Beyond Glucose-Rethinking Prediabetes for Precision Prevention.

Abstract

Prediabetes affects more than one-third of U.S. adults, yet represents a biologically heterogeneous state that is only partly captured by traditional glycemic categories (impaired fasting glucose, impaired glucose tolerance, or borderline elevated HbA1c). Leveraging unsupervised clustering in comprehensively phenotyped cohorts has identified six reproducible prediabetes subtypes integrating insulin sensitivity, insulin secretion, visceral and hepatic fat, and genetic risk. Three high-risk subtypes (progressing prediabetes with fatty liver, progressing prediabetes with β-cell failure, and slow progressors with hyperinsulinemic insulin resistance) show distinct trajectories toward diabetes and unique complication patterns. For example, "slow progressors" develop albuminuria and face excess mortality, despite only modest glycemic deterioration over 10-15 years, showing that complications can arise before diabetes diagnosis. Recognizing these subtypes sharpens risk stratification and opens a path toward precision prevention. Intensive lifestyle modification and bariatric surgery offer the greatest glycemic benefit in the fatty liver subtype, whereas early pharmacologic β-cell protection may be required for the β-cell failure cluster. GLP-1-based therapies offer promising subtype-specific options and should be tested in randomized controlled studies. Future prediabetes intervention trials should move beyond diabetes incidence as the sole end point and systematically evaluate kidney, nerve, eye, and cardiovascular outcomes. While testing for long-term clinical end points might not be feasible in studies where individuals with prediabetes are recruited, the use of surrogate end points could facilitate the assessment of early complications. Such complication-focused, subtype-guided studies will determine whether early, tailored therapy can halt tissue damage and reduce the public health burden linked to prediabetes.