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.
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".)
Liraglutide and cardiovascular outcomes (June 2016)
Glucagon-like peptide-1 (GLP-1) receptor agonists improve glycemic control. However, there are few studies assessing clinically important cardiovascular health outcomes.
●In one trial, 9340 patients with type 2 diabetes (mean A1C 8.7 percent) and underlying cardiovascular disease (prior myocardial infarction or stroke) or risk factors were randomly assigned to liraglutide or placebo . Many patients were taking metformin (76 percent), sulfonylureas (50 percent), and/or insulin (44 percent). After a median follow-up of 3.8 years, the primary endpoint (time to first occurrence of a composite endpoint [death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke]) occurred in fewer patients in the liraglutide group (13 versus 14.9 percent).
●In another trial of liraglutide versus placebo in 300 patients (59 percent with type 2 diabetes) with established heart failure and reduced left ventricular ejection fraction who were recently hospitalized, liraglutide had no significant effect on the composite outcome (time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level) . In a prespecified subgroup analysis, there was no effect of liraglutide compared with placebo on heart failure outcomes in the subset of patients with diabetes.
The choice of additional therapy in metformin-treated patients with type 2 diabetes and persistent hyperglycemia should be individualized based upon patient characteristics, preferences, and costs. Among these considerations, a prior history of myocardial infarction or stroke might favor choosing liraglutide as the second drug to be added to metformin. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
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'.)
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'.)
Hysteroscopy before IVF (May 2016)
Hysteroscopy is often performed to evaluate the uterine cavity before in-vitro fertilization (IVF). In a 2008 meta-analysis of two small randomized trials and three nonrandomized studies, hysteroscopy appeared to improve pregnancy rates in the following IVF cycle despite previous performance of imaging studies of the uterine cavity. However, the added value of hysteroscopy remained unclear due to methodological concerns about the included studies. Recently, a large multicenter randomized trial revaluated this issue in women <38 years of age with two to four prior unsuccessful IVF cycles and a normal ultrasound of the uterine cavity . The live birth rate was the same whether or not precycle hysteroscopy was performed, which suggests that any intrauterine pathology not identified by ultrasound was clinically insignificant. Based on these findings, we believe hysteroscopy is not routinely indicated before IVF, but may be preferable to ultrasound in areas where high-quality uterine ultrasound is unavailable. (See "In vitro fertilization", section on 'Reasons for failure'.)
Weight loss and infertility (May 2016)
Obesity is associated with increased risks for infertility and adverse pregnancy outcome. For this reason, obese women are encouraged to lose weight prior to attempting to conceive. However, the effectiveness of lifestyle-intervention programs in this population had not been evaluated by a large randomized trial. Recently, a multicenter trial randomly assigned 577 infertile women with BMI ≥29 kg/m2 to either a six-month structured weight-loss program preceding infertility treatment or prompt infertility treatment . The intervention group achieved a higher rate of natural conception (26 versus 16 percent); however, the primary outcome, term births of vaginally delivered healthy singletons, was similar in both groups. Only 38 percent of women achieved the target weight loss (5 to 10 percent of the original body weight) and 22 percent dropped out of the program, which limited interpretation of the effectiveness of the intervention. We continue to advise weight loss for infertile obese women because it is an inexpensive, low-risk intervention for improving the likelihood of natural conception and it has long-term benefits for overall health. (See "Overview of treatment of female infertility", section on 'High body weight'.)
Efficacy and safety of flibanserin for low sexual desire in women (May 2016)
Flibanserin, the only drug approved by the US Food and Drug Administration (FDA) for female sexual dysfunction, results in modest increases in sexual desire in women with decreased desire associated with distress. A recent meta-analysis of eight placebo-controlled randomized trials provided the best available evidence of the safety and efficacy of flibanserin . Use of flibanserin resulted in small but significant increases in sexual desire and the number of sexually satisfying events per month, but also increased the risk for mild adverse events, such as dizziness, somnolence, nausea, and fatigue. More severe effects, such as hypotension or syncope, also occur and are magnified with concurrent alcohol use. We believe the clinical role of flibanserin may be limited by the daily dosing regimen, low efficacy, risk of adverse effects, and safety concerns if alcohol is consumed or the woman is taking certain medications (eg, fluconazole, antidepressants). (See "Sexual dysfunction in women: Management", section on 'Flibanserin'.)
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'.)
Menopausal hormone therapy in ovarian cancer survivors (May 2016)
Menopausal hormone therapy (HT) is generally considered safe in survivors of epithelial ovarian cancer (EOC), but data are limited. A meta-analysis of six comparative studies (including two randomized trials) of women with EOC found that those treated with menopausal HT compared with no HT had no difference in EOC recurrence . They also found lower rates of cancer death in the women who were treated with HT, but this might reflect underlying better health status among women in the nonrandomized studies who were prescribed HT treatment. HT does not appear to increase the risk of epithelial ovarian cancer recurrence or mortality. (See "Overview of the approach to survivors of epithelial ovarian, fallopian tube, or peritoneal carcinoma", section on 'Menopause'.)
