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What's new in endocrinology and diabetes mellitus
Official reprint from UpToDate® ©2016 UpToDate®
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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.

Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2016. | This topic last updated: Feb 04, 2016.

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.


Genetic predisposition in pediatric cancer (December 2015)

The prevalence and spectrum of mutations predisposing to cancer are not clear in pediatric cancer patients. In a study that used next-generation sequencing to determine the contribution of known germline predisposition mutations in over 1000 children and adolescents with cancer, pathogenic or probably pathogenic mutations were identified in 8.5 percent of cases [1]. Mutations were most common in patients with adrenocortical cancers and osteosarcoma, but were also identified among patients with retinoblastoma, Ewing sarcoma, central nervous system tumors, rhabdomyosarcoma, leukemia, and neuroblastoma. Importantly, family history did not predict an underlying predisposition syndrome in most patients. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Hereditary cancer syndromes' and "Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and histology", section on 'Inherited conditions'.)


Screening for diabetes mellitus (January 2016)

Although it has not been firmly established that screening for type 2 diabetes improves long-term outcomes, well-established treatments for diabetes can reduce progression to microvascular disease and early identification of diabetes allows interventions to prevent or limit cardiovascular disease. The US Preventive Services Task Force (USPSTF) has issued new recommendations for diabetes screening. Previously, the USPSTF only recommended screening for diabetes in adults with hypertension, but the new guideline recommends screening for diabetes as part of cardiovascular risk assessment in adults aged 40 to 70 years with body mass index (BMI) ≥25 kg/m2 [2]. The USPSTF suggests screening every three years based on limited evidence. We agree with the new USPSTF guideline and also suggest diabetes screening for adults with hypertension or hyperlipidemia. A fasting plasma glucose (FPG) and/or a glycated hemoglobin (A1C) are the preferred screening tests. (See "Screening for type 2 diabetes mellitus", section on 'A suggested approach'.)

Lixisenatide and cardiovascular outcomes (December 2015)

Glucagon-like peptide-1 (GLP-1) receptor agonists improve glycemic control; however, there are few studies assessing clinically important cardiovascular health outcomes. In one such trial, 6068 patients with type 2 diabetes and a recent acute coronary event were randomly assigned to receive the GLP-1 agonist lixisenatide (not yet available in the United States) or placebo, in addition to other diabetes medications (predominantly metformin, insulin, and sulfonylureas) [3]. After a median follow-up of 25 months, the primary endpoint (a composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) occurred in a similar proportion of patients (13.4 and 13.2 percent in the lixisenatide and placebo groups, respectively). There was no significant difference in any of the individual components of the composite endpoint. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

Goal blood pressure in diabetic patients (December 2015)

The Systolic Blood Pressure Intervention Trial (SPRINT) found that more intensive as compared with standard blood pressure control reduced mortality and major cardiovascular events in nondiabetic hypertensive patients at high cardiovascular risk [4]. Despite not enrolling patients with diabetes, SPRINT findings are indirectly applicable to diabetic patients, who also have a high cardiovascular risk. Based upon data from SPRINT, plus information from previous goal blood pressure trials performed in patients with diabetes, UpToDate now suggests a goal blood pressure of 120-125/<90 mmHg in diabetic patients (if automated oscillometric blood pressure readings are used to measure blood pressure), or a goal blood pressure of 125-130/<90 mmHg (if manual ausculatory measurements are used), rather than a goal blood pressure of <140/<90 mmHg (using manual ausculatory measurements). (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Conclusions about goal blood pressure'.)

Effect of finerenone in diabetic nephropathy (October 2015)

Mineralocorticoid receptor antagonists (MRAs) reduce proteinuria in patients with diabetic nephropathy, whether used alone or in combination with an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Finerenone, an investigational nonsteroidal MRA that may be associated with less hyperkalemia than other MRAs, was evaluated in a phase 2 dose-finding trial of 823 patients with type 2 diabetes treated with an ACE inhibitor or ARB [5]. A dose-dependent effect was observed at 90 days, with albuminuria reductions ranging from 21 to 38 percent at doses ranging from 7.5 mg/day to 20 mg/day. The incidence of hyperkalemia with finerenone treatment was low (1.5 percent); acute reductions in glomerular filtration rate were mild and were reversible after cessation of the study drug. The long-term effects of MRAs, including finerenone, in patients with diabetic nephropathy is unknown, and they should not be routinely used in these patients until such data are available. (See "Treatment of diabetic nephropathy", section on 'Mineralocorticoid receptor antagonism'.)

