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What's new in endocrinology and diabetes mellitus
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What's new in endocrinology and diabetes mellitus
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2017. | This topic last updated: Sep 12, 2017.

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

Liraglutide and renal outcomes in type 2 diabetes (September 2017)

In an earlier report of a randomized trial comparing liraglutide with placebo in patients with type 2 diabetes and coexisting cardiovascular disease, liraglutide reduced the incidence of the composite cardiovascular endpoint. In a separate analysis of the secondary microvascular endpoints in the trial, liraglutide reduced the incidence of the renal outcome (a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease) [1]. The results were driven by a lower incidence of new-onset persistent macroalbuminuria. Trials of longer duration with primary microvascular outcomes and in patients who are not at high cardiovascular risk are required in order to better understand the microvascular effects of GLP-1 receptor agonists. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Microvascular outcomes'.)

Effect of insulin degludec and insulin glargine on hypoglycemia and CVD outcomes (July 2017)

Long-acting basal insulin preparations include glargine, detemir, and degludec. Several recent studies have compared outcomes for insulin degludec and insulin glargine.

In two similarly designed crossover trials comparing once-daily insulin degludec with insulin glargine in patients with type 1 and type 2 diabetes mellitus at high risk for hypoglycemia, the rate of overall symptomatic and nocturnal hypoglycemia was lower with degludec [2,3]. Limitations of the trials include a high rate of loss to follow-up and lack of generalizability to patients at lower risk for hypoglycemia.

In a two-year noninferiority trial comparing once-daily insulin degludec with insulin glargine in over 7500 patients with type 2 diabetes and cardiovascular disease, the primary cardiovascular composite outcome (death from cardiovascular causes, or first occurrence of a nonfatal myocardial infarction or nonfatal stroke) occurred in a similar proportion of patients (8.5 and 9.3 percent of the patients receiving degludec and glargine, respectively) [4]. Glycemic control was similar throughout the trial; rates of severe and nocturnal hypoglycemia were lower in patients taking degludec.

The choice of basal insulin (NPH, glargine, detemir, or degludec) primarily depends upon patient preference, lifestyle, and cost issues. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Insulin therapy in type 2 diabetes mellitus", section on 'Basal insulin' and "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Basal insulin'.)

Racial variation in glycated hemoglobin (July 2017)

Several studies have shown that glycated hemoglobin (A1C) concentrations are higher in black than in white persons with diabetes, although it is uncertain if the difference is due to worse glycemic control or racial variation in the glycation of hemoglobin. In a prospective, 12-week study comparing A1C with mean glucose values measured by continuous glucose monitoring (CGM) in black and white persons with type 1 diabetes, both average CGM glucose (191 versus 180 mg/dL [10.6 versus 10 mmol/L]) and A1C (9.1 versus 8.3 percent) were higher in black than white individuals [5]. The mean A1C in black compared with white individuals was 0.4 percentage points higher for any given mean glucose concentration. The racial variation explained only a proportion of the difference in mean A1C levels between the two groups, with higher mean glucose values likely accounting for the rest. The small difference in A1C has not been shown to modify the association between A1C and microvascular and macrovascular outcomes, and diagnostic criteria and target A1C goals remain unchanged. (See "Estimation of blood glucose control in diabetes mellitus", section on 'Racial variation'.)

Canagliflozin in diabetic individuals with overt CVD (June 2017)

The cardiovascular effects of diabetes drugs have been evaluated in a growing number of trials. Two trials evaluated the effects of canagliflozin, compared with placebo, on cardiovascular, renal, and safety outcomes in patients with type 2 diabetes and high cardiovascular risk [6]. The primary composite cardiovascular outcome (cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke), as well as progression of albuminuria, occurred in fewer patients in the canagliflozin group. However, there was an increase in the risk of lower limb amputations and fractures in the canagliflozin group, tempering enthusiasm for this drug. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

GLP-1-based therapies for type 2 diabetes and overall mortality (June 2017)

The effect of glucagon-like peptide-1 (GLP-1)-based therapies (GLP-1 receptor agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors) on overall mortality in patients with type 2 diabetes is uncertain. In a systematic review and meta-analysis of 189 trials, there was no difference in all-cause mortality between any GLP-1-based therapy versus control (placebo or other antidiabetic drug) [7]. In subgroup analyses of the cardiovascular outcomes trials, there was a suggestion of reduced all-cause mortality with GLP-1 receptor agonists versus placebo, but no difference with DPP-4 inhibitors versus placebo. Further studies examining the effect of GLP-1 receptor agonists on overall mortality are warranted. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus" and "Dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)

