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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.
Multitarget therapy and progression of kidney disease in type 2 diabetes (March 2017)
The optimal therapeutic approach to the treatment of diabetic nephropathy may be intensive multifactorial risk factor reduction targeting behavior (ie, counseling on diet, exercise, and smoking cessation), glycemic control, blood pressure, and dyslipidemia. The efficacy of implementing this approach for eight years, compared with usual care, in patients with type 2 diabetes and increased albuminuria was examined in the Steno type 2 trial. At the end of the trial phase, all patients were offered intensive multitarget therapy . After an additional 20 years of follow-up, those who were assigned to intensive multitarget therapy had a significantly lower annual decline in glomerular filtration rate and a higher likelihood of survival without end-stage renal disease (approximately 50 versus 30 percent). (See "Treatment of diabetic nephropathy", section on 'Type 2'.)
Glycated hemoglobin (A1C) in sickle cell trait (March 2017)
In a retrospective cohort study evaluating glycated hemoglobin (A1C) in African Americans with and without sickle cell trait, A1C was lower at any fasting glucose value in patients with sickle cell trait compared with controls . However, the study is limited by its methodology, as mean glucose levels were estimated on the basis of very few measurements, usually a single fasting glucose level or oral glucose tolerance test. A1C correlates best with mean blood glucose over 8 to 12 weeks, raising the possibility that if measured appropriately with frequent glucose measurements over time (multiple daily measurements or continuous glucose monitoring), mean glucose levels may actually have been different between the study populations, with the putative different A1C levels accurately reflecting these different mean glucose levels. We continue to use A1C as one option to diagnose diabetes in patients with sickle cell trait. (See "Estimation of blood glucose control in diabetes mellitus", section on 'Racial variation'.)
Glycemic outcomes following bariatric surgery in obese patients with type 2 diabetes (February 2017)
Additional follow-up from a bariatric surgery trial in obese patients with type 2 diabetes (134 patients in follow-up study, 150 patients in initial trial) continues to show reduced glycated hemoglobin (A1C) in the two surgical arms at five years, although there has been some regression in all groups from the one-year results . The proportion of patients with A1C ≤6 percent was 29 percent for gastric bypass and 23 percent for sleeve gastrectomy, compared with 5 percent for controls (intensive medical therapy). While these results are encouraging, we require longer-term follow-up with documentation of improved clinically important outcomes, such as reduced vascular complications or reduced mortality, before routinely recommending bariatric surgery for obesity-related type 2 diabetes that is resistant to multiple medications. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Surgical treatment of obesity'.)
Metformin use in patients with diabetes and renal impairment, heart failure, or chronic liver disease (January 2017)
In a systematic review of 17 observational studies comparing diabetes regimens with and without metformin, metformin use was associated with lower all-cause mortality among patients with heart failure, renal impairment, or chronic liver disease with hepatic impairment . In addition, metformin use in patients with renal impairment or heart failure was associated with fewer heart failure readmissions. This study supports a recent US Food and Drug Administration (FDA) labeling revision for metformin, which will increase use in patients with renal impairment. Metformin remains contraindicated in patients with estimated glomerular filtration rate (eGFR) <30 mL/min, concurrent active or progressive liver disease, or unstable or acute heart failure with risk of hypoperfusion and hypoxemia. Recommendations regarding metformin use in patients with an eGFR between 30 and 45 mL/min vary and UpToDate authors individualize decisions about metformin use in such patients. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Contraindications'.)
Prognostic implications of albuminuria remission in type 1 diabetes (December 2016)
In patients with type 1 diabetes who have moderately increased albuminuria (formerly "microalbuminuria"), progression and stabilization of albuminuria are associated with high and intermediate risks, respectively, for a decline in glomerular filtration rate (GFR), but whether remission of albuminuria can further improve chronic kidney disease risk has not been known. Among patients with type 1 diabetes in the DCCT study who developed moderately increased albuminuria, the risk of GFR decline at 18 years was the same for those whose albuminuria persisted compared with those whose albuminuria remitted . These data suggest that moderately increased albuminuria is an important risk marker for progression of kidney disease, even if remission of albuminuria can be achieved. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'Regression to normoalbuminuria'.)
