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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.
Metformin use in patients with diabetes and renal impairment, heart failure, or chronic liver disease (January 2017)
The US Food and Drug Administration (FDA) recently revised its labeling of metformin, which will increase its use in patients with renal impairment. This change is supported by the findings of 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. 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. (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'.)
Microvascular outcomes with empagliflozin in patients with type 2 diabetes (July 2016)
There are few trials evaluating microvascular outcomes in patients taking sodium-glucose co-transporter 2 (SGLT2) inhibitors. Microvascular disease was a prespecified secondary outcome in a recent trial designed specifically to evaluate cardiovascular morbidity and mortality in patients with type 2 diabetes and established cardiovascular disease (CVD) . In this trial, 7028 patients with type 2 diabetes and established CVD were randomly assigned to empagliflozin or placebo once daily; the majority of patients were also taking metformin, antihypertensives, and lipid-lowering agents. Incident or worsening nephropathy occurred in 12.7 and 18.8 percent of patients in the empagliflozin and placebo groups, respectively. The reduction in nephropathy drove the improved composite microvascular endpoint (the initiation of retinal photocoagulation, vitreous hemorrhage, diabetes-related blindness, or incident or worsening nephropathy) for empagliflozin. The mechanism behind the reduction in incident or worsening nephropathy with empagliflozin is likely multifactorial, but is thought to be largely related to a direct renovascular effect of empagliflozin. Whether other SGLT2 inhibitors have similar renal effects is unknown. There have been reports of acute kidney injury, some requiring hospitalization and dialysis, in patients taking canagliflozin or dapagliflozin. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)
Frozen versus fresh embryo transfer for women with polycystic ovary syndrome (August 2016)
Traditionally, fresh embryos are transferred at the initial in-vitro fertilization (IVF) cycle and excess embryos are frozen for future use. However, women with polycystic ovary syndrome (PCOS) may have improved outcomes with transfer of frozen embryos. In a recent trial of 1500 subfertile women with PCOS in China randomly assigned to fresh or frozen embryo transfer, frozen embryo transfer resulted in a higher frequency of live birth and lower frequencies of pregnancy loss and ovarian hyperstimulation syndrome (OHSS), but the frequency of preeclampsia was increased . Of note, the study protocol differed from standard IVF protocols in the United States (US) and the mean body mass index (BMI) of the subjects was much lower than the BMI of women with PCOS in the US. Given these concerns and the higher risk for preeclampsia, we do not recommend routine transfer of frozen rather than fresh embryos in women with PCOS undergoing IVF in the US. (See "In vitro fertilization", section on 'Women with polycystic ovary syndrome (PCOS)'.)
IVF and risk of breast cancer (July 2016)
The body of evidence suggests that breast cancer risk is not increased after in vitro fertilization (IVF), but is limited by lack of long-term follow-up data. In a recent Dutch cohort study of over 19,000 women treated with IVF between 1983 and 1995 and followed for a median of 21 years, the risk of breast cancer was similar to that in subfertile women not treated with IVF and in the general population, adjusted for parity and age at first birth . These data are reassuring, but difficult to generalize to women undergoing contemporary IVF treatment since IVF drug regimens have changed over time and improved success rates have reduced the number of cycles women are exposed to these regimens. Additionally, only 14 percent of the cohort was age >60 years, so the risk of postmenopausal breast cancer was not well defined. (See "In vitro fertilization", section on 'Breast cancer risk'.)
Polycystic ovary syndrome: Weight loss before ovulation induction improves live birth rates (July 2016)
For anovulatory women with polycystic ovary syndrome (PCOS) who are overweight or obese, we suggest weight loss prior to initiating ovulation induction therapy. Modest weight loss of 5 to 10 percent has been associated with an improvement in metabolic status, a reduction in serum androgen concentrations, and resumption of ovulation in some studies, but data on pregnancy rates have been limited. In a post hoc comparison of two multicenter, concurrent trials in overweight/obese women with PCOS undergoing ovulation induction with four cycles of clomiphene citrate, a 16-week pretreatment lifestyle intervention (diet, exercise, medication) before starting clomiphene resulted in an approximate 6.5 percent weight loss from baseline and cumulative per-cycle ovulatory and live birth rates of 62 and 25 percent, respectively . In contrast, in women who underwent immediate clomiphene therapy, ovulatory and live birth rates were lower (45 and 10.2 percent, respectively). (See "Treatment of polycystic ovary syndrome in adults", section on 'Weight loss'.)
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'.)
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)'.)
