Pharmacologic Options for the Management of Cachexia


RELEASE DATE:

August 1, 2019

EXPIRATION DATE:

August 31, 2021

FACULTY:

Jessica L. Johnson, PharmD, BCPS
Associate Professor of Pharmacy
William Carey University School of Pharmacy
Biloxi, Mississippi

Colleen McNulty, BBiomedSc, PharmD Candidate 2021
William Carey University School of Pharmacy
Biloxi, Mississippi

Ashlyn K. Simmons, PharmD Candidate 2021
William Carey University School of Pharmacy
Biloxi, Mississippi

FACULTY DISCLOSURE STATEMENTS

Jessica L. Johnson, Colleen McNulty, and Ashlyn K. Simmons have no conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-19-082-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

The purpose of this article is to provide pharmacists with knowledge of cachexia, including terms, definitions, pathophysiologic disease mechanisms, pharmacologic treatment options, and clinical pearls.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. List chronic diseases known to be associated with the development of cachexia.
  2. Describe the pathophysiology and defining characteristics of cachexia.
  3. Describe nonpharmacologic supportive-care approaches to cachexia management.
  4. Recommend pharmacotherapies effective for stimulating appetite and weight gain in patients with cachexia.
  5. Identify emerging hormonal and pharmacologic approaches to preventing and reversing cachexia.

ABSTRACT: Skeletal muscle cachexia is the progressive loss of skeletal muscle and adipose tissue associated with several chronic illnesses, including advanced cancer, AIDS, congestive heart failure, and chronic obstructive pulmonary disease. The progression of cachexia in men occurs much faster and appears to be more virulent than for women and often leads to loss of physical function, decreased quality of life, increased medical costs, and more rapid mortality. Supportive care for cachexia includes appetite stimulants, amino-acid supplementation, high-calorie diet, and exercise. Pharmacotherapies targeting the molecular mechanisms of cachexia include angiotensin converting enzyme inhibitors/angiotensin II receptor blockers, testosterone, ghrelin, and growth hormone. Research continues on investigational pharmacotherapies that target molecular pathways to cachexia in hopes of improving the treatment options for this debilitating muscle-wasting disease.

Cachexia is defined as an unintentional, progressive loss of skeletal muscle and adipose tissue that is triggered by underlying chronic illnesses, such as advanced cancer, AIDS, congestive heart failure (CHF), rheumatoid arthritis, and chronic obstructive pulmonary disease (COPD).1,2 In the United States, approximately 160,000 hospital admissions annually are complicated by cachexia, with a slight majority (53%) of these admissions in male patients.3 Hospitalized patients with cachexia experience higher hospital costs ($4,600 more per admission) and a longer average length of hospital stay than patients without cachexia (6 vs. 3 days).3 The inflammatory processes driving cachexia, which are modulated differently by women due to the protective effect of estrogen, cause the progression of cachexia in men to occur faster and more virulently.4 In addition to being more likely to develop cachexia, in oncology studies men are also more likely to take prescription medications for cachexia.1

When cachexia complicates an underlying chronic illness, patients experience a greater loss of physical function and decreased quality of life (QoL) compared with patients without cachexia.3 Loss of muscle mass, the defining feature of cachexia, affects both men and women; however, men experience a disproportionate decrease in muscle strength that likely contributes to diminished QoL and loss of the ability to live independently, decreased response to treatments, reduced immunity, amplified symptoms of the underlying chronic condition, and a reduced life expectancy.2,4-6 Cachexia accelerates the occurrence of death and is identified as a contributing factor in around one-fifth of deaths due to cancer. One-year mortality in patients with chronic disease complicated by cachexia is significantly higher than in patients who do not have cachexia-related weight loss.2

The primary symptom of cachexia is extensive, involuntary weight loss, plus muscle wasting, often with concurrent loss of appetite or anorexia, reduced functional ability, and edema. These symptoms often have a profound impact on a patient's physical appearance and ability to engage in activities of daily living, which can cause significant distress to affected patients and their families.1,2,5 Cachexia is sometimes difficult to recognize and is therefore probably underdiagnosed. The medical diagnosis of cachexia is defined by patients nondeliberately losing more than 5% of their body weight over 6 to 12 months, a BMI of less than 20 kg/m2 in a person under age 65 years or a BMI of less than 22 kg/m2 in a person over age 65 years, or the presence of less than 10% body fat in patients with a chronic illness known to be associated with cachexia.1,2