Measures of glycemia and risk of cardiovascular disease (December 2016)
There is consistent evidence that the relationship between blood glucose and cardiovascular risk extends into the nondiabetic range. It is uncertain, however, whether the risk of cardiovascular disease varies with the method of glucose measurement. In a meta-analysis of 24 prospective cohort studies with median follow-up of 9.5 years, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or increased glycated hemoglobin (A1C) in the nondiabetic range (5.7 to 6.4 percent) was associated with an increased risk of coronary heart disease compared with normoglycemia . IFG or IGT (but not elevated A1C) was also associated with an increased risk of stroke and overall mortality. (See "Clinical presentation and diagnosis of diabetes mellitus in adults", section on 'A1C, FPG, and OGTT as predictors of cardiovascular risk'.)
Semaglutide and cardiovascular outcomes (November 2016)
Semaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist that is in development for the treatment of type 2 diabetes. In a trial in over 3000 patients with type 2 diabetes and established or increased risk for cardiovascular disease, semaglutide reduced the composite primary cardiovascular endpoint (first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) compared with placebo . Diabetic retinopathy complications occurred more frequently in the semaglutide group, particularly among patients with existing retinopathy, whereas new or worsening nephropathy occurred less frequently. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
Reproductive hormones in women conceived by ICSI (April 2017)
The reproductive potential of children conceived with intracytoplasmic sperm injection (ICSI) for male factor infertility is not known. In the first study comparing the reproductive function of young women conceived by ICSI with peers conceived spontaneously, no differences in reproductive hormone levels or mean follicle count were observed . These data are reassuring regarding the reproductive potential of female ICSI offspring. (See "Intracytoplasmic sperm injection", section on 'Reproductive function'.)
Delayed diagnosis in women with PCOS (February 2017)
Early diagnosis and intervention are important in women with polycystic ovary syndrome (PCOS) because of an associated increase in cardiometabolic risk. In a cross-sectional, international study of diagnosis experiences in over 1300 women with PCOS, almost half saw three or more health professionals prior to diagnosis, and for one-third it took over two years before their diagnosis was made . In addition, only 16 percent were satisfied with the health information and educational materials they received. These observations highlight opportunities for improving the care of women with PCOS. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Delays in diagnosis'.)
Testosterone therapy in older men with low testosterone (April 2017)
The role of testosterone replacement to treat the decline in serum testosterone concentration that occurs in aging men (in the absence of identifiable pituitary or hypothalamic disease) was addressed in the multicenter Testosterone Trials (TTrials), an integrated set of seven trials in nearly 800 men over age 65 years with low testosterone and sexual dysfunction, physical dysfunction, and reduced vitality, who were randomly assigned to testosterone gel or placebo for 12 months. Initial results suggested that testosterone had a beneficial effect on sexual function, depressive symptoms, and mood, and possibly physical function (walking distance), but not on vitality [10,11] Results from recently published individual trials showed the following:
●There was no effect of testosterone replacement on cognitive function in men with age-associated memory impairment .
●Testosterone increased coronary artery noncalcified plaque volume as measured by coronary computed tomographic angiography .
While the small size and short duration of the subtrials are important limitations, the coronary artery plaque trial raises important concerns about the safety of testosterone therapy in older men. (See "Overview of testosterone deficiency in older men".)
Inappropriate use of testosterone therapy: The impact of direct-to-consumer advertising (April 2017)
Direct-to-consumer (DTC) advertising has played an important role in the increase of inappropriate use of testosterone in healthy, middle-aged men. In one study of 75 designated market areas with high rates of DTC advertising of specific testosterone products or testosterone deficiency, each exposure to a DTC advertisement resulted in a 0.6, 0.7, or 0.8 percent increase in testosterone testing, initiation of therapy, or initiation of testosterone therapy without baseline testing, respectively . Although the percentage changes are small, in large populations, the impact is large. (See "Testosterone treatment of male hypogonadism", section on 'Impact of direct-to-consumer advertising'.)
Injectable hormonal contraception for men (November 2016)
Complete suppression of spermatogenesis can be achieved with injectable exogenous testosterone combined with a progestin, but the optimal regimen for use as a male contraceptive has not yet been established. In a study of over 300 normal men receiving a long-acting parenteral regimen of testosterone undecanoate and norethisterone enanthate, 96 percent of continuing users had suppression of spermatogenesis within six months . Contraceptive efficacy was excellent, and 95 percent of men had recovery of normal spermatogenesis within one year of stopping treatment. The external safety review committee terminated the study early because it concluded the risks of continuing outweighed the possible benefits. The adverse events of concern were mood changes, depression, pain at the injection site, and increased libido. (See "Testosterone treatment of male hypogonadism", section on 'Exogenous testosterone for hormonal contraception'.)
