Safety of Diabetes Drugs -- Should We Worry?

Anne L. Peters, MD, CDE; John B. Buse, MD, PhD


July 06, 2011

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Anne L. Peters, MD, CDE: Hi. I am Dr. Anne Peters, Director of the Clinical Diabetes Programs at the University of Southern California. I am currently at the American Diabetes Association (ADA) meeting in San Diego, California. I am joined by Dr. John Buse, Chief of the Division of Endocrinology and Director of the Diabetes Care Center at the University of North Carolina School of Medicine in Chapel Hill. Welcome, John.

John B. Buse, MD, PhD: It's great to be here.

Dr. Peters: Today maybe we could talk on a topic that most of us clinicians are very worried about -- drug safety. Can you tell us what's new?

Dr. Buse: We have all been exposed to a lot of media coverage on issues surrounding drug safety broadly, specifically with respect to diabetes. The clear drug safety issue is hypoglycemia with insulin. Beyond that, the glitazones have issues with fluid retention, and in some cases, heart failure, and bone health with excess fractures. Otherwise, most of the other safety concerns have come from pharmacoepidemiologic analyses, but the follow-up studies generally have not suggested that drug safety is an issue.

My view is that we need to focus on the things that we know are important, which are lowering glucose, blood pressure, and cholesterol, and getting people to avoid weight gain. Hypoglycemia is a real risk, but the balance of evidence (for example, with respect to pancreatitis with dipeptidyl peptidase-4 inhibitors or with glucagon-like polypeptide-1 agonists) from the follow-up studies suggests that there isn't much, if any, signal for safety problems. With respect to cancers (pancreatic cancer, bladder cancer, cancers associated with insulin), the follow-up studies (to the extent that they have been done) suggest that there is probably no signal. If cancer is a problem, it is really small in comparison with the benefits of the drugs on the more important outcomes in diabetes.

Dr. Peters: Here is what happens to me all the time, and I'm sure it happens to you: I have a patient on pioglitazone. The patient reads in the newspaper that there is a risk for bladder cancer. What do you tell that patient? How do you make sense to a patient when they are with you in your office?

Dr. Buse: I would tell the patient that on the basis of the recent studies, there seems to be a very small increased risk for an individual with bladder cancer, but at the same time, there seems to be a lower risk (for instance, in the PROACTIVE [PROspective pioglitAzone Clinical Trial In macroVascular Events] study on cardiovascular endpoints and some other studies), for other cancers such as breast cancer. On balance, it is just not a big threat to the patient with diabetes.

We have numerous choices of drugs, so if it is a really big concern to patients, I would much rather, in a controlled fashion, take them off the drug and put them on another drug. I would always tell them that frankly, we're shifting things around, and it's not clear that shifting the drug is going to result in a better outcome for them than the drug that they are on today.

Dr. Peters: Yes, that is sometimes an issue because many of the drugs are newer than the drugs we're switching them from, and newer drugs may have risks that we don't know about.

Dr. Buse: Right. This is going to be a bigger and bigger problem in clinical medicine because these big databases exist. You can do hundreds, if not thousands, of analyses with these databases, and you know that 1 out of every 20 will be statistically significant. More and more stories about safety issues with diabetes drugs will be coming out. The truth of the matter, as these have been pursued and followed up, almost none of them have "stuck," other than what we have talked about -- hypoglycemia with insulin, sulfonylureas, and the well-known issues with the glitazones.

Dr. Peters: From my perspective, it's important to warn patients of what we do know, try to lower the risk for whatever it is (for example, metformin and renal insufficiency), although even that's up for grabs in terms of what the real cutpoint should be.

Dr. Buse: What I would say about the metformin/renal insufficiency issue is that it's not that metformin causes kidney disease, it's just that metformin is cleared by the kidneys, so if you have renal insufficiency, your metformin levels might be high. Very few cases of metformin-associated lactic acidosis are well documented. Even though there is a pretty strict warning in the package insert (and something that I generally support), to be honest, the evidence of harm from using metformin in the setting of kidney disease is pretty minimal.

Dr. Peters: Yes, and I do believe that we have to follow what the US Food and Drug Administration (FDA) says because that's what the FDA says, but I really try to put it into context. Many of my patients and referring physicians think that metformin causes kidney damage, when in fact, it doesn't. I find that an interesting point to make.

Dr. Buse: One safety concern that metformin does have (not a big one) is its association with B12 deficiency. Some people may need to take B12 supplements, or apparently, if they take their metformin with calcium that prevents this B12 deficiency issue.

Dr. Peters: Thank you, Dr. Buse, for joining us tonight.

Dr. Buse: It was a pleasure.

Dr. Peters: This has been Dr. Anne Peters from the ADA meeting here for Medscape. Thank you.


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