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What's new in endocrinology and diabetes mellitus

Disclosures: Kathryn A Martin, MD Employee of UpToDate, Inc. Jean E Mulder, MD Employee of UpToDate, Inc.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2014. | This topic last updated: Sep 16, 2014.

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

Physical activity reduces risk of type 2 diabetes after gestational diabetes (July 2014)

Increasing evidence suggests that an active lifestyle reduces the risk of developing type 2 diabetes in women with gestational diabetes. In a 16-year prospective observational study, 14 percent of women with a history of gestational diabetes self-reported the development of type 2 diabetes [1]. Women with a total physical activity level equivalent to 150 minutes per week of moderate-intensity physical activity or 75 minutes per week of vigorous-intensity physical activity had a 30 to 50 percent lower risk of developing type 2 diabetes than women with lower levels of physical activity. (See "Gestational diabetes mellitus: Glycemic control and maternal prognosis", section on 'Follow-up and prevention of type 2 diabetes'.)

Inhaled insulin (July 2014)

In June of 2014, the US Food and Drug Administration (FDA) approved a formulation of inhaled insulin (Afrezza) to improve glycemic control in adults with diabetes mellitus [2]. The approval includes a Risk Evaluation and Mitigation Strategy, which consists of informing healthcare professionals about the serious risk of acute bronchospasm associated with use in patients with asthma or other chronic lung diseases. Because of this risk, Afrezza is contraindicated in patients with chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD). Afrezza, which is administered at the beginning of a meal, is expected to become available for clinical use in early 2015. Until more published data about safety and efficacy are available, the role of this insulin preparation is uncertain. (See "Inhaled insulin therapy in diabetes mellitus", section on 'Dose and administration'.)

Automated closed-loop insulin pump (July 2014)

Small studies have compared overnight glycemic control using a fully automated closed-loop system of insulin delivery (eg, patients do not adjust dosing) with conventional insulin pump therapy. In two crossover trials in adults and adolescents, an automated bihormonal (insulin and glucagon) closed-loop system was compared with conventional insulin pump therapy over a five-day period [3]. The delivery of insulin and glucagon during the closed-loop arm was determined automatically by an algorithm that adjusted doses based on continuous glucose monitoring. On days 2 through 5 of the closed-loop system, as compared with the control period, the mean glucose level was lower in both adults and adolescents. There were no severe hypoglycemic events during the closed-loop period. Although these preliminary results are promising, additional trials are needed. (See "Insulin therapy in adults with type 1 diabetes mellitus", section on 'Automated closed-loop insulin pump'.)

Decline in diabetes-related complications (May 2014)

Morbidity from diabetes is a consequence of both macrovascular and microvascular disease. The progression of these complications can be slowed with interventions such as aggressive management of glycemia, blood pressure, and lipids; laser therapy for advanced retinopathy; and administration of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker for nephropathy. These interventions appear to be reducing the incidence of several diabetes-related complications, including myocardial infarction (MI), stroke, lower-extremity amputation, and end-stage renal disease. In the United States, the greatest absolute declines have been reported for acute MI and stroke (between 1990 and 2010, 95.6 and 58.9 fewer cases per 10,000 persons per year for MI and stroke, respectively) [4]. (See "Overview of medical care in adults with diabetes mellitus", section on 'Diabetes-related complications'.)

ACE inhibitors and ARBs in diabetic patients (May 2014)

A meta-analysis of 48 trials in patients with diabetes that compared angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) with either placebo or another antihypertensive drug found that ACE inhibitors, but not ARBs, significantly reduced mortality compared with placebo [5]. However, differences in patient populations may explain some of these findings; the overall mortality in the trials comparing ARBs with placebo was substantially lower than trials comparing ACE inhibitors with placebo. Both ACE-inhibitors and ARBs had similar, nonsignificant benefits on mortality when compared with another antihypertensive drug, and both agents had significant benefits on heart failure. Other meta-analyses in both diabetic and nondiabetic patients have reported that ACE inhibitors and ARBs have identical effects on mortality and kidney disease. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Overall approach to selecting a therapy'.)