Cachexia differs from sarcopenia or frailty in that those two muscle-wasting syndromes are primarily the result of a combination of malnutrition, disuse, and other factors associated only with aging. Cachexia weight loss involves both fat and muscle mass and is associated with the abovementioned chronic illnesses, regardless of age.1,2,5 Although loss of appetite is commonly observed in patients with chronic diseases, the extensive weight loss experienced by patients with cachexia cannot be solely attributed to a lack in sufficient caloric intake. Complex metabolic abnormalities described below lead to increased basal energy expenditure and loss of lean body mass from skeletal muscle wasting. Unlike simple starvation, which is distinguished by a caloric deficiency that can be reversed with proper feeding, weight loss due to cachexia cannot be adequately treated with aggressive feeding. Patients with cachexia will continue to lose weight despite adequate caloric intake, due to the proinflammatory processes underlying the condition.1,2

MECHANISMS OF DISEASE

Cachexia is the result of multiple systemic molecular pathways initiated by oxidative stress on muscle cells that result in apoptosis, autophagy, and dysregulated protein metabolism.7 Because cachexia is physiologically more complex than starvation, interrupting the four underlying molecular pathways resulting in cachexia is essential to prevention and treatment.

Oxidative Stress: Oxidative stress is the most significant underlying pathway to cachexia. The human body, and muscle cells in particular, naturally produce reactive oxygen species (ROS) as a byproduct of cellular metabolism and respiration. The body also maintains a balanced antioxidant system to absorb ROS and prevent cellular damage.7 Chronic diseases result in increased ROS (specifically superoxide and hydrogen peroxide) and decreased quantity and effectiveness of antioxidant enzymes such as catalase, glutathione peroxidase, and superoxide dismutase. Increased levels of intracellular ROS cause oxidative damage to DNA, lipids, and cellular proteins, leading to decreases in cell structure integrity and functionality.7,8 Cells injured by ROS are targeted for destruction, eventually leading to cachexia.

In chronic inflammation, cellular genes regulating antioxidant pathways are suppressed, resulting in oxidative stress.7 Future targets of cachexia pharmacotherapy include medications that prevent antioxidant pathways from being suppressed and may lead to upregulated gene expression of endogenous antiinflammatory and antioxidant mediators, interfering with cachexia progression.

In patients with heart failure, angiotensin II contributes to oxidative stress in cachexia by increasing ROS through two separate mechanisms: increased activity of NADPH oxidase and enhanced depolarization of mitochondria, both resulting in increased ROS concentrations in skeletal muscle.8 Medications that decrease angiotensin II levels and effects, such as angiotensinconverting enzyme (ACE) inhibitors and angiotension II receptor blockers (ARBs), thus reduce ROS and intracellular inflammation. Angiotensin II also upregulates the ubiquitin-proteasome system (UPS), one of two major degradative pathways in human cells.9

If the body's natural antioxidants are overwhelmed by oxidative stress, then it should follow that supplementing a patient in oxidative stress with exogenous antioxidants could help restore that balance. However, multiple small, preliminary trials of antioxidant therapy in cancer found that antioxidant therapy in patients without antioxidant deficiency appeared to increase cancer-related mortality and actually worsen cachexia.10 In these instances, antioxidant therapy was associated with increased tumor progression, and the worsening cancer led to more rapid weight loss and further development of cachexia.10 Therefore, antioxidant therapy with vitamin C, vitamin E, beta carotene, or lycopene should only be administered in patients with documented antioxidant deficiency.

Protein Synthesis/Degradation Imbalance: Overproduction of neuromodulatory hormones (angiotensin II) and inflammatory cytokines (tumor necrosis factor α [TNFα] or transforming growth factor) leads to an imbalance between the synthesis and degradation of muscle protein. Proinflammatory signaling mediators set off intracellular degrading pathways, which stimulate skeletal muscle protein breakdown through UPS in patients with cancer.7,9 Within a cell, UPS recycles proteins damaged by ROS and inflammation.11 Androgens, including testosterone, prevent the formation of inflammatory cytokines and downregulate UPS to decrease the cumulative impact of protein degradation.9 Additionally, medications such as statins and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the formation of anti-inflammatory cytokines.12 Another approach is to make up for muscle proteins that have been lost by supplementing with essential amino acids to stimulate the synthesis of new muscle proteins.9

