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Article of the week: What does metformin use have to do with NMIBC outcomes?

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by prominent members of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of Dr. Rieken discussing his paper.

If you only have time to read one article this week, it should be this one.

Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer

Malte Rieken1,3, Evanguelos Xylinas1,4, Luis Kluth1,5, Joseph J. Crivelli1, James Chrystal1, Talia Faison1, Yair Lotan6, Pierre I. Karakiewicz7, Harun Fajkovic10, Marek Babjuk8, Alexandra Kautzky-Willer10, Alexander Bachmann3, Douglas S. Scherr1 and Shahrokh F. Shariat1,2,10

1Department of Urology, 2Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA, 3Department of Urology, University Hospital Basel, Basel, Switzerland, 4Department of Urology Cochin Hospital, APHP, Paris Descartes University, Paris, France, 5Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 6Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA, 7Department of Urology, University of Montreal, Montreal, QC, Canada, 8Department of Urology, Hospital Motol, Second Faculty of Medicine, Charles University, Prague, Czech Republic, 9Unit of Gender Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, and 10Department of Urology, Medical University of Vienna, Vienna, Austria

OBJECTIVE

• To assess the association between diabetes mellitus (DM) and metformin use with prognosis and outcomes of non-muscle-invasive bladder cancer (NMIBC)

PATIENTS AND METHODS

• We retrospectively evaluated 1117 patients with NMIBC treated at four institutions between 1996 and 2007.

• Cox regression models were used to analyse the association of DM and metformin use with disease recurrence, disease progression, cancer-specific mortality and any-cause mortality.

RESULTS

• Of the 1117 patients, 125 (11.1%) had DM and 43 (3.8%) used metformin.

• Within a median (interquartile range) follow-up of 64 (22–106) months, 469 (42.0%) patients experienced disease recurrence, 103 (9.2%) experienced disease progression, 50 (4.5%) died from bladder cancer and 249 (22.3%) died from other causes.

• In multivariable Cox regression analyses, patients with DM who did not take metformin had a greater risk of disease recurrence (hazard ratio [HR]: 1.45, 95% confidence interval [CI] 1.09–1.94, P = 0.01) and progression (HR: 2.38, 95% CI 1.40-4.06, P = 0.001) but not any-cause mortality than patients without DM.

• DM with metformin use was independently associated with a lower risk of disease recurrence (HR: 0.50, 95% CI 0.27–0.94, P = 0.03).

CONCLUSION

• Patients with DM and NMIBC who do not take metformin seem to be at an increased risk of disease recurrence and progression; metformin use seems to exert a protective effect with regard to disease recurrence.

• The mechanisms behind the impact of DM on patients with NMIBC and the potential protective effect of metformin need further elucidation.

 

Read Previous Articles of the Week

 

Editorial: Diabetes mellitus and non-muscle-invasive bladder cancer: not just a coincidence?

Urologists are familiar with the plethora of comorbidities affecting patients with bladder cancer. Many are smoking-related, such as respiratory disease, ischaemic heart disease and peripheral vascular disease. Other conditions are associated with an ageing, increasingly obese population. Rieken et al. [1], present intriguing observations suggesting an association between diabetes mellitus (DM), its treatment and the prognosis of non-muscle-invasive bladder cancer (NMIBC). In a retrospective, multicentre cohort study of 1117 patients diagnosed with NMIBC, the authors conclude that patients taking metformin have better recurrence-free survival compared with patients with diabetes who did not take metformin. The Kaplan–Meier curves even hint at improved outcomes for patients taking metformin compared with the population without diabetes, although the difference did not reach statistical significance. Only 125 patients (out of 1117) had DM, of whom 43 were prescribed metformin. Outcome measures were recurrence and progression, with comparison of cancer-specific mortality not possible because of the low frequency of events. The study population was treated between 1996 and 2007, so re-resection was not routine, and rates of postoperative intravesical chemotherapy and adjuvant chemotherapy/immunotherapy were low. Treatment for some patients was therefore suboptimal by current standards, and there may have been differences between the multinational institutions.

The association between type 2 diabetes and the incidence of several cancer types (e.g. breast, colorectal and pancreatic) is well documented. The biological mechanisms responsible are unclear [2], and a causal relationship is debated. Postulated mechanisms include the effects of hyperinsulinaemia, hyperglycaemia and signalling pathways involving the IGF receptors. The protective effect of metformin is similarly unclear, although the authors cite studies indicating anti-proliferative properties.

A number of large cohort studies have endeavoured to show there is a higher risk of cancers in populations with diabetes. The challenge for such studies is the relatively low incident rate of bladder cancer in the population (17.1 per 100 000) [3]. Additionally, studies using general practice databases encounter problems obtaining data relating to bladder cancer characteristics. The increased detection of bladder cancer in the population with diabetes is a potential confounder, as monitoring using urine analysis is more likely.

Rieken et al. [1], in taking the opposite approach by identifying their cohorts on the basis of confirmed diagnosis of NMIBC, present accurate data regarding cancer characteristics but accept there is a potential for lack of accuracy in the recording of DM and treatment using chart review. We are not able to draw any conclusions regarding the severity of DM, its complications or compliance with prescribed medication. Future studies would be strengthened by incorporating tests such as HbA1c concentration as a marker for glycaemic control. Additionally, they do not specify the type of diabetes, although the reader can speculate that patients treated with metformin had type 2 DM. It is important to recognize that the pattern of cancer risk appears to be different for type 1 diabetes [4].

