Retrospective #223: Adding Insulin to Metformin for Type 2s questioned.

“Adding Insulin to Metformin for T2s May Increase Risk of Death,” was a scary headline of a 2014 Diabetes in Control article about a JAMA paper: “Association between Intensification of Metformin Treatment with Insulin vs. Sulfonylureas and Cardiovascular Events and All-Cause Mortality Among Patients with Diabetes.”

Both the Diabetes in Control piece and the JAMA paper were qualified and raised more questions than they answered. In my mind, so did the objectives and design of the study. 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 Award keynote address to the 2008 ADA Convention in San Francisco and his 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 a progressive LOSS of ß-cell function.”

The “Adding Insulin…” 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 GLP-1 (or today a SGLT-2), rather than one that causes more harm than good to 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.” They quickly dispel this most alarming outcome objective: “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’s 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 even in 2014 sulfonylureas weren’t the only oral agent available! And they overwork the remaining working beta cells that you have, leading to their destruction! Go back and read Dr. DeFronzo’s speech/paper.

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 the US 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 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 (Micronase, glyburide, glipizide, etc.), just as I would never agree to take a statin to lower my Total Cholesterol and LDL-C. Both my doctor and I are very happy with my lipid (cholesterol) levels as they are, thank you very much.

So, where do we go from here? It’s confusing. The first “Practice Pearl” in 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.” Yes! More studies!

But it comes as no surprise to me that the VA 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 that particular “oral agent” (a sulfonylurea). It is dirt cheap. And insulin, especially since this was originally published in 2014, has become really expensive. But isn’t that what drives our national health policy today?