Kasia Lipska, MD

June 25, 2013

CHICAGO — Meet one of my patients, a 68-year-old man with type 2 diabetes, whom I will call Mr. Adams.

He is retired and spends his summers gardening. It's rare that you meet someone so passionate about planting. But he lives in Connecticut, so the winters are tough and he rarely goes out when the cold weather hits. As a result, his weight predictably goes up by 10 pounds year after year during the winter months. I once suggested that he move to Florida so he can garden year-round, but his grandchildren keep him rooted in place.

He is obese, with a body mass index (BMI) around 38, and has been on metformin for the past 3 years. He's done quite well, but his HbA1c has started to creep up into the 8%s, despite the warmer weather and more time spent outside. He is quite healthy otherwise, except for the usual mix of hypertension and dyslipidemia. So he came to discuss what to do next after a trial of nutrition and exercise. "Doc, I think I will have to take another pill to get my sugar down. What do you suggest?"

I was thinking of him at the American Diabetes Association (ADA) 2013 Scientific Sessions debate, where Dr. Saul Genuth and Dr. Martin Abrahamson discussed whether sulfonylureas should remain acceptable first-line add-on therapy after metformin. Shouldn't we abandon this old class of drugs and move on to the newer, sexier alternatives? Shouldn't we use drugs that do not induce hypoglycemia as sulfonylureas surely do?

After all, we all have seen disasters with this drug class. When I was still in training, I took care of a 79-year-old woman transferred from an assisted-living facility with prolonged and scary hypoglycemia due to glyburide. We never quite figured out what triggered it, but both my attending and I came to the conclusion it was an extremely poor choice for the elderly. "It should be contraindicated in the elderly!" my attending convinced me. Well, others thought so, too, and now glyburide is on the Beers list of inappropriate medications for the elderly.

No Free Lunch When It Comes to Glucose-Lowering Meds

Dr. Kasia Lipska

Of course, the logical next question is — if not sulfonylureas, then what?

There is no free lunch when it comes to glucose-lowering medications. They are all capable of causing harm, with risk better defined for some drugs and still unknown for others. Sulfonylureas have been in use since the 1950s, so we have plenty of collective experience. Unfortunately, even for this drug class, we don't have good data with respect to long-term outcomes. One lingering concern since the University Group Diabetes Study has been the risk of cardiovascular events associated with this drug class. The experts still can't agree on this. Dr. Abrahamson considers sulfonylureas neutral with regard to cardiovascular events, while Dr. Genuth remains worried about cardiovascular harms.

Mr. Adams is concerned about his sugar levels, but he wants to know whether the new medication will be safe and protect him from diabetes complications. "I don't want to take Avandia," he told me quickly, "I heard about it on the news."

Are we sure sulfonylureas are safe in terms of cardiovascular events? Most observational studies show worse outcomes with sulfonylureas compared with metformin, but it's unclear whether metformin is beneficial, patients using metformin are healthier, or sulfonylureas are harmful. It's all pretty confusing, and you can find evidence that fits both sides of the argument if you look hard enough. With the new comparative-effectiveness GRADE trial that's just starting, we will know more about 4 agents added to metformin and their side effects, but we are unlikely to settle the clinical-outcomes questions.

When there is a lot of uncertainty and the balance of risks and benefits does not overwhelmingly tip the scale for one particular drug over another, it's clearly time to get Mr. Adams involved and discuss all the pros and cons with him.

Sulfonylureas increase the risk of hypoglycemia and cause weight gain; there is no doubt about it. But there are problems with other agents as well — the risk of edema, heart failure, weight gain, and fractures with pioglitazone and the risk of pancreatitis and possibly pancreatic cancer with incretin-mimetics. If experts disagree and would recommend different medications after metformin, our patients ought to know. Why should they end up on glimepiride if they happen to see a doctor in one practice and pioglitazone if they happen to go to another?

Mr. Adams and I discussed the different choices. I had been initially worried that by acknowledging how much we (as a medical profession) still don't know about the drugs we prescribe, I would disappoint him. Would he turn away and go find someone else, who would swiftly and authoritatively tell him: "For you, I think sitagliptin [Januvia, Merck] is best"?

Well, Mr. Adams still comes back to see me. We started glipizide for him, despite my worry about hypoglycemia. He was reassured by our long-term experience with the drug, and cost was very important to him, too.

So I don't think the sun has set on sulfonylureas. Not yet. Not until we have drugs that are cheap, safer, and as effective. But the sun is setting on paternalistic models of medicine. It's really time to bring the debate out of the ballroom at the American Diabetes Association Scientific Sessions and into the office with our patients.


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