Automated closed-loop insulin pump for the treatment of type 1 diabetes (September 2015)

There are several studies in patients with type 1 diabetes evaluating the efficacy of continuous subcutaneous insulin delivery based upon continuous glucose sensing. With a sensor-augmented insulin pump, the patient uses information from a continuous glucose monitoring (CGM) device to manually adjust insulin dosing, whereas with an automated closed-loop insulin pump, the delivery of insulin is automated based upon continuous glucose sensing. 

In a crossover, random-order trial, 33 adults with type 1 diabetes were assigned to either 12 weeks of partially automated closed-loop insulin delivery (intervention) followed by 12 weeks of sensor-augmented pump therapy (control), or to the opposite order [6]. The closed-loop system was a "hybrid" system and was not entirely automated, as the dose of premeal bolus insulin was calculated using a standard bolus calculator that required patients to enter the carbohydrate amount and premeal fingerstick capillary glucose. Patients performed their usual daily activities and were not monitored remotely by study staff. Compared with the sensor-augmented pump, the automated closed-loop system resulted in a greater proportion of time spent in the target range of 70 to 180 mg/dL (3.9 to 10 mmol/L) (67.7 versus 56.8 percent). The mean glucose level (157 versus 168 mg/dL [8.7 to 9.3 mmol/L]), the mean A1C level (7.3 versus 7.6 percent), and time spent with hypoglycemia were also lower during the closed-loop phase of insulin delivery. Although these preliminary results using an automated system are promising, additional trials are needed. (See "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Automated closed-loop insulin pump'.)

Empagliflozin in diabetic individuals with overt cardiovascular disease (September 2015)

The cardiovascular effects of diabetes drugs have been evaluated in a growing number of trials. In a trial designed to evaluate the sodium-glucose co-transporter 2 (SGLT-2) inhibitor empagliflozin and cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease (CVD), 7028 patients were randomly assigned to empagliflozin or placebo once daily [7]. The majority of patients were taking metformin, antihypertensives, and lipid-lowering agents, and approximately half in each group were taking insulin.

After three years, the primary outcome (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in fewer patients assigned to empagliflozin than to placebo (10.5 versus 12.1 percent), driven by a significant reduction in risk of death from cardiovascular causes (3.7 versus 5.9 percent). The difference in glycemia between the groups was minimal (glycated hemoglobin [A1C] 7.8 versus 8.2 percent), suggesting that extra-glycemic effects of the drug were responsible for the CVD outcome. Whether empagliflozin or other SGLT-2 inhibitors will have similar CVD effects in individuals with type 2 diabetes who do not have overt CVD is unknown. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'SGLT2 inhibitors'.)

Bariatric surgery for diabetic patients and glycemic control (September 2015)

Bariatric surgical treatment of obese patients with diabetes results in significant sustained weight loss (20 to 30 percent after one to two years) and, in parallel, large improvements in blood glucose control. However, there are few data on long-term success rates in maintaining weight loss and glucose control. In a report of five-year outcomes (53 patients) from a randomized trial evaluating gastric bypass, biliopancreatic diversion, or medical therapy (pharmacologic therapy, education, lifestyle modification) in 60 patients with obesity and type 2 diabetes, diabetes remission (A1C <6.5 percent without diabetes medication) was maintained in only 56 percent of patients in the surgical groups who had experienced remission at two years [8]. Compared with the medical group, patients treated surgically had significantly lower diabetes and cardiovascular medication use, serum total and LDL cholesterol, and weight, although weight regain occurred in both surgical groups (+6.09 and +4.56 kg, respectively). The study was not powered to assess long-term diabetes complications. Longer-term follow-up of microvascular and macrovascular complications and mortality are required before laparoscopic banding or other bariatric surgery procedures can be routinely recommended for the treatment of persistent hyperglycemia in obesity-related type 2 diabetes. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Surgical treatment of obesity'.)

SGLT2 inhibitors may predispose to DKA (July 2015)

Sodium-glucose co-transporter 2 (SGLT2) inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes. “Euglycemic” (usually meaning plasma glucose <250 mg/dL) diabetic ketoacidosis (DKA) has been reported in patients with type 2 diabetes taking SGLT2 inhibitors [9,10]. The absence of substantial hyperglycemia delayed recognition of DKA by both the patients and the clinicians. Thus, serum ketones should be obtained in any patient with nausea, vomiting, or malaise while taking SGLT2 inhibitors, and SGLT2 inhibitors should be discontinued if acidosis is confirmed. A warning about SGLT2 inhibitors and ketoacidosis was issued by the US Food and Drug Administration in May 2015. Given the absence of long-term efficacy and safety data, we do not recommend SGLT2 inhibitors for routine use in patients with type 2 diabetes. In addition, off-label use in type 1 diabetes is discouraged in the absence of sufficient safety data. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'SGLT2 inhibitors'.)