Autophagy Deregulation: Human cells use lysosomes to digest and recycle unwanted parts of the cell in a normal physiologic process called autophagy. Autophagy often occurs after high levels of oxidative stress and uses enzyme reactions to selectively recycle certain proteins within the cytosol. When balanced with the production of new protein, autophagy is an essential benefit to human cells.11 However, if autophagy occurs faster than protein synthesis, or if pathogenic organelles (i.e., defective mitochondria) escape autophagy, cachexia occurs. Mouse models suggest that enhancing autophagy of defective mitochondria by using ghrelin therapy directly improves muscle atrophy caused by oxidative stress, and this is supported by early human clinical trials.11,13-15

Increased Myonuclear Apoptosis: Cellular resistance factors help cells downregulate and resist apoptosis through inhibition of TNFα and may be theoretical therapeutic targets in cachexia.16 However, in treating neoplasm, the goal of therapy is to encourage apoptosis of tumor cells, so this pathway may not be a good target for cancer-related cachexia. Few medications targeting myonuclear apoptosis have been studied in the management of cachexia, so human efficacy data are limited. However, the glutamic acid derivative thalidomide has been found to exhibit anti-inflammatory and immunomodulatory effects, specifically by suppressing several cytokines including TNFα and interleukin-6, which may help skeletal muscle cells resist myonuclear apoptosis.17

SUPPORTIVE CARE

Patients with cachexia often have related gastrointestinal symptoms such as pain, nausea, and vomiting or dry mouth, which, along with depression and other mood disturbances, lead to decreased interest and enjoyment of food. Decreased caloric consumption is often one factor in the overall picture of cachexia, and nutrition support and appetite stimulants can be used as part of a comprehensive approach to the pharmacologic management of anorexia-associated cachexia. Similarly, some medications can cause anorexia as a side effect, including antidepressants, amphetamines, antibiotics, iron supplements, or digoxin. It is important to address any of the abovementioned reversible or treatable causes of anorexia in the initial phases of cachexia management.5

Appetite loss is a multifactorial issue that challenges patients with cachexia. First-line approaches should be to promote preparation and consumption of soft, calorie-dense meals that avoid very strong odors and flavors that might be off-putting to nauseated patients. Dieticians can assist in the development of personalized nutrition plans as well as emotional support for patients and families struggling with anorexia and related weight loss.18

Supplements of pharmaceutical amino acids have also been studied in cachexia with mixed results. Specifically, arginine, glycine, lysine, leucine, carnitine, creatine, and beta-hydroxy-beta-methylbutyrate (HMB, a metabolite of leucine) have all been studied for the purpose of specifically increasing lean muscle mass rather than simple weight gain.18 In one study of HMB/L-arginine/L-glutamine, 14 patients on amino acid supplements (approximately 14 g/day) gained up to 1 kg body weight while the 18 control patients lost weight over the same 6-month time period.19 This benefit was not sustained in a larger follow-up trial that cited low adherence and high drop-out rates as the reason for lack of clinical benefit. Authors emphasized the challenges inherent to studies of oral nutrition supplements in patients with lack of appetite and suggest that a nutritional approach to weight gain may be most effective when combined with appetite-stimulant medications to synergistically increase caloric intake.20

Exercise is defined as "a planned, structured and repetitive bodily movement done to maintain or improve one or more components of physical fitness" and is known to increase muscle strength and muscle mass. Exercise may also modulate muscle metabolism, insulin sensitivity, and inflammation, all of which are linked to the proposed pathophysiologic mechanisms of cachexia.6,21,22 Exercise makes logical sense as a treatment for muscle-wasting disorders such as cachexia, and patients with severe cachexia symptoms have the potential to respond to exercise therapy. However, there are major limitations to implementing exercise programs in cachexia patients, including poor exercise tolerance and underlying chronic illness.22 No clinical evidence to support exercise is yet available, though ongoing trials may help determine the potential therapeutic effects of physical activity on cachexia-induced muscle wasting.6

Additionally, anemia and iron deficiency, both known complications of malnutrition and chronic disease, are potentially linked to cachexia development through decreased exercise tolerance. Decreased exercise capacity will prevent muscle development and could contribute to worsening atrophy through disuse. For patients with CHFrelated cachexia and low iron levels, IV iron improves QoL and functional status.23

PHARMACOTHERAPY

Appetite Stimulants

Each of the following four medication categories have some evidence for efficacy in stimulating appetite and potentially increasing body weight in cachexia. A summary of drugs and doses is provided in TABLE 1.

