Disease-modifying anti-diabetic drugs (DMADDs): bridging the SIMPLE approach to disease interception.

Commentary proposing a new classification framework (DMADDs) based on a narrative synthesis of existing trial evidence.

“This figure presents a narrative synthesis of trial-level evidence, as judged by the authors: the categories reflect the type of endpoint available, not a quantitative ranking, and no statistical comparisons between cells are implied.”

Patients with type 2 diabetes, obesity, and related cardiovascular or renal conditions.

“The SOUL trial established cardiovascular superiority for oral semaglutide, extending disease-modifying properties beyond injectable formulations, while Phase 3 TRIUMPH data position retatrutide as an emerging triple-agonist candidate awaiting cardiovascular outcome data.”

Varies by cited trial; e.g., the SOUL trial included 9,650 patients, and a meta-analysis of GLP-1RAs included more than 70,000 people.

“A meta-analysis encompassing ten CVOTs of GLP-1RAs in more than 70,000 people with T2DM demonstrated consistent cardiorenal benefits”

Varies by cited trial; e.g., the SOUL trial had a median follow-up of nearly 4 years, and TRIUMPH-1 data were reported at 80 weeks.

“The SOUL trial, the first cardiovascular outcomes trial for oral semaglutide, which demonstrated a 14% reduction in MACE in 9,650 patients with T2DM and established atherosclerotic cardiovascular disease and/or chronic kidney disease, with a median follow-up of nearly 4 years”

SGLT2 inhibitors, GLP-1 receptor agonists, and pioglitazone meet the proposed criteria for Disease-Modifying Anti-Diabetic Drugs (DMADDs), while metformin and DPP-4 inhibitors do not.

“Using these criteria, SGLT2i, GLP-1RA, and pioglitazone emerge as prototypical agents, while metformin, dipeptidyl peptidase−4 (DPP-4) inhibitors, insulin, and sulfonylureas do not meet the full threshold.”

Oral semaglutide demonstrated cardiovascular superiority in high-risk type 2 diabetes patients, confirming disease-modifying properties across formulations.

“The SOUL trial has now added a critical dimension to this picture: oral semaglutide achieved cardiovascular superiority in a high-risk T2DM population, demonstrating that the disease-modifying properties of GLP-1RA are preserved across formulations and delivery routes”

Retatrutide is designated as a candidate DMADD awaiting cardiovascular outcome data, having shown weight reduction and metabolic improvements in Phase 3 trials.

“On the criteria set out here, retatrutide should be designated a candidate DMADD awaiting cardiovascular outcome trials, not an established one.”

The DMADD criteria are a proposal not yet validated with explicit thresholds, and much supporting evidence derives from high-risk populations or post hoc analyses rather than primary endpoints for disease modification.

“First, the DMADD criteria are a proposal, not a validated instrument: they have not been operationalized with explicit thresholds, weighted against one another, or tested for reproducibility between assessors, and the assignment of agents in this Commentary reflects the authors’ reading of the trial evidence rather than a systematic assessment.”