Optimal first line therapies for patients with Cardiovascular-Kidney-Metabolic (CKM) Syndrome.

Optimal first line therapies for patients with Cardiovascular-Kidney-Metabolic (CKM) Syndrome Approximately 30 million adults have diabetes (DM) in the United States and DM confers a risk for cardiovascular disease (CVD). Whether CVD is prevented by antidiabetic therapies remains relatively unknown. Glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) demonstrate reduction in CVD and kidney outcomes among those with pre-existing CVD. There is less known about prevention in those without CVD. Metformin has long been recommended as a first line treatment for patients and VA guidance is consistent with metformin as a first treatment for DM. The 2022 American Diabetes Association (ADA) guidelines2 differ, however and consider the impact of antidiabetic medications on prevention of cardiovascular and kidney outcomes. ADA guidance recommends GLP1RA and SGLT2i as first line for high-risk patients who have no underlying CVD (Stage 2 Cardiovascular Kidney Metabolic Syndrome (CKM- age 55+ years with hypertension, obesity, dyslipidemia and HbA1c >6.5%). This represents most older Veterans with new onset DM.2,3 The difference in the optimal treatment in high-risk, drug-naïve patients will not resolve until we have data from a head-to-head comparison of metformin with newer hypoglycemic medications. We propose to conduct a national longitudinal study using patient reported, administrative, clinical and laboratory data to quantify the relative risks/ benefits of first line treatments of DM among Veterans. This proposal will answer the question: Among patients with Stage 2 CKM and an HbA1c of >6.5% what are the absolute potential cardiovascular and renal benefits for those who begin treatment with GLP1RA compared to Metformin? Further is there benefit to use of SGLT2i as a first line treatment? We will rebuild the National Diabetes cohort of Veterans with an HbA1c of >6.5% and no prior treatment utilizing national Veterans Health Administration (VHA) data (corporate data warehouse-vital signs; pharmacy, medical datasets, Medicare/ Medicaid data and vital status files), national death index and additional data on echocardiograms. Eligible veterans will have new DM and are a new user of an antidiabetic medication (no use of any DM medications in the prior 180 days). New users of SGLT2i, GLP1RA or Metformin aged >18 years who utilize VHA from 10/1/2000 through 09/30/2023 will be included. We will evaluate the risks and benefits in those without CVD and conduct a validation analysis in those with CVD. The proposed study follows this cohort from DM onset and new drug initiation until an outcome or censoring event (leave VHA, change therapy or death). The comparisons will be: SGLT2 or GLP1RA vs. Metformin. A sample of patients will be surveyed for validation of drug exposure and covariates. Aim 1 will test the hypothesis that major adverse cardiovascular events (MACE - AMI/ Stroke/ CV death) in patients treated with GLP1RA or SGLT2i is lower than Metformin treated patients. Aim 2 will evaluate if CKD progression is lower in patients treated with GLP1RA or SGLT2 vs. Metformin. Aim 3 will test the hypothesis that heart failure hospitalization and all-cause mortality is lower for patients treated with GLP1RA or SGLT2 vs. Metformin. Aim 4 will evaluate 2 mediators (cumulative weight change and systolic blood pressure) as mediating the impact of GLP1RA on MACE outcomes. Propensity score weighting will be used to achieve similar groups. Cause-specific hazard ratios will account for baseline covariates and a competing risk of death or non-persistence. The execution of the proposed research will provide actionable evidence for patients with DM, impact VHA policy and addresses the research strategic priorities of real-world impact of VA research. Our team has been extremely productive in the last 11 years and will conduct a rigorous evaluation of the effectiveness of DM medications leading to impactful o Project Number: 2I01CX000570-13 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Christianne Roumie | Institution: VETERANS HEALTH ADMINISTRATION, NASHVILLE, TN | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 ENDA-L (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11046133