The Nutrition Debate #245: “…in patients on sulfonylureas.”

Lots of type 2 diabetes patients are on sulfonylureas. They were the first class of oral anti-diabetic medications approved in the U.S. (1955) and remained so until 1995 when metformin (Glucophage) was added. Metformin eventually took over and became the first-line drug, used even for the treatment of “pre-diabetes.”  (Note I put pre-diabetes in quotes since it was only defined by the American Diabetes Association in 2002, and the definitions of both clinical type 2 diabetes and pre-diabetes are both controversial. See the last few paragraphs of #244 here for a fuller explanation.

The second generation of sulfonylureas, approved in 1984, includes the familiar generics (and trade names) glyburide (Micronase, Diabeta) and glipizide (Glucotrol). They act by increasing insulin release from the beta cells in the pancreas. For that reason, “Some diabetes experts feel that sulfonylureas accelerate the loss of beta cells from the pancreas, and should be avoided, ^[1]” according to Wikipedia. Ralph A. DeFronzo, MD, in his 2008 Banting Award lecture at the ADA convention, said, “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” (emphasis mine). See #86 here for more info on this.

There is also some evidence, again according to Wikipedia, that sulfonylureas “decrease lipolysis (breakdown and release of fatty acids by adipose tissue) and decrease clearance of insulin by the liver.” Thus, “like insulin, sulfonylureas can induce weight gain…” (emphasis mine). In addition, “All sulfonylureas carry an FDA-required warning about increased risk of cardiovascular death.” You think that’s all? It’s just the beginning.

Wikipedia continues, “First line therapy with sulfonylureas significantly increases the risk for death in patients with type 2 diabetes when compared with treatment with metformin. Additional research showed that the combination of metformin and a sulfonylurea was also associated with a significantly increased risk for death when compared with combination therapy with metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor.” For more, see “Side Effects and Cautions” here.

“Sulfonylureas are potentially teratogenic [think 2-headed calf] and cannot be used in pregnancy or in patients who may become pregnant. Impairment of liver or kidney function increases the risk of hypoglycemia, and are contraindications.”

And then there are the Interactions. Wikipedia: “Drugs that potentiate or prolong the effects of sulfonylureas and therefore increase the risk of hypoglycemia include acetylsalicylic acid [aspirin] and derivatives, allopurinol, sulfonamides, and fibrates. Drugs that worsen glucose tolerance, contravening the effects of antidiabetics, include corticosteroids, isoniazide, oral contraceptives and other estrogens, sympathomimetics, and thyroid hormones. Sulfonylureas tend to interact with a wide variety of other drugs, but these interactions, as well as their clinical significance, vary from substance to substance.” Sympathomimetics include caffeine, some decongestants.

Now there’s a brand new report in JAMA Internal Medicine regarding interactions of sulfonylureas and antibiotics resulting in hospitalizations or emergency department visits. The lede: “Use of certain antimicrobial agents is linked to an increased risk of hypoglycemia in older patients on sulfonylureas, according to a study of Medicare claims.” Older is defined as 66. The JAMA finding: “Physicians should definitely avoid using those antibiotics in patients on sulfonylureas,” Medscape advised. The sulfonamide class of antibiotics is already known to be problematic, but some of these antibiotics are outside that class. Bactrim was shown to have “particularly high risks,” and the number needed to harm for clarithromycin was just 71. Adding the NNH (number needed to harm), makes this study particularly useful. For an intro to NNH, see this YouTube video.

I was on a sulfonylurea (Micronase and then glyburide) from my initial T2 diagnosis in 1986. When Glucophage (metformin) was permitted the U.S., my doctor added it. As I continued to eat a “balanced diet” (“one-size-fits-all”) with “moderation- in-all-things,” and 55% to 60% carbohydrates as recommended since 1980 for everyone by the USDA’s Dietary Guidelines, my diabetes got progressively worse. Eventually, I was “maxed out” on both metformin and glyburide and starting Avandia, a TZD class of oral antidiabetic drug. (This was before the DPP-4 inhibitors came to market.) Of course, with my doctor’s and his RD’s help, I was trying to lose weight (I weighed 375lbs), but I knew in my heart-of hearts that my oral “cocktail” of antidiabetic meds was soon destined to be replaced by injected insulin.

Then, after reading Gary Taubes’s “What If It's All Been a Big Fat Lie,” the NYT Magazine cover story on July 7, 2002, my doctor suggested I try Atkins Induction. I did. The first day I had serious hypoglycemia. I ate a candy bar and called the doc. He said, “Drop the Avandia.” The second day, as the severe hypoglycemia continued, he said, “Cut the glyburide and metformin in half. I did, and the next day, he said, “Cut them in half again.” Over time I eliminated the glyburide altogether and today, and for the last 10 years, I take just 500mg of metformin, with dinner, in case I eat too much protein! And I lost and have kept off 125 pounds, and my triglycerides have been cut by two-thirds and my HDL doubled. My A1cs are now usually in the high 5s (up from mid 5s when I was losing weight), and my blood pressure is “normal” (on the same “cocktail” of meds as before). And my hsCRPs, a systemic inflammation marker for heart disease risk, are in the low-average range.

So, for patients still on sulfonylureas – itself hard for me to believe, that a doctor would still prescribe them – I ask myself, in view of all the downside risks, why don’t patients just change the foods they eat? They won’t need to take a sulfonylurea.