Novel genetic mutations identified as cause of female infertility (January 2016)

The genetic events that disrupt normal human oocyte maturation are unknown. In a recent study, seven novel mutations in the gene TUBB8 were identified in women with primary infertility [11]. TUBB8 mutations impact only oocytes and result in oocyte meiosis I arrest, which leads to fertilization failure. Although a clinical test is not available, identification of these gene mutations opens new pathways for fertility research and diagnosis for women with primary infertility. (See "Causes of female infertility", section on 'Genetic causes'.)

Vaginal progesterone does not reduce recurrent pregnancy loss (December 2015)

Progesterone produced by the corpus luteum is essential to achieve and maintain pregnancy during most of the first trimester. Vaginal progesterone supplements have been prescribed for women with unexplained recurrent pregnancy loss (RPL) in an attempt to improve outcome, but the benefit has been unclear. In a recent trial that randomly assigned over 800 women with unexplained RPL (defined as three or more consecutive or non-consecutive unexplained first trimester miscarriages) to vaginal progesterone or placebo therapy from diagnosis of pregnancy through 12 weeks of gestation, approximately two-thirds of women in both groups delivered a live infant after 24 weeks of gestation [12]. This trial provides the best evidence to date that vaginal progesterone therapy does not improve live birth rates once a pregnancy has been established. We recommend not using supplemental vaginal progesterone for women with unexplained RPL. (See "Management of couples with recurrent pregnancy loss", section on 'Progesterone'.)

Letrozole treatment for women with unexplained infertility (December 2015)

For women with unexplained infertility, clomiphene citrate (CC) with intrauterine insemination (IUI) is typically first-line therapy; women who do not conceive are offered in vitro fertilization (IVF). When IVF is unsuccessful or not available, off-label treatment with the aromatase inhibitor letrozole appears to result in similar live birth and multiple gestation rates as CC/IUI. In a trial of 900 women with unexplained infertility randomly assigned to receive letrozole, CC, or gonadotropin therapy with IUI, the overall live birth rates were 19, 23, and 32 percent, respectively, and multiple gestation rates were 3, 1, and 13 percent, respectively [13]. For women who do not conceive with CC/IUI or IVF, we continue to suggest gonadotropin treatment rather than letrozole as it results in higher birth rates and is approved for ovulation induction. Women are counseled about the high risk of multiple gestation, particularly triplets. (See "Unexplained infertility", section on 'Our approach'.)

Frozen donor oocyte use impacts live birth rate (August 2015)

Use of donor oocytes (eggs) in assisted reproductive technology has allowed women unable to conceive with their own eggs the opportunity to achieve pregnancy. The use of frozen oocytes is more convenient and less costly compared with fresh oocytes because the donor and recipient don't have to be hormonally synchronized and frozen eggs can be shipped anywhere. Although initial studies reported equivalent pregnancy and live birth rates for donor egg transfers, a study of over 11,000 oocyte donation cycles, including 20 percent using frozen eggs, reported the live birth rate per transfer for frozen donor oocytes was lower than the live birth rate for fresh donor oocytes (47 versus 56 percent) [14]. Despite the possible discrepancy in live birth rate, the improved efficiency and lower cost of cryopreserved donor oocytes makes their use a reasonable and attractive option. (See "Management of infertility and pregnancy in women of advanced age", section on 'Oocyte or embryo donation'.)

Medication approved for low sexual desire in women (August 2015)

Flibanserin is the first and currently only drug approved by the US Food and Drug Administration (FDA) for female sexual dysfunction [15]. Daily use results in modest increases in the frequency of sexually satisfying events and sexual desire. The clinical role of flibanserin may be limited by the need for daily dosing, common adverse effects (eg, somnolence, dizziness), and by safety concerns or lack of safety data regarding combining flibanserin with alcohol or certain medications (eg, fluconazole, CYP3A4 inhibitors, antidepressants). (See "Sexual dysfunction in women: Management", section on 'Flibanserin'.)


