Improving Sexual Function and Mood

SOURCE: Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med 2016;374:7:611-624.

Male hypogonadism is best defined as a clinical syndrome (changes in libido, sexual function, mood, and strength) confirmed by subnormal testosterone. This definition dissuades clinicians from measuring testosterone in asymptomatic men and instituting treatment solely on the basis of low testosterone levels. On one hand, clinical trials of testosterone in asymptomatic men have not demonstrated salutary outcomes. On the other hand, numerous trials confirm improvements in symptoms of hypogonadism through testosterone replacement, albeit with some uncertainty about potential toxicity of testosterone replacement.

Snyder et al performed a double-blind, randomized, placebo-controlled 12-month trial of testosterone replacement (using testosterone gel) in symptomatic hypogonadal men (n = 790) ≥ 65 years of age. Testosterone replacement restored testosterone levels to the mid-normal range for young adult men.

Testosterone replacement resulted in statistically significant improvements in sexual function, desire, mood, and depression. Testosterone replacement did not improve walking distance. Testosterone generally was well tolerated, although seven men in the testosterone treatment group developed a hemoglobin > 17.5 mg/dL (none in the placebo group). There was no signal for increased cardiovascular risk, although a much larger trial would be necessary to provide definitive evidence of cardiovascular safety. The authors did not observe any worsening of symptoms relevant to benign prostatic hyperplasia. Testosterone replacement provides several areas of potential symptomatic improvement for hypogonadal men, but ongoing monitoring for adverse events (such as polycythemia) is necessary.

Liraglutide Improves Non-alcoholic Steatohepatitis

SOURCE: Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): A multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387:679-690.

Hepatosteatosis indicates deposition of fat in the liver in the absence of inflammation. Steatohepatitis is the term for deposition of fat in the liver that is associated with inflammation and fibrosis, which ultimately can lead to end-stage liver disease if untreated. Indeed, it has been suggested that within the next five years, non-alcoholic steatohepatitis (NASH) may become the most common disorder leading to the need for liver transplantation worldwide. As is perhaps implied in the name, the most common NASH etiologies are diabetes and obesity. The prevalence of both continues increasing.

The Liraglutide Efficacy and Action in NASH trial was a double-blind, randomized 48-week study of liraglutide (titrated to 1.8 mg/d subcutaneous) vs. placebo (n = 52). All patients were confirmed by biopsy at baseline to have NASH, and were again biopsied at week 48. Specific biopsy-based outcomes included disappearance of hepatocyte ballooning (which indicates resolution of inflammation) without worsening fibrosis, liver function tests, and other hepatic biomarkers. The number of study subjects who attained resolution of NASH was more than four-fold greater in the liraglutide group than placebo (39% vs. 9%).

Liraglutide already is recognized to be a generally safe and well-tolerated medication, including doses up to 3 mg/d subcutaneous in obese patients. These favorable outcomes should prompt a much larger trial to definitively determine the role of liraglutide in treatment of NASH.

Long-acting Anticholinergics and Beta Agonists for COPD

SOURCE: Calzetta L, Rogliani P, Matera MG, Cazzola M. A systematic review with meta-analysis of dual bronchodilation with LAMA/LABA for the treatment of stable COPD. Chest 2016;149:1181-1196.

There has been some suggestion that the bronchodilation afforded by anticholinergic agents, commonly referred to as long-acting antimuscarinic agents (LAMA, e.g., tiotropium, umeclidinium) is at least as good as that provided by long-acting beta-agonists (LABA, e.g., salmeterol, formoterol). Additionally, there does not appear to be any tachyphylaxis associated with LAMA as has been seen with LABA. Since most patients with COPD experience disease progression, pharmacologic augmentation is the rule rather than the exception. Only recently have LAMA/LABA combinations become available. Is LAMA + LABA really better than either alone? And if so, is there a best LAMA/LABA combination?

Calzetta et al performed a systematic review and meta-analysis of controlled trials (n = 23,168) that addressed LAMA/LABA combination treatment compared to individual component (LAMA or LABA) monotherapy.

As measured by trough FEV1, dyspnea indices, and the St. George’s Respiratory Questionnaire scores, LAMA/LABA consistently outperformed either monotherapy. Although there are a variety of different LAMA/LABA combinations, no particular combination emerged as distinctly superior. Combining LAMA with LABA provides meaningfully better symptomatic improvement than either agent alone.