FEMALE REPRODUCTION

Injectable progestins and risk of venous thrombosis (September 2014)

In contrast to other progestin-only contraceptives, depot medroxyprogesterone acetate (DMPA) use may be associated with an increased risk of venous thrombosis and embolism (VTE). In a case-control study, women with a first episode of VTE were twice as likely to be DMPA users than were controls in the general population [6]. In this study, VTE was not associated with use of progestin-only pills, the levonorgestrel-releasing intrauterine device, or the progestin-only contraceptive implant. However, in the absence of data about absolute risk of VTE in DMPA users, we continue to think that the advantages of using DMPA generally outweigh the risks for women with a history of VTE. (See "Depot medroxyprogesterone acetate for contraception", section on 'Cardiovascular risk'.)

Oral emergency contraception in overweight women (August 2014)

In Europe, product labeling for levonorgestrel-based emergency contraception (NorLevo) was updated in February 2014 to indicate that it may be less effective in women ≥75 kg (165 pounds). In July 2014, the European Medicines Association concluded that the available data were not robust enough to be certain the contraceptive efficacy of levonorgestrel emergency contraception is reduced with increased bodyweight and that the benefits of taking the medication outweighed any risks [7]. We counsel overweight and obese women of potentially reduced efficacy of levonorgestrel emergency contraception as BMI increases above the normal range (25 kg/m2) or at weights ≥75 kg (165 pounds), and offer them a copper-releasing IUD as first-line therapy to prevent pregnancy. If the IUD is not an option, ulipristal is more likely to be effective than levonorgestrel. (See "Emergency contraception", section on 'Overweight and obese women'.)

MALE REPRODUCTION

Testosterone products: Revised labeling for venous thromboembolism risk (July 2014)

While previous labeling of testosterone products in the United States has included information about the risk of venous thromboembolism (VTE) as a consequence of erythrocytosis, a recent study found that venous thromboses and pulmonary emboli may occur unrelated to polycythemia in patients taking testosterone [8]. In this study, among 40 men who had thrombotic events at a median of five months after starting testosterone therapy, 39 were found to have previously undiagnosed thrombophilia-hypofibrinolysis, highlighting the importance of a careful personal and family VTE history prior to initiating treatment. Routine screening for thrombophilias in men considering testosterone therapy is not currently suggested. The US Food and Drug Administration (FDA) will now require a more general warning about the risk of thrombosis in the labeling of all approved testosterone products [9]. (See "Testosterone treatment of male hypogonadism", section on 'Erythrocytosis' and "Testosterone treatment of male hypogonadism", section on 'Venous thromboembolism'.)

Nasal testosterone gel for male hypogonadism (June 2014)

The first nasal testosterone gel (Natesto) has been approved in the United States for the treatment of male hypogonadism [10]. The gel is administered into the nostrils via a metered-dose pump applicator. One advantage over other formulations is the minimal risk of gel transfer to a partner or child. On the other hand, some men may find the three times daily regimen inconvenient, and those with allergies or underlying nasal or sinus pathology may have trouble tolerating the formulation as rhinorrhea, nasopharyngitis, and sinusitis are among the most common side effects. Until further published data are available, we suggest using other available testosterone gels, patches, or injectable esters over this new formulation. (See "Testosterone treatment of male hypogonadism", section on 'Other'.)

Extra-long acting injectable testosterone preparation approved in US (March 2014)

Testosterone undecanoate is an extra-long acting parenteral testosterone ester developed for the treatment of male hypogonadism; it has been available in several countries outside the United States, but is now approved in the US as well [11]. Unlike other testosterone esters (enanthate and cypionate) that require injection every one to two weeks, testosterone undecanoate is administered every 10 to 14 weeks. However, this preparation has been associated with rare, but important adverse events: pulmonary oil microembolism (POME) and anaphylaxis (1.5 and 0.4 cases per 10,000 injections, respectively) [12]. In the United States, the drug will only be available through a restricted program called the AVEED Risk Evaluation and Mitigation Strategy (REMS) Program. All injections must be administered in an office or hospital setting and monitored for 30 minutes afterwards for adverse reactions. (See "Testosterone treatment of male hypogonadism", section on 'Extra-long-acting injections'.)

