The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study
BMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e3645 (Published 31 May 2012) Cite this as: BMJ 2012;344:e3645
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Competing interests: No competing interests
Recently several pharmacoepiodemiology studies have investigated the risk of bladder cancer in type 2 diabetic patients treated with pioglitazone.[1-11] The strength of association between ever use of pioglitazone and risk of bladder cancer in these studies was weak (Relative Risk <2.0) with point estimates ranging from 0.93 to 1.83. In the subgroup of patents within each study with longest duration of exposure (ranging from 1+ year to 5+ years), the strength of association was also weak with Relative Risk point estimates ranging from 0.82 to 1.99. A limitation of many of these studies is the absence of information on cigarette smoking and BMI, both of which are risk factors for bladder cancer and could confound the reported association with pioglitazone.
An important consideration in assessing if the observed association for bladder cancer is causal is the ruling out of alternative explanations. Unlike in clinical trials where treatment is allocated by randomization, in real clinical practice the physician takes careful consideration of a range of factors in deciding the best treatment strategy for a patient. This includes how well HbA1c is being controlled with present treatment strategy, presence of diabetic complications, renal function, obesity, cardiovascular history, lipid profile and many other factors. The drug utilization pattern of pioglitazone in the UK reflects the NICE guideline [12], with pioglitazone most commonly prescribed as a 3rd line addition to metformin + sulphonylurea dual therapy, or as a 2nd line addition to metformin or sulphonylurea monotherapy. Could the reported association between the use of pioglitazone and bladder cancer be an artefact due to confounding by the prescribing pattern of pioglitazone?
As pioglitazone is predominantly used as a 3rd line or 2nd line add-on therapy, patients initiating pioglitazone are likely to have had diabetes for longer, with a longer period of inadequate glycaemic control than diabetic patients who remained just on metformin or sulphonylurea monotherapy or on metformin + sulphonylurea dual therapy. As prolonged diabetic history increases risk of cardiovascular and other diabetic complications, one might expect patients initiating pioglitazone to be at higher risk of diabetic complications. This assumption is supported by the large KPNC prospective cohort study which observed that the prevalence of diabetic complications was higher among patients initiating pioglitazone than other diabetic patients.[5]
Of particular relevance to bladder cancer is the observation in the recently reported 8-year update to the KPNC cohort study of higher prevalence of proteinuria, microalbuminuria and elevated serum creatinine (≥2mg/dL) in patients initiating pioglitazone compared to other diabetic patients.[13] Each of these is an indicator that a patient is developing renal impairment and diabetic nephropathy. The bladder cancer hazard ratio for ever exposed to pioglitazone was 1.06 (95% CI 0.87-1.30) in the 8-year update to the KPNC cohort study. This hazard ratio fell to 1.01 (95% CI 0.83-1.23) with the additional adjustment for microalbuminuria. Among the subgroup of patients with longest exposure (4+ years of pioglitazone use), the hazard ratio decreased from 1.38 (95% CI 0.97-1.96) to 1.27 (95% CI 0.90-1.81) after adjusting for microalbuminuria or proteinuria.[13]
Interestingly the KPNC study observed that microalbuminuria and proteinuria, were each strongly and independently associated with bladder cancer, with hazard ratios of 4.80 (4.11-5.61) and 5.49 (95% CI 4.65-6.47).[13] However, neither of these factors are recognized causes of bladder cancer. A likely explanation suggested by the KPNC investigators for this finding was that the presence of proteinuria may prompt a treating physician to order complete and serial urinalyses, which in turn may detect haematuria and prompt an evaluation that leads to increased detection of bladder cancer. If this is indeed the case, then the reported association between use of pioglitazone and bladder cancer may be an artefact and result from detection bias.