Testosterone therapy did not improve symptoms in ejaculatory disorders (September 2015)

Although low serum testosterone concentrations have been associated with ejaculatory dysfunction in observational studies, exogenous testosterone does not appear to be an effective therapy for ejaculatory disorders, suggesting that the relationship is not causal. This was illustrated in a randomized trial of 76 men with one or more ejaculatory symptoms (delayed ejaculation, anejaculation, low ejaculate volume, and/or decreased force of ejaculation) and low serum testosterone concentrations (<300 ng/dL [<10.41 nmol/L]), comparing 16 weeks of testosterone solution (2%, 60 mg) or placebo applied to the axilla [16]. Although testosterone therapy increased mean serum testosterone concentrations to the normal male range, there were no improvements in parameters of ejaculatory function. (See "Treatment of male sexual dysfunction", section on 'Other'.)


Menopausal hormone therapy: Endocrine Society clinical practice guideline (October 2015)

Menopausal hormone therapy (MHT) continues to play an important role in the management of hot flashes. A new clinical practice guideline, published by the Endocrine Society, presents an individualized approach to the management of menopausal symptoms based upon calculating a woman’s baseline cardiovascular and breast cancer risks prior to initiating therapy [17]. Similar to many other guidelines, the Endocrine Society suggests that MHT is indicated for the management of menopausal symptoms, but not for the prevention of cardiovascular disease, osteoporosis, or dementia. (See "Menopausal hormone therapy: Benefits and risks", section on 'Guidelines'.)


Normal-weight central obesity and mortality (December 2015)

Overall obesity, as defined by body mass index (BMI), has been thought to play the major role in the obesity-associated excess risk of cardiovascular morbidity and mortality, with abdominal or central obesity (as defined by an increased waist-to-hip ratio [WHR]) playing an independent but lesser role. However, data from the Third National Health and Nutrition Examination Survey suggest that normal-weight central obesity (normal BMI with increased WHR) is associated with higher mortality than BMI-defined obesity, particularly when compared with individuals without central obesity [18]. In a cross-sectional survey of over 15,000 individuals, men with a normal BMI but central obesity (WHR ≥0.90) had the highest total mortality risk when compared with men without central obesity who were normal weight, overweight, or obese (hazard ratio [HR] 1.87, 2.24, 2.42, respectively). A similar pattern was seen in normal weight women with central obesity, but the excess risk was not as great. A limitation of the study is that central obesity was determined by WHR only; no quantitative imaging studies of adipose tissue were performed. These data suggest that normal weight individuals with central obesity appear to have an increased mortality risk, and should be targeted for lifestyle modification strategies. (See "Obesity in adults: Health hazards", section on 'Normal weight central obesity'.)

Intragastric balloon device for weight loss (October 2015)

Intragastric balloon devices, which are placed endoscopically and promote a feeling of satiety and food restriction, can result in modest weight loss and have been available outside of the United States. One such device, the ReShape Integrated Dual Balloon System, was recently approved by the US Food and Drug Administration to treat obesity in adults with a body mass index (BMI) of 30 to 40 kg/m2 and one or more comorbid conditions such as diabetes, hypertension, or hypercholesterolemia. It is intended for patients who have failed previous attempts at weight loss through diet and exercise alone and is generally left in place for a maximum of six months. In a trial of 326 patients with BMI 30 to 40 kg/m2, those who were randomly assigned to ReShape balloon placement lost more weight than the control group, who received endoscopy without balloon insertion (6.8 versus 3.3 percent of total body weight) [19]. Six months after removal of the device, patients maintained 70 percent of their initial weight loss. (See "Bariatric procedures for the management of severe obesity: Descriptions", section on 'Expected weight loss IGB'.)

FTO variant and obesity (September 2015)

Large genome wide association studies have demonstrated that variants in the FTO gene have the strongest association with obesity risk in the general population, but the mechanism of the association has been unclear. However, a nonocoding causal variant in FTO has now been identified that changes the function of adipocytes from energy utilization (beige fat) to energy storage (white fat) with a fivefold decrease in mitochondrial thermogenesis [20]. When the effect of the variant was blocked in genetically engineered mice, thermogenesis increased and weight gain did not occur, despite eating a high-fat diet. Blocking the gene's effect in human adipocytes also increased energy utilization. This observation has important implications for potential new anti-obesity drugs. (See "Pathogenesis of obesity", section on 'FTO variants'.)

Liraglutide for the treatment of obesity (July 2015)

Along with diet, exercise, and behavior modification, drug therapy may be a helpful component of treatment for select patients who are overweight or obese. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, used for the treatment of type 2 diabetes, and can promote weight loss in patients with diabetes, as well as those without diabetes.

