Changing the natural history of type 2 diabetes ? ?change? Study - we will test the hypothesis that the typical worsening of hyperglycemia in type 2 diabetes (DM) will be reduced by keeping glucose…

Changing the natural history of type 2 diabetes ? ?change? Study - we will test the hypothesis that the typical worsening of hyperglycemia in type 2 diabetes (DM) will be reduced by keeping glucose normal compared to usual care. Progression of hyperglycemia is mediated by loss of SS-cell function, which will be mitigated by normalizing glucose, reducing the "excitotoxicity" leading to SS-cell dedifferentiation and apoptosis. In multiple studies, when lifestyle change or RX reduced progression from predm to DM, there was no "catch-up" after the interventions ended - cumulative DM remained less than in controls, consistent with a change in the natural history. Reaching normal glucose is beneficial regardless of the mechanism: in the diabetes prevention program (DPP), predm subjects who achieved normal glucose levels only once, had 56% less DM in the DPP outcomes study (dppos) - similar in lifestyle change, metformin, and control groups. This study will be novel, but the approach will be easy to translate into practice: 1) aim for normal glucose, instead of testing an RX or mechanisms. 2) start early in the natural history, allowing use of RX with a very low risk of hypoglycemia. 3) target early DM instead of predm, using RX already FDA approved for DM. 4) use accelerated stepped intensification of RX to keep glucose normal with intensive RX. Aims: assess effect size, SS-cell function, retinopathy, nephropathy, CGM, and cost-effectiveness. Methods: we will study 126 adults, 1/3 each in 3 groups of early DM (A1C 6.0-6.9%, no RX; A1C 6.0-6.9% on metformin; A1C 7.0-7.4%, on metformin). After a 2-week run-in [to establish tolerance to metformin (if not on IT already), and adherence to self monitoring of blood glucose (smbg)], all subjects will have lifestyle change support; HBA1C and continuous glucose monitoring (CGM) every 3 months; and be randomized 1:1, to intensive RX: adding RX if smbg levels are > goal (