This alternative explanation is in part supported by a further analysis by the KPNC investigators of the type of bladder cancer detected. Ninety two percent of bladder cancers detected in pioglitazone patients were carcinoma in situ or localised neoplasms, and only 5% had regional or distant neoplams.[13] By comparison, among other diabetic patients in the KPNC study, there were fewer (87%) carcinoma in situ or local neoplasms, and more (9%) regional or distant neoplasm. While these differences were not statistically significant, they do raise the question of confounding due to detection bias.
To further evaluate this alternative explanation, the US Food and Drug Administration and European Medicines Agency (EMA) have requested further analyses of the KPNC cohort study. In addition, the EMA has requested a large independent pan-European bladder cancer cohort study, which is due to report in mid 2014.
Competing interests: The author is an employee of Takeda, which has Marketing Authorizations for pioglitazone
I thank Professor Azoulay and colleagues for the points that they make in defence of their paper. As a clinician working on the front line treating people with diabetes for approaching 30 years I watched the coming of the glitazones. First the disaster of troglitazone and then pioglitazone and rosiglitazone in the wake of that disaster coming onto the market with a great deal of caution surrounding them. What was clear from the start was that patients were carefully and cautiously selected before being prescribed these new agents – they were not just different from those who did not receive them – they were very different. The glitazones were very much used when other agents did not work or were failing and, as agents which reduced insulin resistance, were used in patients who were perceived to be more insulin resistant – more obese, already on high doses of insulin. Patients who are not responding to other agents are those with more “advanced”, and poorly controlled diabetes, more down the line in terms of beta cell failure.
Thus clinical experience by those treating patients with diabetes is that the pioglitazone patients were heavier, more poorly controlled, more insulin resistant, more likely to be on insulin, on higher doses of insulin – i.e. very different from those not treated with pioglitazone. Since, as I pointed out in my previous comments on the paper by Professor Azoulay and colleagues, these factors may be associated with increased bladder cancer risk on their own, this will naturally lead to clinicians being very suspicious of observational studies comparing those treated with pioglitazone with those not so treated. In as far as the data is available, the observational studies would seem to confirm the difference between pioglitazone users and non pioglitazone users that is the day to day experience of clinicians treating diabetes – though obviously in a limited way. I accept Professor Azoulay and colleague’s robust defence of their study and that they made every attempt to try to compensate for the factors differentiating pioglitazone from non pioglitazone users; nevertheless Professor Azoulay and colleagues accept the biases inherent in observational studies remain. I attempt to show below how difficult it is to compensate using statistics for the factors differentiating pioglitazone from non pioglitazone users and how great are the potential biases that remain in observational studies.
It is important to recognise that while some attempt can be made to adjust for differences using regression analysis, this are limited by the extent of data available. To be able to fully compensate for the factors in the differences (if this is indeed possible) we have to completely know the extent of the differences and potential impact of that extent. Associations between risk factors and outcomes may be complex. For example with the observational studies finding more smokers amongst pioglitazone users, it is not a simple matter to compensate for this using regression analysis. One also needs to take into account the extent of the smoking. Does heavier smoking lead to more bladder cancer? Is the relationship linear or exponential? Was the smoking amongst pioglitazone users much heavier than non pioglitazone users and could this much heavier smoking lead to a much greater effect? Without truly knowing how heavy the smoking was in the pioglitazone users compared to the non pioglitazone users and the extent of the risk one cannot truly compensate.
Similarly with uncontrolled diabetes. What factor could connect uncontrolled diabetes to increased risk of bladder cancer? Could it be, by way of example, through glycosuria? If so in order to assess the true impact of the poorly controlled diabetes on the risk of bladder cancer one would need to know the extent of the excess of glycosuria in the pioglitazone users compared to the non pioglitazone users. Also whether relationship between the glycosuria and bladder cancer risk is linear or exponential? Also whether microvascular damage (which might be greater in the “more advanced diabetes” pioglitazone users) exacerbates the risk? If there is considerably more glycosuria amongst the pioglitazone users could this lead to a considerably greater risk of bladder cancer. Similar arguments could be made with regard to obesity, insulin resistance, insulin use, and ‘more advanced diabetes’ with perhaps more microvascular and macrovascular damage amongst the pioglitazone treated patients. Thus one does have to be very wary when concluding from observational studies.
