CHANGING THE NATURAL HISTORY OF TYPE 2 DIABETES – “CHANGE” STUDY

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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 β-cell function, which will be mitigated by normalizing glucose, reducing the “excitotoxicity” leading to β-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, β-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 (<100 mg/dl premeal, <130 postmeal, total 7 tests/week) at least 3x/week for 2 weeks in a row after ≥4 weeks of maximum tolerated dosage (MTD) of each Rx: metformin (if not on it at baseline) + TZD pioglitazone + GLP-1 RA semaglutide + SGLT2 empagliflozin + glargine U300 insulin; or control Rx: in the same order, based on A1c every 3 months: metformin if ≥7.0%, other Rx if ≥7.5%. Outcomes: Over 2.5 years, plus a 3-month washout, we will quantitate i) effect size – differences in HbA1c with intensive Rx vs. controls; and (ii) β-cell function, primarily using 3-hour OGTTs with modeling as in RISE, since trends with intensive Rx vs. controls post-washout may indicate whether β-cell function is likely to be sustained. We will also explore (iii) retinopathy (by blinded grading of fundus photos); (iv) nephropathy (microalbuminuria and eGFR); (v) whether 14 days of CGM could be substituted for SMBG in identifying the need to add another Rx (since CGM might be easier to use in primary care), and (vi) cost-effectiveness. Impact: A positive study will lead to a change in medical practice, since early diagnosis and normalizing glucose should produce longterm benefits, including reduced diabetes complications, mortality, and costs.