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Principal Investigator: LAWRENCE S PHILLIPS
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $363,824
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <21+ years old><Acceleration><Adherence><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Apoptosis><Apoptosis Pathway><Beta Cell><Blinded><Blood Glucose><Blood Glucose Self-Monitoring><Blood Sugar><Blood Sugar Self-Monitoring><Body Weight decreased><Caring><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Clinical><Complications of Diabetes Mellitus><Continuous Glucose Monitor><Control Groups><D-Glucose><Dextrose><Diabetes Complications><Diabetes Mellitus><Diabetes-Related Complications><Diabetic Complications><Dimethylbiguanidine><Dimethylguanylguanidine><Disease><Disease remission><Disorder><Dropout><Drugs><Early Diagnosis><Ensure><Evaluation><Eye><Eyeball><FDA approved><Fundus><GLP-1><Glucose><Glycohemoglobin A><Glycosylated hemoglobin A><Goals><Hb A1><Hb A1a+b><Hb A1c><HbA1><HbA1c><Hemoglobin A(1)><Home Blood Glucose Monitoring><Hour><Humulin R><Hyperglycemia><Hypoglycemia><Insulin><Insulin Cell><Insulin Secreting Cell><Intervention><Intervention Strategies><Intervention Studies><Ketosis-Resistant Diabetes Mellitus><Kidney><Kidney Diseases><Kidney Urinary System><Life Style><Lifestyle><Maintenance><Maturity-Onset Diabetes Mellitus><Mediating><Medical><Medication><Metformin><Methods><Microalbuminuria><Modeling><N,N-dimethyl-imidodicarbonimidic diamide><NIDDM><Natural History><Nephropathy><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><OGTT><Oral Glucose Tolerance Test><Outcome><Outcome Study><Patients><Pattern><Pharmaceutical Preparations><Pioglitazone><Prediabetes><Prediabetes syndrome><Prediabetic State><Prevention><Primary Care><Programmed Cell Death><Randomized><Regular Insulin><Remission><Renal Disease><Retinal Diseases><Retinal Disorder><Risk><Running><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Subcellular Process><T2 DM><T2D><T2DM><Testing><Time><Translating><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Weight Loss><Weight Reduction><Work><adult onset diabetes><adulthood><body weight loss><care as usual><cell dedifferentiation><continuous blood glucose monitor><continuous blood sugar monitor><continuous glucose measurement><continuous sugar monitor><cost><cost effective><cost effectiveness><diabetes><diabetes prevention program><dosage><drug/agent><early detection><excitotoxic><excitotoxicity><glargine><glucagon-like peptide 1><hemoglobin A1c><hyperglycemic><hypoglycemic><hypoglycemic episodes><improved><intervention arm><intervention research><interventional research><interventional strategy><interventional study><interventions research><ketosis resistant diabetes><kidney disorder><life style intervention><lifestyle intervention><maturity onset diabetes><mortality><novel><pre-diabetes><pre-diabetic><prediabetic><preservation><prevent><preventing><progression risk><randomisation><randomization><randomly assigned><renal><renal disorder><retina disease><retina disorder><retinopathy><treatment arm><treatment as usual><trend><type 2 DM><type II DM><type two diabetes><usual care><wt-loss><β-cell><β-cells><βCell>