In a randomized trial in nondiabetic patients who had a body mass index (BMI) of ≥30 kg/m2 or ≥27 kg/m2 with dyslipidemia and/or hypertension, liraglutide 3 mg once daily, compared with placebo, resulted in greater mean weight loss (-8.0 versus -2.6 kg with placebo) [21]. In addition, cardiometabolic risk factors, glycated hemoglobin (A1C), and quality of life improved modestly. Gastrointestinal side effects transiently affected at least 40 percent of the liraglutide group and were the most common reason for withdrawal (6.4 percent). Liraglutide is an option for select overweight or obese patients, although gastrointestinal side effects (nausea, vomiting) and the need for a daily injection may limit the use of this drug. (See "Obesity in adults: Drug therapy", section on 'Liraglutide'.)

In a trial designed specifically to evaluate the effect of liraglutide on weight loss in overweight or obese patients with type 2 diabetes (mean weight 106 kg), liraglutide, compared with placebo, resulted in greater mean weight loss (-6.4 kg and -5.0 kg for liraglutide 3 mg and 1.8 mg, respectively, versus -2.2 kg for placebo) [22]. Treatment with liraglutide was associated with better glycemic control, a reduction in the use of oral hypoglycemic agents, and a reduction in systolic blood pressure. Although liraglutide is not considered as initial therapy for the majority of patients with type 2 diabetes, it is an option for select overweight or obese patients with type 2 diabetes who fail initial therapy with lifestyle intervention and metformin.  (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Weight loss'.)


High-dose vitamin D may increase risk of falls (February 2016)

Evidence conflicts on the effectiveness of vitamin D for fall prevention in older adults, with emerging evidence that high-dose vitamin D administered monthly may increase fall risk. A randomized trial compared monthly high-dose vitamin D (60,000 international units of vitamin D3 in one group; 24,000 international units vitamin D3 plus 300 microg calcifediol in another) with a lower dose (24,000 units vitamin D3) in community-dwelling men and women age 70 and older who had a history of a prior fall [23]. Lower extremity function at 12 months did not differ among the groups, but there was a higher incidence of falls and mean number of falls in both groups that received high-dose vitamin D. Of note, there was no placebo group in this trial. See "Falls: Prevention in community-dwelling older persons", section on 'Vitamin D supplementation' and "Vitamin D and extraskeletal health", section on 'Muscle function'.)


Enzyme replacement therapy for hypophosphatasia (November 2015)

Hypophosphatasia is a rare, autosomal disease that is associated with low levels of alkaline phosphatase in serum and bone and the development of osteomalacia and severe periodontal disease. It may present in the perinatal period, when it is lethal; in infancy, where rachitic deformities develop by age six months; in childhood, with premature loss of deciduous teeth, delayed walking, and waddling gait; or in adulthood, where it is characterized by the presence of recurrent metatarsal stress fractures and bone pain, and an increased incidence of chondrocalcinosis. Historically, there have been few treatment options. However, enzyme replacement therapy (asfotase alfa) for perinatal, infantile, and juvenile-onset hypophosphatasia became available in October 2015, based upon the results of open-label prospective studies in 99 patients with perinatal, infantile, or juvenile-onset hypophosphatasia, in whom enzyme replacement therapy was associated with improved overall survival, ventilator-free survival, growth, and bone mineralization compared with a historic cohort [24]. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia", section on 'Other causes'.)

PCSK9 antibodies for cardiovascular risk reduction (September 2015)

Monoclonal antibodies that inhibit proprotein convertase subtilisin kexin 9 (PCSK9-abs) reduce LDL-cholesterol levels by as much as 70 percent. Randomized trials with small numbers of events and limited follow-up suggest that at least two of these agents, alirocumab and evolocumab, substantially reduce cardiovascular events and mortality when used for secondary prevention, both as monotherapy and in combination with statin therapy [25,26]. (See "Lipid lowering with drugs other than statins and fibrates", section on 'PCSK9 inhibitors'.)

PCSK9-abs are becoming available for clinical use. The agents require subcutaneous injection every two to four weeks and are very expensive. While awaiting greater experience with these agents, we would use them in situations where the expected reductions in cardiovascular events are likely to outweigh any as yet unknown adverse events from a new therapy. These include using them in combination with statin therapy in very high-risk patients with stable cardiovascular disease, such as those in the proposed NCEP guidelines (table 1), and as monotherapy in very high-risk and higher-risk patients who are intolerant of statin therapy. Other experts, including other authors for UpToDate, would make decisions about adding medications to statin therapy based on goal LDL-cholesterol. (See "Intensity of lipid lowering therapy in secondary prevention of cardiovascular disease", section on 'Stable CVD' and "Treatment of lipids (including hypercholesterolemia) in secondary prevention", section on 'Summary and recommendations'.)

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