Metabolic Aberrations Associated With ADT

Transcript:

Dipti Gupta, MD, MPH: Let’s talk about the metabolic changes with androgen deprivation therapy or, rather, the metabolic aberrations that occur with androgen deprivation therapy. And what is the timeline that we’re looking at in terms of how long it takes to develop some of these aberrations? Androgens are important determinates of body composition in men. Like I said, they promote lean body mass. They promote muscle mass and suppress fat deposition—both being things that we like. Epidemiological studies have observed a bidirectional relationship between low testosterone level and obesity. What this means is obesity is really the single most powerful predictor for low testosterone levels in men and vice versa. It’s also true that low levels of testosterone then predict central obesity, intra-abdominal fat, as well as the risk for metabolic syndrome in these patients.

There have been several studies that have shown that in men on ADT, the body weight and body composite changes. These changes mainly occur during the first year of treatment, but they continue for at least 1 or 2 more years after that. The weight gain after a year on treatment has been anywhere from 5 to 10 pounds, on an average. Interestingly, it appears to be greater in younger patients, less than age 65, and it appears to be more in nonobese patients with a BMI of less than 30. Regarding the changes in total body fat, the increase can be up to an alarming increase of 11% and the decrease in lean body mass or the muscle mass can be in the order of 3% to 4%—so, very impressive. The fat accumulation that happens with ADT is primarily subcutaneous rather than visceral, and the subcutaneous fat is about 94% of the total abdominal fat that is gained during treatment.

Let’s talk about changes in lipid profile. This has been an area that is sort of difficult to study because the study design needs to be very meticulous. The studies that we have are sort of heterogeneous in design. They’re small. And so, while we don’t universally know this, there is seemingly a signal that ADT increases LDL levels and triglycerides. LDL levels go up about 17%. This is the bad cholesterol that I’m talking about. Triglycerides go up much more than that, about 27%. There is also a signal that the total cholesterol goes up and the good cholesterol, the HDL, also goes up.

One could argue that if the HDL is going up, does it then mitigate what we’re doing by increasing the LDL? It turns out that for the HDL to work properly and get rid of some of that cholesterol from the plaques, it needs testosterone to help accomplish that. When there is no testosterone, high HDL doesn’t really mean very much. The net effect is still proatherogenic, even in these patients.

And then we come to diabetes, hyperglycemia, and insulin resistance—extremely important side effects that occur in these patients. A 3-month prospective study showed that ADT decreases insulin sensitivity in nondiabetics by as much as 26% and it worsens glycemic control in patients who have known diabetes. There was a landmark study that was published in 2006. That study showed about a 42% increase in the incidence of diabetes in patients with prostate cancer who were on treatment with GnRH agonists. This theme has been replicated in multiple studies. There was a retrospective study of over 14,000 patients that published not too long ago. That study showed about a 60% increase in incidence.

This is definitely a problem, and there do not seem to be evidence-based guidelines for recommendations on when we should check blood sugars and what we should do in terms of monitoring. And so, what we recommend, and what has been our practice, is to do something called risk-adapted screening. The ADA recommends a certain kind of screening for high-risk patients. We definitely consider these patients as high risk. We will get a blood glucose, fasting blood glucose, and a hemoglobin A1C at baseline. We would like to follow that up in a year. We would like for these patients to undergo counseling. For patients who already have diabetes, we want to be very meticulous, telling them that their control might get a little bit worse and that this is to be expected. And we want to be more meticulous with surveillance and treatment in known diabetics as well.

Transcript Edited for Clarity