February 2025

The trial design for the two largest studies ever conducted on a GLP-1 drug in Alzheimer's disease was published in early January. EVOKE and EVOKE+ are randomized, double-blind, placebo-controlled Phase 3 trials investigating daily oral semaglutide (14 mg) in 3,808 adults aged 55–85 with mild cognitive impairment or mild dementia due to amyloid-confirmed AD. The primary endpoint is change in CDR-SB (Clinical Dementia Rating—Sum of Boxes) over 104 weeks. Both studies include biomarker-rich secondary endpoints spanning MRI volumetrics, plasma/CSF markers, and cognitive composites. Enrollment completed September 2023 across 400+ sites in 40 countries; main-phase results are anticipated in late 2025.

A new meta-analysis pooling 4 RCTs (n = 19,663) demonstrated that semaglutide significantly reduced the composite primary cardiovascular outcome. The effect was consistent across both subcutaneous and oral formulations — an important finding for clinicians weighing delivery route options.

A sweeping narrative review published in early 2025 consolidates evidence on semaglutide's expanding therapeutic profile. Beyond T2D and weight management, the review evaluates emerging data across PCOS, CKD, NAFLD/NASH, cardiovascular risk, and neurodegenerative disease. Of particular clinical interest: semaglutide demonstrated improvement in liver enzyme levels, steatosis, and hepatic stiffness in non-fibrotic patients. Preclinical Alzheimer's data were also highlighted, though human cognitive trials remain underway. The review underscores that semaglutide has evolved well beyond a "diabetes drug."

The long-anticipated SURMOUNT-5 trial began circulating in the clinical community in early 2025 as design and enrollment data became available. This Phase 3b, open-label trial (n = 751) is the first head-to-head comparison of the two most prescribed incretin-based obesity therapeutics. At 72 weeks, tirzepatide (max tolerated dose) achieved a mean weight loss of −20.2% vs. −13.7% for semaglutide. Tirzepatide was also superior for waist circumference reduction and for achieving ≥15%, ≥20%, and ≥25% body weight thresholds. This study will be central to prescribing decisions going forward.

Eli Lilly's triple GLP-1/GIP/glucagon agonist entered its Phase 3 TRIUMPH program, enrolling 5,800 participants across seven late-stage studies. Phase 2 data (published 2023) showed average weight loss of 24.2% at 48 weeks at the highest dose — rivaling bariatric surgery outcomes. The TRIUMPH program is evaluating retatrutide across obesity, obstructive sleep apnea, and knee osteoarthritis, with readouts expected throughout 2025–2026. A network meta-analysis comparing retatrutide and tirzepatide found retatrutide produced greater absolute and percentage weight reduction, though with a higher frequency of adverse events.

A comprehensive review published in HSS Journal surveyed six electronic databases for BPC-157 literature through March 2025. The review identified only three published human studies to date, but all showed positive signals. In a 16-patient retrospective study, 87.5% of patients reported significant pain relief after intra-articular knee injections with BPC-157 or BPC-157 + TB-500. A 12-patient pilot study in interstitial cystitis demonstrated resolution of detrusor hyperemia on cystoscopy. Most recently, a 2-patient pilot assessed IV BPC-157 infusions up to 20 mg with no adverse events reported. While animal data remains robust (tendon, ligament, gut, nerve), the field is still early in its clinical translation.

A peer-reviewed article published in the Journal of the American Academy of Orthopaedic Surgeons formally reviewed therapeutic peptides — including BPC-157, TB-500, and GHK-Cu — in the context of musculoskeletal repair. The paper frames these compounds as "promising adjuncts" acting on PI3K/Akt, mTOR, MAPK, TGF-β, and AMPK signaling networks. For TB-500 specifically, the paper notes its primary mechanism of G-actin sequestration facilitating cell migration during wound healing, along with its angiogenic and anti-fibrotic properties. This is a notable signal: orthopedic surgery literature is beginning to take regenerative peptides seriously as a therapeutic class.

In the same JAAOS review, GHK-Cu was highlighted for its ability to modulate over 4,000 genes, upregulate collagen and elastin synthesis, and activate copper-dependent enzymes critical for ECM crosslinking. The review positioned GHK-Cu as a tissue repair and longevity compound with orthopedic applications in wound healing and post-surgical recovery. While clinical trial data in orthopedic populations is limited, the inclusion in a major surgical journal reflects growing interest from the procedural medicine community.

