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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: Sep 2014. | This topic last updated: Oct 21, 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.


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 [1]. 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 [2]. 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 [1]. 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 [3]. 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'.)

GLP-1 receptor agonists for the treatment of type 2 diabetes (July 2014)

Albiglutide and dulaglutide are new long-acting (administered by subcutaneous injection once weekly) glucagon-like peptide-1 (GLP-1) receptor agonists available for use in the United States and Europe as monotherapy (in addition to diet and exercise) or in combination with metformin, glimepiride, or pioglitazone in adults with type 2 diabetes [4-7]. The side effect profiles are similar (nausea, vomiting, and diarrhea). We do not consider GLP-1 receptor agonists to be first-line therapy, but they can be prescribed in combination with metformin (and/or another oral agent) for patients who fail initial therapy with one or two oral agents, particularly when weight loss or avoidance of hypoglycemia is a primary consideration, the A1C level is close to target, and cost is not a major barrier. Among the long-acting GLP-1 agonists, patient preference and payer coverage are important considerations in choosing an agent. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Albiglutide'.)

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 [8]. 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 [9]. 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 [10]. 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) [11]. (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 [12]. 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'.)


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) [13]. 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 [14].

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 [15]. 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 [16]. 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'.)


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 [17]. 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 [18]. (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 [19]. 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'.)


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) [20]. 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'.)


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 [21]. 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) [22]. 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 [23]. 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'.)

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