Review
The 11th Cardiovascular Outcome Trial (CVOT) Summit (November 2025) was a virtual multidisciplinary conference convening experts in endocrinology, diabetology, cardiology, nephrology, hepatology, and general practice to review recent outcome trials and emerging therapies along the cardiovascular-kidney-metabolic (CKM) disease continuum. The report summarizes key 2025 developments, including the first head-to-head CVOT (SURPASS-CVOT), the CONFIDENCE trial examining combination therapy with finerenone (a non-steroidal mineralocorticoid receptor antagonist) and empagliflozin (an SGLT2 inhibitor), the ATTAIN-1 trial of the oral GLP-1 receptor agonist orforglipron, and the BaxHTN trial of the aldosterone synthase inhibitor baxdrostat. The report also covers updated clinical guidelines, policy developments, advances in continuous glucose and ketone monitoring technology, and emerging pharmacological strategies for metabolic liver disease and type 1 diabetes. As a conference summary report rather than a primary trial, this document does not present original trial data and primarily synthesizes and contextualizes findings from multiple studies. Key limitations include the narrative, consensus-driven format and the absence of new primary data.
Cardiovascular diabetology · May 2026DOI ↗ Limited · human
This study investigated the role of two mitochondrial-derived peptides (MDPs) — humanin (HN) and MOTS-c — in atrial fibrillation (AF), a common heart rhythm disorder. Researchers first examined human atrial tissue using public gene expression data, immunohistochemistry, and immunofluorescence, and measured plasma levels in a matched cohort of 39 AF patients and 39 sinus rhythm controls. They found that both peptides were significantly downregulated in AF tissue, with levels inversely correlated with fibrosis extent. Plasma MOTS-c was also reduced in AF patients and inversely correlated with NT-proBNP, a heart stress biomarker. Using an angiotensin II (AngII)-induced mouse AF model (n=36, male C57BL/6J), the study found that treatment with HNG (an HN analogue) or MOTS-c reduced AF inducibility and attenuated atrial fibrosis and hypertrophy. Peptide treatment was associated with improved mitochondrial structure, reduced fission proteins (Drp1, Fis1), and lower inflammatory cytokines. In vitro experiments in rat cardiomyocytes and fibroblasts showed reduced oxidative stress, fibroblast activation, proliferation, and migration. Exploratory RNA-sequencing suggested distinct mechanistic pathways. Key limitations include the small human cohort, the use of an animal model that may not fully replicate clinical AF, and the exploratory nature of mechanistic findings.
Biomedicines · May 2026DOI ↗ Animal only
This study investigated whether GHK-Cu (the tripeptide Glycine-Histidine-Lysine complexed with copper, naturally found in human plasma and urine) could delay aging using the roundworm Caenorhabditis elegans as a model organism. The researchers measured lifespan, stress resistance (oxidative and thermal), physical function (motility, pharyngeal pumping, defecation rhythm), and markers of cellular aging such as lipofuscin and lipid accumulation. They also examined mitochondrial health and key longevity signaling pathways. The study found that GHK-Cu extended worm lifespan, improved multiple age-related functional measures, and reduced aging biomarkers. At the mechanistic level, GHK-Cu appeared to preserve mitochondrial function—maintaining membrane potential, reducing age-related mitochondrial fragmentation, promoting mitochondrial fusion (via regulation of drp-1 and fzo-1), and increasing ATP production. Additionally, GHK-Cu activated the DAF-16 and SKN-1 longevity pathways and upregulated downstream target genes including sod-3, gst-4, gcs-1, lys-7, and lys-8. A key limitation is that all experiments were conducted in C. elegans; whether these findings translate to mammals or humans remains unknown.
Biogerontology · May 2026DOI ↗ Limited · humanPreprint
This large-scale observational study used an EHR-linked body-composition "digital phenotyping" pipeline — incorporating large language model (LLM)-based data extraction — to compare lean body mass (LBM) changes in routine clinical care among adults initiating GLP-1 receptor agonists (GLP-1RAs). Of 670,422 first-episode GLP-1RA users (456,742 on semaglutide; 213,680 on tirzepatide), 7,965 had paired pre- and post-initiation body-composition measurements analyzable over 12 months. The study found that tirzepatide was associated with greater relative LBM loss than semaglutide at each time point assessed (3, 6, 9, and 12 months), with excess LBM losses ranging from approximately 1.1% to 2.0%. The authors also identified two GLP-1 "metabotypes": a "Depletive" metabotype (>20% total body weight loss with >5% LBM loss), which was more frequent with tirzepatide (10.3%) than semaglutide (6.7%), and a "Prime" metabotype (>10% total body weight loss with preserved LBM). Key limitations include the observational, real-world design; reliance on LLM-extracted EHR data; potential unmeasured confounding; and the relatively small subset with paired body-composition data relative to the overall cohort.