Testosterone and cardiovascular safety (March 2014)

The US Food and Drug Administration (FDA) is investigating data about a possible increase in cardiovascular events in men taking testosterone replacement therapy [13]. Earlier studies did not find evidence of excess cardiovascular risk in hypogonadal men receiving testosterone, but a 2010 trial in men aged 65 and older was stopped early because of adverse cardiovascular events. Two more recent retrospective cohort studies also suggest there might be a higher rate of cardiovascular events in some men who take testosterone [14,15]. However, all three studies have important methodological limitations. Given the uncertainty of these data, we continue to recommend that testosterone be administered only to men who are hypogonadal, as evidenced by clinical symptoms and signs consistent with androgen deficiency and a subnormal morning serum total testosterone concentration on three occasions. (See "Testosterone treatment of male hypogonadism", section on 'Cardiovascular risks'.)

Tamoxifen in dietary supplements for athletic performance (March 2014)

Tamoxifen, an antiestrogen, has been identified as an unlabeled ingredient in dietary supplements marketed to enhance athletic performance [16]. Bodybuilders and other athletes who take exogenous testosterone frequently take tamoxifen (10 to 20 mg/day) to prevent gynecomastia. Tamoxifen doses in one supplement, EstoSuppress, were as high as 7.6 mg/day, close to the therapeutic doses (10 to 20 mg/day for painful gynecomastia and male breast cancer) that have been associated with venous thromboembolism (VTE) [17]. In athletes using androgens and tamoxifen, inadvertent use of additional tamoxifen from dietary supplements could add to the already elevated VTE risk. (See "Use of androgens and other hormones to enhance athletic performance", section on 'Antiestrogens'.)

MENOPAUSE

KEEPS hormone therapy trial in newly menopausal women (September 2014)

The Women's Health Initiative (WHI), a set of menopausal hormone therapy (MHT) trials in older postmenopausal women (average age 63 years) reported an excess risk of coronary heart disease (CHD) with MHT. Emerging data, including secondary analyses from the WHI, now suggest that use of MHT in the early menopausal years is not associated with excess CHD risk. The Kronos Early Estrogen Prevention Study (KEEPS) is the first randomized trial of MHT in younger menopausal women (727 women ages 45 to 54 years) [18]. When combined with cyclical monthly oral progesterone, low dose oral conjugated estrogen (0.45 mg daily) or transdermal estradiol (50 mcg daily) for four years relieved menopausal symptoms. While several markers of cardiovascular risk improved in the MHT group, there was no significant effect on surrogate markers of atherosclerosis progression (coronary artery calcium and carotid intima-medial thickness) when compared to placebo. This trial provides additional reassurance that early use of MHT is safe for the treatment of menopausal symptoms, though does not support a role for MHT in prevention. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Timing of exposure'.)

OBESITY

Obesity as independent risk for coronary heart disease (April 2014)

Obesity is associated with an increased risk of coronary heart disease (CHD), but the extent to which this association is due to concurrent factors (hypertension, dyslipidemia, and insulin resistance) or to obesity independent of other risks is uncertain. In an analysis of pooled data from 97 prospective cohort studies from multiple countries (1.8 million individuals), blood pressure, serum cholesterol, and blood glucose accounted for approximately 50 percent of the excess risk of high body mass index (BMI) for CHD [19]. Blood pressure was the most important mediator, which accounted for approximately one-third of the excess risk. (See "Obesity in adults: Health hazards", section on 'Coronary disease'.)

