Metformin Confers Short-Term IGF-1 Improvement in Cancer Survivors With Obesity

Metformin may lead to a short-term reduction in insulin-like growth factor-1 (IGF-1) in cancer survivors with obesity, according to research results published in The Journal of Clinical Endocrinology and Metabolism.

Previous research has associated higher levels of IGF-1 with increased cancer risk and mortality. Additional preliminary evidence suggests that metformin therapy might decrease circulating levels of both IGF-1 and other growth factors. For this reason, metformin — in conjunction with behavioral weight loss — is an “appealing intervention.”

Researchers therefore conducted the phase 2, randomized, 3-parallel-arm SPIRIT trial (ClinicalTrials.gov Identifier: NCT02431676) to evaluate how coach-directed behavioral weight loss, self-directed weight loss, and metformin therapy affect cancer-related biomarkers.

The study cohort included 121 participants (mean age, 60 y) who had survived cancer with a malignant solid tumor diagnosis and who were either overweight or obese (BMI ≥25 kg/m²). Participants were randomly assigned to 1 of 3 study groups: coach-directed behavioral weight loss, self-directed weight loss, or metformin therapy.

The behavioral weight loss intervention was delivered remotely by a health coach who encouraged participants to lose 5% of their baseline body weight within 6 months and then maintain that weight through the end of the study. Participants in the comparison arm were assigned to self-directed weight loss; the participants met briefly with a weight loss coach at baseline and 12 months, if desired. Participants in the metformin arm took up to 2000 mg/d of metformin and received medication-related education and counseling. The primary study outcome included 6-month change in IGF-1 and IGF-1 to IGFBP3 molar ratio (IGF-1:IGFBP3).

Those in the coach-directed weight loss group had a median call completion of 13 of 15 possible calls in the first 6 months and 7 of 7 possible calls in the last 6 months. The rate of participant log in to the study website was similarly high. Weight was tracked for a median of 17 weeks in the first 6 months and 14 weeks in the last 6 months of the trial.

In the metformin group, 11 participants discontinued metformin due to either cancer recurrence or treatment adverse effects. Adherence to treatment was high for those who completed treatment.

At baseline, average body mass index for all study participants was 35 kg/m². At 6 months, the magnitude of changes were -4.2% (95% CI, -5.9 to -2.4) and -2.8% (95% CI, -4.1 to -1.5) in the coach-directed weight loss and metformin arms, respectively. By 12 months, no further reduction was noted in the coach-directed arm, although weight reduction continued in the metformin arm (-3.7%; 95% CI, -5.7 to 1.9). Those in the self-directed weight loss arm experienced “slight” weight loss during the study period (-1.00% and -0.63% at 6 and 12 months, respectively).

At the 6-month mark, at least 5% weight loss was achieved by 15% of participants in the self-directed arm, 38.6% of participants in the coach-directed arm, and 30% of participants in the metformin arm. At 12 months, these proportions were 12.5%, 36.8%, and 35.1%, respectively. Those in the coach-directed weight loss arm achieved “significant, greater net percent” weight loss of 3.2% and 2.8% at the 6- and 12-month time points. Those in the metformin group also experienced significantly greater net percent weight loss vs the self-directed group (1.8% and 3.1%).

Mean IGF-1 for all participants at baseline was 72.9±21.7 ng/mL and was similar across all study arms. At 6 months, mean change in IGF-1 was 2.19 ng/mL, 3.98 ng/mL, and -2.29 ng/ml in the self-directed, coach-directed, and metformin arms, respectively. At 6 months, change in IGF-1 was not significantly different in the coach-directed or metformin arms vs the self-directed arm.

At baseline, mean IGF-1:IGFBP3 molar ratio was 0.17±0.05. Mean change at 6 months was 0.0077, 0.0085, and -0.0006 in the self-directed, coach-directed, and metformin arms, respectively. This 6-month change was not significantly different in either the coach-directed or metformin arms vs the self-directed arm.

No significant between-group changes were noted in IGF-1 and IGF-1:IGFBP3 molar ratio at 12 months.

Subgroup analyses were performed to explore potential differential intervention effects. The researchers found significantly decreased IGF-1 at 6 months in participants in the metformin group who were obese, but not overweight, at baseline vs those in the self-directed weight loss group. Intervention effects did not significantly differ by sex, race, or baseline IGF-1 at 6 months.

IGF-1 and IGF-1:IGFBP3 ratios were also evaluated at 3 months, in response to the typically shorter length of time during which metformin studies tend to be conducted. Mean change in IGF-1 was 1.07 ng/mL, 0.42 ng/mL, and -4.42 ng/mL for the self-directed, coach-directed, and metformin arms, respectively. At 3 months, change in IGF-1 in the metformin arm vs the self-directed arm was statistically significant, but this IGF-1 change did not appear to be mediated through weight change.

At the same time point, mean IGF-1:IGFBP3 molar ratio was 0.0066, 0.0061, and -0.0054 for the self-directed, coach-directed, and metformin arms, respectively. Net ratio change in the metformin vs the self-directed arm was statistically significant at 3 months.

In an evaluation of other metabolic biomarkers at baseline, 6 months, and 12 months, the researchers found that fasting insulin was found to be significantly decreased in the self-directed arm at 6 months (mean change, -2.2), in the coach-directed arm at 6 and 12 months (mean change, -3.7 and -2.1), and in the metformin arm at 12 months (-5.6).

No serious adverse events related to the study were noted.

Study limitations include the modest sample size, lack of a run-in period, and self-reported information on solid tumor diagnosis.

“IGF1 and IGF1:IGFBP3 molar ratio did not change after behavioral weight loss intervention in cancer survivors,” the researchers concluded. “Metformin reduced [these markers] significantly at 3 to 6 months, but levels returned to baseline at 1 year.”

“Additional studies of metformin and behavioral weight loss are warranted in order to understand their effects on other cancer-related biomarkers and potentially clinical outcomes,” they added.

Reference

Yeh H-C, Maruthur NM, Wang N-Y, et al. Effects of behavioral weight loss and metformin on insulin-like growth factors in cancer survivors: a randomized trial. J Clin Endocrinol Metab. Published online April 22, 2021. doi:10.1210/clinem.dgab266