BACKGROUND Eligibility for glucagon-like peptide 1 receptor agonists (GLP-1RA) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) has been expanded to patients with diabetes at lower cardiovascular risk, but whether treatment benefits differ by risk levels is not clear. PURPOSE To investigate whether patients with varying risks differ in cardiovascular and renal benefits from GLP-1RA and SGLT2i with use of meta-analysis and meta-regression. DATA SOURCES We performed a systematic review using PubMed through 7 November 2022. STUDY SELECTION We included reports of GLP-1RA and SGLT2i confirmatory randomized trials in adult patients with safety or efficacy end point data. DATA EXTRACTION Hazard ratio (HR) and event rate data were extracted for mortality, cardiovascular, and renal outcomes. DATA SYNTHESIS We analyzed 9 GLP-1RA and 13 SGLT2i trials comprising 154,649 patients. Summary HRs were significant for cardiovascular mortality (GLP-1RA 0.87 and SGLT2i 0.86), major adverse cardiovascular events (0.87 and 0.88), heart failure (0.89 and 0.70), and renal (0.84 and 0.65) outcomes. For stroke, efficacy was significant for GLP-1RA (0.84) but not for SGLT2i (0.92). Associations between control arm cardiovascular mortality rates and HRs were nonsignificant. Five-year absolute risk reductions (0.80–4.25%) increased to 11.6% for heart failure in SGLT2i trials in patients with high risk (Pslope < 0.001). For GLP1-RAs, associations were nonsignificant. LIMITATIONS Analyses were limited by lack of patient-level data, consistency in end point definitions, and variation in cardiovascular mortality rates for GLP-1RA trials. CONCLUSIONS Relative effects of novel diabetes drugs are preserved across baseline cardiovascular risk, whereas absolute benefits increase at higher risks, particularly regarding heart failure. Our findings suggest a need for baseline risk assessment tools to identify variation in absolute treatment benefits and improve decision-making.

Background: Prior research suggests cardiovascular (CV) benefits of glucose-lowering interventions may be mediated by changes in hemoglobin A1c (HbA1c), bodyweight, systolic blood pressure (SBP), hematocrit, and urine albumin-creatinine ratio (uACR). We evaluated the heterogeneity of CV benefits by these potential mediators for sodium-glucose transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) using a meta-analytic approach. Methods: We performed a systematic review and meta-regression analyses of 12 SGLT2i and 9 GLP-1RA CV outcome trials using linear mixed models of treatment efficacy measured as log hazard ratios (HRs) vs changes in potential mediators. We extracted follow-up mediator data for treatment and control, preferably at 12 months post randomization. Outcomes included MI, stroke, and MACE (a composite of MI, stroke, or CV death). We investigated slope differences between drug classes using interaction terms and likelihood-ratio tests. Results: Treatment efficacy for MACE improved with more HbA1c reduction among GLP-1RA (slope .26; P slope .02) but not among SGLT2i trials (slope -.22; P slope .39; P interaction .06), see Figure . Treatment efficacy for MACE, MI, and stroke decreased with more weight loss for SGLT2i (slope –.17, –.29, –.39; P slope <.05) but not for GLP-1RA trials (slope .05, .03, .07; P slope .30, .62, .32). Slopes differed significantly between drug classes: P interaction <.05. For stroke, we observed a trend of less treatment efficacy with increases in hematocrit among five SGLT2i trials with available data (slope .96; P slope .07). We did not find any indication of mediation effects by SBP and uACR for SGLT2i or GLP-1RAs (slopes -.11 -.07; P slopes ≥ .05). Conclusion: We confirm previous findings of increased CV benefits with reductions in HbA1c for GLP1-RAs. Further research is needed to investigate the potential loss of SGLT2i efficacy with greater weight loss and increase in hematocrit.

<p>  </p> <p><strong>Objective</strong></p> <p>Eligibility for glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) has been expanded to patients with diabetes at lower cardiovascular risk, but it is not clear whether expected treatment benefits differ by risk levels. We investigated whether patients with varying risks differ in cardiovascular and renal benefits from GLP-1RAs and SGLT2i using meta-analysis and meta-regression. </p> <p><strong>Research Design and Methods</strong></p> <p>We updated searches of recent meta-analyses using PubMed through November 7, 2022. We included reports of confirmatory randomized trials of GLP-1RA and SGLT2i in adult patients with safety or efficacy endpoint data. We extracted hazard ratio (HR) and event rate data for mortality, cardiovascular, and renal outcomes.</p> <p><strong>Results</strong></p> <p>We analyzed 9 GLP-1RA and 13 SGLT2i trials comprising 154,649 patients. Summary HRs were significant for cardiovascular mortality (GLP-1RA: 0.87; SGLT2i: 0.86), major adverse cardiovascular events (0.87; 0.88), heart failure (0.89; 0.70), and composite renal (0.84; 0.65) outcomes. For stroke, efficacy was significant for GLP-1RAs (0.84), but not for SGLT2i (0.92). We did not find statistically significant associations between control arm cardiovascular mortality rates and HRs. Five-year absolute risk differences ranged from -4.25% to -0.80%, with larger reductions (11.6%) for heart failure with SGLT2i in high risk (p for slope <.001). For GLP1-RAs, associations were nonsignificant.</p> <p><strong>Conclusions</strong></p> <p>Relative effects of novel diabetes drugs are preserved across baseline cardiovascular risk, whereas absolute benefits increase at higher risks, particularly regarding heart failure. Our findings suggest a need for baseline risk assessment tools to identify variation in absolute treatment benefits and improve decision-making. </p>

<p>  </p> <p><strong>Objective</strong></p> <p>Eligibility for glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) has been expanded to patients with diabetes at lower cardiovascular risk, but it is not clear whether expected treatment benefits differ by risk levels. We investigated whether patients with varying risks differ in cardiovascular and renal benefits from GLP-1RAs and SGLT2i using meta-analysis and meta-regression. </p> <p><strong>Research Design and Methods</strong></p> <p>We updated searches of recent meta-analyses using PubMed through November 7, 2022. We included reports of confirmatory randomized trials of GLP-1RA and SGLT2i in adult patients with safety or efficacy endpoint data. We extracted hazard ratio (HR) and event rate data for mortality, cardiovascular, and renal outcomes.</p> <p><strong>Results</strong></p> <p>We analyzed 9 GLP-1RA and 13 SGLT2i trials comprising 154,649 patients. Summary HRs were significant for cardiovascular mortality (GLP-1RA: 0.87; SGLT2i: 0.86), major adverse cardiovascular events (0.87; 0.88), heart failure (0.89; 0.70), and composite renal (0.84; 0.65) outcomes. For stroke, efficacy was significant for GLP-1RAs (0.84), but not for SGLT2i (0.92). We did not find statistically significant associations between control arm cardiovascular mortality rates and HRs. Five-year absolute risk differences ranged from -4.25% to -0.80%, with larger reductions (11.6%) for heart failure with SGLT2i in high risk (p for slope <.001). For GLP1-RAs, associations were nonsignificant.</p> <p><strong>Conclusions</strong></p> <p>Relative effects of novel diabetes drugs are preserved across baseline cardiovascular risk, whereas absolute benefits increase at higher risks, particularly regarding heart failure. Our findings suggest a need for baseline risk assessment tools to identify variation in absolute treatment benefits and improve decision-making. </p>