Unknown journal · May 2026DOI ↗ Limited · human
This study investigated whether the synthetic peptide BPC 157 (Body Protection Compound-157) could relax human arterial tissue and whether that effect depends on the endothelium and nitric oxide (NO) signaling. Researchers used residual segments of internal mammary artery (IMA) collected from 12 patients undergoing elective coronary artery bypass graft surgery. Arterial rings were prepared with the endothelium either intact or deliberately removed, then pre-contracted with phenylephrine. Cumulative doses of BPC 157 were applied, and separate experiments used the NOS inhibitor L-NAME to assess NO involvement. The study found that BPC 157 produced a concentration-dependent reduction in arterial contraction in both endothelium-intact and endothelium-denuded rings, but relaxation was significantly greater when the endothelium was present. L-NAME pre-treatment blunted the relaxation response, implicating the endothelial NO pathway as the primary mechanism. Residual relaxation in denuded rings suggested that additional, endothelium-independent mechanisms also contribute. The authors acknowledge limitations including the small sample size (n = 12), the ex vivo nature of the tissue model, and the absence of in vivo or molecular mechanistic data, calling for further research before clinical conclusions can be drawn.
Journal of clinical medicine · May 2026DOI ↗ Review
This review traces the historical development and clinical adoption of FDA-approved drugs that incorporate d-amino acids — the non-natural mirror-image enantiomers of standard l-amino acids. The authors survey more than 20 FDA-approved drugs spanning therapeutic areas including infectious diseases, endocrine disorders, rare dermatologic conditions, and diagnostic imaging. Key examples discussed include naturally derived compounds such as gramicidin D and synthetic analogs including desmopressin, leuprolide, bremelanotide, and etelcalcetide — the latter highlighted as the first fully d-amino acid peptide to receive FDA approval. The review explains why d-amino acids are pharmacologically attractive: their resistance to proteolytic degradation, enhanced conformational rigidity, and reduced immunogenicity make them well-suited for long-acting and receptor-selective drug design. The authors also discuss enabling technologies, particularly solid-phase peptide synthesis and mirror-image phage display, that have accelerated the field. As a narrative review, the paper does not present new experimental data, conduct meta-analytic comparisons, or include a systematic literature search, which limits its ability to draw novel evidence-based conclusions. Its primary value lies in synthesizing the historical trajectory and mechanistic rationale of a growing drug class.
Drug development research · May 2026DOI ↗ Limited · human
This case report describes two adults living with well-controlled HIV-1 who presented with excess visceral abdominal fat (EVAF) under distinct clinical phenotypes. The first patient had a non-obese visceral adiposity phenotype (BMI 27 kg/m²) with increased waist circumference; treatment with tesamorelin, a growth hormone-releasing hormone analog, was associated with reductions in waist circumference, improved lipid levels, and enhanced functional well-being. The second patient had obesity (higher BMI) and received a GLP-1 receptor agonist; intermittent medication access led to fluctuating weight and persistent abdominal fat, after which the addition of tesamorelin was reported to provide more targeted visceral fat reduction. The authors argue that EVAF in people living with HIV can occur across BMI categories and may not be adequately captured by weight-based assessments alone. They conclude that individualized management informed by fat distribution patterns—rather than BMI or weight—is warranted. Key limitations include the single case-report design (n=2), absence of a control condition, lack of imaging-based visceral fat quantification reporting, and inability to draw generalizable conclusions about comparative efficacy.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · May 2026DOI ↗ Review
This paper is a commentary/review examining the rapidly evolving landscape of weight-loss pharmacotherapy, focusing on the progression from standard GLP-1 receptor agonists to dual and triple agonists capable of achieving 30–40% body weight reduction — outcomes previously only attainable through bariatric surgery. The authors argue that the pharmaceutical industry's competitive focus on maximizing weight-loss percentages is creating a disconnect between the metric of total body mass reduction and the broader goal of metabolic health. A central concern raised is that aggressive pursuit of high weight-loss targets may come at the cost of metabolic integrity and lean muscle mass preservation. The paper also touches on how escalating clinical benchmarks are influencing investor expectations and market dynamics. Notable limitations include the absence of primary data; the piece offers no original clinical trial results, relies on narrative argument rather than systematic evidence synthesis, and does not present a structured methodology for evaluating the compounds discussed. It does not provide specific dosing guidance but situates the debate within a broader physiological and economic context.
