Metformin and colonic polyps in acromegaly: is the solution closer than we think?

in European Journal of Endocrinology
View More View Less
  • 1 Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, Bucharest

Correspondence should be addressed to D A Niculescu; Email: dan.niculescu@umfcd.ro

Whether acromegaly is associated with an increased risk of colorectal cancer or cancer-related mortality is a never-ending debate, with pro or against evidences coming to light at a similar rate (1, 2). As the rate of cured or controlled patients with acromegaly is constantly rising, the residual risk of malignancy due to previous years of exposure to growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess is becoming one of the hot-topics in acromegaly research. Conversely, insulin resistance and secondary diabetes mellitus are well-known features of acromegaly, with more than a quarter of patients being affected (3). Metformin, the most widely prescribed insulin sensitizer, is an obvious and frequently used drug for glucose intolerance in acromegaly (3).

Recently, Albertelli et al. (4) published in this journal a very interesting cross-sectional study on the possible protective role of metformin on colonic polyps, as a premalignant lesion, in patients with acromegaly ('Possible protective role of metformin therapy on colonic polyps in acromegaly: an exploratory cross-sectional study'). They found a lower prevalence of colonic polyps (odds ratio: 0.22) in metformin treated patients without digestive symptoms. No other independent variable, such as sex, age, disease duration or medical treatment for acromegaly, were significant predictors for colonic polyps. Of note, 51.7% of patients had diabetes mellitus (DM). The study is of importance both from a clinical practice, but also research point of view.

If the results of this study are to be confirmed, clinicians will be able to use a single drug to tackle two of the most important complications of acromegaly: colonic cancer and diabetes. However, of greater importance is the clinical trial model proposed by this study. Currently, there are tens of studies assessing the potential antineoplastic roles of metformin, notably prevention, on various populations and tumors (5). These studies require extensive resources due to a low general risk of a particular malignancy and the large number of subjects required by the statistical significance, long-term follow-up during intervention (metformin) and side effects. Acromegaly might prove to be a good model to demonstrate the antineoplastic effects of metformin due, at least partially, to the following reasons: (1) higher incidence of colonic polyps than in the general population; (2) a reasonable proportion of patients with and without DM and particularly insulin resistance; (3) the possibility to investigate the mechanisms of antineoplastic effects of metformin (direct antineoplastic or through insulin-related pathways); (4) natural evolution of the disease, with regular follow-up over decades; (5) the possibility to investigate the role of IGF-1 as a tumor growth promoter.

Acromegaly is associated with a significantly higher incidence of colonic polyps than the general population (1). This means that a lower number of patients have to be enrolled for an adequate powered study. For example, a study from 2012 (6) enrolled more than 80 000 diabetic patients and recorded over 500 events (colorectal cancers) for a 0.9 hazard ratio. These numbers are impossible to achieve in a prospective study in the general population; for population with a higher risk for colonic adenomatous and hyperplastic colonic polyps (2.5–3.5 greater) than in the general population, numbers needed become significantly lower.

The prevalence of insulin resistance and diabetes mellitus is more than 25% in acromegaly, a feature considerably higher than in the general population, but lower than in classic metformin studies (the vast majority were performed on diabetic populations). This offers the possibility to perform subgroup analysis (diabetes vs no diabetes, insulin resistance vs no insulin resistance) and to unravel the pathways involved in the antineoplastic effects of metformin. An HbA1c-independent mechanism, proved in an insulin-resistant vs non-insulin-resistant non-diabetic setting, would help to solve the prescription bias suggested for studies on diabetic populations.

Additionally, patients with acromegaly are followed-up sometimes for decades which offers the opportunity to perform longitudinal studies in the frame of regular check-ups for acromegaly, without dedicated site visits or extensive resources. Moreover, colonoscopy should be regularly performed in patients with acromegaly according to current guidelines (3, 7) and consensus groups (8).

And last, but not least, the role of IGF-1 as a tumor growth promoter would be ideal to evaluate in an acromegaly setting. Preclinical studies and general population analyses have shown that higher GH and IGF-1 levels, even within normal limits, are associated with colorectal cancer risk (1, 9). Evidence points not only to the classic endocrine GH/IGF-1 axis but also to local GH and IGF-1 effects. Medical therapy for acromegaly can influence this risk by modulating only systemic GH/IGF-1, like somatostatin ligands, or both systemic and local GH/IGF-1, like GH receptor antagonists (9). Furthermore, both preclinical and clinical studies showed that IGF-1 and IGF-1 receptor modulates insulin action and insulin resistance and can be linked to metformin effects. Interestingly, the study of Albertelli et al. did not support a predictive role of IGF-1 for colorectal cancer.

