Antihyperglycemic Interventions Decrease MACE Risk Dependent on Hemoglobin A1C Levels

In patients receiving antihyperglycemic therapy, changes to hemoglobin A1c have been shown to affect risk for MACE.

Risk for major adverse cardiovascular events (MACEs) in patients receiving antihyperglycemic therapy is affected by glycated hemoglobin (HbA1C) levels, according to results of a systematic review and meta-analysis published in Cardiovascular Diabetology.

Trials of antihyperglycemic therapies have reported various cardiovascular benefits. This review and analysis was designed to assess the effects of newer antihyperglycemic medications on cardiovascular outcomes.

To that end, investigators from Medical Research Institute Kitano Hospital in Japan searched publication databases through January 2023 for randomized trials of antihyperglycemic interventions with MACE outcomes is the setting of type 2 diabetes (T2D) or prediabetes. A total of 35 trials comprising 256,524 patients were included in this analysis.

The interventions included glucagon-like peptide-1 receptor (GLP-1R) agonists (n=9), peroxisome proliferator-activated receptor (PPAR) agonists (n=8), sodium-glucose cotransporter-2 (SGLT2) inhibitors (n=6), dipeptidyl-peptidase-4 (DPP-4) inhibitors (n=5), intensive glycemic control (n=4), intensive lifestyle interventions focusing on weight loss (n=1), insulin glargine (n=1), and acarbose (n=1).

The patients had mean ages of 53.3 to 69.0 years, 66.2% had established atherosclerotic cardiovascular disease, and 13.4% had a history of heart failure (HF).

. . . glycemic control conferred by a wide range of antihyperglycemic drugs decreases MACE risk in an HbA1C-dependent manner, and the degree of HbA1C reduction is a useful surrogate of cardiovascular benefits.

During follow-up, MACE occurred among 9.9% of patients. Patients that received antihyperglycemic interventions had a 9% reduction in MACE events compared with control patients (risk ratio [RR], 0.91; 95% CI, 0.88-0.94; I2, 36.5%; P <.001). Stratified by intervention, MACE was reduced by intensive glycemic control (RR, 0.90; 95% CI, 0.83-0.97; I2, 0.0%; P =.008), PPAR agonists (RR, 0.91; 95% CI, 0.84-0.97; I2, 25.2%; P =.006), SGLT2 inhibitors (RR, 0.88; 95% CI, 0.82-0.94; I2, 28.1%; P <.001), and GLP-1R agonists (RR, 0.87; 95% CI, 0.81-0.94; I2, 53.3%; P =.001).

In the metaregression analysis, every 1% greater reduction in HbA1C was associated with a 14% relative reduction in RR for MACE, explaining 52% of the variance (P =.010), whereas the change in bodyweight from baseline did not have a moderating effect (P =.41).

During follow-up, 3.6% of patients experienced HF outcomes. The antihyperglycemic interventions were not associated with a significant effect on HF overall (RR, 0.95; 95% CI, 0.87-1.04; I2, 75.9%; P =.28). Stratified by intervention, significant reductions were associated with SGLT2 inhibitors (RR, 0.68; 95% CI, 0.62-0.75; I2, 0.0%; P <.001) and GLP-1R agonists (RR, 0.90; 95% CI, 0.83-0.98; I2, 0.0%; P =.019). Conversely, HF risk was increased by 38% with PPAR agonists (RR, 1.38; 95% CI, 1.19-1.60; I2, 53.0%; P <.001).

In contrast to the MACE analysis, for every 1 kg greater reduction in bodyweight from baseline, HF risk decreased by 7% (P <.001) and explained 52% of the variance. Whereas HbA1C changes did not have an effect on HF outcomes (P =.46).

This analysis may be limited by not using individual participant data.

“…glycemic control conferred by a wide range of antihyperglycemic drugs decreases MACE risk in an HbA1C-dependent manner, and the degree of HbA1C reduction is a useful surrogate of cardiovascular benefits,” the study authors wrote. “Contrary to MACE risk reduction, HF risk modulation was not associated with HbA1C reduction but was associated with bodyweight reduction.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Hasebe M, Yoshiji S, Keidai Y, et al. Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta‑analysis and meta‑regression analysis of 35 randomized cardiovascular outcome trials. Cardiovasc Diabetol. Published online March 19, 2023. doi:10.1186/s12933-023-01773-z