Diabetes and risk for prostate cancer

There have long been suggestions that men already diagnosed with and receiving treatment for diabetes are at lower risk for a subsequent diagnosis of prostate cancer than non-diabetics. However, a very large, new, epidemiological analysis seems to suggest strongly that this may not be the case at all.

Beckman et al. conducted a careful analysis of data from > 500,000 men (all aged between 40 and 79 years) listed in the Stockhom PSA and Biopsy Register who were living in Stockholm, Sweden, between January 1, 2006, and December 31, 2015.

The research team sought to explore the associations between the use of anti-diabetic medications (metformin, sulfonylurea, and insulin) and four other prostate cancer-related factors:

  • Patients’ PSA levels
  • Frequency of PSA testing
  • Receipt of a biopsy following elevated PSA results
  • Prostate cancer detection at biopsy

The total number of men eligible for inclusion in this study was 564,666, and their average (median) age was 65 years.

Of these 500,000+ men,

  • 4,583 were diabetics initially exposed to metformin
  • 1.104 were diabetics exposed to sulfonylurea
  • 978 were diabetics exposed to insulin

These men were then all age-matched to men who had had no exposure to anti-diabetic medications.

Here are the core study findings:

  • Men exposed to the anti-diabetic medications had lower average PSA levels before starting anti-diabetic medications compared with unexposed men (1.2 vs 1.6 ng/mL).
  • After accounting for baseline differences, PSA levels of men exposed to anti-diabetic medications did not vary from those of unexposed men.
  • Frequency of PSA testing was somewhat higher for those receiving metformin (rate ratio, 1.07) and sulfonylurea (rate ratio, 1.06) but was lower for those receiving insulin (rate ratio, 0.79).
  • Likelihood of biopsy after elevated PSA (i.e., ≥3.0 ng/ml) was lower among men receiving metformin (odds ratio [OR] = 0.87) and insulin (OR = 0.83).
  • There were no differences in prostate cancer detection at biopsy, regardless of PSA levels that triggered the biopsy.

Beckman et al., conclude that

This study’s findings do not support the hypothesis that the inverse association between diabetes and prostate cancer is mediated through antidiabetic medications lowering PSA levels to mask prostate cancer. They do suggest potential detection bias due to fewer biopsies among men receiving antidiabetic medications, which may explain the lower prostate cancer risk in men with diabetes.

In other words, men with diabetes are less likely to ever get a biopsy for risk of prostate cancer than men without diabetes. And this can in and of itself explain why it seems as though men with diabetes are at lower risk for a diagnosis of prostate cancer than non-diabetic men.

An editorial commentary by Velaer and Leppert is supportive of the conclusions reached by Beckman et al. Velaer and Leppert also note that these data are going to raise questions about whether the use of anti-diabetic medications like metformin to prevent or delay the progression of at least early stage prostate cancer may also be highly questionable.

A report on the MedPage Today web site also addresses this research and its findings.

3 Responses

  1. A number of trials addressing the anti-prostate caner effects of metformin are in progress — some completed. It may may be of interest to list these — and also comment on metformin benefit to reduce changes associated with metabolic syndrome in association with ADT.

    Thanks for article review.

  2. The ClinicalTrials.gov web site lists 25+ trials in which metformin is or has been used in the management of various groups of men with differing types of prostate cancer. Of these trials:

    — Two are new trials and are not yet recruiting patients
    — Nine are currently recruiting patients
    — One is no longer recruiting patients (but is not yet completed)
    — Seven are “Completed”
    — Six were either terminated early or withdrawn for some reason

    The trials that we can identify results from have all been relatively small, and the results have been variable to date. It would be hard to state that there has been any “compelling” evidence of the benefits of taking metformin to date. And a couple of the small but best-designed and implemented trials have shown no clinical benefit (see for example here and here).

    However, there are still some reasons to think that metformin may have value in the treatment of prostate cancer. We are certainly going to need stronger evidence than that which is currently available to prove this.

  3. While there have been many conflicting retrospective studies, there have been two small Level 1 prospective randomized clinical trials. Both were unable to detect any effect.

    The TAXOMET trial (n = 99) showed that metformin did not increase survival when added to docetaxel.

    Mahalingam et al. reported on a randomized, double-blind, placebo-controlled study (n = 36) of metformin in non-diabetic men initiating ADT for advanced prostate cancer and found no short-term PSA response.

    It is possible that larger, longer-term trials may show an effect, but the prospects are looking slim, especially with this study showing the source of detection bias in previous retrospective studies.

    There are a couple of Phase III trials in the works: STAMPEDE has a Phase III trial (Group K), and there is the MAST trial to see if it can extend time on active surveillance.

    It is also worth noting that studies of potent IGF-1 blockers have been unsuccessful, so an alternative case for the plausibility of any effect has yet to be made.

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