TCR: Dr. Buse, as an endocrinologist with a specialty in diabetes, I'm hoping you can help educate both myself and my psychiatrist readers about diabetes and antipsychotics. To begin with, we've been hearing a lot lately about the "metabolic syndrome." What is it?
Dr. Buse: The metabolic syndrome specifically refers to the presence of central obesity with hypertension, dyslipidemia (which is high triglycerides and low HDL), and diabetes or glucose intolerance. This syndrome is associated with an increased risk of vascular disease.

TCR: And how is "insulin resistance" related to diabetes?
Dr. Buse: You have to have two defects to get type 2 diabetes: one is a defect in insulin sensitivity we call insulin resistance, and the other is a defect in insulin secretion. So insulin resistance is part of the pathophysiology of type 2 diabetes and may contribute to hypertension, dyslipidemia, and accelerated atherosclerosis, but that is less clear.

TCR: So, typically, when you are making a diagnosis of type 2 diabetes, what do you require?
Dr. Buse: To make a diagnosis of type 2 diabetes, you need a fasting glucose of 126 or greater or a random glucose of 200 or greater plus classic symptoms of diabetes. We also have a new diagnosis of "pre-diabetes" which is defined as a fasting glucose of 100-125; these people are at excess risk of cardiovascular disease and the metabolic syndrome and have an approximately 5-10% chance per year of developing full blown diabetes.

TCR: Now, where does weight gain fit into this? Most people would agree that clozapine and olanzapine have a higher risk of weight gain than other atypicals. How does that fit into the risk of diabetes?
Dr. Buse: "Visceral obesity," which refers to fat wrapped around the intestines and in the liver, is highly correlated with insulin resistance and the development of diabetes.

“Patients who developed diabetes were older, heavier, had higher glucose at baseline, often had hypertension, and more often belonged to an ethnic minority group.”
⁠— John Buse, M.D.

TCR: Do you have any idea or does anybody know why olanzapine or clozapine would cause more weight gain than any of the other antipsychotics?
Dr. Buse: There is no clear answer to that. It is also not clear that weight gain per se is what causes patients on antipsychotics to become diabetic. At least in my studies, there was no association between weight gain and risk of diabetes, so about half the people who developed diabetes (in the data set to published in the British Journal of Psychiatry), gained little or no weight, some of them lost weight, and about half gained a moderate amounts of weight, and a relatively small proportion gained a lot of weight. So, I am not sure the weight gain is the whole story.

TCR: Can you expand on that study?
Dr. Buse: We looked at all the randomized trials in the Eli Lilly data set where patients were randomized to olanzapine vs. placebo, haloperidol, risperidone, or clozapine. We looked at random glucose levels and we used a cut-off point of 200. There were somewhat more than 100 patients who developed treatment-emergent diabetes. The major feature of these patients was that they seemed to have a lot more risk factors for having diabetes than the general population. They were older and heavier and had higher glucoses at baseline and they more often belonged to ethnic minority groups and more often had hypertension than the people who didn't develop diabetes. Only 8% of the people who developed diabetes had no risk factors, whereas 45% of the people who didn't develop diabetes has no risk factors. So it looks like this risk factor approach can define most of the people at risk of developing diabetes while being treated with antipsychotics.

TCR: Was the particular type of antipsychotic related to the risk of diabetes?
Dr. Buse: Not in a statistically significant way, but there was a trend toward a higher risk of developing diabetes with clozapine and olanzapine. But basically all of the drugs were associated with an increased risk of diabetes. So, my view of things is that there is about a three-fold increased risk of having diabetes because of schizophrenia alone. And while there might be small difference between drugs, the bulk of the risk comes from the underlying condition and not from the drug therapy that you used.

TCR: You recently published a paper in the Journal of Clinical Epidemiology which reported that Zyprexa and Risperdal had about the same risk of leading to diabetes. And yet there are several other epidemiologic studies showing that Zyprexa is worse than Risperdal in this regard.
Dr. Buse: It's true, there are a lot of studies out there and they all have their flaws, including ours. Our data set has two major flaws. The first is that it did not include information about diagnosis, so we don't know how many of these patients had schizophrenia vs. other diagnoses, such as dementia with agitation. The other problem is that it was not randomized therapy, and it's quite possible that clinicians might have been sophisticated enough in 1999 to suspect that there was a higher risk of developing diabetes on clozapine or olanzapine and so they might have specifically took their heaviest patients and put them on ziprasidone or other medications, leading to a biased result.

TCR: So when I now begin a patient on an antipsychotic medication associated with diabetes, how do you recommend I monitor?
Dr. Buse: I recommend getting a fasting glucose at baseline in people who have risk factors for diabetes. Risk factors include higher age - 40 or 45 being a reasonable cut off of where risk really starts; being overweight, with a body mass index (BMI) over 27; hypertension; and a known lipid disorder.

TCR: Any other risk factors to consider?
Dr. Buse: All ethnic minorities other than Caucasians of Western European extraction are at higher risk -- this includes African Americans, Hispanic Americans, Asian Americans, Native Americans. Also, women with a history of gestational diabetes, anybody with a history of any glucose being abnormal in the past, and people with a prior history of vascular disease. After the baseline fasting glucose, I would check a random or fasting glucose again in a month or two, and then I would try and check it every 3-6 months for the first year and at least yearly thereafter. And the discussion that the psychiatrist should have with the patient is: "Because you have this disease schizophrenia, you have three times the risk of the general population of developing diabetes, and in the general population, the lifetime risk is about 35%, so your lifetime risk of getting diabetes is very, very high."

TCR: What else should we be telling our patients?
Dr. Buse: You should talk to them about symptoms of diabetes and about diet. Symptoms of diabetes include urinary frequency (and nocturia in particular), blurred vision, fatigue, and poorly healing skin lesions. Unfortunately, a lot of people will get those symptoms with different psychiatric medications and so the symptoms aren’t very specific. But if they do develop those symptoms their blood sugar needs to be checked. In terms of diet, patients should stay away from sugary drinks that don't say "diet" on the label. They can drink all the diet Coke they want, but they shouldn't drink regular soda, and they shouldn't drink any juices.

TCR: Is this advice specifically to people who have diabetes?
Dr. Buse: No, this is for people who have schizophrenia.

TCR: So, anyone who has schizophrenia shouldn't drink fruit juice?
Dr. Buse: No, I don't think so. Or if they do, it should be a 4-oz serving; you know one of those little tiny glasses that people laugh at when they get in the buffet line.

TCR: Is this because if people drink too much sugary liquid, it is actually increasing their risk of getting diabetes?
Dr. Buse: It is because people can drink a lot of calories. It is all about calories. The whole idea is to try and avoid weight gain and the thing that I hear from a lot of my patients with schizophrenia is that they drink a lot of soda and a lot of juice. But it is all about calorie restriction to either achieve a normal weight or certainly not to gain weight, and to try and get 30 minutes of moderately vigorous physical activity a day; walking is fine. My advice as a diabetes doctor who is very comfortable taking care of diabetes and very uncomfortable taking care of schizophrenia, is do what it takes to take care of their schizophrenia and screen for the diabetes and give some of this preventive advice, and if they develop diabetes, treat them for their diabetes.

TCR: Thank you Dr. Buse.