were seen). These data provide additional evidence that oral MHT use in younger postmenopausal women is not associated with excess CHD risk. (See "Menopausal hormone therapy: Benefits and risks", section on 'Younger postmenopausal women'.)
Menopausal hormone therapy effect on cognition and mood in younger menopausal women (June 2015)
Menopausal hormone therapy (MHT) in older menopausal women (>65 years) has an adverse effect on cognitive function and an inconsistent effect on mood. The KEEPS study (Kronos Early Estrogen Prevention Study), a trial of menopausal hormone therapy (MHT) in younger menopausal women ages 45 to 54 years who underwent extensive cognitive and mood testing, reported that four years of MHT had no overall effect on cognition when compared with placebo . However, oral estrogen appeared to improve mood, as women receiving oral conjugated estrogen combined with micronized progesterone had lower depression and anxiety scores than those receiving either transdermal estradiol (with micronized progesterone) or placebo. (See "Menopausal hormone therapy: Benefits and risks", section on 'Cognitive function and dementia'.)
Long duration of hot flashes (March 2015)
For many if not most menopausal women, hot flashes last considerably longer than the duration currently recommended for treatment of symptoms (maximum 4 to 5 years to minimize excess breast cancer risk). Among 1449 women with hot flashes followed longitudinally in the Study of Women Across the Nation (SWAN), the median total hot flash duration was 7.4 years, with symptoms persisting for a median of 4.5 years after the final menstrual period (FMP) . Women who were premenopausal or early perimenopausal when they first experienced hot flashes had the longest total duration (>11.8 years, post-FMP median duration 9.4 years). The long duration of hot flashes raises important treatment challenges for many women, particularly those with early onset symptoms. (See "Menopausal hot flashes", section on 'Duration'.)
Menopausal hormone therapy and risk of ovarian cancer (March 2015)
There have been concerns that menopausal hormone therapy (MHT) may be associated with an increase in ovarian cancer risk, but data are conflicting. A meta-analysis of 52 epidemiologic studies including 21,488 postmenopausal women with ovarian cancer now suggests that there is a small excess risk of ovarian cancer with MHT . While the relative risk of ovarian cancer was greater in ever-users than never-users of MHT (RR 1.14), the calculated absolute excess risk associated with MHT was very low: five years of MHT use in women ages 50 to 54 years would result in about one additional ovarian cancer case per 1000 users and one ovarian cancer death per 1700 users. Given these low absolute risks, we do not consider ovarian cancer to be a major consideration when deciding to take MHT for symptomatic relief. (See "Menopausal hormone therapy: Benefits and risks", section on 'Ovarian cancer'.)
Comparison of commercial weight loss programs in the United States (April 2015)
A comprehensive lifestyle intervention (combined diet, exercise, and behavioral treatment) is the most important strategy for weight management. Self-help or commercial weight loss programs incorporate varying degrees of behavioral modification strategies with dietary change. A systematic review of the major available programs in the United States reported outcomes based upon a variety of measures . Only two programs (Weight Watchers and Jenny Craig) reported 12-month outcomes. Compared with control groups that included education or education plus counseling, trials found an approximately 3 to 5 percent greater weight loss at 12 months for participants in the intervention arms. Longer-term outcomes are needed to better evaluate the effectiveness of other commercial programs. Commercial programs are an option for weight management of overweight or obese patients, with the recommendation that programs with clinically demonstrated efficacy be the first choice. (See "Obesity in adults: Behavioral therapy", section on 'Self-help or commercial weight loss programs'.)
Pregnancy outcomes after bariatric surgery (March 2015)
Bariatric surgery prior to pregnancy appears to reduce the risk of certain adverse pregnancy outcomes associated with maternal obesity. In the largest study to date evaluating this issue, women who had bariatric surgery prior to pregnancy were less likely to have gestational diabetes and large-for-gestational-age infants compared with women matched for age and presurgical body mass index (BMI) who had not undergone bariatric surgery . However, they were more likely to have small-for-gestational-age infants. The risks of preterm birth, stillbirth or neonatal death, and congenital malformations were not statistically different between the two groups. (See "Fertility and pregnancy after bariatric surgery", section on 'Pregnancy outcomes'.)
Vagal blockade for the treatment of obesity (February 2015)
The abdominal vagal nerve controls gastric emptying and signals the satiety center in the brain. A surgically implanted device that sends intermittent electrical pulses to the abdominal vagal nerve has been studied as a possible treatment for obesity. A randomized trial assigned 239 patients with a BMI ≥35 kg/m2 to receive either an active or sham pulse generator device . After 12 months, patients in the active vagal blockade group lost a greater percentage of their initial body weight (9.2 versus 6.0 percent in the sham group), although the study did not meet its prespecified endpoint (mean difference in excess weight loss between groups of ≥10 percentage points). Nevertheless, based on the results of this trial, a vagal blockade device was approved in the United States by the Food and Drug Administration for the treatment of adults with a BMI of 40 to 45 kg/m2 or of 35 to 39.9 kg/m2 with at least one obesity-related comorbidity (eg, type 2 diabetes), who have failed a supervised weight management program . Adverse events include nausea and vomiting, pain at the neuroregulator site, surgical complications, heartburn, dysphagia, and belching. Owing to the paucity of efficacy and safety data, the relatively modest effect on weight loss compared with traditional bariatric surgeries, and the absence of long-term efficacy data, we do not recommend the use of vagal blockade devices for weight management. (See "Obesity in adults: Overview of management", section on 'Vagal blockade'.)