Postmenopausal estrogen and cognitive function (August 2016)
While limited observational and clinical trial data have suggested that early, but not late, postmenopausal exposure to estrogen provides protection against later cognitive impairment, a new randomized trial found no benefit of estrogen regardless of when it was started. In the Early versus Late Intervention Trial with Estradiol (ELITE), 643 postmenopausal women, stratified according to time since menopause (<6 years [early] versus >10 years [late]), received oral estradiol (with progesterone for women with a uterus) or placebo for a median of five years . When compared with placebo, estradiol, whether it was started early or late, had no effect on verbal memory, executive function, or global cognition. (See "Estrogen and cognitive function", section on 'Younger menopausal women'.)
Sleep disorders in the menopausal transition: Telephone-based cognitive behavioral therapy (August 2016)
New-onset sleep disturbances are common in perimenopausal and menopausal women, occurring most often in women with hot flashes, but also in women without hot flashes. Midlife women with insomnia are usually treated with pharmacologic therapies (estrogen or hypnotic agents), but effective behavioral therapies are also available, including in-person cognitive behavioral training (CBT) for insomnia. In-person CBT, while effective, has practical limitations (availability, cost, and scheduling challenges), so alternative CBT strategies have been explored. In one trial, 106 peri- and postmenopausal women with insomnia and hot flashes were randomly assigned to an eight-week intervention with telephone-based cognitive behavioral therapy for insomnia (CBT-I) versus standard menopause education control (MEC) (also telephone-based) . After eight weeks, CBT-I, but not MEC, resulted in a clinically meaningful insomnia score reduction. The percentage of women who achieved Insomnia Index Severity scores in the “no insomnia” range was 70 and 24 percent for CBT-I and MEC, respectively. CBT-I reduced hot flash “bother” but not frequency. (See "Menopausal hot flashes", section on 'Promising therapies: Need further study'.)
Impact of adding activity trackers to behavioral weight loss programs (October 2016)
Wearable devices that monitor and provide feedback on physical activity and diet do not appear to provide additional benefit over standard behavioral weight loss interventions. In a 24-month trial of 470 overweight or obese adults who were randomly assigned to a standard intervention (self-monitoring of diet and exercise) or an enhanced intervention (use of a wearable device with a web interface to monitor diet and physical activity), there were similar improvements in body composition, fitness, physical activity, and diet, but the addition of a wearable device resulted in less weight loss than the standard behavioral weight loss program (3.5 versus 5.9 kg) . (See "Obesity in adults: Role of physical activity and exercise", section on 'Addition of "activity trackers"'.)
Genetic variants and BMI: Impact of obesogenic environment (August 2016)
Environmental factors appear to modify the known genetic associations with body mass index (BMI). In an observational study of 8788 adults aged 50 years or older (born between 1900 and 1958), the magnitude of association between BMI and a polygenic risk score (a weighted sum of alleles of 29 single nucleotide polymorphisms) was stronger in more recent birth cohorts than in earlier birth cohorts . The difference was thought to be related to exposure to the “obesogenic” environment (lifestyle changes that developed in the late 1970s: increased food and sugar-sweetened beverage intake and a decrease in physical activity). More recent cohorts were exposed to this environment beginning early in life, while earlier birth cohorts were not exposed until late in life. (See "Pathogenesis of obesity", section on 'Other'.)
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 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'.)
Investigational parathyroid hormone-related peptide analog for postmenopausal osteoporosis (October 2016)
Abaloparatide is an investigational synthetic analog of parathyroid hormone-related peptide (PTHrP) that binds more selectively than parathyroid hormone 1-34 (teriparatide) to the PTH1 receptor, conferring a more transient response favoring bone formation and minimizing bone resorption and hypercalcemia. In a phase III trial, nearly 2500 postmenopausal women with osteoporosis were randomly assigned to abaloparatide, placebo, or open-label teriparatide . Compared with placebo, new radiographic vertebral fractures occurred less frequently in the abaloparatide and teriparatide groups. The incidence of hypercalcemia was lower with abaloparatide than teriparatide. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Emerging therapies'.)
Investigational monoclonal anti-sclerostin antibody for postmenopausal osteoporosis (September 2016)
Sclerostin is secreted by osteocytes and inhibits bone formation. Romosozumab, a monoclonal anti-sclerostin antibody under investigation for the treatment of osteoporosis, has been shown to improve bone density in postmenopausal women. In a trial specifically designed to assess radiographic vertebral fracture outcomes, 7180 postmenopausal women with osteoporosis were randomly assigned to romosozumab (210 mg subcutaneously once monthly) or placebo for 12 months . Thereafter, all women received denosumab (60 mg subcutaneously every six months) for an additional 12 months. The incidence of radiographic vertebral fracture was lower in the romosozumab group at 12 months (0.5 versus 1.8 percent) and 24 months (0.6 versus 2.5 percent). There was an increased frequency of injection site reactions in the romosozumab group. Ongoing trials should provide more information about safety and efficacy, including nonvertebral fracture reduction. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Emerging therapies'.)
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