Abstract Type 2 diabetes mellitus (T2DM) remains a major public health concern in the United States, especially in Louisiana where mortality from diabetes complications and cardiovascular disease (CVD) is high due to poor diabetes management. Medication treatment non-adherence is prevalent and costly in diabetes management where Cost-Related Non-adherence (CRN) with medication therapies has to be addressed as part of the social determinants of health. We propose a Louisiana Natural Experiment Center (LNEC) that includes academic/research institutions, payers, community non-profit organizations and community/patient partners, and health systems to improve care for diabetes and reduce risk factors and complications. The LNEC will be enhanced by the infrastructure of Research Action for Health Network (REACHnet). The LNEC's Louisiana Experiment to Address Diabetes: Zero-Dollar Copayment (LEAD-ZDC) project will examine the policy intervention of lowering out-of-pocket cost by ZDC for select medications (antidiabetics, antihypertensives, and statins) among fully insured Blue Cross and Blue Shield of Louisiana (BCBSLA) members with T2DM. The hypothesis is that the ZDC program will improve medication adherence and ultimately improve health outcomes. The overall goal is to study how ZDC may reduce CRN, overall medication non-adherence, health care utilization, and diabetes complications. The three specific aims will be evaluated according to the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework. The first aim is to evaluate how health impacts of the ZDC program improve the primary effectiveness measure: medication adherence with ZDC list of antidiabetics and multiple secondary effectiveness measures such as overall medication adherence, adherence with medications for risk factors (antihypertensives and statins), diabetes control, complications, health care utilization, and patient-reported outcomes. The second aim is to evaluate the barriers (e.g. racial/ethnic and rural/urban disparities) and facilitators related to the ZDC program in Louisiana. The third aim is to estimate the cost-effectiveness of the ZDC program from health system and social perspectives using modelling techniques. Patient and stakeholder engagement will be implemented as a cornerstone of the LEAD-ZDC project, which will explore the barriers at patient, provider, health system, and community levels, to inform, engage and empower patients, and to partner with and support T2DM patients to achieve better health outcomes. The proposed study will generate urgently needed data on effective, practical, and sustainable programs for eliminating health disparities and reducing diabetes-related disease burden. The study findings will assist (1) patients with better access to needed medications, and (2) providers and payers with improved understanding of how to address barriers to adherence so that they may better work with patients to make medications affordable...