Screening interval for diabetic retinopathy (May 2017)

There are few data evaluating the optimal frequency of follow-up retinal examinations after initial screening in patients with diabetes, particularly type 1 diabetes. In an analysis of almost 24,000 retinopathy examinations over 24 years in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study, the probability of progressing from lower to higher categories of retinopathy was dependent upon the previous retinal exam and glycated hemoglobin (A1C), with optimal screening intervals ranging from every three months among patients with severe nonproliferative retinopathy to every four years among those who had no retinopathy [8]. Compared with annual or biannual examinations, this model for an individualized schedule resulted in an overall reduction in the frequency of eye examinations and a substantial reduction in cost. (See "Diabetic retinopathy: Screening", section on 'Frequency of examinations'.)

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 [9]. 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'.)

FEMALE REPRODUCTION

Fertility preservation with cryopreserved ovarian tissue transplantation (July 2017)

For women at risk of ovarian failure due to planned gonadotoxic therapy and who desire fertility preservation, increasing evidence supports use of ovarian tissue cryopreservation followed by autotransplantation (OTT) after completion of therapy. In a 2017 meta-analysis, endocrine function was restored for at least four months after OTT in over 60 percent of women [10]. OTT was associated with similar live birth rates as conventional frozen embryo transfer, and over 60 percent of women who conceived after an orthotopic transplant conceived naturally. (See "Fertility preservation in patients undergoing gonadotoxic treatment or gonadal resection", section on 'Outcomes'.)

Menopausal hot flashes: A novel nonhormonal treatment (July 2017)

A neurokinin 3 receptor (NK3R) antagonist is a potential new nonhormonal therapy for menopausal hot flashes. In a randomized, crossover trial of an oral NK3R antagonist or placebo administered for four weeks each in symptomatic postmenopausal women, the average total weekly number of hot flashes decreased from approximately 85 at baseline to 20 and 50 in the treatment and placebo groups, respectively [11]. Residual hot flashes in the treatment group were also less severe and less bothersome. Three subjects in the treatment group had transient increases in transaminases that were asymptomatic and returned to baseline post-trial. Although results of this trial are encouraging, larger and longer duration trials are needed to determine the efficacy and safety of this drug. (See "Menopausal hot flashes", section on 'Neurokinin 3 receptor antagonist'.)

Primary ovarian insufficiency: ACOG statement on hormone therapy (June 2017)

Many clinicians have become reluctant to prescribe estrogen to women of any age based upon the safety concerns raised by clinical trials performed in older postmenopausal women (the Women's Health Initiative, WHI). The American College of Obstetrics and Gynecology issued a Committee Opinion on the importance of long-term hormone therapy in women with primary ovarian insufficiency (POI, menopause before age 40), for whom the results of the WHI are not applicable [12]. They recommend systemic hormone therapy for all women with POI without contraindications until age 50/51 years (the average age of natural menopause) for the multiple issues associated with estrogen deficiency (eg, treatment of symptoms [hot flashes, genitourinary atrophy, diminished quality of life], prevention of adverse health consequences [osteoporosis, early coronary heart disease, and dementia], and maintenance of normal sexual function). (See "Management of spontaneous primary ovarian insufficiency (premature ovarian failure)", section on 'Estrogen therapy'.)

Oral contraceptives and ovarian cancer risk (June 2017)

Use of oral estrogen-progestin contraceptives is associated with a reduction in risk of ovarian cancer. In the largest and longest duration study of oral contraceptive use, the Royal College of General Practitioners’ Oral Contraception Study followed over 46,000 women for up to 44 years and found that ever-use of oral contraceptives was associated with a 33 percent reduction in ovarian cancer risk [13]. This finding supports previous data and our recommendation for use of oral contraceptives in women who desire ovarian cancer risk reduction who have not undergone risk reduction surgery and who are not trying to conceive. (See "Risk-reducing bilateral salpingo-oophorectomy in women at high risk of epithelial ovarian and fallopian tubal cancer" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Epidemiology and risk factors", section on 'Oral contraceptives'.)