Professor Azoulay and colleagues suggest that their results are supported by signals from randomised controlled trials. I would like to challenge that statement. The ‘randomised controlled trials’ is effectively the PROactive study (1). It is important to point out that in that study the 19 bladder cancer cases (I have removed the one case from the placebo group since considered to be benign (2)) were reviewed by external experts prior to unblinding of the study and that these experts considered that 11 tumours that occurred within one year of randomisation could not plausibly be related to treatment. Once these 11 cases are removed we are left with six in the pioglitazone group and two in the placebo group (Chi-Sq = 2•046, p = 0•153). It is important to point out that Professor Azoulay and colleagues, in the main analysis of their study, also excluded cases of bladder cancer occurring in the first year of pioglitazone treatment to take into account a ‘biologically meaningful latency time’ – thus Professor Azoulay and colleagues came to the same conclusion as the external experts in the PROactive study about the likelihood of cases occurring in the first year of treatment being related to treatment. Once these cases are removed there is no association between bladder cancer and pioglitazone in randomised controlled trials. One could argue that this obviates the need to do observational studies. Either way, one should be particularly wary of the results from observational studies given the context of no support from randomised controlled trials.
Finally it must be stressed that many observational studies find no link between pioglitazone and bladder cancer (3-5), in particular the latest eight year interim analysis of the 10 year KPNC study (6).
References
1. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–1289.
2. Hillaire-Buys D, Faillie JL, Montastruc JL. Pioglitazone and bladder cancer. Lancet 2011;378:1543-4; author reply 4-5.
3. Tseng CH. Pioglitazone and bladder cancer: a population-based study of Taiwanese. Diabetes Care 2012; 35: 278-80.
4. Chang CH, Lin JW, Wu LC, Lai MS, Chuang LM, Arnold Chan K. Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus. Hepatology 2012;55:1462-72
5. Li W, Macdonald TM, Mackenzie IS. Pioglitazone and bladder cancer: A propensity score matched cohort study. Br J Clin Pharmacol. 2012 May 11. doi: 10.1111/j.1365-2125.2012.04325.x. [Epub ahead of print]
6. Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry CP Jr, Vaughn DJ, Nessel L, Selby J, Habel, L, Strom BL. Cohort Study of Pioglitazone and Bladder Cancer in Patients with Diabetes: Fourth Interim Analysis (8-Year) Report with Data from January 1, 1997 to December 31, 2010. May 30, 2012. http://www.tpna.com/research_development/pdf/01-03-TL-OPI-524_8-year_Int... (accessed July 9, 2012)
Competing interests: I have received speaker fees, consultancy fees and educational sponsorship from Eli Lilly, GlaxoSmithKline, Novo Nordisk, Sanofi-Aventis, and Takeda.
We thank Dr. Ryder for his interest in our paper and for raising the important issues of confounding and switching of high-risk patients to pioglitazone. As discussed in our paper (1), pioglitazone users were in fact different from non-thiazolidinedione (TZD) users. For this reason, we also included a comparison between patients ever exposed to pioglitazone and those ever exposed to rosiglitazone. Overall, these two TZD groups were similar for most characteristics (see Web Extra for data supplement). In addition, we adjusted for known bladder cancer risk factors, including smoking, obesity, and uncontrolled diabetes, in all of our regression analyses.