However, this study has important limitations that have to be accounted for. The first and most important is that the study endpoint is the presence/absence of colonic polyps instead of colonic cancer. Only 3 out of 21 patients with colonic polyps had adenocarcinomas (14.2%), a number too small to perform any subgroup analysis. Although colonic polyps are premalignant lesions, any possible effect of metformin cannot be translated per se into an anti-malignant one. Also, the study was retrospective, as most studies with metformin on cancer in the diabetic population share the same prescription bias.

Another possible weak point is the low rate of colonoscopy. Only 58 patients (28.8% out of the total population with acromegaly of study sites) had a colonoscopy within 2 years of diagnosis and one can suspect a selection bias for performing it. However, it suggests that referral centers with a higher rate of colonoscopy at diagnosis (let’s say over 80%) would be able to enroll an adequate number of patients for more reliable analysis, including subgroups analysis. Additionally, 24 patients who had a negative colonoscopy, performed for other reasons, within 2 years before the diagnosis of acromegaly were excluded. All these patients probably had active acromegaly at the time of colonoscopy and the reason for their exclusion is not clear. The presence or absence of diabetes and metformin treatment in these patients (41.4% of the study group) could significantly change the results if they are to be included in the final analysis.

The dose and duration of metformin therapy were highly variable due to the retrospective nature of the study. Interesting, the metformin dose was 1797 ± 926 mg/day in the 'no polyp' group compared with 1100 ± 540 mg/day in the 'polyp group'. Although the difference was statistically not significant, it might suggest a dose modulation of the effect that could be speculated in future studies.

At last, statistically speaking, diabetes seemed to be a protective factor for colonic polyps. Per authors, 'only biological plausibility dictated the choice to include metformin use instead of diabetes in multivariate analyses'. As this significant association between diabetes and absence of colonic polyps lies against the published evidence analyses should look to cofactors like metformin or other unexplored confounding variables like diet or shared genetic variants that while increasing the risk of diabetes protect from polyp development.

The author believes that this study opened a door that was present for all to see and that many studies will follow to refine this analysis. The complex relationship between diabetes mellitus and cancer is currently unfolding before our eyes and acromegaly might be one of the best research models in the field. If metformin will prove to have anti-neoplastic effects, the endocrinologist might be the first to know.

Declaration of interest

The author states that he has received research grant funding and speaker honoraria from Pfizer.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • 1

    Terzolo M, Puglisi S, Reimondo G, Dimopoulou C & Stalla GK Thyroid and colorectal cancer screening in acromegaly patients: should it be different from that in the general population? European Journal of Endocrinology 2020 183 D1D13. (https://doi.org/10.1530/EJE-19-1009)

    • Search Google Scholar
    • Export Citation
  • 2

    Boguszewski CL & Ayuk J MANAGEMENT OF ENDOCRINE DISEASE: Acromegaly and cancer: an old debate revisited. European Journal of Endocrinology 2016 175 R147R156. (https://doi.org/10.1530/EJE-16-0178)

    • Search Google Scholar
    • Export Citation
  • 3

    Gadelha MR, Kasuki L, Lim DST & Fleseriu M Systemic complications of acromegaly and the impact of the current treatment landscape: an update. Endocrine Reviews 2019 40 268332. (https://doi.org/10.1210/er.2018-00115)

    • Search Google Scholar
    • Export Citation
  • 4

    Albertelli M, Nazzari E, Dotto A, Grasso LF, Sciallero S, Pirchio R, Rebora A, Boschetti M, Pivonello R & Ricci Bitti S et al. Possible protective role of metformin therapy on colonic polyps in acromegaly: an exploratory cross-sectional study. European Journal of Endocrinology 2021 184 423429. (https://doi.org/10.1530/EJE-20-0795)

    • Search Google Scholar
    • Export Citation
  • 5

    Farmer RE, Ford D, Forbes HJ, Chaturvedi N, Kaplan R, Smeeth L & Bhaskaran K Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation. International Journal of Epidemiology 2017 46 728744. (https://doi.org/10.1093/ije/dyw275)

    • Search Google Scholar
    • Export Citation
  • 6

    Ruiter R, Visser LE, Van Herk-Sukel MPP, Coebergh JWW, Haak HR, Geelhoed-Duijvestijn PH, Straus SMJM, Herings RMC & Stricker BHC Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. Diabetes Care 2012 35 119124. (https://doi.org/10.2337/dc11-0857)