Corticosteroids: Small doses of corticosteroids may increase appetite and therefore increase caloric consumption by promoting a sense of well-being and euphoria in palliative-care patients. Dexamethasone, prednisolone, and methylprednisolone all have demonstrated efficacy as appetite stimulants.20,24 Chronic use of corticosteroids is strongly associated with serious adverse events, including myopathy, thrombosis, edema, and fracture, and they are therefore not recommended for long-term use. Because of the high rate of these side effects, patients are more likely to refuse treatment or discontinue treatment.25 Thus, corticosteroids are best reserved for palliative care in patients with terminal disease and short life expectancy where their systemic effects may have a significant impact on QoL.24,26

Progesterone Analogues: For longer term use in patients with anorexia and cachexia related to heart disease, AIDS, or cancer, megestrol is the most commonly studied agent. Megestrol, through an unknown mechanism, is associated with increased appetite in most patients and an average weight gain of 2 kg compared with placebo.27 Megestrol improves QoL and is associated with decreased rates of nausea and vomiting (risk ratio [RR] = 0.58; 95% CI, 0.45-bophlebitis, which may occur at rates as high as 5%, especially when used in patients with other proinflammatory risk factors.25 Megestrol exerts a dose-related response, with higher doses demonstrating a greater effect, though doses greater than 800 mg/day are not more effective and are associated with an increased risk of death (RR, 1.66; 95% CI, 1.08-2.57).27 Generally, megestrol requires at least 4 to 6 weeks of treatment before any effects on weight are observed. The medication is available in tablet or liquid formulations; the liquid formulation may be preferred due to increased bioavailability and therefore increased effectiveness at lower daily doses. Patients should be advised that megestrol is associated with risk of thrombosis, hypogonadism, and glucose dysregulation, and abrupt discontinuation of megestrol can cause adrenal insufficiency or abnormal menstrual bleeding.27

Cannabinoids: Cannabis exerts a wide variety of effects on the central nervous system and other body systems by binding to cellular cannabinoid 1 and 2 receptors to effect mood and appetite. The primary active compounds are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), though hundreds of other chemical compounds are present in the plant. Popular interest in medical uses of cannabis is driving a recent increase in studies evaluating the effects of synthetic THC, CBD, or natural cannabis extract in cachexia.28 Dronabinol (synthetic THC, U.S.) and nabiximol (natural extract, Germany) are both approved in their respective countries for treatment of anorexia/ cachexia in late-stage AIDS.29 These approvals are based on research suggesting that THC increases appetite, improves mood and QoL, and promotes weight stability in patients with AIDS.29 However, two small studies of cannabis for the treatment of cachexia in patients with cancer failed to demonstrate any significant benefit. In one of these studies, high rates of appetite improvement were seen in both the treatment and placebo groups after 6 weeks.30 In another study, megestrol was significantly more effective than cannabis at stimulating appetite and weight gain (75% vs. 49% [P = .0001] for appetite and 11% vs. 3% [P = .02] for weight gain).31 However, research in this area continues as access to marijuana products for recreational and research purposes increases.

Serotonin Antagonists: Serotonin is a major driver of the body's gastrointestinal system and is one neurotransmitter responsible for nausea and vomiting. Mirtazapine, olanzapine, and cyproheptadine are wellknown for causing weight gain in healthy patients when used for mood disorders. However, supporting evidence for use in cachexia is usually from a single, small study, and so the effectiveness of these drugs in cachexia is not well-characterized.20 Olanzapine, alone or when combined with megestrol, has demonstrated efficacy as a mood and appetite stimulant in patients with cancer-associated cachexia.32

Hormone Therapy

ACE Inhibitors/ARBs: Elevated angiotensin II levels, a driving pathophysiologic force in heart-failure disease progression, also activates hormonal pathways in skeletal muscle that lead to muscle wasting and cachexia.8,9 In addition to slowing heart-failure disease progression, ACE inhibitors are associated with reduced risk of cachexia weight loss in heart-failure patients.33 Efficacy of ACE inhibitors to prevent cachexia in cancer patients is less clear, but in unpublished studies imidapril was associated with significantly reduced weight loss in patients with non–small-cell lung cancer and colon cancer.34 These small preliminary trials offer some limited evidence that ACE inhibitors can reduce the effects of cachexia in heart-failure or cancer patients by blocking complex, neurohormonal cellular-signaling pathways, but future studies are needed.34 Similar evidence is emerging from mouse models of heart failure to support the use of ARBs for similar indications.35

Testosterone: In skeletal muscle, testosterone reduces protein breakdown, increases protein synthesis, and increases muscle mass and strength while improving exercise capacity. Testosterone levels are known to decrease with age, but in men with chronic illnesses, androgen deficiency develops at a faster rate.36 This may explain how androgen deficiency contributes to the muscle wasting involved in cachexia caused by chronic illnesses. Anabolic hormone therapy has thus been studied to preserve or increase muscle mass in patients with cancerand heart failure–associated cachexia.36,37