Whilst detailed discussion of the management of DM is outside the remit of a urological study, there are some important factors to be considered. Metformin is frequently recommended as a first-line agent in the management of type 2 DM [5]. It follows, therefore, that patients treated with metformin may be different from those requiring second- or third-line drugs and drug combinations; thus the cohort treated with metformin may be younger, exhibit better glycaemic control, and have improved renal function compared with those treated with other drugs and exogenous insulin. An important consideration is that rather than a protective effect being exerted by metformin, it may be that other hypoglycaemic agents have an adverse effect on NMIBC outcomes. Pioglitazone has recently been associated with an increased incidence of urothelial cancer when taken for >2 years, although effects on prognosis are not established [6]. Were the patients with diabetes not taking metformin in fact treated with hypoglycaemic agents implicated in the aetiology of bladder cancer? When considering the plausibility of biological mechanisms, the time-lag between exposure to carcinogen and the development of bladder cancer is pertinent. There is a prolonged time-lag between exposure to cigarette smoking and the development of bladder cancer, so are we ready to accept that drug exposure for a short time-scale is protective or causative? Finally, we must consider the clinical relevance of these findings. As metformin is the current first-line therapy, it may be contraindicated in those not prescribed it and conversion may not be possible.

Notwithstanding the above caveats, when treating patients with NMIBC we are often embarking on a lifelong process of treatment and surveillance. We are obliged as doctors to consider the implications of common comorbidities in order to tailor treatment. In much the same way that we now consider metabolic syndrome when evaluating erectile dysfunction, in the future we may need to consider NMIBC and DM together, and work collaboratively with other healthcare professionals to optimize the management of both conditions.

Joanne Cresswell
Department of Urology, James Cook University Hospital, Middlesbrough, UK

References

  1. Rieken M, Xylinas E, Kluth L et al. Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. BJU Int 2013; 112: 1105–1112
  2. Johnson JA, Carstensen B, Witte D et al. Diabetes and cancer (1). Evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologica 2012; 55: 1607–1618
  3. Cancer Research UK. Bladder cancer, average number of new cases per year and age-specific incidence rates, 2006–2008. Cancer Research UK, 2012
  4. Zendehdel K, Nyren O, Ostenson CG, Adami HO, Ekbom A, Ye W. Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Natl Cancer Inst 2003; 95: 1797–1800
  5. NICE. NICE Clinical Guideline, 66, 2008
  6. Azoulay L, Yin H, Filion K et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012; 344: e3645

Video: Metformin for diabetics with NMIBC

Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer

Malte Rieken1,3, Evanguelos Xylinas1,4, Luis Kluth1,5, Joseph J. Crivelli1, James Chrystal1, Talia Faison1, Yair Lotan6, Pierre I. Karakiewicz7, Harun Fajkovic10, Marek Babjuk8, Alexandra Kautzky-Willer10, Alexander Bachmann3, Douglas S. Scherr1 and Shahrokh F. Shariat1,2,10

1Department of Urology, 2Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA, 3Department of Urology, University Hospital Basel, Basel, Switzerland, 4Department of Urology Cochin Hospital, APHP, Paris Descartes University, Paris, France, 5Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 6Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA, 7Department of Urology, University of Montreal, Montreal, QC, Canada, 8Department of Urology, Hospital Motol, Second Faculty of Medicine, Charles University, Prague, Czech Republic, 9Unit of Gender Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, and 10Department of Urology, Medical University of Vienna, Vienna, Austria

OBJECTIVE

• To assess the association between diabetes mellitus (DM) and metformin use with prognosis and outcomes of non-muscle-invasive bladder cancer (NMIBC)

PATIENTS AND METHODS

• We retrospectively evaluated 1117 patients with NMIBC treated at four institutions between 1996 and 2007.

• Cox regression models were used to analyse the association of DM and metformin use with disease recurrence, disease progression, cancer-specific mortality and any-cause mortality.

RESULTS

• Of the 1117 patients, 125 (11.1%) had DM and 43 (3.8%) used metformin.

• Within a median (interquartile range) follow-up of 64 (22–106) months, 469 (42.0%) patients experienced disease recurrence, 103 (9.2%) experienced disease progression, 50 (4.5%) died from bladder cancer and 249 (22.3%) died from other causes.

• In multivariable Cox regression analyses, patients with DM who did not take metformin had a greater risk of disease recurrence (hazard ratio [HR]: 1.45, 95% confidence interval [CI] 1.09–1.94, P = 0.01) and progression (HR: 2.38, 95% CI 1.40-4.06, P = 0.001) but not any-cause mortality than patients without DM.

• DM with metformin use was independently associated with a lower risk of disease recurrence (HR: 0.50, 95% CI 0.27–0.94, P = 0.03).

CONCLUSION

• Patients with DM and NMIBC who do not take metformin seem to be at an increased risk of disease recurrence and progression; metformin use seems to exert a protective effect with regard to disease recurrence.

• The mechanisms behind the impact of DM on patients with NMIBC and the potential protective effect of metformin need further elucidation.

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