Trial misses insulin-resistance endpoint but may have potential.

A very low-carbohydrate diet failed to prevent insulin resistance in men taking androgen deprivation therapy for prostate cancer, but led to significant weight loss and preserved bone health, a small trial showed.

The dietary intervention led to a significant reduction in homeostatic model assessment (HOMA) of insulin resistance at 3 months, as compared with a control group, but not at 6 months, the primary endpoint. Men on the very low-carbohydrate diet had significant reductions in weight and percent body fat and stable bone mineral content (BMC) versus weight and body fat increases and a reduction in BMC in the control group.

Though the trial missed its primary endpoint, a follow-up study has already begun to test the oncologic benefits of the very low-carbohydrate diet, Stephen Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles, reported here at the American Urological Association (AUA) meeting.

“Carbohydrate restriction is a promising tool to prevent androgen deprivation therapy (ADT) -induced metabolic side effects,” said Freedland. “Given that weight loss is generally anticancer, coupled with animal data that this diet slows prostate cancer growth, studies evaluating oncological efficacy and safety are ongoing.”

The diet would pose an adherence challenge for many men, but the challenge has to be weighed against the reality of the disease, said Benjamin Davies, MD, of the University of Pittsburgh.

“These are men who have recurrent cancer,” said Davies, who moderated an AUA press briefing where Freedland discussed the study. “If you tell them that there is preliminary data that this may help them with their physiology and their health, you might be more apt to induce them to follow a proactive approach to change their lifestyle. Whereas if this were just a regular guy without the kind of medical challenge, you can see where there might be some reluctance.”

“Usually, people are more apt to change their lifestyles when their health is at risk,” he added. “I think that gives me some hope that we could actually do that for patients. Obviously, it’s challenging. I don’t know that I could do it … actually, I know that I couldn’t.”

For decades, hormonal therapy, or ADT, has represented standard of care for advanced prostate cancer. Multiple studies have demonstrated survival benefits with ADT. However, recent investigations have documented major side effects, especially metabolic effects (weight gain, insulin resistance, dyslipidemia), in addition to hot flashes, loss of libido, erectile dysfunction, memory loss, and bone mineral loss and osteoporosis.

“Hormonal therapy for prostate cancer increases the risk of diabetes by 40%,” said Freedland. “Diabetes is a problem controlling blood sugar levels. We wondered, what happens if you don’t eat sugar?”

Low-carbohydrate diets have demonstrated the potential to achieve significant weight loss and improve diabetes control, he continued. In animal models, low-carbohydrate diets have been associated with slowing of prostate cancer growth. Such a diet has never been evaluated in a randomized trial involving patients with cancer.

Investigators hypothesized that a very low-carbohydrate diet could prevent insulin resistance and other metabolic side effects in men initiating hormonal therapy for advanced prostate cancer. To test the hypothesis, Freedland and colleagues conducted a prospective, randomized trial, comparing a very low-carbohydrate diet versus usual diet in men initiating ADT.

Men randomized to the intervention arm followed a diet that limited daily carbohydrate consumption to 20 g, similar to the Atkins diet, said Freedland. They also were instructed to exercise 30 minutes a day, 5 days a week. Men assigned to the control arm continued their usual practices regarding diet and exercise.

Investigators randomized 42 patients, and 40 completed the baseline assessment. Subsequently, 14 men in the intervention arm and 20 in the control group completed the 6-month trial. Complete data were available for 11 men in the very low-carbohydrate group and 18 in the control group, and those 29 patients formed the basis for data analysis.

The primary endpoint was change in HOMA at 6 months. The intervention group had a mean change in HOMA of -4 compared with an increase of 36 in the control group (P=0.127). The 3-month values showed a significant difference in favor of the intervention arm (-19 versus +7, P=0.015).

The dietary intervention was not expected to affect PSA values, and the change from baseline (in response to hormonal therapy) ranged from -97% to -99% in both arms at 3 and 6 months. Men in the very low-carbohydrate arm had weight loss that averaged about 15 lbs at 3 months, increasing to 20.5 lbs at 6 months. In the control group, men had gained almost a pound at 3 months and almost 3 lbs at 6 months (P<0.001 versus intervention group at both time points).

Bone mineral content remained unchanged at 6 months in the intervention group as compared with a reduction of 2.3% in the control group (P=0.025). Percent body fat decreased by 16.2 % at 6 months in the intervention group and increased by 11% in the control group (P=0.002).