    • Search Google Scholar
    • Export Citation
  • 7

    Katznelson L, Laws ER, Melmed S, Molitch ME, Murad MH, Utz A, Wass JAHEndocrine Society. Acromegaly: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2014 99 39333951. (https://doi.org/10.1210/jc.2014-2700)

    • Search Google Scholar
    • Export Citation
  • 8

    Giustina A, Barkan A, Beckers A, Biermasz N, Biller BMK, Boguszewski C, Bolanowski M, Bonert V, Bronstein MD & Casanueva FF et al. A consensus on the diagnosis and treatment of acromegaly comorbidities: an update. Journal of Clinical Endocrinology and Metabolism 2020 105 E937E946. (https://doi.org/10.1210/clinem/dgz096)

    • Search Google Scholar
    • Export Citation
  • 9

    Perry JK, Wu ZS, Mertani HC, Zhu T & Lobie PE Tumour-derived human growth hormone as a therapeutic target in oncology. Trends in Endocrinology and Metabolism 2017 28 587596. (https://doi.org/10.1016/j.tem.2017.05.003)

    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 38 38 38
PDF Downloads 36 36 36
  • 1

    Terzolo M, Puglisi S, Reimondo G, Dimopoulou C & Stalla GK Thyroid and colorectal cancer screening in acromegaly patients: should it be different from that in the general population? European Journal of Endocrinology 2020 183 D1D13. (https://doi.org/10.1530/EJE-19-1009)

    • Search Google Scholar
    • Export Citation
  • 2

    Boguszewski CL & Ayuk J MANAGEMENT OF ENDOCRINE DISEASE: Acromegaly and cancer: an old debate revisited. European Journal of Endocrinology 2016 175 R147R156. (https://doi.org/10.1530/EJE-16-0178)

    • Search Google Scholar
    • Export Citation
  • 3

    Gadelha MR, Kasuki L, Lim DST & Fleseriu M Systemic complications of acromegaly and the impact of the current treatment landscape: an update. Endocrine Reviews 2019 40 268332. (https://doi.org/10.1210/er.2018-00115)

    • Search Google Scholar
    • Export Citation
  • 4

    Albertelli M, Nazzari E, Dotto A, Grasso LF, Sciallero S, Pirchio R, Rebora A, Boschetti M, Pivonello R & Ricci Bitti S et al. Possible protective role of metformin therapy on colonic polyps in acromegaly: an exploratory cross-sectional study. European Journal of Endocrinology 2021 184 423429. (https://doi.org/10.1530/EJE-20-0795)

    • Search Google Scholar
    • Export Citation
  • 5

    Farmer RE, Ford D, Forbes HJ, Chaturvedi N, Kaplan R, Smeeth L & Bhaskaran K Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation. International Journal of Epidemiology 2017 46 728744. (https://doi.org/10.1093/ije/dyw275)

    • Search Google Scholar
    • Export Citation
  • 6

    Ruiter R, Visser LE, Van Herk-Sukel MPP, Coebergh JWW, Haak HR, Geelhoed-Duijvestijn PH, Straus SMJM, Herings RMC & Stricker BHC Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. Diabetes Care 2012 35 119124. (https://doi.org/10.2337/dc11-0857)

    • Search Google Scholar
    • Export Citation
  • 7

    Katznelson L, Laws ER, Melmed S, Molitch ME, Murad MH, Utz A, Wass JAHEndocrine Society. Acromegaly: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2014 99 39333951. (https://doi.org/10.1210/jc.2014-2700)

    • Search Google Scholar
    • Export Citation
  • 8

    Giustina A, Barkan A, Beckers A, Biermasz N, Biller BMK, Boguszewski C, Bolanowski M, Bonert V, Bronstein MD & Casanueva FF et al. A consensus on the diagnosis and treatment of acromegaly comorbidities: an update. Journal of Clinical Endocrinology and Metabolism 2020 105 E937E946. (https://doi.org/10.1210/clinem/dgz096)

    • Search Google Scholar
    • Export Citation
  • 9

    Perry JK, Wu ZS, Mertani HC, Zhu T & Lobie PE Tumour-derived human growth hormone as a therapeutic target in oncology. Trends in Endocrinology and Metabolism 2017 28 587596. (https://doi.org/10.1016/j.tem.2017.05.003)

    • Search Google Scholar
    • Export Citation