Heterogeneity of Cardiovascular Effects of Second‐Line Glucose‐Lowering Therapies in Adults With Type 2 Diabetes Across the Range of Moderate Baseline Cardiovascular Risk

Jul 17, 2025Journal of the American Heart Association

Varied Heart and Blood Vessel Effects of Second-Choice Diabetes Medicines in Adults with Moderate Heart Risk

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Abstract

Among 386,276 adults with type 2 diabetes, 25.2% had a predicted major adverse cardiovascular event (MACE) risk of more than 1% to 2%.

Higher-risk patients experienced greater absolute reductions in MACE rates when treated with GLP-1 receptor agonists (3.1%) and sodium-glucose cotransporter-2 inhibitors (3.9%) compared to lower-risk patients (1.6% and 1.3%, respectively).
The relative benefits of SGLT2 inhibitors versus DPP-4 inhibitors were significantly better in higher-risk patients (hazard ratio 0.78) compared to lower-risk patients (hazard ratio 0.99).
Conversely, the relative benefits of DPP-4 inhibitors and GLP-1 receptor agonists compared to sulfonylureas were greater in lower-risk patients (hazard ratios of 0.76 and 0.67, respectively).
SGLT2 inhibitors and GLP-1 receptor agonists showed comparable cardiovascular benefits across all levels of moderate cardiovascular risk.

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BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have favorable cardiovascular outcomes compared with dipeptidyl peptidase-4 inhibitors (DPP4is) and sulfonylureas in adults with type 2 diabetes and high cardiovascular risk. How these benefits vary across lower levels of cardiovascular risk is unknown.

METHODS: We used nationwide claims data to emulate a comparative effectiveness trial and examine the heterogeneity of treatment effects of GLP-1RAs, SGLT2is, DPP4is, and sulfonylureas on major adverse cardiovascular events (MACEs) among adults with type 2 diabetes and moderate cardiovascular risk (annualized MACE risk 1%-5%, estimated using the annualized claims-based MACE estimator).

RESULTS: Among 386 276 included adults with type 2 diabetes, 25.2% had baseline ACME-predicted MACE risk >1% to ≤2% (lower-risk patients) and 13.3% had ACME-predicted risk >4% to ≤5% (higher-risk patients). By year 3 of treatment, higher-risk patients derived greater absolute benefit than lower-risk patients when treated with GLP-1RAs versus sulfonylureas (absolute reduction in the estimated rate of MACE of 3.1% in higher-risk patients and 1.6% in lower-risk patients), SGLT2is versus sulfonylureas (absolute reduction, 3.9% in higher-risk patients and 1.3% in lower-risk patients), and GLP-1RAs versus DPP4is (absolute reduction, 1.6% in higher-risk patients and 0.5% in lower-risk patients). The relative benefits for MACE were also greater in higher-risk than lower-risk patients with SGLT2is versus DPP4is (hazard ratio [HR], 0.78 [95% CI, 0.70-0.87] in higher-risk patients; HR, 0.99 [95% CI, 0.88-1.12] in lower-risk patients). Conversely, the relative benefits of DPP4is and GLP-1RAs versus sulfonylureas were greater in lower-risk patients: HR 0.76 (95% CI, 0.71-0.81) in lower-risk and HR 0.91 (95% CI, 0.97-0.96) in higher-risk patients for DPP4is versus sulfonylureas; HR 0.67 (95% CI, 0.58-0.78) in lower-risk and HR 0.80 (95% CI, 0.70-0.93) in higher-risk patients for GLP-1RAs versus sulfonylurea. Benefits of SGLT2is and GLP-1RAs were comparable across all risk levels.

CONCLUSIONS: Cardiovascular benefits of SGLT2is and GLP-1RAs exist across all levels of moderate cardiovascular risk, reinforcing the importance of choosing glucose-lowering therapies that can prevent MACE in all people with type 2 diabetes.

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Heterogeneity of Cardiovascular Effects of Second‐Line Glucose‐Lowering Therapies in Adults With Type 2 Diabetes Across the Range of Moderate Baseline Cardiovascular Risk

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