PROJECT SUMMARY
More than 12 million Americans currently live with both obesity and type 2 diabetes (T2D), putting them in one
of the highest risk groups for developing serious microvascular and macrovascular complications. The Ameri-
can Diabetes Association’s clinical practice guidelines recommend metabolic/bariatric surgery (MBS) and/or
pharmacologic treatment of obesity for patients with obesity and T2D. In particular, glucagon-like peptide-1 re-
ceptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have both demonstrated
efficacy in weight loss and preventing microvascular and macrovascular complications and are more accessi-
ble than MBS. However, there are no long-term studies comparing GLP-1RAs or SGLT2is with MBS head-to-
head with respect to effectiveness and safety, overall and in groups disproportionately affected by obesity and
T2D but underrepresented in clinical trials such as racial and ethnic minority populations and rural residents.
There is a clear and urgent need for large, real-world comparative effectiveness research studies to help pa-
tients and their clinicians make evidence-informed decisions regarding the risks and benefits of surgical and
medical approaches to reduce the long-term complications of concurrent obesity and T2D. We propose a com-
parative effectiveness and safety study using administrative claims and linked electronic health record data on
a diverse nationwide cohort (~40% racial/ethnic minority) of >500,000 patients with T2D and obesity treated
with MBS, GLP-1RA, or SGLT-2i from 2010 to 2025, encompassing patients covered in commercial, Medicare
Advantage, and 100% of Medicare fee-for-service plans. Our specific aims will compare the effectiveness of
GLP-1RAs and SGLT-2is versus MBS in improving metabolic outcomes (weight, blood pressure, and hemoglo-
bin A1c), reducing rates of micro- and macrovascular disease, and all-cause mortality among patients with obe-
sity and T2D. We will also compare the safety of GLP-1RAs and SGLT-2is versus MBS among patients with
obesity and T2D by examining rates of all-cause hospitalizations and by exploring other safety outcomes
(emergency department care, severe hypoglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemia, acute
kidney injury, and severe genitourinary infections). A prospective randomized trial investigating these questions
would be prohibitively expensive and logistically challenging to conduct given the high costs of these treat-
ments and the very large sample sizes needed to examine incident micro- and macrovascular outcomes, par-
ticularly in high priority patient subgroups. Our proposed study will be the largest and longest study to date
comparing the real-world effectiveness and safety of GLP-1RA, SGLT-2i, and MBS to manage obesity and
T2D while also generating evidence for subgroups that are often underrepresented in clinical trials. The study
will provide timely and rigorous comparative effectiveness and safety evidence to help inform clinical decisions.
