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What's new in endocrinology and diabetes mellitus
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What's new in endocrinology and diabetes mellitus

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.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2015. | This topic last updated: Apr 16, 2015.

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.

DIABETES MELLITUS

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) [1]. 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 [2]. 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'.)

Exercise reduces risk of gestational diabetes (March 2015)

Regular moderate exercise may lower the risk of developing gestational diabetes. In a 2015 meta-analysis of 10 randomized trials, initiating an exercise program during pregnancy reduced the risk of developing gestational diabetes compared with routine care (RR 0.74, 95% CI 0.57-0.97), although the confidence interval was wide [3]. (See "Diabetes mellitus in pregnancy: Screening and diagnosis", section on 'Approaches for risk reduction'.)

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 [4]. 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 [5]. 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 [6]. 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 [7]. 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 [8]. 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 [9]. (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) [10]. 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'.)

Long-term effect of intensive glycemic control on macrovascular outcomes in type 2 diabetes (October 2014)

The ADVANCE trial randomly assigned 11,140 patients with long-standing type 2 diabetes to either standard therapy or modified release gliclazide plus other drugs as required to achieve an A1C of <6.5 percent, and found no benefit of intensive therapy on the primary composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke after a median of five years. Of the 10,082 surviving trial participants, 8494 enrolled in a post-trial monitoring study [4]. A 2000-patient random subset of the surviving cohort that agreed to participate in the post-trial monitoring study had periodic laboratory testing for A1C, fasting blood glucose, serum creatinine, blood pressure, and weight. Mean A1C, which had been significantly different during the trial, became similar by the first post-trial visit and remained similar throughout the monitoring period (7.2 and 7.4 percent in the original intensive and standard groups, respectively). After a median total follow-up of 9.9 years, similar to the findings in the randomized trial, there was no benefit of intensive therapy on macrovascular outcomes. (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'ADVANCE'.)

FEMALE REPRODUCTION

First live birth after uterine transplantation (October 2014)

Uterine transplantation is an investigational procedure performed in a few centers worldwide. The first live birth after uterine transplantation was recently reported  [11]. The donor was a 61-year-old unrelated family friend. The recipient was a 35-year-old woman with congenital Müllerian agenesis who delivered a healthy, appropriately grown infant via cesarean section at 32 weeks because of preeclampsia. The mother and baby were doing well two weeks postdelivery. This report supports the feasibility of uterine transplantation as a potential treatment for uterus-associated infertility. (See "Surgical management of congenital uterine anomalies", section on 'Uterine transplantation'.)

MENOPAUSE

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) [12]. 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 [13]. 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'.)

OBESITY

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 [14]. 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 [15]. 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 [16]. 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'.)

Combination bupropion-naltrexone for the treatment of obesity (October 2014)

In September 2014, the combination of bupropion-naltrexone was approved in the United States by the Food and Drug Administration (FDA) as an adjunct to diet and exercise in patients with BMI ≥30 kg/m2 or ≥27 kg/m2 in the presence of at least one weight-related comorbidity [17]. Because bupropion-naltrexone can raise blood pressure and heart rate, the FDA is requiring post-marketing studies to evaluate cardiovascular outcomes and the effect of the combination on cardiac conduction. Pending these further studies, we prefer to use orlistat or lorcaserin when medical treatment of obesity is indicated, rather than bupropion-naltrexone. (See "Obesity in adults: Drug therapy", section on 'Bupropion-naltrexone'.)

PITUITARY DISORDERS

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 [18]. 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'.)

Genetic defects associated with gigantism and acromegaly (December 2014)

Microduplications in the Xp26.3 region that include the GPR101 (G protein-coupled receptor 101) gene are associated with gigantism due to an excess of growth hormone, termed X-linked acrogigantism (X-LAG) [19]. All patients identified with this microduplication had disease onset before five years of age. The G protein-coupled receptor was overexpressed in the patients' pituitary lesions. A recurrent mutation in GPR101 is found in some adults with acromegaly. (See "Pituitary gigantism" and "Causes and clinical manifestations of acromegaly", section on 'Causes' and "Sex chromosome abnormalities", section on 'Xp26.3 microduplication'.)

THYROID DISORDERS

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 [20]. 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'.)

Mutational analysis of thyroid FNA aspirates (December 2014)

When thyroid nodule aspirate results show follicular lesion/atypia of undetermined significance or follicular neoplasm, the results are often called indeterminate. The risk of malignancy with these cytologic classifications ranges from 5 to 32 percent, and the majority of these patients undergo diagnostic thyroid surgery, although benign disease is ultimately confirmed in 75 to 95 percent of patients undergoing surgery. New approaches aim to improve the assessment of indeterminate aspirates. In a study using a next-generation sequencing assay with an expanded panel of point mutations and gene fusions that occur in thyroid cancer, 143 nodule aspirates with follicular neoplasm cytology and surgical follow-up (39 of which were malignant) were analyzed [21]. The expanded panel had a negative predictive value for malignancy of 96 percent and a positive predictive value of 83 percent. The routine use of molecular analysis for indeterminate FNA aspirates may reduce the number of patients who are referred for diagnostic thyroid surgery. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Mutational analysis'.)

OTHER ENDOCRINOLOGY

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 [22]. 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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REFERENCES

  1. Cavender MA, Scirica BM, Bonaca MP, et al. Vorapaxar in Patients With Diabetes Mellitus and Previous Myocardial Infarction: Findings From the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50 Trial. Circulation 2015; 131:1047.
  2. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015; 372:1193.
  3. Russo LM, Nobles C, Ertel KA, et al. Physical Activity Interventions in Pregnancy and Risk of Gestational Diabetes Mellitus: A Systematic Review and Meta-analysis. Obstet Gynecol 2015; 125:576.
  4. Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med 2014; 371:1392.
  5. Emdin CA, Rahimi K, Neal B, et al. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA 2015; 313:603.
  6. Balsells M, García-Patterson A, Solà I, et al. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 2015; 350:h102.
  7. Gibbons CH, Freeman R. Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes. Brain 2015; 138:43.
  8. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 2015; 385:351.
  9. Frayling TM. Statins and type 2 diabetes: genetic studies on target. Lancet 2015; 385:310.
  10. Writing Group for the DCCT/EDIC Research Group, Orchard TJ, Nathan DM, et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA 2015; 313:45.
  11. Brännström M, Johannesson L, Bokström H, et al. Livebirth after uterus transplantation. Lancet 2015; 385:607.
  12. Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med 2015; 175:531.
  13. . Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet 2015.
  14. Johansson K, Cnattingius S, Näslund I, et al. Outcomes of pregnancy after bariatric surgery. N Engl J Med 2015; 372:814.
  15. Ikramuddin S, Blackstone RP, Brancatisano A, et al. Effect of reversible intermittent intra-abdominal vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial. JAMA 2014; 312:915.
  16. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm430223.htm (Accessed on January 16, 2015).
  17. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm413896.htm.
  18. Chang AM, Aeschbach D, Duffy JF, Czeisler CA. Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. Proc Natl Acad Sci U S A 2015; 112:1232.
  19. Trivellin G, Daly AF, Faucz FR, et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 2014; 371:2363.
  20. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372:621.
  21. Nikiforov YE, Carty SE, Chiosea SI, et al. Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer 2014; 120:3627.
  22. Singer FR, Bone HG 3rd, Hosking DJ, et al. Paget's disease of bone: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014; 99:4408.
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