Sex differences in memory at midlife (February 2017)
Women, unlike men, undergo dynamic hormonal changes at midlife (the menopausal transition), and some women describe memory symptoms such as forgetfulness, difficulties with word retrieval, and "brain fog." While these symptoms are bothersome, little is known about memory function in midlife as a function of sex, gonadal steroid hormones, and reproductive status. This was addressed in a cross-sectional study of over 200 men and women ages 45 to 55, in which women in their late reproductive and perimenopausal years outperformed age-matched men on all memory tasks . These differences were attenuated in the postmenopausal years. Higher serum estradiol concentrations, a reflection of ovarian activity, were associated with better performance. (See "Estrogen and cognitive function", section on 'Effect of endogenous estrogen'.)
Vaginal prasterone for dyspareunia in postmenopausal women (November 2016)
In November 2016, the US Food and Drug Administration approved the use of prasterone (also known as dehydroepiandrosterone [DHEA]) for treatment of dyspareunia in women with vulvovaginal atrophy (VVA) due to menopause . In an earlier randomized trial of women with VVA and moderate to severe dyspareunia, 12 weeks of daily intravaginal DHEA resulted in improved scores for pain during sexual activity and other key domains of female sexual function (desire, arousal, lubrication, orgasm, satisfaction) compared with placebo . However, patients may find daily dosing more cumbersome than twice-weekly dosing with vaginal estrogen preparations. (See "Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)", section on 'Dehydroepiandrosterone (prasterone)'.)
Types of cancers associated with obesity (April 2017)
Excess weight is associated with an increased risk of developing and dying from cancer, but the number and types of cancers are inconsistent across studies. In a review of 204 meta-analyses that investigated the association between indices of adiposity and developing 36 primary cancers and their subtypes, associations were identified for esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract, pancreas, breast (in women who had never taken hormones), endometrium, ovary, and kidney . (See "Obesity in adults: Health consequences", section on 'Cancer'.)
Effect of antihypertensive drug class on fracture rates (January 2017)
Thiazide diuretics stimulate distal tubular reabsorption of calcium, leading to a decrease in urinary calcium excretion and a possible benefit on bone mineral density. The rates of hip or pelvic fractures among patients treated with thiazide-like diuretics, angiotensin converting enzyme (ACE) inhibitors, or calcium channel blockers were compared in a post-hoc analysis of the ALLHAT trial . At approximately five years, those randomly assigned chlorthalidone had fewer hip or pelvic fractures as compared with those assigned to either lisinopril or amlodipine. Thus, if monotherapy is appropriate in a patient with hypertension and osteoporosis, thiazide-like diuretics may have advantages over ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers. (See "Choice of drug therapy in primary (essential) hypertension", section on 'Thiazide diuretics'.)
Vertebroplasty for osteoporotic compression fractures (November 2016)
The indications for and timing of vertebroplasty for the treatment of osteoporotic compression fractures are controversial. In a trial comparing vertebroplasty or simulated vertebroplasty (sham) in 120 patients with acute (less than six weeks) vertebral fracture and back pain, more patients in the vertebroplasty group achieved clinically significant lower pain scores at 14 days . Two previous sham-controlled trials, however, did not show a significant reduction in pain with vertebroplasty, likely due to differences in study design, including different sham procedures for the control arm and varying definitions of acute vertebral fracture. (See "Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment", section on 'Vertebroplasty'.)
