Denosumab single dose fails broad metabolic benefit, lowers HbA1c in high-cortisol infertile men.
Background
Infertile men often face an elevated risk of metabolic syndrome, a cluster of conditions including impaired glucose and lipid homeostasis. Current interventions for metabolic dysfunction in this population are often insufficient or have undesirable side effects. HbA1c is a key biomarker for long-term glucose control, and previous research in older patients with impaired glucose tolerance suggested that denosumab could lower it. This study investigated if a single dose of denosumab could similarly improve metabolic parameters in young infertile men, addressing a potential therapeutic gap.
Study Design
This was a secondary analysis from a single-center, placebo-controlled randomized clinical trial involving infertile men without serious co-morbidities. Participants were randomized 1:1 to receive a single subcutaneous (SC) injection of 60 mg denosumab or placebo. The study included 100 infertile men at randomization, with 92 included in the final analysis. Prespecified secondary outcome variables, assessed at day 80 and day 160, included HbA1c, fasting glucose, fasting insulin, C-peptide, LDL, HDL, and total cholesterol. Semen quality was the primary endpoint, reported separately.
Results
The study found no significant differences between the denosumab and placebo groups at day 80 or day 160 for HbA1c, LDL, HDL, or total cholesterol. For the n=44 fasting patients, there were also no differences observed in plasma glucose, plasma insulin, C-peptide, or HOMA-IR. However, a safety signal emerged: at day 160, alanine aminotransferase (ALT) was higher in the denosumab group compared to placebo, specifically by 8.3 U/L (95% CI 3.3 to 13.3). Importantly, in a subgroup of participants with high baseline serum cortisol, denosumab did reduce HbA1c by 2.5 mmol/mol (95% CI -5.0 to -0.1) compared to placebo. This specific finding suggests a nuanced effect of denosumab on glucose metabolism in a particular patient subset.
In a subgroup with high baseline serum cortisol, denosumab reduced HbA1c by 2.5 mmol/mol (95% CI -5.0 to -0.1) compared to placebo.
Key Findings
- A single dose of denosumab showed no significant effect on
HbA1c, LDL, HDL, or total cholesterol at day 80 or 160. - No differences were found in fasting glucose, insulin, C-peptide, or
HOMA-IRin fasting patients (n=44). - Alanine aminotransferase (ALT) was higher in the denosumab group by 8.3 U/L (95% CI 3.3 to 13.3) at day 160.
- In a subgroup with high baseline serum cortisol, denosumab reduced
HbA1cby 2.5 mmol/mol (95% CI -5.0 to -0.1).
Why It Matters
This study indicates that a single dose of denosumab is not a broad solution for improving glucose or lipid homeostasis in young infertile men. Peptide users and clinicians should note that while the primary metabolic outcomes were null, the observed increase in ALT warrants caution regarding liver function with denosumab use. The finding of reduced HbA1c in the high-cortisol subgroup is a crucial insight, suggesting that denosumab's metabolic effects might be context-dependent, potentially beneficial for infertile men with underlying hypercortisolism. This points towards a more targeted application rather than a general protocol. Further research is needed to understand this subgroup effect and whether repeated dosing or different populations could yield broader metabolic benefits, moving beyond a single-dose protocol.
denosumab
infertile men
metabolic syndrome
glucose homeostasis
lipid homeostasis
hba1c