ADT and the Risk of Major Adverse Cardiovascular Events - Episode 5
Dipti Gupta, MD, MPH: There’s a whole gamut of metabolic aberrations as well as cardiovascular disease that is associated with androgen deprivation therapy [ADT]. Among the metabolic aberrations, what we tend to see are obesity, deleterious effects to the lipid profile, metabolic syndrome, insulin resistance, and diabetes. And as a result of this and other factors, then increased incidence of cardiovascular disease.
Obesity. Let’s talk about one of these at a time. Obesity and low testosterone actually have a bidirectional relationship, and it’s a very strong relationship such that obesity is the single most important predictor of low testosterone in men, and vice versa is true as well. Within the first year of ADT itself, what we find is an increase in body weight, up to 10 pounds. And this is seen not only in older and obese patients, this is seen in younger and nonobese patients as well. What is even more concerning is the changes in body composition, by which I mean that what we gain is actually body fat. So we gain up to 9% to 11% of body fat, and what we lose is the good muscle mass or the lean body mass, which we tend to lose about 3% to 4% of it as early as 1 year into treatment. This phenomenon is called sarcopenic obesity, which basically means central obesity accompanied by loss of muscle mass. And this has been associated with downstream increase in mortality.
Talking about effects to the lipid profile, what ADT tends to do, it tends to increase every parameter across the board. So it increases HDL [high-density lipoprotein] which is the good cholesterol, it increases LDL [low-density lipoprotein], the bad cholesterol, it increases total cholesterol, all in the order of 7% to 10%. It increases triglycerides much more than that, in the order of 25% to 27%.
Now, one might think that since it is also increasing the good cholesterol, the HDL, that negates its action on the bad cholesterol. However, that is not the case. And the reason being that with the bad, you need testosterone to actually do something called reverse cholesterol transport, which is taking cholesterol and promoting the efflux of cholesterol from the arterial wall to the liver. Now, when we don’t have testosterone, even the higher levels of HDL are unable to accomplish this. So the net effect is still proatherogenic.
Coming on to diabetes and insulin resistance…data have been somewhat limited in terms of doing the rigorous studies. But we do have a very clear signal from large-scale observational trials. We have seen that as early as 12 weeks, there is a significant decrease in insulin sensitivity in patients, in nondiabetics who go on ADT. We have also seen that patients who are diabetics, it worsens their diabetic control. It increases their A1C [glycated hemoglobin].
In terms of the data already published for diabetes, one of the landmark studies that was published in 2006, in over 70,000 patients, this was SEER-Medicare [database] patients with prostate cancer, GnRH [gonadotropin-releasing hormone] agonists led to a significant increase with a hazard ratio of 1.4 of incident diabetes. Now, this finding has been replicated time and again in other large-scale observational trials.
Talking about metabolic syndrome; metabolic syndrome is a cluster of conditions. When present it increases risk of cardiovascular disease, and those conditions include low HDL, high triglycerides, high blood pressure or hypertension, insulin resistance, or high fasting blood glucose, as well as obesity. So you need 3 out of these 5 things to actually merit a diagnosis of metabolic syndrome. In the general population, it is estimated that about 20% to 25% of the people have metabolic syndrome.
Now coming to prostate cancer patients that are on GnRH agonists, it is estimated that up to 55%, and in some studies even more than that, of patients then develop metabolic syndrome. And it is not surprising because we just reviewed all the metabolic aberrations that are related to androgen deprivation. So the fact that this all culminates in a higher incidence of metabolic syndrome is not surprising but very concerning.
Transcript Edited for Clarity