Over 34 million Americans have diabetes, and cardiovascular disease is the leading cause of illness and death in this population. In recent randomized controlled trials (RCTs) mostly including patients with diabetes at high cardiovascular risk, two classes of medications to treat hyperglycemia, SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1RA), reduced the risk of cardiovascular events, mortality, and kidney disease. Current clinical guidelines do not offer clear guidance regarding the optimal second-line glucose-lowering treatment in patients with type 2 diabetes. This barrier results from (1) unavailability of RCTs comparing diabetes medications head-to-head for hard clinical endpoints or drug-related harms, and (2) underrepresentation of patients at low to moderate cardiovascular risk in RCTs. This gap leaves the majority of patients with type 2 diabetes, their clinicians, and other stakeholders seeking more information to help select the best second-line medication to treat hyperglycemia.

This study will answer the question that most patients and their healthcare providers face when metformin is insufficient to manage hyperglycemia: Which glucose-lowering medications should patients with type 2 diabetes with moderate cardiovascular disease and their providers add, to best balance tradeoffs in benefits and risks? The results of this study will have an immediate and widespread impact on medical practice by informing decision making related to the comparative effectiveness and safety of the four most frequently used second-line agents for patients with type 2 diabetes, their clinicians, and other key stakeholders.

The comparative effectiveness and safety of four second-line pharmacological strategies in the type 2 diabetes study (The CER-4-T2D Study) aims to compare SGLT2i, GLP-1RA, dipeptidyl peptidase-4 inhibitors (DPP-4i), and sulfonylureas (SU) head-to-head, focusing on the following:

• Their effectiveness, including their effect on cardiovascular events, mortality, renal events, and other patient-centered outcomes, in the overall population of patients with type 2 diabetes and moderate cardiovascular risk, and in subgroups of interest, such as patients with chronic kidney disease and older frail individuals
• Their safety, including their association with previously reported drug-related harms (e.g., diabetic ketoacidosis, fractures, amputations, pancreatitis, severe hypoglycemia) and unanticipated drug-related adverse events. The study will also develop tools to identify patients with a higher likelihood of drug-related harms.

The CER-4-T2D study will use real-world data from health insurance claims and electronic health records to study patients with type 2 diabetes routinely treated with glucose-lowering medications. Specifically, the study will identify real-world patients who start treatment with SGLT2i, GLP-1RA, DPP-4i, or SU, and will follow them for outcomes that might occur after treatment initiation. SGLT2i, GLP-1RA, DPP-4i, or SU will be compared among each other at the class and at the individual medication levels.

Primary outcomes will include major cardiovascular events (e.g., myocardial infarction, stroke, heart failure) and mortality. Secondary outcomes of interest will include kidney disease, blood sugar control, weight, persistence on prescribed medication and patterns of medication switching, home time (i.e., time spent outside of hospital or nursing facilities), and potential drug-related harms (e.g., diabetic ketoacidosis, bone fractures, lower limb amputations, urogenital infections, low blood sugar episodes, acute kidney injury, pancreatitis, gallbladder or biliary events, retinopathy).

We convened and engaged a Stakeholder Advisory Panel to ensure that we are able to prioritize study aspects that are of substantial interest to stakeholders. The panel assisted us in formulating the study proposal and will partner with us to conduct the work to advise on study questions, outcomes, and specific analyses. The panel is currently composed of four patients with diabetes and four professional stakeholders. Our patient advisers are individuals who have used many of the medications being studied and are at moderate cardiovascular risk. They include three women and one man, ranging in age from 54 to 73. Three are white and one is black. Three are married and one is single. The professional stakeholders represent a variety of end-users of the proposed work, whose decisions will be informed by study findings. They include a community-based endocrinologist, a primary care physician with expertise in decision sciences, a pharmacist and pharmacoepidemiologist who directs the Pharmacy Quality & Utilization Program at a local hospital, and a primary care physician with expertise in academic detailing and health services research.