Prediction of Cardiometabolic Health Through Changes in Plasma Proteins With Intentional Weight Loss in the DiRECT and DIADEM-I Randomized Clinical Trials of Type 2 Diabetes Remission

Objective: To determine to what extent changes in plasma proteins, previously predictive of cardiometabolic outcomes, predict changes in two diabetes remission trials.

Research Design and Methods: SomaSignal® predictive tests (each derived from ~5000 plasma proteins measurements using aptamer-based proteomics assay) were assessed in baseline and 1-year samples in trials (DiRECT n=118, DIADEM-I n=66) and control (DiRECT n=144, DIADEM-I n=76) participants.

Results: Mean weight losses in DiRECT (UK) and DIADEM-I (Qatar) were 10.2 (SD 7.4) kg and 12.1 (SD 9.5) kg, respectively, versus 1.0 (3.7) kg and 4.0 (SD 5.4) kg in control groups. Cardiometabolic SomaSignal tests improved significantly (Bonferroni-adjusted p< 0.05) in DiRECT and DIADEM-I (expressed as relative difference in intervention minus control) as follows, respectively: liver fat (-26.4%, -37.3%), glucose tolerance (-36.6%, -37.4%), body fat percentage (-8.6%, -8.7%), resting metabolic rate (-8.0%, -5.1%), visceral fat (-34.3%, -26.1%) and cardiorespiratory fitness (+9.5%, +10.3%). Cardiovascular risk (measured by SomaSignal tests) also improved in interventions groups relative to control but significant only in DiRECT (DiRECT: -44.2%, DIADEM-I: -9.2%). However, weight loss >10kg predicted significant reductions in CV risk of -19.1% (CI -33.4 to -4.91) in DiRECT and -33.4% (CI -57.3, -9.6) in DIADEM-I. DIADEM-I also demonstrated rapid emergence of metabolic improvements at 3 months.

Conclusion: Intentional weight loss in recent onset type 2 diabetes rapidly induces changes in protein-based risk models consistent with widespread cardiometabolic improvements, including cardiorespiratory fitness. Protein changes with larger (>10kg) weight loss also predicted lower cardiovascular risk, providing a positive outlook for relevant ongoing trials.