For patients with type 2 diabetes (T2D) and preexisting cardiovascular disease, the addition of a sodium-glucose cotransporter 2 (SGLT2) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist to a therapeutic regimen may reduce the risk for major cardiovascular events (MACE), according to the results of a meta-analysis published in the Journal of the American Heart Association.

Investigators conducted this systematic review and meta-analysis to explore the relationship between glycemic control, preexisting cardiovascular disease, and MACE in patients with T2D. PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov were searched for intensive glucose control trials and cardiovascular outcome trials.

Intensive glucose control trials were required to be large in size (≥1000 person-years of follow-up) and evaluated the relationship between glycemic control and MACE. Cardiovascular outcome trials compared add-on therapy with newer antidiabetic medications (a dipeptidyl peptidase-4 inhibitor, GLP-1 receptor agonist, or SGLT2 inhibitor) with placebo for effect on MACE.

The investigators evaluated 4 intensive glucose control trials consisting of 27,049 patients. Overall, average hemoglobin A1c (HbA1c) was reduced by 0.9% (95% CI, -1.30% to -0.50%) which was linked to a 9% reduced risk for MACE (hazard ratio [HR], 0.91; 95% CI, 0.84-0.99). In addition, risk for serious hypoglycemia increased with intensive glycemic control (HR, 2.48; 95% CI, 1.91-3.21).

The cardiovascular outcome trials included 12 randomized trials with a total of 120,765 patients. Overall, average HbA1c was reduced by -0.42% (95% CI, -0.53% to -0.30%) which corresponded to an 8% risk reduction for MACE (HR, 0.92; 95% CI, 0.87-0.96).

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In the intensive glucose control trials, risk for MACE was not reduced in patients with preexisting cardiovascular disease (HR, 1.00; 95% CI, 0.91-1.10) and was only reduced in patients without cardiovascular disease at baseline. The cardiovascular outcome trials demonstrated the opposite; risk for MACE was reduced by 14% in patients with preexisting cardiovascular disease receiving SGLT2 inhibitors (P =.002) or GLP-1 receptor agonists (P <.001).

A comparison of these 2 analyses indicated that while the weighted average HbA1c reduction was more than halved in the cardiovascular outcome trials compared with the intensive glucose control trials, the risk for MACE was comparable between the 2 trial types. This suggests that newer glucose-lowering medications might reduce the risk for MACE independent of glycemic control.

Limitations of this study included potential reporting biases and the possibility of incomplete retrieval of identified research outcomes.

The researchers concluded that SGLT2 inhibitors and GLP-1 receptor agonists “should be included in the therapeutic plan of patients with [T2D] and overt cardiovascular disease, with due attention paid to improvement of glycemic control, which may amplify their benefit on MACE.”

Multiple authors declared associations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

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Reference

Giugliano D, Maiorino MI, Bellastella G, Chiodini P, Esposito K. Glycemic control, preexisting cardiovascular disease, and risk of major cardiovascular events in patients with type 2 diabetes mellitus: systematic review with meta-analysis of cardiovascular outcome trials and intensive glucose control trials. J Am Heart Assoc. 2019;8:e012356.