Oral GnRH antagonist for endometriosis-related pain (May 2017)

Endometriosis can cause chronic debilitating dysmenorrhea and pelvic pain. In phase 3 trials, elagolix (a novel oral gonadotropin-releasing [GnRH] antagonist) reduced endometriosis-related dysmenorrhea and noncyclic pelvic pain compared with placebo at three months of treatment, and these reductions were sustained at six months of treatment [14]. Oral GnRH antagonists, such as elagolix, provide a treatment option for women who do not respond to standard oral therapies and are more convenient than intramuscular GnRH agonists. However, they are associated with hypoestrogenic side effects. (See "Endometriosis: Treatment of pelvic pain", section on 'Gonadotropin-releasing hormone (GnRH) antagonists'.)

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 [15]. These data are reassuring regarding the reproductive potential of female ICSI offspring. (See "Intracytoplasmic sperm injection", section on 'Reproductive function'.)

MALE REPRODUCTION

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 [16,17] 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 [18].

There was a beneficial effect on anemia [19] and bone density [20].

Testosterone increased coronary artery noncalcified plaque volume as measured by coronary computed tomographic angiography [21].

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 [22]. 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'.)

OBESITY

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 [23]. (See "Obesity in adults: Health consequences", section on 'Cancer'.)

OSTEOPOROSIS

Bisphosphonates not protective against breast cancer in postmenopausal women (August 2017)

Although some studies have suggested a protective effect of bisphosphonates against breast cancer, others, including a large observational cohort of over 64,000 postmenopausal women followed for approximately seven years [24], have not. Studies may be confounded by the frequent use of bisphosphonates to treat osteoporosis, and women with osteoporosis are more likely to have a lower estrogen environment and therefore a lower baseline risk of breast cancer regardless of bisphosphonate exposure. (See "Factors that modify breast cancer risk in women", section on 'Bisphosphonates'.)

THYROID DISORDERS

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 [25]. 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'.)

VITAMIN D

Vitamin D and all-cause mortality in patients with advanced heart failure (August 2017)

Some, but not all, observational studies suggest that low 25-hydroxyvitamin D levels (especially <10 to 20 ng/mL [25 to 50 nmol/L]) are associated with higher mortality. There are few randomized trials of vitamin D supplementation with mortality as a primary endpoint. In one such trial, vitamin D supplementation (4000 international units daily for three years) compared with placebo did not reduce overall mortality in patients with advanced heart failure and baseline vitamin D levels <30 ng/dL (75 nmol/L) [26]. (See "Vitamin D and extraskeletal health", section on 'Mortality'.)

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 [27]. 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 [28]. 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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REFERENCES

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  2. Lane W, Bailey TS, Gerety G, et al. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial. JAMA 2017; 318:33.
  3. Wysham C, Bhargava A, Chaykin L, et al. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial. JAMA 2017; 318:45.
  4. Marso SP, McGuire DK, Zinman B, et al. Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes. N Engl J Med 2017; 377:723.
  5. Bergenstal RM, Gal RL, Connor CG, et al. Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels. Ann Intern Med 2017; 167:95.
  6. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644.
  7. Liu J, Li L, Deng K, et al. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ 2017; 357:j2499.
  8. DCCT/EDIC Research Group, Nathan DM, Bebu I, et al. Frequency of Evidence-Based Screening for Retinopathy in Type 1 Diabetes. N Engl J Med 2017; 376:1507.
  9. Oellgaard J, Gæde P, Rossing P, et al. Intensified multifactorial intervention in type 2 diabetics with microalbuminuria leads to long-term renal benefits. Kidney Int 2017; 91:982.
  10. Pacheco F, Oktay K. Current Success and Efficiency of Autologous Ovarian Transplantation: A Meta-Analysis. Reprod Sci 2017; 24:1111.
  11. Prague JK, Roberts RE, Comninos AN, et al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2017; 389:1809.
  12. Committee on Gynecologic Practice. Committee Opinion No. 698: Hormone Therapy in Primary Ovarian Insufficiency. Obstet Gynecol 2017; 129:e134.
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  15. Belva F, Roelants M, Vloeberghs V, et al. Serum reproductive hormone levels and ultrasound findings in female offspring after intracytoplasmic sperm injection: first results. Fertil Steril 2017; 107:934.
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