Second-Line Therapy for Type 2 Diabetes Management: The Treatment/Benefit Paradox of Cardiovascular and Kidney Comorbidities

Objective: To examine whether GLP-1 receptor agonists (GLP-1RA) and SGLT2 inhibitors (SGLT2i) are preferentially initiated among patients with cardiovascular disease, heart failure (HF), or nephropathy, where these drug classes have established benefit, as compared to DPP-4 inhibitors (DPP-4i), for which corresponding benefits have not been demonstrated.

Research Design and Methods: We retrospectively analyzed claims of adults with type 2 diabetes included in OptumLabs^® Data Warehouse, a de-identified database of commercially-insured and Medicare Advantage beneficiaries, who first started GLP-1RA, SGLT2i, or DPP-4i therapy between 2016 and 2019. Using multinomial logistic regression, we examined the relative risk ratios (RRR) of starting GLP-1RA and SGLT2i, as compared to DPP-4i, for those with history of myocardial infarction (MI), cerebrovascular disease, HF, and nephropathy after adjusting for demographic and other clinical factors.

Results: We identified 75,395 patients who started GLP-1RA, 58,234 who started SGLT2i, and 91,884 who started DPP-4i. Patients with prior MI, cerebrovascular disease, or nephropathy were less likely to start GLP-1RA rather than DPP-4i compared to patients without these conditions; RRR=0.83 (95% CI 0.78-0.88) for MI, RRR=0.77 (0.74-0.81) for cerebrovascular disease, and RRR= 0.87 (0.84-0.91) for nephropathy. Patients with HF or nephropathy were less likely to start SGLT2i; RRR=0.83 (0.80-0.87) for HF and RRR=0.57 (0.55-0.60) for nephropathy. Both medication classes were less likely to be started by non-White and older patients.

Conclusions: Patients with cardiovascular disease, HF, and nephropathy, for whom evidence suggests a greater likelihood of benefiting from GLP-1RA and/or SGLT2i therapy, were less likely to start these drugs. Addressing this treatment/benefit paradox, which was most pronounced in non-White and older patients, may help reduce the morbidity associated with these conditions.