Lifestyle intervention may mitigate metabolic sequelae of ADT

Following a program that combines a low carbohydrate diet (LCD) and modest walking may be an effective strategy for blocking many of the adverse metabolic effects of androgen deprivation therapy (ADT), according to findings of a randomized controlled trial.

“Our study was stopped early due to low accrual and limited funding and was thus underpowered for the primary endpoint analysis that looked at change in insulin resistance at 6 months, even though a suggestion of benefit was seen. Importantly, secondary analyses, however, showed that most secondary outcomes were improved at 3 months and maintained at least numeric superiority at 6 months. Furthermore, there were no apparent downsides associated with the intervention in terms of cancer control,” said lead author Stephen Freedland, MD, of Cedars-Sinai, Los Angeles. The study was published online ahead of print in Prostate Cancer and Prostatic Diseases (Jan. 21, 2019).

“We are now planning another study to see if we can establish benefit of the intervention with diet and a more intense exercise regimen for reducing ADT-induced metabolic disturbances. In the meantime, although we cannot recommend that all men starting ADT follow the LCD diet and walking program, there seems to be no reason to dissuade any man who might be interested in following this approach as it seems to have little risk and a reasonable chance of some benefit,” Dr. Freedland added.

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Recognizing that the changes in plasma insulin, insulin sensitivity, and insulin resistance in non-diabetic men starting on ADT translate to a 40% increased diabetes risk, Dr. Freedland said that the intervention to mitigate the risk was designed on the simplistic view that diabetes is a problem of blood glucose control.

“We hypothesized that the changes in blood insulin and insulin resistance that develop after starting on ADT could be avoided by drastically limiting carbohydrate intake. There is evidence that an LCD diet leads to weight loss and favorable changes in serum insulin and lipids, and we considered that exercise could augment the benefits,” Dr. Freedland told Urology Times.

“We also reasoned that the intervention would not be harmful because animal data show that a low carbohydrate diet slows tumor growth.”

The study planned to randomize 100 men 1:1 into its intervention and control arms. The intervention consisted of a dietary intake of ≤20 g carbohydrates/day plus walking at least 30 minutes on at least 5 days/week. Men in the control group were to follow their usual diet and exercise patterns. Enrollment was stopped after 42 men were randomized, and only 29 of 34 men seen at 6 months had complete baseline and follow-up data.

“Several issues contributed to the slow patient accrual. Some men did not want to participate because they thought the diet was too burdensome whereas others did not want to be in the control group. Logistical factors prevented other men from participating,” Dr. Freedland explained.

Next: At 6 months, insulin resistance was reduced by 4% in the intervention arm compared with baseline pre-ADTAt 6 months, insulin resistance was reduced by 4% in the intervention arm compared with baseline pre-ADT while it increased by 36% in the control group, but the treatment effect was not statistically significant (p=.13). However, findings of secondary analyses showed that the intervention was associated with a statistically significant benefit for reducing insulin resistance over the study period and at the 3-month visit.

In addition, statistically significant differences were seen favoring the intervention in analyses of changes in hemoglobin A1c, fasting glucose, plasma insulin, weight, body mass index, high density lipoprotein, and triglycerides at 3 months. The benefits associated with the intervention persisted at 6 months, although differences between groups were not always statistically significant.

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At 6 months, the intervention was also associated with significant benefits for preserving total body bone mineral count, and reducing fat mass and percent body fat, although men in the intervention group had significant loss of lean mass. Percent change in PSA did not differ significantly between groups at 3 or 6 months.

Now, Dr. Freedland and colleagues hope to obtain funding for a larger study that will have sufficient statistical power to investigate the potential benefit of lifestyle interventions to mitigate the metabolic disturbances caused by ADT. While they plan to use the same LCD diet, because men in the intervention arm lost lean body mass, the exercise component for the intervention group will include a program aimed at maintaining or building muscle mass.