Molecules and cells · May 2026DOI ↗ Moderate · human
This network meta-analysis (NMA) synthesized evidence from six randomized controlled trials (N = 4,642; durations 12–68 weeks) to compare novel amylin-based therapies (ABTs) — amycretin, eloralintide, and cagrilintide/semaglutide (CagriSema) — against placebo and established anti-obesity agents (semaglutide 2.4 mg, liraglutide 3.0 mg) in adults with overweight or obesity without diabetes. Using a frequentist random-effects framework, the study found that high-dose subcutaneous amycretin produced the largest estimated reduction in percent body weight versus placebo (mean difference approximately −24%), followed by high-dose eloralintide (−18%) and high-dose CagriSema (−17%), all exceeding reductions seen with semaglutide 2.4 mg (−11%) and liraglutide 3.0 mg (−6%). Similar ranking patterns emerged for absolute weight, BMI, waist circumference, and categorical weight-loss thresholds. Gastrointestinal adverse events — particularly nausea, vomiting, and constipation — were more frequent with high-dose ABTs, and only high-dose CagriSema significantly increased treatment-discontinuation due to adverse events. The authors acknowledge that the included trials are few, relatively short-to-medium term, and carry low certainty of evidence, characterizing findings as preliminary and requiring confirmation in larger trials.
Endocrinology, diabetes & metabolism · May 2026DOI ↗ Moderate · human
This observational study used two target-trial emulations to compare cardiovascular outcomes among commercially insured U.S. adults with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) who initiated tirzepatide, dulaglutide, or semaglutide between June 2022 and December 2024. Using propensity-score (PS) 1:1 matching to reduce confounding, the researchers formed two cohorts: 9,233 tirzepatide–dulaglutide pairs and 25,266 tirzepatide–semaglutide pairs. The primary outcome was a modified MACE composite (nonfatal myocardial infarction, nonfatal stroke, and all-cause death). The study found that tirzepatide initiators had a statistically significantly lower rate of modified MACE compared with dulaglutide initiators (HR 0.80; 95% CI 0.65–0.99), largely driven by reduced all-cause mortality (HR 0.60; 95% CI 0.43–0.83); tirzepatide was also associated with fewer pneumonia-related hospitalizations versus dulaglutide. No significant difference in modified MACE was observed between tirzepatide and semaglutide initiators (HR 1.03; 95% CI 0.90–1.17). Key limitations include the observational design, potential residual confounding, reliance on administrative claims data, and a relatively short follow-up window.
Diabetes care · May 2026DOI ↗ Limited · human
This pharmacovigilance study used the U.S. FDA Adverse Event Reporting System (FAERS) database (Q2 2022–Q2 2025) to examine whether specific GLP-1 receptor agonists (GLP-1 RAs) — exenatide, lixisenatide, liraglutide, dulaglutide, semaglutide, and tirzepatide — differ in their association with alopecia and reproductive or endocrine-related adverse events. Researchers identified 1,276 alopecia-related and 759 reproductive/endocrine-related cases, then applied disproportionality analyses using crude and adjusted reporting odds ratios (cROR/aROR) from logistic regression, controlling for potential confounders. Sensitivity analyses with positive and negative control drugs were used to validate signal robustness. The study found that semaglutide was significantly associated with disproportionate reporting of alopecia (aROR 1.23) and several hormonal conditions, including polycystic ovary syndrome (aROR 6.59) and menstrual abnormalities. By contrast, dulaglutide and tirzepatide showed negative or non-significant associations for several reproductive outcomes. Important limitations include the inherent biases of spontaneous reporting systems (e.g., underreporting, notoriety bias, inability to establish causation), lack of denominator data, and absence of clinical detail. The authors conclude that agent-specific differences in endocrine and dermatologic safety profiles may warrant personalised prescribing decisions and ongoing surveillance.
Diabetes/metabolism research and reviews · May 2026DOI ↗ Review
This review examines the perioperative safety implications of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug class increasingly used for type 2 diabetes and obesity management. The authors focus on the mechanism by which GLP-1 RAs delay gastric emptying and how this pharmacological effect may elevate the risk of pulmonary aspiration during general anesthesia—specifically at induction and emergence—even when patients have followed standard preoperative fasting protocols. The review distinguishes between short-acting GLP-1 RAs, which reportedly cause more pronounced gastric emptying delays, and long-acting agents, whose residual effects may vary by dose and duration of treatment. The authors also survey updated guidance issued by international anesthesia societies in response to these concerns. Key limitations acknowledged include the overall scarcity and inconsistency of available clinical evidence. The review concludes by advocating for individualized, interdisciplinary perioperative management involving collaboration between endocrinologists and anesthesiologists. As a narrative review, it does not generate new primary data, and the conclusions are constrained by the quality of the underlying literature.
