The Nutrition Debate #223: Adding Insulin to Metformin for T2s: a scary “outcome”

“Adding Insulin to Metformin for T2s May Increase Risk of Death” was the scary headline of a recent Diabetes in Control story that caught my attention. It stunned me, actually. The story was based on the full JAMA paper (now by payment only), “Association between Intensification of Metformin Treatment with Insulin vs. Sulfonylureas and Cardiovascular Events and All-Cause Mortality Among Patients With Diabetes.” The ABSTRACT can be viewed here.

Both the Diabetes in Control piece and the JAMA scientific paper are qualified and raise more questions than they answer. And so do the objectives and design of the study, in my mind. Why, for example, would anyone today want to compare adding insulin to adding a sulfonylurea? Haven’t the sulfonylureas as a class been thoroughly discredited? I cite Dr. Ralph DeFronzo’s Banting Lecture (keynote address) to the 2008 ADA Convention in San Francisco and his full paper published in Diabetes in which he wrote, “Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1c and progressive loss of ß-cell function.” Scripts are declining dramatically.

Perhaps because that was what they had to work with. The study took place in the Veterans Administration (VA) hospital system in Nashville.  The Vanderbilt University researchers reported more patients in the sulfonylurea cohort than in any other. (“Among 178,341 metformin monotherapy patients, 2,948 added insulin and 39,990 added a sulfonylurea.”) That reminds me of the story of the person who lost a ring in a dark alley and was looking for it under a street light. When asked why, he replied, “There’s more light here.” But couldn’t they have used a more current treatment modality than a sulfonylurea, like a TZD or GLP-1, rather than one that causes more harm than good to the pancreas (and the patient!).

The OBJECTIVE of the study was alarming in itself: “To compare time to acute myocardial infarction (AMI), stroke or death in a cohort of metformin initiators who added insulin or a sulfonylurea.” So, let me quickly dispel the most alarming of these outcome objectives: “Acute myocardial infarction and stroke risks were statistically similar.” Whew! That’s the good news. The bad news? The CONCLUSION (from the full-paper): “Among patients with diabetes who are receiving metformin, the addition of insulin compared with sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality.”

Of course, this finding of an “association” was followed by, “These findings require further investigation to understand risks associated with insulin use in these patients…” Okay, that’s pretty much pro-forma these days. It also just a plea for more taxpayer funding for further investigations (a medical school research department jobs program). But that final sentence of the CONCLUSIONS section has a compound predicate; it continues, “…and call into question recommendations that insulin is equivalent to sulfonylurea for patients who may be able to receive an oral agent.” Okay, okay, but sulfonylureas aren’t the only oral agent available! And they overwork the remaining working beta cells that you have, leading to their destruction!

Sulfonylureas have been in use in the U.S. since the late 40s. Metformin was introduced in Britain in 1958, in Canada in 1972, and finally permitted by the FDA in 1994. Now, it is the preferred first course of treatment both in Europe and the U.S. for pre-diabetes and is used as a monotherapy by many full-blown T2s (like me), who rely primarily on diet for blood sugar control. But if I needed a 2^nd therapeutic, I WOULD NEVER AGAIN AGREE TO TAKE A SULFONLUREA, just as I would never agree to take a statin to lower my Total Cholesterol and LDL-C. I’m very happy with my lipid levels as they are, thank you very much.

So, where do we go from here? It’s confusing…in fact, it’s confounding. The first “Practice Pearl” in the Diabetes in Control raises a very good issue: “Many variables were not considered in choosing the participants in this study.” Their takeaway: “These findings require further investigation to understand risks associated with insulin use in these patients.” It must be noted, that “these patients” were all in the Veterans Administration (VA) hospital system in Nashville. To my knowledge, this particular VA hospital has not been implicated (so far) in the spreading scandal in our VA hospital system. Period.

But it comes as no surprise to me that that system is still administering sulfonylureas; or that the researchers at the Vanderbilt University Department of Medicine, Department of Biostatistics, and Department of Health Policy continue to advocate for this particular “oral agent” (a sulfonylurea). After all, it’s cheaper than an insulin regimen, and isn’t that what Health Policy is all about when the Federal Government gets involved in your health care? Am I piling on? I don’t think so.