Treatment with levothyroxine provides no symptomatic benefit in older adults with subclinical hypothyroidism (April 2017)
Subclinical hypothyroidism is defined biochemically as an elevated serum thyroid-stimulating hormone (TSH) and a normal serum-free thyroxine (T4) level. Some patients with subclinical hypothyroidism may have vague, nonspecific symptoms. Although virtually all experts recommend treatment of subclinical hypothyroidism when serum TSH concentrations are ≥10 mU/L, treatment of patients with TSH values between the upper reference limit and 9.9 mU/L remains controversial, particularly in older patients who are more likely to have complications from unintended overtreatment. In a randomized trial evaluating the effect of levothyroxine versus placebo on quality of life measures in over 700 older patients (mean age 74.4 years) with mean TSH 6.4 mU/L, there was no difference in hypothyroid symptoms or tiredness scores after one year . We do not routinely treat older patients with TSH between the upper reference limit and 9.9 mU/L (algorithm 1). (See "Subclinical hypothyroidism in nonpregnant adults", section on 'Hypothyroid signs and symptoms'.)
Treatment of subclinical hypothyroidism and maternal hypothyroxinemia during pregnancy (March 2017)
In parallel multicenter trials, over 600 pregnant women with subclinical hypothyroidism (median thyroid-stimulating hormone [TSH] 4.4 mU/L, normal free T4) or isolated maternal hypothyroxinemia (low free T4, normal TSH) were randomly assigned to levothyroxine or placebo . There was no significant effect of treatment on adverse pregnancy outcomes or on neurodevelopmental outcomes in the children at five years of age. The main limitation of the study is the late initiation of treatment at a mean gestational age of almost 17 weeks, at which time fetal thyroid tissue is beginning to function. We suggest levothyroxine (with earlier initiation when possible) for pregnant women with subclinical hypothyroidism, defined as a TSH above a trimester-specific normal reference range (or above 4.0 mU/L if trimester-specific range unavailable) with normal free T4. (See "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment", section on 'Effect of thyroid hormone replacement'.)
Vitamin D and prevention of cancer (April 2017)
In a trial comparing the effect of vitamin D and calcium supplementation with placebo on the incidence of cancer in over 2000 postmenopausal women, there was no difference between groups in the incidence of cancer at four years . An analysis by cancer site showed no difference in the incidence of breast cancer between the two groups; there were too few cancers at other sites to analyze. Although several study limitations may have contributed to the absence of an effect, including enrollment of patients with a relatively high baseline vitamin D level and permission to take vitamin D supplements (up to 800 international units daily) outside of the intervention, vitamin D supplementation for the prevention of cancer is not warranted. (See "Vitamin D and extraskeletal health", section on 'Cancer'.)
Vitamin D and prevention of infection (March 2017)
In a meta-analysis of 25 trials (almost 11,000 patients) evaluating the incidence of acute respiratory infection, vitamin D supplementation slightly reduced the proportion of patients experiencing one acute respiratory tract infection . In prespecified subgroup analyses, supplementation was most effective in patients with vitamin D levels <10 ng/mL and in those treated with daily or weekly, rather than bolus, doses. As the meta-analysis showed significant effects predominantly in patients with very severe vitamin D deficiency, who require treatment regardless of infection prevention because of the risk of osteomalacia, vitamin D supplementation for the prevention of infection alone is not warranted. (See "Vitamin D and extraskeletal health", section on 'Innate'.)
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- Lacy ME, Wellenius GA, Sumner AE, et al. Association of Sickle Cell Trait With Hemoglobin A1c in African Americans. JAMA 2017; 317:507.
- Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric Surgery versus Intensive Medical Therapy for Diabetes - 5-Year Outcomes. N Engl J Med 2017; 376:641.
- Crowley MJ, Diamantidis CJ, McDuffie JR, et al. Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. Ann Intern Med 2017; 166:191.
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- Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA Intern Med 2017; 177:471.
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- Behre HM, Zitzmann M, Anderson RA, et al. Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men. J Clin Endocrinol Metab 2016; 101:4779.
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- Kyrgiou M, Kalliala I, Markozannes G, et al. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ 2017; 356:j477.
- Puttnam R, Davis BR, Pressel SL, et al. Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults: Secondary Analysis of a Randomized Clinical Trial. JAMA Intern Med 2017; 177:67.
- Clark W, Bird P, Gonski P, et al. Safety and efficacy of vertebroplasty for acute painful osteoporotic fractures (VAPOUR): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2016; 388:1408.
- Stott DJ, Rodondi N, Kearney PM, et al. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med 2017.
- Casey BM, Thom EA, Peaceman AM, et al. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med 2017; 376:815.
- Lappe J, Watson P, Travers-Gustafson D, et al. Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial. JAMA 2017; 317:1234.
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