A thorough review of elamipretide (SS-31) was published in International Journal of Molecular Sciences in January 2025, synthesizing the compound's structural biology, mitochondrial targeting mechanism, and clinical trial data. The peptide binds cardiolipin in the inner mitochondrial membrane, stabilizing cristae structure, reducing ROS, and enhancing ATP production. Clinical trials in heart failure (HFpEF), Barth syndrome, primary mitochondrial myopathies, and age-related macular degeneration were comprehensively catalogued. Of note: the Barth syndrome program was advancing toward an FDA decision (later approved September 2025), which would make elamipretide the first FDA-approved mitochondria-targeted therapeutic.

No new peer-reviewed clinical trials were published for Epitalon in this reporting period. However, the compound continues to generate discussion in the longevity research community based on Khavinson's original telomerase activation data (hTERT upregulation and telomere elongation in somatic cells). Emerging stacking protocols pairing Epitalon with SS-31 are being discussed in integrative medicine circles — the rationale being dual-pathway anti-aging: telomere maintenance plus mitochondrial optimization. Clinical validation of these combinations remains absent.

MOTS-c, a mitochondrial-derived peptide encoded within mtDNA, continues to accumulate preclinical evidence as a metabolic signaling molecule. Published reviews in this period highlight its role in enhancing insulin sensitivity, improving glucose metabolism, and promoting fat oxidation through AMPK pathway activation. MOTS-c is increasingly being studied as a molecular probe for understanding mitochondrial-nuclear crosstalk in aging. No human clinical trials were initiated in this period. MOTS-c remains in the "promising preclinical" category, with its primary clinical translation pathway likely through metabolic disease and sarcopenia.

No new randomized controlled trials were published for CJC-1295, Ipamorelin, or Sermorelin in this reporting period. These compounds remain widely used in integrative and anti-aging medicine practices based on established pharmacology: CJC-1295 (GHRH analogue with 6–8 day half-life via DAC), Ipamorelin (selective GHSR-1a agonist without cortisol/prolactin elevation), and Sermorelin (FDA-previously-approved GHRH(1-29) fragment). The CJC-1295 + Ipamorelin combination continues to be the most commonly prescribed GH secretagogue stack in clinical practice, leveraging complementary receptor pathways (GHRHR + GHSR) for synergistic pulsatile GH release.

AOD-9604, the modified fragment (176–191) of human growth hormone, had no new clinical trial publications in this period. The peptide retains GRAS (Generally Recognized as Safe) status from the FDA as a food ingredient but remains unapproved as a therapeutic. Its mechanism — stimulating lipolysis without affecting IGF-1 or insulin — continues to make it a staple in peptide clinic protocols for fat loss, though evidence remains limited to early-phase human data and preclinical models.

Our surveillance of PubMed, Cochrane, and major medical databases found no new English-language clinical trials published for Selank, Semax, DSIP, or Dihexa during this reporting period. Selank and Semax remain approved in Russia for anxiety and cognitive applications, respectively, with most published data in Russian-language journals. Dihexa continues to draw interest from the nootropics community based on its angiotensin IV analogue mechanism and preclinical HGF/c-Met pathway data, but no human safety or efficacy trials have been initiated. We will continue monitoring these compounds monthly.

KPV (α-MSH tripeptide fragment with NF-κB inhibition) and LL-37 (cathelicidin-derived antimicrobial/immunomodulatory peptide) had no new clinical trial data published in this period. KPV remains of interest for gut inflammation (IBD) applications based on murine colitis models. LL-37 continues to be studied for its broad-spectrum antimicrobial properties and wound healing potential. Both compounds are available in compounding pharmacy settings but lack the clinical trial infrastructure of the GLP-1 class.

Humanin, a 24-amino-acid mitochondrial-derived peptide (MDP) with cytoprotective and neuroprotective properties, had no new clinical publications in this period. The compound remains in preclinical investigation for its role in protecting against Alzheimer's pathology, age-related metabolic decline, and oxidative stress. Like MOTS-c, Humanin is increasingly discussed as part of the broader mitochondrial-derived peptide class that may offer endogenous aging biomarkers and therapeutic targets.

PT-141 (Bremelanotide / Vyleesi) remains FDA-approved for hypoactive sexual desire disorder (HSDD) in premenopausal women. No new indication expansions or major clinical publications were identified in this period. Melanotan II remains unapproved and is associated with known risks including nausea, flushing, and the theoretical concern of nevi progression. No new safety or efficacy studies were published.