The Korean journal of internal medicine · May 2026DOI ↗ Review
This state-of-the-art review synthesizes available evidence on how glucagon-like peptide-1 receptor agonists (GLP-1 RAs) — drugs used for type 2 diabetes and weight management — affect blood pressure (BP). The authors examined data across populations including people with diabetes, obesity, and high cardiovascular risk. The review reports that GLP-1 RAs are associated with modest systolic BP reductions, typically in the range of 2–5 mm Hg, which the authors attribute primarily to weight loss, with potential additional contributions from weight-independent mechanisms such as natriuresis (increased urinary sodium excretion), improved endothelial function, and reduced vascular inflammation. The review notes that while these reductions are smaller than those achieved with traditional antihypertensive medications, they may translate to meaningful cardiovascular risk reduction at a population level and may offer additive benefit alongside conventional therapies. The authors also highlight that small increases in heart rate and possible interactions with volume-regulating medications may require clinical monitoring. Limitations acknowledged include the indirect and heterogeneous nature of the synthesized evidence. The review concludes by calling for further research as newer GLP-based therapies emerge to better inform integrated cardiometabolic care strategies.
American journal of hypertension · May 2026DOI ↗ Review
This review examines the emerging role of GLP-1-based medications (such as GLP-1 receptor agonists) in the prevention and treatment of heart failure (HF), with a particular focus on heart failure with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF). The authors summarize and discuss findings from recent clinical studies reporting HF-related outcomes with these agents. The review highlights the strong pathophysiological connections between type 2 diabetes, obesity, and heart failure, positioning GLP-1-based therapies as potentially beneficial across these overlapping conditions. The authors conclude that accumulating evidence supports beneficial effects on HF outcomes—particularly in HFpEF and possibly HFmrEF—while noting that the utility of these medications in heart failure with reduced ejection fraction (HFrEF) remains unclear and requires further investigation. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and its conclusions are therefore dependent on the quality and scope of the studies it includes. It does not establish causality or provide definitive clinical guidance on specific patient populations.
Medicina (Kaunas, Lithuania) · May 2026DOI ↗ Insufficient
TRANSCEND-CKD (NCT05936151) is a double-blind, placebo-controlled Phase 2b mechanistic trial evaluating retatrutide — a triple agonist of the GIP, GLP-1, and glucagon receptors — in adults with overweight or obesity and chronic kidney disease (CKD). The publication describes the trial's rationale, design, and baseline characteristics of the 146 randomized participants (out of 367 screened). Participants had a mean age of 65.1 years, mean BMI of 35.7 kg/m², and mean measured GFR of 49.3 mL/min/1.73 m² (eGFR range 25–75). Roughly 38% had type 2 diabetes. Participants were randomized 1:1 to once-weekly retatrutide (maximum tolerated dose up to 12 mg) or matched placebo. The primary endpoint is change in measured GFR via iohexol clearance at 24 weeks; secondary endpoints include MRI-assessed kidney hemodynamics, volumes, and perirenal/renal sinus fat. The study is explicitly designed as a mechanistic precursor to the larger cardio-kidney outcomes trial TRIUMPH-Outcomes. Because this paper reports only design and baseline data — with no efficacy or safety outcomes yet — no conclusions about retatrutide's effects on kidney function can be drawn from it.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · May 2026DOI ↗ Review
This narrative review evaluates the emerging evidence for glucagon-like peptide-1 receptor agonists (GLP-1RAs) — a drug class established for type 2 diabetes and obesity — as potential treatments for alcohol use disorder (AUD), a condition with currently limited pharmacological options. The authors searched PubMed, Google Scholar, and ClinicalTrials.gov, ultimately including 13 preclinical studies, 14 clinical studies, and 4 published interventional trials, while noting 19 additional trials in progress or completed but unpublished. The review describes convergent signals from both animal models and human studies suggesting that GLP-1RAs may reduce alcohol consumption and improve alcohol-related outcomes. Mechanistic preclinical work is highlighted to contextualize how these agents might modulate reward-related pathways. Clinical evidence includes observational studies drawing on real-world and electronic health record data, as well as a small number of randomized controlled trials. The authors acknowledge that the existing RCT evidence base remains limited and that further trials are needed to firmly establish efficacy. Mechanistic studies are also called for to more fully explain how GLP-1RAs may reduce alcohol intake. Case reports, commentaries, and preprints were excluded. This review does not itself generate new primary data.