Ovary-sparing hysterectomy reduces ovarian reserve (April 2016)
Hysterectomy with ovarian conservation has been associated with earlier menopause, but the reason is unclear. One theory is that the procedure hastens follicular depletion, and another theory is that women with underlying follicular depletion are at risk for having symptoms that prompt hysterectomy. Anti-Mullerian hormone (AMH) is a marker for the size of the ovarian follicle pool. A study including nearly 150 women who underwent ovary-sparing hysterectomy found that at one year post-hysterectomy, hysterectomized women had AMH levels that were on average 77 percent of the levels in a control group of similar age and baseline AMH levels who did not undergo hysterectomy . This finding supports the hypothesis that the surgical procedure itself hastens follicular depletion and thus increases the risk for early menopause. (See "Choosing a route of hysterectomy for benign disease", section on 'Earlier menopause or decreased ovarian reserve'.)
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'.)
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'.)
Mediterranean compared with low-fat or low-carbohydrate diet for weight loss (May 2016)
The impact of specific dietary composition on weight change remains uncertain. In a systematic review of five trials with follow-up ≥12 months, a Mediterranean diet resulted in similar weight loss (-4.1 to -10.1 kg) as a low-carbohydrate diet (-4.7 to -7.7 kg) and greater weight loss than a low-fat diet (2.9 to -5 kg) . There was a similar reduction in lipid levels among the diets studied. The degree of adherence to the diet, irrespective of the particular macronutrient composition, is an important determinant of weight loss. We suggest choosing a diet or eating plan based upon patient preferences, which may improve long-term adherence. The diet should emphasize reductions in refined carbohydrates, processed meats, foods high in sodium and trans fat and higher intakes of fruits, nuts, fish, vegetables, and whole grains. (See "Obesity in adults: Dietary therapy", section on 'Weight loss diets'.)
- Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016; 375:323.
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375:311.
- Margulies KB, Hernandez AF, Redfield MM, et al. Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA 2016; 316:500.
- http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494829.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery (Accessed on April 11, 2016).
- Chen ZJ, Shi Y, Sun Y, et al. Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome. N Engl J Med 2016; 375:523.
- van den Belt-Dusebout AW, Spaan M, Lambalk CB, et al. Ovarian Stimulation for In Vitro Fertilization and Long-term Risk of Breast Cancer. JAMA 2016; 316:300.
- Legro RS, Dodson WC, Kunselman AR, et al. Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS. J Clin Endocrinol Metab 2016; 101:2658.
- El-Toukhy T, Campo R, Khalaf Y, et al. Hysteroscopy in recurrent in-vitro fertilisation failure (TROPHY): a multicentre, randomised controlled trial. Lancet 2016; 387:2614.
- Mutsaerts MA, van Oers AM, Groen H, et al. Randomized Trial of a Lifestyle Program in Obese Infertile Women. N Engl J Med 2016; 374:1942.
- Jaspers L, Feys F, Bramer WM, et al. Efficacy and Safety of Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Women: A Systematic Review and Meta-analysis. JAMA Intern Med 2016; 176:453.
- Henderson VW, St John JA, Hodis HN, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology 2016; 87:699.
- McCurry SM, Guthrie KA, Morin CM, et al. Telephone-Based Cognitive Behavioral Therapy for Insomnia in Perimenopausal and Postmenopausal Women With Vasomotor Symptoms: A MsFLASH Randomized Clinical Trial. JAMA Intern Med 2016; 176:913.
- Pergialiotis V, Pitsouni E, Prodromidou A, et al. Hormone therapy for ovarian cancer survivors: systematic review and meta-analysis. Menopause 2016; 23:335.
- Trabuco EC, Moorman PG, Algeciras-Schimnich A, et al. Association of Ovary-Sparing Hysterectomy With Ovarian Reserve. Obstet Gynecol 2016; 127:819.
- Hodis HN, Mack WJ, Henderson VW, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med 2016; 374:1221.
- Santoro N, Braunstein GD, Butts CL, et al. Compounded Bioidentical Hormones in Endocrinology Practice: An Endocrine Society Scientific Statement. J Clin Endocrinol Metab 2016; 101:1318.
- Jakicic JM, Davis KK, Rogers RJ, et al. Effect of Wearable Technology Combined With a Lifestyle Intervention on Long-term Weight Loss: The IDEA Randomized Clinical Trial. JAMA 2016; 316:1161.
- Walter S, Mejía-Guevara I, Estrada K, et al. Association of a Genetic Risk Score With Body Mass Index Across Different Birth Cohorts. JAMA 2016; 316:63.
- Mancini JG, Filion KB, Atallah R, Eisenberg MJ. Systematic Review of the Mediterranean Diet for Long-Term Weight Loss. Am J Med 2016; 129:407.