Cachexia therapies – the need to take a broader look

KEYWORDS:

• Cachexia
• clinical research
• cardiac cachexia
• randomised controlled trials

1. To the editor

I read with interest the recent review by Molfino and colleagues in the journal [1]. While an excellent overview of some exciting new therapeutic developments in cachexia and sarcopenia, the initial section on current therapeutic research in these areas misses out a significant area of research activity, that of anti-catabolic neurohormonal blockade.

Cachexia constitutes a highly complex and overlapping series of systemic changes with multiple manifestations, some likely to be protective mechanisms and others certainly harmful body responses. These vary from hormonal imbalance, reflex disturbances, anabolic failure, hormone resistance syndromes, immune dysfunction, and cytokine activation in a way that may need a multi-targeted approach. There are many potential therapies whose logic derives from an appreciation of the pathophysiology of cachexia as seen as a complication of cancer. These have been reviewed in Molfino’s article. Others come from work being undertaken to repair muscle in other disease processes [2,3]. In this regard therefore I write to remind readers of the logic and phase-2 trial success of another approach, that of neurohormonal antagonists. Imidapril, an ACE inhibitor no longer in development, had early suggestions of benefit in terms of muscle bulk in selected cancers [4]. The fourth-generation beta-blocker espindolol has been shown to significantly improve lean muscle mass, body weight, and functional capacity (hand grip strength) in advanced colorectal and non-small cell cancer [5,6]. Other cardiac drugs which act metabolically are also being evaluated, such as trimetazidine [7]. Trimetazidine affects both myocardial and skeletal substrate utilization, switching oxidation from free fatty acids to glucose, with the effect of improving glycolysis to glucose oxidation coupling, thereby improving muscle performance and hence exercise capacity in those patients limited by muscular failure. It has also been shown to protect skeletal muscle cells in culture from toxic wasting effects and in animal models to improve skeletal muscle strength. Other therapies under investigation include the specific proteasome inhibitor bortezomib [8], the growth hormone secretagogue hormone Ghrelin and its analogs [9], the non-purine selective Xanthine Oxidase inhibitor, febuxostat [10] along with more traditional muscle focused interventions, such as exercise training [11,12]. There is increasing effort to define the biological pathways underpinning muscle wasting to better identify biomarkers [13] and to evaluate missed opportunities [14] as we seek novel therapies for this, as yet, untreatable condition.

In the future I feel it is more likely than not that we will need to combine anti-catabolic, pro-anabolic, and immune modulation strategies with neurohormonal blockade, nutritional, and exercise support to achieve optimal clinical outcomes. As we focus on the common cachectic syndromes including cardiac cachexia [15] where many of the neurohormonal antagonists are already part of background therapy we may reach the desired for outcomes sooner rather than later.

Declaration of Interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This manuscript has not been funded.