Alcohol, clinical & experimental research · May 2026DOI ↗ 🧪 TrialInsufficient
Registered Phase 1 interventional trial (recruiting). Background: Glucagon-like peptide 1 (GLP-1) agonist drugs are used to treat diabetes and aid weight loss. They may also help reduce cravings for drugs and alcohol. Researchers want to know if a GLP-1 drug (tirzepatide) can lessen the urge to drink in people with alcohol use disorder (AUD). Objective: To learn how the brains of people with AUD respond to a GLP-1 drug. Eligibility: People aged 21 to 65 years with AUD who are non-treatment seeking. They must be enrolled in protocol 14-AA-0181. Healthy volunteers are also needed. Design: This s
ClinicalTrials.gov · Apr 2026View trial ↗ Insufficient
This analytical chemistry study examined compounded tirzepatide products combined with vitamin B12 analogs that are widely marketed in the United States as alternatives to FDA-approved tirzepatide. Researchers collected samples from multiple U.S. market sources and subjected them to various analytical methods to assess peptide-related impurity profiles and potency. The key finding was the identification of a previously unknown chemical impurity generated by a reaction between tirzepatide and certain B12 analogs. This impurity was described as widespread across the tested samples and present at substantial levels. The authors note that compounded tirzepatide-B12 combinations are mass-marketed without undergoing formal evaluation of potency or impurity profiles, unlike FDA-approved products. The study does not characterize the clinical effects of the identified impurity, which remains unknown. Limitations include the absence of clinical outcome data, lack of information on the specific analytical thresholds used, and no assessment of patient exposure or harm. The authors conclude that the findings highlight quality-control risks associated with compounded therapies marketed outside the drug-approval regulatory framework and reinforce the rationale for pre-market testing and FDA oversight.
Expert opinion on drug safety · Apr 2026DOI ↗ Limited · human
This pharmacovigilance study examined safety signals associated with potentially counterfeit semaglutide products by conducting a descriptive and disproportionality analysis of Individual Case Safety Reports (ICSRs) submitted to the European pharmacovigilance database EudraVigilance between January 2018 and December 2025. Researchers identified 234 ICSRs linked to suspected counterfeit semaglutide, of which 73.5% involved female patients and 35.5% involved adults. Notably, 89.3% of reported suspected adverse drug reactions (ADRs) were classified as serious. The most commonly reported suspected ADRs were vomiting, nausea, and hypoglycemia. Disproportionality analysis revealed a statistically higher reporting frequency for hypoglycemia, product use in an unapproved indication, malaise, and drug ineffectiveness compared with reports involving non-counterfeit semaglutide. The authors suggest these signals may reflect contamination, incorrect active ingredients, or subtherapeutic dosing in counterfeit products. Limitations include the inherent biases of spontaneous pharmacovigilance reporting (underreporting, lack of denominator data, and inability to confirm causality), reliance on database classifications of "counterfeit," and the descriptive nature of the analysis. The study concludes that pharmacovigilance databases can play a useful role in detecting safety concerns related to counterfeit medicines, and calls for further research.
Frontiers in pharmacology · Apr 2026DOI ↗ In vitro
This cell-culture study investigated whether the endogenous tripeptide Lysine-Proline-Valine (KPV), derived from α-melanocyte-stimulating hormone, could protect liver cells from fat accumulation. Using the human hepatocellular carcinoma cell line HepG2, researchers induced a hepatic steatosis model by exposing cells to oleic acid (OA), which mimics lipid overload seen in non-alcoholic fatty liver disease (NAFLD). The study found that OA treatment increased intracellular lipid deposits and upregulated fatty acid synthase (FAS), a key enzyme in fat production. KPV treatment was reported to attenuate these effects without causing cytotoxicity. Mechanistically, the authors propose that KPV reduced reactive oxygen species (ROS), which in turn blunted activation of ERK, reduced AKT/mTORC1 phosphorylation, and normalized phosphorylation of PPARγ — a transcription factor central to de novo lipogenesis — ultimately suppressing FAS expression. The study is limited to a single in vitro cell line model, with no animal or human data, meaning findings cannot yet be extrapolated to living organisms. Concentrations used in cell culture do not translate directly to physiological dosing. Results are hypothesis-generating and require further validation in vivo.
Cytotechnology · Apr 2026DOI ↗