Does metformin prevent recurrent events in diabetic patients with CAD?

- Jennifer Middleton, MD, MPH

Metformin can help reverse pre-diabetes, improve fertility in women with polycystic ovarian disease, and may even limit weight gain due to antipsychotic medications. We may be able to add prevention of recurrent cardiovascular disease to that list, as a POEM reviewed in last week's AFP describes.

The POEM reviews a study from China which enrolled approximately 300 diabetics with known coronary artery disease (CAD). The researchers randomized participants into 2 groups; the groups continued their medications for CAD and any other co-morbid conditions, but for their diabetes each group initially received only one medication. One group received metformin, and the other glipizide. Eventually, about a quarter of these participants did require insulin to bring their A1Cs near the researchers' goal of 7.0 %. After at least a three-year follow-up, the participants in the metformin group had a lower incidence of the study's composite outcome of heart attack, stroke, and death (hazard ratio 0.54 [0.30-0.90]; p=0.026) compared to participants in the glipizide group, with a number needed to treat (NNT) of only 9.4 for five years. In diabetic patients who already have CAD, metformin decreased the risk of a further cardiovascular insult.

Overall, this study's design is solid, but it raises some interesting questions worthy of future research. The dosing for both medications in this study was three times a day (TID), but patients typically prefer once or twice daily dosing to more frequent dosing patterns. Metformin is more commonly used once or twice daily. Could metformin dosed less frequently still yield the same CAD protective benefit as taking it TID?

Along the same lines, the authors did not describe any measure of participants' adherence to these TID medication regimens. That decision has some positives, as it may best simulate "real life" practice, but I am curious to know how well these participants did with remembering to take all three doses of their medications day after day.

Lastly, what about patients who are taking other medications besides metformin (and, possibly, insulin)? Diabetics and their physicians have multiple drug classes to choose from these days - would metformin's benefit persist in patients who are also using a thiazolidinedione (such as pioglitazone), a dipeptidyl peptidase IV inhibitor (such as sitagliptin), and/or a glucagon-like peptide-1 receptor agonist (such as exenatide)? CAD is not a strict contraindication for any of these medication classes (thiazolidinediones, however, are only to be used with caution in patients with CAD).

Despite these research opportunities, this study helps to reinforce that metformin (rather than a sulfonylurea) is the right choice when initiating treatment for type 2 diabetes. What to add when additional glycemic control is needed, however, remains up to each physician's clinical judgment, as this is yet another area in need of further studies. You can read more about metformin, and other treatments for type 2 diabetes, in this AFP By Topic.

Will this study change how you prescribe metformin for patients with both type 2 diabetes and CAD?