It is important to note that this statistical adjustment had a minimal effect on our point estimates (crude rate ratio: 1.87 versus adjusted rate ratio: 1.83), suggesting a minimal effect of confounding. Furthermore, given the large point estimates observed, a very strong confounder (i.e. one strongly associated with both the exposure and outcome) would be required to fully explain the observed association. It is unclear whether such a variable exists beyond those considered, although residual confounding is possible. We acknowledge this possible limitation in our paper. As for Dr. Ryder’s concern regarding the switching of high-risk patients from rosiglitazone to pioglitazone, we explicitly dealt with this possibility by creating an exposure group consisting of patients who were exposed to both TZDs. We observed no increased risk with this group, although only 2 cases and 56 controls were ever exposed to both TZDs.
In summary, residual confounding is a limitation of any observational study. With respect to our study question, we were able to adjust for known bladder cancer risk factors. Such adjustment did not materially affect the point estimates, suggesting that confounding had a limited role in the association. Finally, our results are supported by signals observed in randomized controlled trials, which were not subjected to the biases described above.
1. Azoulay L, Yin H, Filion KB, Assayag J, Majdan A, Pollak MN, Suissa S. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012: 30;344:e3645.
Competing interests: No competing interests
The problem with the observational study of Azoulay and colleagues (1), as with all the observational studies regarding pioglitazone and bladder cancer, is that patients who were prescribed pioglitazone were prescribed this medication for reason and this makes these patients different from those who were not. For example, as stated by Azoulay and colleagues “participants prescribed thiazolidinediones were more likely to be obese, to have ever smoked, and to have uncontrolled diabetes than those who never used any thiazolidinedione" (1). Thus in their study three factors which on their own might lead to increased bladder cancer (2-7) were increased among pioglitazone users, removing the validity of proposing a link to pioglitazone itself.
In an attempt to alleviate this problem for their case, Azoulay and colleagues note that exclusive ever users of pioglitazone and rosiglitazone were generally similar on most variables and yet there did not seem to be an increased bladder cancer risk in rosiglitazone users (1). Even though Azoulay and colleagues did not detect a difference between the groups with the limited information available to them to try, there will nevertheless have been important differences with regard to bladder cancer risk because of two major confounders.
1) The cardiovascular benefits of pioglitazone were exposed to many in the PROactive study in 2005 (8). Once this study was published more cardiovascular disease patients will have been put on pioglitazone than rosiglitazone. The risk factors for cardiovascular disease are similar to those of increased bladder cancer risk – for example the factors found more commonly among pioglitazone users in the study of of Azoulay and colleagues – smoking, obesity and uncontrolled diabetes, are risk factors for both cardiovascular disease and bladder cancer. Thus following the PROactive study the patients put onto pioglitazone, as opposed to rosiglitazone, for cardiovascular reasons would also be those more at risk of bladder cancer.
2) Even more impact will have come from the second major confounder - the well publicised paper in the New England Journal of Medicine which first raised the possibility that rosiglitazone is harmful from the cardiovascular point of view (9). This will have provided even more impetus for the “cardiovascular” diabetes patients (i.e. those with more risk factors for bladder cancer) being put on pioglitazone rather than rosiglitazone. Furthermore many of these bladder cancer risk “cardiovascular” patients will have been switched from rosiglitazone to pioglitazone and hence the more problematic, complex, “cardiovascular” (high bladder cancer risk) cases would have ended up on pioglitazone with those who were more stable and well controlled, low cardiovascular risk, diabetes (the low bladder cancer risk patients) remaining on rosiglitazone. Thus not only do we have higher bladder cancer risk patients going onto pioglitazone rather than rosiglitazone and therefore being available for a spurious link between pioglitazone and bladder cancer to be found, but also those who were switched (high bladder cancer risk patients) would have been removed from the exclusive ever users of rosiglitazone who were studied by Azoulay and colleagues, reducing the numbers at risk of bladder cancer in that group.
Azoulay and colleagues conclude that the use of pioglitazone is associated with an increased risk of incident bladder cancer among people with type 2 diabetes (1). Fortunately the association they found was likely because pioglitazone users were at high risk of bladder cancer already because of other factors such as obesity, smoking and uncontrolled diabetes making their proposed causal link between bladder cancer and pioglitazone use spurious.