A randomized, double-blind, placebo-controlled phase II clinical trial assessed the role of 100 mg of testosterone enanthate versus placebo in limiting loss of body mass in 21 patients with cancer. Secondary outcomes of the study included assessment of QoL, tests of physical performance, muscle strength, daily activity levels, resting energy expenditure, nutritional intake, and overall survival.37 The addition of testosterone increased lean body mass by 3.2%, whereas those receiving placebo lost 3.3% (P = .015). Patients treated with testosterone maintained more favorable body condition, sustained daily activities, and showed significant improvements in their QoL and physical capabilities; however, the survival rate was similar in both treatment groups.37

Testosterone is available in a wide variety of oral, injectable, and transdermal dosage forms to suit patient preferences. The main side effects and risks of this off-label use of testosterone therapy include hepatotoxicity, acne, edema, increased hematocrit or hemoglobin, increased serum prostate-specific antigen or serum estradiol concentrations, insomnia, irritability, mood swings, and hypogonadism.36,37

Ghrelin: Ghrelin, a 28-amino-acid-appetite-stimulant gut hormone, has shown prospective benefits in reversing the breakdown of protein and weight loss in cachexia.13-15 Ghrelin increases the secretion of growth hormone and reduces the body's energy expenditure. Ghrelin has anti-inflammatory, antiapoptotic, and anxiolytic effects—all of which play an important role in the mechanism of cachexia. Ghrelin is currently being studied for efficacy and use in the treatment of cachexia. In general, clinical trials find that daily administration of ghrelin improves daily food intake, body weight, exercise capacity, muscle mass, and strength.14,15

Studies have evaluated IV or SC administration of ghrelin in doses ranging from 2 μg/kg to 8 μg/kg daily for treatment of cachexia. Common side effects of ghrelin include flushing and mild gastric rumbles. Patients experiencing the few serious adverse events during clinical studies (pneumonia, enteritis, and lung cancer) also suffered from advanced illness, making it difficult to attribute those harms to ghrelin administration.38 Ghrelin shows potential, but further research is necessary to identify the best therapeutic strategies for the use of ghrelin in the treatment of cachexia.

Growth Hormone: Growth hormone (GH) is another anabolic peptide hormone that stimulates the liver and other tissues to produce insulin-like growth factor 1 (IGF-1). IGF-1 stimulates protein synthesis, myoblast differentiation, and muscle growth. It also suppresses protein oxidation and proteolysis. In patients with malnutrition and other catabolic states such as cachexia, recombinant GH has continually generated anabolic effects.39

Recombinant GH is currently FDA approved for AIDS wasting based on data that recombinant GH therapy increased both lean body mass and total body weight, improved physical endurance and QoL, and decreased fat mass and rate of protein breakdown in patients with cachexia and AIDS.39 Additional studies offer preliminary support for potential off-label use in other patients with cachexia. Recombinant GH therapy has also increased weight and lean body mass in malnourished patients with COPD (+2.3 ± 1.6 kg compared with 1.1 ± 0.9 kg; P <.05).39 In patients with cachexia and CHF, acquired GH resistance is common, and GH therapy improved QoL scores and increased exercise duration in one clinical trial. Other studies have shown no clinical impact, and further research is necessary to resolve the discrepancy between studies and determine the efficacy of GH on cachectic CHF patients. To date, there is little data on the use of GH therapy and the treatment of cancer cachexia.

The side effects of growth hormone include dosedependent paresthesia and arthralgias, insulin resistance, sodium retention, and peripheral edema. Recombinant GH is administered as a SC injection according to a variety of dosing regimens.39

CONCLUSION

Cachexia is the unintentional progressive loss of skeletal muscle tissue and adipose tissue caused by chronic illnesses. Men are more likely be diagnosed with cachexia, to experience more severe symptoms, and to receive medications for cachexia. Supportive care emphasizes nutrition and exercise, and appetite stimulants can be somewhat effective in helping patients maintain weight and muscle mass. Additional pharmacotherapy options target the mechanisms of underlying disease, particularly oxidative stress and imbalances of protein metabolism. Pharmacotherapies with some evidence for limited efficacy in managing cachexia include ACE inhibitors/ ARBs, testosterone, ghrelin, and GH. Research continues to identify investigational pharmacotherapies that target molecular pathways to cachexia in hopes of improving the treatment options for this debilitating muscle-wasting disease.

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