HMD HISTORICAL GUIDELINE SERIES

HMD HISTORICAL GUIDELINE SERIES

Incretins as a systemic platform

Milestone 19 | Heart, liver, kidney, inflammation and metabolic neuroscience

Historical technical review and scientific curation document. It does not constitute therapeutic advice, a clinical indication, a use recommendation, commercial availability, or a claim of affiliation with manufacturers, academic institutions or cited investigators.

Executive summary

Milestone 19 closes the first historical line of the series by interpreting incretins not only as therapies for glucose or body weight, but as a systemic platform for metabolic research. Recent evidence connects GLP-1 agonists with cardiovascular, kidney, liver, inflammatory and neuro-metabolic outcomes [1-6].

The SELECT trial showed that semaglutide reduced major cardiovascular events in people with overweight or obesity and established cardiovascular disease, without diabetes. The FLOW trial showed kidney and cardiovascular benefit in patients with type 2 diabetes and chronic kidney disease [1,2].

For HMD, the conceptual shift is not to call GLP-1 a universal molecule, but to recognize that the GLP-1 receptor and incretin systems function as integration nodes between organs, eating behavior, inflammation, vascular function and metabolic adaptation.

Milestone timeline

1. From incretin molecule to systemic signal

Previous milestones documented the evolution from secretin, the incretin concept, GIP, proglucagon, active GLP-1, GLP-1 agonism, semaglutide, tirzepatide, cagrilintide and retatrutide. This milestone organizes the next level: expansion of the field toward organs and clinical systems beyond glucose and obesity.

Contemporary literature describes pleiotropic effects of GLP-1RAs on metabolic regulation, inflammation, cardiovascular function, kidney, liver and the nervous system. This reading does not replace the approved clinical indication of each medicine, but it explains why the field is moving toward systemic metabolic medicine [4-6].

2. Cardiovascular, kidney and liver evidence

In cardiovascular medicine, SELECT was a turning point because it studied people with overweight or obesity and established cardiovascular disease without diabetes, reporting a reduction in major adverse cardiovascular events with semaglutide 2.4 mg [1].

In kidney disease, FLOW evaluated semaglutide in type 2 diabetes and chronic kidney disease, reporting reduced clinically important kidney outcomes and cardiovascular death [2]. In liver disease, the phase 3 ESSENCE trial in MASH reported histological improvement, including steatohepatitis resolution and fibrosis reduction without worsening of steatohepatitis [3].

Table 1. Systemic research domains

3. Inflammation and metabolic neuroscience

Recent reviews propose that part of the GLP-1 field expansion relates to anti-inflammatory mechanisms, mitochondrial function, vascular signaling and neuro-metabolic communication [4,5].

In neurodegeneration, scientific interest should not be confused with an established clinical indication. The appropriate reading is investigational: GLP-1RAs are studied for potential effects on neuroinflammation, mitochondrial function, autophagy and synaptic protection, but the level of evidence varies across preclinical models, observational studies and clinical trials [5,6].

4. Independent HMD analysis

The HMD reading of milestone 19 is that incretins moved from intestinal hormones into a platform of systemic architecture. The common axis is not “weight loss”, but signal integration: feeding, pancreatic secretion, liver, kidney, endothelium, inflammation, adipose tissue, muscle and brain.

The interpretive risk is to overextend the field and convert a promising platform into an all-purpose narrative. HMD proposes distinguishing established evidence, emerging evidence and mechanistic hypotheses. That separation should govern every documentary profile or investigational product file within HMD.

Table 2. HMD documentary classification criterion

5. Closing of the first historical series

This milestone closes the 1902-2026 arc: from the first demonstration of intestinal hormonal communication to a view in which incretins organize a modern program of multiorgan research. Subsequent HMD documents may function as special articles, molecular profiles or clinical-area dossiers rather than basic historical milestones.

References

1. Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389:2221-2232. doi:10.1056/NEJMoa2307563.

2. Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391:109-121. doi:10.1056/NEJMoa2403347.

3. Sanyal AJ, Newsome PN, Kahn SE, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392:2089-2099. doi:10.1056/NEJMoa2413258.

4. Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024;9:234. doi:10.1038/s41392-024-01931-z.

5. Patel S, Silchenko S, Gangwish DD, et al. Emerging frontiers in GLP-1 therapeutics: beyond glycemic control and weight management. Cureus. 2025;17:e86077. doi:10.7759/cureus.86077.

6. Athauda D, Foltynie T. The promise of GLP-1 receptor agonists for neurodegenerative diseases. Nat Rev Neurol. 2026. doi:10.1038/s41582-026-01134-2.

7. Galli M, Andreotti F, D’Amario D, et al. Cardiovascular effects and tolerability of GLP-1 receptor agonists: systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2026;12:50-61. doi:10.1093/ehjcvp/pvaf077.

8. Badve SV, Bilal S, Lee MMY, et al. Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis. Lancet Diabetes Endocrinol. 2025;13:15-27. doi:10.1016/S2213-8587(24)00271-7.