Fish Oil and HMB Supplementation in COPD

Weight loss commonly occurs in patients with Chronic Obstructive Pulmonary Disease (COPD),
negatively influencing their quality of life, treatment response and survival. Furthermore,
limb muscle dysfunction (weakness and/or enhanced fatigue) is a major systemic comorbidity in
patients with Chronic Obstructive Pulmonary Disease (COPD), negatively affecting their
exercise performance, physical activity, quality of life, and mortality. As nutritional
abnormalities are main contributors to muscle loss and dysfunction in COPD, nutritional
support is viewed as an essential component of integrated care in these patients.

Although nutritional support is effective in the treatment of weight loss in COPD, attempts
to increase muscle mass and function in COPD by supplying large amounts of protein or
calories to these patients have been small. This suggests that gains in muscle mass and
function are difficult to achieve in COPD unless specific metabolic abnormalities are
targeted. The investigators and other researchers found that low muscle mass in COPD was
strongly associated with elevated whole body protein turnover and increased myofibrillar
protein breakdown rates indicative of muscle contractile protein loss. The investigators have
extended this finding recently to normal weight COPD patients characterized by muscle
weakness using a more precise and accurate pulse method of tau-methylhistidine tracer.

A substantial number of COPD patients, underweight as well as normal weight to obese, are
characterized by an increased inflammatory response as evidenced by elevated levels of the
pro-inflammatory cytokines (Tumor Necrosis Factor (TNF)-α, Interleukin (IL) 6 and 8, and the
soluble TNF-α receptors (55 and 75). Furthermore, CRP levels are elevated in COPD and
associated with reduced quadriceps strength, lower maximal and submaximal exercise capacity
and increased morbidity.

One of the few agents capable to suppress the generation of pro-inflammatory cytokines are
eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), primary ω-3 fatty acids found in
fish oils.

Previous experimental research and clinical studies in cachectic conditions (mostly
malignancy) indicate that polyunsaturated fatty acids (PUFA) are able to attenuate protein
degradation by improving the anabolic response to feeding and by decreasing the acute phase
response. Eicosapentaenoic acid (EPA), in combination with docosahexaenoic acid (DHA), has
been shown to effectively inhibit weight loss in several disease states, however weight
weight and muscle mass and function increase was not present or minimal. Also in healthy
older adults, fish oil can slow the decline in muscle mass and function. A randomized
clinical trial in COPD patients showed that extra nutritional supplementation with PUFAs
daily of 1000 mg EPA+DHA as adjunct to exercise training during 8 weeks enhanced exercise
capacity but did not lead to muscle mass gain. The patients who did not respond adequately (<
2% gain in weight), had a higher TNF-α level than those who did gain sufficient weight, which
is in line with previous data in COPD showing an association between an increased systemic
inflammation with non-response to nutritional therapy.

Although previous studies support the concept of EPA+DHA supplementation to ameliorate the
systemic inflammatory response and decrease protein breakdown, there is no information
present on the effects of EPA+DHA supplementation on whole body and muscle protein metabolism
in COPD. The investigators have recently examined the dose-response effects of 0, 2 and 3.5 g
of EPA+DHA intervention ( EPA / DHA) for 4 weeks in stable moderate to severe COPD patients
(8pts /group) (unpublished data) but were not able to find a positive effect of muscle mass
and strength, even with the highest dose, likely related to the relatively short (4 week)
supplementation period. The effect of EPA+DHA intervention on whole body and muscle protein
synthesis and breakdown rates is currently being analysed.

Although numerous animal studies have shown the benefit of HMB in downregulating muscle
protein breakdown under catabolic conditions, there is very little data in COPD patients.
Others have tested HMB (3g/d) in COPD patients in the ICU and reported anti-inflammatory
benefits and improvement in pulmonary function. In patients with bronchiectasis, 24 week
supplementation with an ONS containing HMB (1.5g/d) versus standard of care during pulmonary
rehabilitation program, resulted in benefits on body composition, muscle strength and QoL. A
combination of HMB and EPA/DHA in a mouse model of cancer cachexia showed a synergy between
the two ingredients on preventing muscle loss and downregulation of muscle protein
degradation.

Inclusion criteria

- Ability to walk, sit down and stand up independently

- Ability to lie in supine or slightly elevated position for 8.5 hours

- Age 45 - 100

- Clinical diagnosis of COPD, including moderate to very severe chronic airflow
limitation, and an FEV1 < 70% of reference FEV1 (GOLD II-III). If subjects are on β2
agonists, only those subjects with <10% improvement in FEV1 will be included.

- Clinically stable condition and not suffering from a respiratory tract infection or
exacerbation of their disease (defined as a combination of increased cough, sputum
purulence, shortness of breath, systemic symptoms such as fever, and a decrease in
FEV1 > 10% compared with values when clinically stable in the preceding year) at least
4 weeks prior to the first test day

- Shortness of breath on exertion

- Willingness and ability to comply with the protocol, including:

- Refraining from intense physical activities (72h) prior to each study visit

- Adhering to fasting state and no smoking from 10 pm ± 2h onwards the day prior to
each study visit

Exclusion Criteria

- Participants 86 and older that fail to get physician approval

- Established diagnosis of malignancy

- Established diagnosis of Insulin Dependent Diabetes Mellitus

- History of untreated metabolic diseases including hepatic or renal disorder

- Presence of acute illness or metabolically unstable chronic illness

- Recent myocardial infarction (less than 1 year)

- Any other condition according to the PI or nurse that was found during the screening
visit, that would interfere with the study or safety of the patient

- BMI ≥ 45 kg/m2

- Dietary or lifestyle characteristics:

- Daily use of supplements containing EPA+DHA or HMB prior to the first test day

- Use of protein or amino acid containing nutritional supplements within 5 days of
first test day

- Indications related to interaction with study products. Known hypersensitivity to
fish and/or shellfish and/or soy

- Use of long-term oral corticosteroids or short course of oral corticosteroids 4
weeks preceding first test day

- Failure to give informed consent or Investigator's uncertainty about the willingness
or ability of the subject to comply with the protocol requirements