BACKGROUND: Evidence from clinical trials shows that newer second-line diabetes medications-glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is)-have cardio-renal protective effects in addition to their glucose-lowering properties. Despite strong evidence of benefits, there is limited evidence regarding prescribing patterns for these medications, especially among populations at high risk for disparities. OBJECTIVE: To examine the associations of cardio-renal and obesity comorbidities and neighborhood factors with the prescribing of GLP-1RAs or SGLT2is in comparison with dipeptidyl peptidase 4 inhibitors (DPP-4is) or sulfonylureas (SFUs) and for each of the newer second-line diabetes medications (GLP-1RA vs DPP-4i, SGLT2i vs DPP-4i, GLP-1RA vs SFU, and SGLT2i vs SFU) in medically underserved populations. METHODS: A retrospective cohort study was conducted using electronic medical records from a health care delivery system that serves medically underserved populations in the Mid-South region of the United States. Metformin-treated adult patients with type 2 diabetes, and at least 1 prescription for GLP-1RA, SGLT2i, DPP-4i, or SFU class medications, were identified between April 2016 and August 2021. Neighborhood factors were assessed at the census tract level by geocoding and linking patient addresses to neighborhood-level risk factors. Using multilevel logistic regression models, we examined the associations of comorbidities and neighborhood factors with the prescription of newer second-line diabetes medications. RESULTS: 7,723 patients received newer second-line diabetes medications, with 16% prescribed GLP-1RAs, 11% prescribed SGLT2is, 28% prescribed DPP-4is, and 45% prescribed SFUs. Patients with cerebrovascular disease were significantly less likely to receive newer second-line diabetes medications (odds ratio [OR] = 0.65, 95% CI = 0.52-0.80). Patients with obesity were more likely to receive newer second-line diabetes medications (OR = 1.68, 95% CI = 1.48-1.90). Living in neighborhoods with higher proportions of college graduates was associated with a higher likelihood of receiving newer second-line diabetes medications (quartile 3 vs 1: OR = 1.30, 95% CI = 1.06-1.59; and quartile 4 vs 1: OR = 1.46, 95% CI = 1.13-1.88). CONCLUSIONS: Our findings demonstrate substantial underprescribing and significant clinical and neighborhood variations in the use of newer second-line diabetes medications. We found lower use of newer second-line diabetes medications among patients with cerebrovascular disease and higher use in those with obesity. Our findings also suggest that newer second-line diabetes medications are first adopted by those in higher socioeconomic groups, thus increasing disparities in care. DISCLOSURES: Dr Surbhi reports grants or contracts from the Tennessee Department of Health, Agency for Healthcare Research and Quality, and PhRMA Foundation. Dr Bailey reports honoraria from the SouthEast Texas Chapter of the American College of Healthcare Executives, leadership or fiduciary role in the Coalition for Better Health and The Healthy City, Inc., and stock or stock options in Proctor and Gamble, Walmart, and Apple. Dr Kovesdy reports personal fees from Bayer, Abbott, AstraZeneca, Takeda, Tricida, Akebia, Cara Therapeutics, Vifor, Rockwell, CSL Behring, Boehringer Ingelheim, and GSK, outside the submitted work. The other authors report no conflicts of interest.