Exercise and vitamin D for fall prevention in older women (March 2015)
A randomized trial in home-dwelling women aged 70 to 80 years old with a history of at least one fall in the previous year evaluated the effect of exercise and/or vitamin D supplementation (800 IU per day) on fall prevention . Strength and balance training did not affect the rate of falls, but halved the number of injurious falls and injured fallers, and improved muscle strength and balance compared with no exercise. Vitamin D, compared with placebo, did not prevent falls or fall-related injuries. Baseline 25-hydroxyvitamin D levels in the trial participants (26 to 28 ng/mL) were above the threshold for what is generally considered deficient. Prior meta-analyses have inconsistent findings on the effectiveness of vitamin D in fall prevention. We continue to suggest an exercise program to improve strength and balance for older adults at risk for falls. Given the low risk associated with vitamin D supplementation, and the possibility of benefit at least in adults with low baseline levels of vitamin D, we also continue to advise vitamin D supplementation. (See "Falls: Prevention in community-dwelling older persons", section on 'Exercise' and "Falls: Prevention in community-dwelling older persons", section on 'Vitamin D supplementation'.)
Light-emitting e-readers delay normal circadian rhythms and interfere with sleep (February 2015)
Prolonged use of portable light-emitting devices (laptops, tablets, smartphones) before bedtime can have a negative impact on melatonin secretion, circadian rhythms, and sleep. One study compared the effects of reading an electronic book on a light-emitting device (LE-ebook) versus a printed book (by reflected light) for four hours prior to bedtime for five consecutive nights . Subjects in the LE-ebook group had suppressed melatonin concentrations in the early part of the night, a delayed endogenous circadian melatonin phase, felt less sleepy before bed, took longer to fall asleep, and reported feeling sleepier the following morning. These observations suggest that evening use of light-emitting devices may contribute to phase-delays in the circadian clock and difficulty initiating sleep. (See "Physiology and available preparations of melatonin", section on 'Effects of drugs or light'.)
Subclinical hyperthyroidism and fracture risk (July 2015)
Patients with subclinical hyperthyroidism have normal serum concentrations of free thyroxine (T4) and triiodothyronine (T3), but subnormal concentrations of thyroid-stimulating hormone (TSH). Common causes of subclinical hyperthyroidism include autonomously functioning thyroid adenomas and multinodular goiters, Graves’ disease, or excessive thyroid hormone therapy. Subclinical hyperthyroidism is associated with reduced bone density, particularly in cortical-rich bone in postmenopausal women. The risk of fracture has been less certain. A meta-analysis of 13 prospective cohort studies showed that compared with euthyroidism, endogenous subclinical hyperthyroidism (autonomy or Graves' disease) was associated with an increased risk of hip fracture (6.1 versus 4.4 percent) . In this analysis, lower TSH levels (<0.10 mU/L) were associated with higher fracture rates. (See "Bone disease with hyperthyroidism and thyroid hormone therapy", section on 'Fracture risk'.)
Lenvatinib for progressive unresponsive differentiated thyroid cancer (February 2015)
For patients with metastatic differentiated thyroid cancer (DTC) that progresses despite traditional therapy, treatment with kinase inhibitors can stabilize disease. In an international, randomized, double-blind trial, 392 patients with progressive, radioiodine refractory thyroid cancer were randomly assigned to lenvatinib, a multitargeted kinase inhibitor (MKI), or placebo . The median progression-free survival (18.3 versus 3.6 months) and the response rate (64.8 versus 1.5 percent) were significantly better in the lenvatinib group. For most patients with progressive unresponsive DTC, we prefer enrollment in a clinical trial of therapies targeting the molecular and cellular pathogenesis of DTC. For patients who are unable to participate in clinical trials, we suggest an oral MKI, such as lenvatinib. (See "Differentiated thyroid cancer refractory to standard treatment: Chemotherapy", section on 'Lenvatinib'.)
Vitamin D supplementation during pregnancy (May 2015)
Several observational studies suggest an association between poor maternal vitamin D status and adverse pregnancy outcomes. A meta-analysis of 13 trials showed that, compared with a control group, vitamin D administration (in varied dosing, types, and schedules) resulted in higher serum 25(OH)D levels at delivery but no difference in the incidence rates of preeclampsia or gestational diabetes . There was also no difference in the incidence rates of small for gestational age, low birth weight, and preterm birth in the neonates. Although routine prenatal vitamin D supplementation does not appear to prevent low birthweight, preterm birth, or preeclampsia, the earliest interventions in the published trials were made in the late first trimester. Initiation of therapy with vitamin D prior to conception has not been evaluated. (See "Vitamin D and extraskeletal health", section on 'Pregnancy outcomes'.)
Clinical practice guideline for Paget disease of bone (February 2015)
Comprehensive clinical practice guidelines for the diagnosis and treatment of Paget disease of bone have been developed by The Endocrine Society and were co-sponsored by the European Society of Endocrinology . Our approach to the evaluation and management of Paget disease is generally consistent with these guidelines. (See "Treatment of Paget disease of bone", section on 'Guidelines of major professional societies'.)
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