Some glucose-lowering drugs reduce risk for major adverse cardiac events

An umbrella review of 232 meta-analyses quantified the effects of various diabetes drugs on patients' cardiovascular (CV) risk. Researchers evaluated 10 classes of drugs and found six risk associations, which included higher rates of stroke with glimepiride, heart failure with pioglitazone, and both myocardial infarction and heart failure with rosiglitazone. There were 38 protective associations, including beneficial class effects of both glucagon-like peptide-1 receptor agonists and sodium–glucose co-transporter-2 inhibitors on CV risk.

The study was published in the March 1 issue of The Lancet Diabetes & Endocrinology. The following commentary by Aris Liakos, MD, MSc, PhD; Apostolos Tsapas, MD, PhD, MSc (Oxon); and Eleni Bekiari, MD, MSc, PhD, was published in the ACP Journal Club section of the July 21 Annals of Internal Medicine.

Pharmacologic management of type 2 diabetes is broadening the focus from improvement of glycemic control and other metabolic outcomes to include mitigation of CV risk. Zhu and colleagues conducted an umbrella review to explore the effect of available antihyperglycemic agents on CV outcomes in type 2 diabetes. The review corroborates that most sodium–glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists confer substantive CV benefits. It also confirms that use of SGLT2 inhibitors should be prioritized in patients with heart failure, whereas pioglitazone and saxagliptin must be avoided. Meta-analytic findings also indicate that metformin probably has only a modest effect on CV outcomes.

Zhu and colleagues used a pragmatic approach, summarizing evidence from existing meta-analyses supplemented by a bridge search for CV outcomes trials, potentially omitting recent informative non-CV outcomes trials. Although the review intuitively summarizes benefits and harms of available treatments and respective certainty of the evidence, external validity is undermined by the diversity of inclusion criteria of each individual meta-analysis and CV outcomes trials included. The review includes both patients with, and at risk for, type 2 diabetes and a wide array of background treatments. It does not explore differential effects in clinically relevant subgroups, and more important, the analysis did not incorporate underlying CV risk despite current treatment recommendations.

In all, SGLT2 inhibitors and GLP-1 receptor agonists do reduce CV events in high-risk groups, but to what extent this also applies to patients at lower baseline CV risk is uncertain. Finally, the role of metformin as first-line therapy for primary prevention might be justified given its long-term safety and low cost, yet its primacy for drug-naive patients at high CV risk is still a matter of debate.