References
1. Azoulay L, Yin H, Filion KB, Assayag J, Majdan A, Pollak MN, Suissa S. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ. 2012; 344: 15. doi: 10.1136/bmj.e3645.
2. Koebnick C, Michaud D, Moore SC, Park Y, Hollenbeck A, Ballard-Barbash R, Schatzkin A, Leitzmann MF. Body mass index, physical activity, and bladder cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev. 2008; 17(5): 1214-21.
3. Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA 2011; 306(7): 737-45.
4. Yeung NG, Husain I, Waterfall N. Diabetes mellitus and bladder cancer - an epidemiological relationship? Pathology Oncology Research 2003; 91: 30-31.
5. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol. 2004;159(12): 1160-7.
6. Larsson SC, Orsini N, Brismar K, Wolk A. Diabetes mellitus and risk of bladder cancer: a meta-analysis.Diabetologia. 2006 49(12): 2819-23
7. MacKenzie T, Zens MS, Ferrara A, Schned A, Karagas MR. Diabetes and risk of bladder cancer: evidence from a case-control study in New England. Cancer 2011; 117: 1552-6.
8. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–1289.
9. Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med 2007; 356: 2457–2471.
Competing interests: I have received speaker fees, consultancy fees and educational sponsorship from Eli Lilly, GlaxoSmithKline, Novo Nordisk, Sanofi-Aventis, and Takeda.
Diabetics have ≥2 fold risk of cancers of the liver, pancreas, and endometrium due to exposure of liver and pancreas to high level of insulin from pancreatic beta cells via portal vein and metabolic changes in liver (non-alcoholic fatty liver, steastosis and cirrhosis). 1.2–1.5 fold risk of cancers of the colon and rectum, breast, and bladder is imparted by diabetes. Prostate cancer occurs less frequently in diabetic men due to reduced testosterone levels, but not related to differential Prostate-specific antigen (PSA) utilization bias. There is no association between lung cancer and for other malignancy (kidney, non-Hodgkin’s lymphoma) evidences are inconclusive. [1,2,3]
Diabetics with cancer have increased age-adjusted mortality rate, poorer disease-specific survival as compared to non-diabetics. This may be partly or largely attributable to diabetes itself. [4] Obesity and hyperinsulinemia that are associated with diabetes may also delay diagnosis and blunt the effect of treatment. [2]
The association between diabetes and cancer maybe due to shared modifiable and non-modifiable risk factors common to both of these conditions. Common risk factors are aging, sex, obesity, physical activity, diet, alcohol, and smoking. [1]
Diabetes and cancer increase in incidence with age. [5] Overall cancers and age-adjusted risk of diabetes is higher among male than females. African Americans have higher incidence of both cancer and diabetes and suffer more morbidity and mortality of type 2 diabetes mellitus and cancer. Hispanic whites, Native Americans, Asian Americans/Pacific Islanders have lower cancer incidence and death, while non-Hispanic whites have lower incidence of diabetes and its morbidity. [6,7]
Obesity and weight gain are associated with increased incidence of cancer. [3,8] Adipose tissue is an active endocrine organ producing free fatty acids, interleukin-6 (IL-6), monocyte chemoattractant protein, plasminogen activator inhibitor-1 (PAI-1), adiponectin, leptin, and tumor necrosis factor-ἀ. Each of these factors might play an etiologic role in regulating malignant transformation or cancer progression. [9] Although obesity is not associated, sometimes inversely associated, with prostate cancer, obese men have higher prostate cancer mortality compared to normal men. [3] Weight loss is inversely associated with risk of both diabetes and cancer. [8]
Diets low in red and processed meats and higher in vegetables, fruits, and whole grains (low-calorie, low-fat and high-fiber diet) lower the risk of cancer and diabetes. Higher levels of physical activities reduce the risk of cancer and improved survival after the diagnosis. [10,11]