Obesity prevalence in preschool children (March 2014)

In the United States, the overall prevalence of childhood obesity tripled between the early 1980s and 2000, then reached a plateau. Now, a nationwide population study has reported a dramatic decrease in obesity among preschool aged children (two to five years) [20]. In this age group, obesity rates peaked at 13.9 percent in 2004, then fell by 40 percent to 8.4 percent in 2011-2012. In the same study, the rates of obesity among older children and adolescents remained stable. (See "Definition; epidemiology; and etiology of obesity in children and adolescents", section on 'Trends'.)

THYROID DISORDERS

Paraneoplastic hypothyroidism with large gastrointestinal stromal tumors (April 2014)

Hypothyroidism is a common side effect of antiangiogenic tyrosine kinase inhibitors (TKIs), such as sunitinib and regorafenib, which are used to treat advanced gastrointestinal stromal tumors (GIST). Newly emerging data suggest that patients with large GISTs may also develop paraneoplastic hypothyroidism that is unrelated to treatment [21]. The mechanism appears to be excessive degradation of thyroid hormone caused by overexpression of the thyroid hormone inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. The frequency with which this occurs is unclear. Clinicians should have a low index of suspicion for hypothyroidism in patients with a large GIST tumor burden even if antiangiogenic TKIs have never been used. (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'Clinical manifestations'.)

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REFERENCES

  1. Bao W, Tobias DK, Bowers K, et al. Physical activity and sedentary behaviors associated with risk of progression from gestational diabetes mellitus to type 2 diabetes mellitus: a prospective cohort study. JAMA Intern Med 2014; 174:1047.
  2. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403122.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery (Accessed on June 30, 2014).
  3. Russell SJ, El-Khatib FH, Sinha M, et al. Outpatient glycemic control with a bionic pancreas in type 1 diabetes. N Engl J Med 2014; 371:313.
  4. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med 2014; 370:1514.
  5. Cheng J, Zhang W, Zhang X, et al. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med 2014; 174:773.
  6. Bergendal A, Persson I, Odeberg J, et al. Association of venous thromboembolism with hormonal contraception and thrombophilic genotypes. Obstet Gynecol 2014; 124:600.
  7. Levonorgestrel and ulipristal remain suitable emergency contraceptives for all women, regardless of bodyweight http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/07/news_detail_002145.jsp&mid=WC0b01ac058004d5c1 (Accessed on August 04, 2014).
  8. Glueck CJ, Wang P. Testosterone therapy, thrombosis, thrombophilia, cardiovascular events. Metabolism 2014; 63:989.
  9. FDA adding general warning to testosterone products about potential for venous blood clots. US Food and Drug Administration (FDA) Drug Safety and Availability. Last updated June 25, 2014. (Available online at http://www.fda.gov/Drugs/DrugSafety/ucm401746.htm (accessed June 30, 2014)).
  10. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails (Accessed on June 03, 2014).
  11. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails (Accessed on March 11, 2014).
  12. http://www.scribd.com/doc/211471259/69/Overlap-of-Cases-Adjudicated-as-POME-and-Anaphylaxis (Accessed on March 11, 2014).
  13. http://www.fda.gov/drugs/drugsafety/ucm383904.htm (Accessed on March 12, 2014).
  14. Vigen R, O'Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310:1829.
  15. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014; 9:e85805.
  16. Evans-Brown M, Kimergård A, McVeigh J, et al. Is the breast cancer drug tamoxifen being sold as a bodybuilding dietary supplement? BMJ 2014; 348:g1476.
  17. Pemmaraju N, Munsell MF, Hortobagyi GN, Giordano SH. Retrospective review of male breast cancer patients: analysis of tamoxifen-related side-effects. Ann Oncol 2012; 23:1471.
  18. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014; 161:249.
  19. Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (BMI Mediated Effects), Lu Y, Hajifathalian K, et al. Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1·8 million participants. Lancet 2014; 383:970.
  20. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 2014; 311:806.
  21. Maynard MA, Marino-Enriquez A, Fletcher JA, et al. Thyroid hormone inactivation in gastrointestinal stromal tumors. N Engl J Med 2014; 370:1327.
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