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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 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: Jan 2015. | This topic last updated: Feb 26, 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.


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 [1]. 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 [2]. (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) [3]. 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'.)

Renal prognosis in patients with type 1 diabetes and nephropathy (October 2014)

Historically, the majority of patients with type 1 diabetes who develop severely increased albuminuria (urine albumin excretion >300 mg per day, formerly "macroalbuminuria" or "overt nephropathy") progressed to end-stage renal disease (ESRD). However, with modern management, severely increased albuminuria may regress, and rates of ESRD may be less than 20 percent at 10 years. In the DCCT/EDIC type 1 diabetes cohort, 123 patients developed severely increased albuminuria that was persistent at two consecutive study visits [5]. During the subsequent 10 years, 58 percent of these patients regressed to <300 mg of albuminuria per day, and 12 percent regressed to <30 mg per day. The 10-year rates of reduced estimated glomerular filtration rate (eGFR, <60 mL/min/1.73 m2) and ESRD in these patients with severely increased albuminuria were 34 and 18 percent, respectively. Lower HbA1c and blood pressure values were associated with a greater frequency of albuminuria regression and a lower incidence of reduced eGFR and ESRD. Thus, even patients who develop overt nephropathy can avoid progressive renal impairment. (See "Overview of diabetic nephropathy", section on 'Type 1 diabetes'.)

Long-term effect of antihypertensive therapy in diabetic patients (October 2014)

The ADVANCE trial randomly assigned 11,000 diabetic patients to a fixed combination of perindopril-indapamide or placebo for approximately four years. The trial included both patients with and without hypertension, and concomitant therapy with other blood pressure medication during the trial was at the discretion of the patient's physician. 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 after completion of the trial 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 significantly lower among those in the treatment group (hazard ratio 0.91, 95% CI 0.84-0.99). 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'.)

Albiglutide for the treatment of type 2 diabetes (September 2014)

Albiglutide is a new long-acting GLP-1 receptor agonist for use as monotherapy or in combination with other agents for the treatment of adults with type 2 diabetes who have inadequate glycemic control with initial therapy. In a one-year trial of albiglutide (subcutaneous injection once weekly) versus insulin glargine (subcutaneous injection once daily) in 779 patients with type 2 diabetes inadequately controlled with metformin (with or without a sulfonylurea), mean A1C in the albiglutide group was non-inferior to the glargine group [6]. However, the dose of glargine was not aggressively or systematically uptitrated based upon glucose measurements. The albiglutide group exhibited weight loss (-1.1 kg) as opposed to weight gain in the insulin group (+1.6 kg). The incidence of severe hypoglycemia (0.4 percent) was the same in both groups. Overall, there were more treatment-related adverse events in the albiglutide group, and more albiglutide-treated patients withdrew because of an adverse event. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Albiglutide'.)


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  [7]. 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'.)

Letrozole versus clomiphene citrate for ovulation induction in PCOS (October 2014)

Clomiphene citrate (CC) has been the first line ovulation induction drug for women with polycystic ovary syndrome (PCOS) for many years. However, a multicenter trial in 750 women with PCOS suggests that letrozole results in higher cumulative birth rates (over five cycles) when compared to CC (27.5 percent and 19.1 percent, respectively) [8]. Body mass index (BMI) had a significant impact on live birth rates. For women with a BMI ≤30.3, the cumulative live birth rate (approximately 30 percent) was similar in the CC and letrozole groups. For women with a BMI ≥30.3, the cumulative live birth rates were significantly higher with letrozole when compared to CC (20 versus 10 percent). The possible advantage of letrozole was supported by a meta-analysis of six trials, including this multicenter trial, comparing letrozole and CC, which found higher birth rates with letrozole although BMI data were not provided [9].

Safety data suggest that letrozole is not associated with an increased risk of congenital malformations, but the evidence is based upon a relatively small number of pregnancies. Unlike CC, letrozole is not approved in any country for ovulation induction. However, based upon available data, for women with PCOS pursuing ovulation induction, we now suggest letrozole for those with a BMI >30 kg/m2, while we still suggest CC for those with a BMI ≤30 kg/m2.

(See "Ovulation induction with letrozole", section on 'Ovulation induction in PCOS'.)

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 [10]. 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'.)


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) [11]. 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 it does not support a role for MHT in prevention. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Timing of exposure'.)


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 [12]. 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 [13]. 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 [14]. 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'.)

Weight loss diets (September 2014)

If adhered to, any diet that reduces caloric intake below expenditure will result in weight loss that is related to the energy deficit. This was illustrated by the findings of a meta-analysis of 48 randomized trials (7286 individuals) comparing different dietary programs (predominantly low carbohydrate, moderate macronutrient, or low fat) with a comparator (no diet or competing dietary program) [15]. Compared with no diet, all diet programs resulted in significant weight loss (approximately 6 to 8 kg at six months). At 12-month follow-up, the average weight losses of all diet programs were 1 to 2 kg less than at six-month follow-up. Weight loss differences between individual diets were minimal. (See "Obesity in adults: Dietary therapy", section on 'Weight loss diets'.)


Pharmacologic therapy for osteoporosis (September 2014)

In the absence of high quality head-to-head drug comparison trials to determine the relative efficacy of the individual drugs, choice of therapy should be based upon efficacy, safety, cost, convenience, and other patient-related factors. A systematic review of trials published between 2005 and 2014 confirmed the fracture prevention efficacy of multiple agents compared with placebo [16]. Alendronate, risedronate, zoledronic acid, teriparatide, and denosumab reduce the risk of both vertebral and nonvertebral fractures, while raloxifene reduces risk for vertebral fractures only. Ibandronate reduces the risk of vertebral fracture but its effectiveness for hip fracture risk reduction is unclear because hip fracture was not a separately reported outcome in placebo-controlled trials of this agent. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Choice of drug'.)


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) [17]. 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'.)


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 [18]. 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'.)


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 [19]. 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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