Cardiovascular and Renal Benefits of Novel Diabetes Drugs by Baseline Cardiovascular Risk: A Systematic Review, Meta-analysis, and Meta-regression

Abstract

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.

Graphical abstract

Figure 1

Forest plots of HRs for primary outcomes among GLP-1RA and SGLT2i trials. 95% CIs displayed were computed with use of the natural logarithm of reported HRs and estimated SEs based on the following formula: $\frac{\text{log}(\text{uci}) - \text{log}(\text{lci})}{2\times 1.96}$. uci and lci correspond to the upper and lower limits of the 95% CIs. Small differences in 95% CIs may have been caused by rounding to two decimals. However, the underlying variance data used for estimating summary estimates are the same as reported in the studies. DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-KIDNEY, The Study of Heart and Kidney Protection With Empagliflozin; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EMPEROR-Preserved, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure with Preserved Ejection Fraction; EMPEROR-Reduced, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure and a Reduced Ejection Fraction; EXSCEL, EXenatide Study of Cardiovascular Event Lowering; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; PIONEER 6, Peptide Innovation for Early Diabetes Treatment 6; REWIND, Researching Cardiovascular Events With a Weekly INcretin in Diabetes; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial.

Figure 2

Forest plots of 5-year ARDs for primary outcomes among GLP-1RA and SGLT2i trials. DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-KIDNEY, The Study of Heart and Kidney Protection With Empagliflozin; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EMPEROR-Preserved, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure with Preserved Ejection Fraction; EMPEROR-Reduced, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure and a Reduced Ejection Fraction; EXSCEL, EXenatide Study of Cardiovascular Event Lowering; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; PIONEER 6, Peptide Innovation for Early Diabetes Treatment 6; RD, risk difference; REWIND, Researching Cardiovascular Events With a Weekly INcretin in Diabetes; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial.

Figure 3

Relative and absolute treatment benefits for clinical outcomes by baseline cardiovascular mortality rate. Five-year ARDs as computed for each trial are shown. The size of each trial’s circle is proportional to the inverse of the variance of its ARD. The line and shaded area refer to point estimates and 95% confidence bands from the meta-regression analyses. MACE is defined as nonfatal MI, nonfatal stroke, or cardiovascular death. For GLP-1RA trials, 1, AMPLITUDE-O; 2, Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA); 3, EXenatide Study of Cardiovascular Event Lowering (EXSCEL); 4, FREEDOM-CVO; 5, Harmony Outcomes; 6, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER); 7, Peptide Innovation for Early Diabetes Treatment (PIONEER) 6; 8, Researching Cardiovascular Events With a Weekly INcretin in Diabetes (REWIND); 9, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6). For SGLT2i trials, 1, CANVAS; 2, CREDENCE; 3, DAPA-CKD; 4, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF); 5, DECLARE-TIMI 58; 6, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER); 7, The Study of Heart and Kidney Protection With Empagliflozin (EMPA-KIDNEY); 8, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial; 9, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure with Preserved Ejection Fraction (EMPEROR-Preserved); 10, EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure and a Reduced Ejection Fraction (EMPEROR-Reduced); 11, SCORED; 12, SOLOIST-WHF; 13, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV). /100 py, per 100 person-years.