HMB Supplement Study: Immune & Protein Findings

When patients are admitted to an intensive care unit (ICU), their bodies undergo profound metabolic stress — muscle tissue breaks down rapidly, inflammatory signaling goes into overdrive, and the immune system struggles to mount an organized response. For decades, researchers have searched for nutritional interventions that might blunt these effects and support recovery. A 2026 post-hoc analysis published in Clinical Nutrition by Berger, Viana, Engelen, and colleagues now adds new detail to how beta-hydroxy-beta-methylbutyrate (HMB) — a naturally occurring metabolite of the amino acid leucine — may influence inflammation and intracellular protein dynamics in critically ill patients.

What This Study Found

This secondary post-hoc analysis drew on data from a previously published randomized controlled trial (ClinicalTrials.gov: NCT03628365), in which critically ill ICU patients received either 3 grams of HMB per day or a placebo for at least 10 days. Study procedures were conducted on days 4 and 15 after ICU admission, with participants assessed in a postabsorptive (fasting) state. Thirty-seven patients were included in this analysis, with a mean age of 65 years and moderate-to-high illness severity scores (SAPS2: 48; APACHE II: 23).

Researchers measured a broad panel of 37 cytokines using Luminex technology, along with C-reactive protein (CRP), amino acid plasma concentrations, urea, and creatinine. Amino acid whole-body production and pool sizes — both extracellular and intracellular — were tracked using stable isotope tracer methodology, providing a granular look at protein metabolism at the cellular level.

Key findings included:

• Cytokine patterns differed between groups. While most of the 37 cytokines declined by day 15 in both groups (except for certain growth factors), 12 cytokines were significantly different between the HMB and placebo groups after the intervention period. Notably, 7 of those were proinflammatory cytokines that were higher in the HMB group (p < 0.05). The researchers suggest this pattern may reflect a more active, organized immune response rather than uncontrolled inflammation.
• Intracellular amino acid pools shifted significantly. While whole-body production of amino acids and extracellular pool sizes did not differ significantly between groups by day 15, the intracellular pool sizes of citrulline, glutamine, HMB, KMV (α-keto-β-methylvaleric acid), taurine, and tau-methylhistidine were significantly higher in the HMB group compared to placebo.
• Glutamine and HMB production increased more in the HMB group. Taurine production rose significantly in both groups, but glutamine and HMB production increased significantly more in the HMB-supplemented patients — a finding researchers describe as clinically relevant given glutamine's central role in immune function and gut integrity.
• The urea-to-creatinine ratio declined in the HMB group. By day 15, this ratio dropped significantly in the HMB group (125 vs. 181 in placebo, p = 0.002), suggesting a relative reduction in protein catabolism — consistent with the group's earlier finding of reduced net protein breakdown in the original RCT.

Clinical Significance

The findings of this study carry several layers of clinical relevance, though it is important to note that this is a post-hoc secondary analysis of a relatively small trial (n=37), and results should be interpreted with appropriate caution pending larger, prospectively powered studies.

The cytokine data is particularly thought-provoking. Conventional wisdom might suggest that higher proinflammatory cytokine levels are always harmful. However, the study authors propose that in the context of critical illness — where immune dysfunction often manifests as an inadequate or dysregulated response — the higher proinflammatory cytokine levels seen in the HMB group may reflect a more efficient, coordinated immune response rather than harmful hyperinflammation. This interpretation aligns with emerging research on immunonutrition in ICU settings.

The intracellular glutamine finding deserves special attention. Glutamine is conditionally essential during critical illness; it fuels rapidly dividing immune cells, supports intestinal barrier function, and is a precursor to glutathione, the body's primary endogenous antioxidant. The fact that HMB supplementation was associated with significantly greater intracellular glutamine production and pool sizes suggests a potential mechanism by which HMB could support multiple downstream physiological processes simultaneously.

The reduction in the urea-to-creatinine ratio in the HMB group also supports the hypothesis that HMB supplementation may help attenuate the accelerated muscle protein catabolism that is a hallmark of critical illness — a finding consistent with HMB's known mechanism as an activator of protein synthesis pathways in skeletal muscle.

Current Access and Compliance Context

HMB is commercially available as a dietary supplement in both calcium salt (HMB-Ca) and free acid (HMB-FA) forms and is generally well-tolerated across populations, from older adults and athletes to clinical patients. In this study, the dose used was 3 grams per day — a dosage consistent with what has been evaluated in the broader HMB literature for muscle preservation and recovery.

In clinical settings such as ICUs, nutritional supplementation compliance can be challenging due to feeding intolerance, enteral or parenteral nutrition protocols, and evolving patient status. However, the study protocol was feasible within this demanding context, suggesting that HMB delivery at this dose can be successfully integrated into critical care nutrition plans. Researchers and clinicians interested in nutritional support strategies for critically ill populations may consider this data when designing future protocols or informing clinical practice guidelines — keeping in mind that current evidence, while promising, remains preliminary.

What Patients Should Know

If you or a loved one has experienced critical illness, or if you are interested in the role of nutritional compounds like HMB for recovery or muscle health, here is what the current evidence suggests:

• HMB is a naturally occurring metabolite. It is produced in small amounts by the body when the amino acid leucine is metabolized. Supplemental HMB provides levels that exceed what diet alone typically delivers.
• The research context matters. This particular study was conducted in critically ill ICU patients. The results may not be directly applicable to healthy individuals or those with different medical conditions. The study authors themselves note the need for larger, confirmatory trials.
• HMB is not a replacement for medical care. Nutritional interventions, including HMB supplementation, are studied as adjuncts to — not replacements for — comprehensive medical and nutritional support strategies guided by qualified healthcare professionals.
• Speak with a qualified provider. If you are considering HMB supplementation for yourself or a family member recovering from serious illness, muscle wasting, or other conditions, consult with a physician or registered dietitian who is knowledgeable about evidence-based nutritional medicine.

Conclusion

This 2026 post-hoc analysis by Berger, Viana, Engelen, and colleagues adds meaningful detail to our understanding of how HMB supplementation may influence the immune and metabolic landscape in critically ill patients. The study suggests that HMB is associated with a distinct cytokine profile that researchers interpret as potentially reflecting a more efficient immune response, alongside significant increases in intracellular glutamine and other amino acid pools, and a reduction in markers of protein catabolism. While the sample size is small and the post-hoc design limits definitive conclusions, these findings provide a compelling rationale for larger, prospectively designed trials investigating HMB as a component of critical care nutritional strategy.

If you are interested in learning more about evidence-based peptide and nutritional therapies and how they may be relevant to your health, we encourage you to connect with a knowledgeable medical professional. Visit peptideassociation.org/find-a-doctor to find a qualified provider in your area who can help guide your decisions based on the latest clinical research.

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Medical Disclaimer: This article is intended for educational and informational purposes only and does not constitute medical advice, diagnosis, or treatment. The content summarizes published research and is not intended to replace the guidance of a licensed healthcare professional. Always consult a qualified physician or registered dietitian before beginning any new supplementation regimen, particularly if you have an existing medical condition or are under medical care.

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AMA Citation: Berger MM, Viana MV, Engelen MPKJ, et al. Does β-hydroxy-β-methylbutyrate (HMB) have an anti-inflammatory impact in critically ill patients? A secondary post hoc analysis of an RCT. Clin Nutr. 2026;(published online ahead of print). doi:10.1016/j.clnu.2026.106690. PMID: 42202485.