Smoking causes cancer and is risk factor for development of diabetes, increases risk of diabetes-related complication and impact diabetes-related health outcomes. [12-15] Moderate is associated with increased risk of cancer and reduced incidence of diabetes in both sexes. Excess alcohol consumption is associated with raised diabetes risk. [16]
Most cancer cells express A isoform of insulin and IGF-I receptors. These receptors stimulate multiple cancer phenotypes including proliferation, protection from apoptotic stimuli, invasion, metastasis, promotion and progression of cancer cells. [17] Hyperglycemia allows IGF-I to stimulate vascular smooth muscle cell proliferation and migration. [18] Insulin reduces the hepatic production of IGF and sex hormone binding proteins thereby increases circulating free, bioactive IGF, estrogen in both sexes and testosterone in women. [19-20]
Anti-diabetic medications except metformin increases risk of cancer in either or both in vitro and in vivo studies. Association of diabetes and cancer may be direct (hyperglycemia), indirect (due to common risk factors such as obesity) or due to underlying biological factors (insulin resistance and hyperinsulinemia). Influence of diabetes duration on cancer risk is unclear and complicated by multi-drug anti-diabetic therapy. [1]
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2. Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer 2009;16:1103–1123.
3. Ma J, Li H, Giovannucci E, Mucci L, Qiu W, Nguyen PL, Gaziano JM, Pollak M, Stampfer MJ. Prediagnostic body-mass index, plasma C-peptide concentration and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol 2008;9:1039–1047.
4. Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL, Wolff AC, Brancati FL. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 2008;300:2754–2764.
5. Garcia M, Jemal A, Ward EM, Center MM, Hao Y, Siegel RL, Thun MJ. Global Cancer Facts & Figures 2007. Atlanta, Georgia, American Cancer Society, 2007.
6. National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2007 [article online], 2008. Atlanta, Georgia, Centers for Disease Control and Prevention. Available from http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed 1 April 2010
7. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin 59:225–249, 2009.
8. Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective [article online], 2007. London, World Cancer Research Fund, American Institute for Cancer Research. Available from http://www.dietandcancerreport.org/. Accessed 1 April 2010.
9. van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev 2009;18:2569–2578.
10. Kushi LH, Byers T, Doyle C, Bandera EV, McCullough M, McTiernan A, Gansler T, Andrews KS, Thun MJ, American Cancer Society 2006 Nutrition and Physical Activity Guidelines Advisory Committee. American Cancer Society guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin 2006;56:254–281.
11. Tomuta V, Wylie-Rosett J. Nutritional management of diabetes in diabetes and exercise. In Exercise and Diabetes. Regensteiner JG, Reusch JEB, Steward KJ, Veves A, Eds.NewYork,Humana Press, 2009; p.231–262.
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16. Howard AA, Arnsten JH, Gourevitch MN. Effect of alcohol consumption on diabetes mellitus: a systematic review. Ann Intern Med 2004;140:211–219.
17. Denley A, Carroll JM, Brierley GV, Cosgrove L,Wallace J, Forbes B, Roberts CT, Jr.: Differential activation of insulin receptor substrates 1 and 2 by insulin-like growth factor-activated insulin recep tors. Mol Cell Biol 2007;27:3569–3577.
18. Clemmons DR, Maile LA, Ling Y, Yarber J, Busby WH. Role of the integrin alphaVbeta3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycaemic stress. Growth Horm IGF Res 2007;17:265–270.
19. Powell DR, Suwanichkul A, Cubbage ML, DePaolis LA, Snuggs MB, Lee PD. Insulin inhibits transcription of the human gene for insulin-like growth factor binding protein-1. J Biol Chem1991;266:18868–18876.
20. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004;4:579–591
Competing interests: No competing interests
Re: The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study
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Competing interests: No competing interests