Thiazolidinedione Therapy Is Not Associated With Increased Colonic Neoplasia Risk in Patients With Diabetes Mellitus

doi:10.1053/j.gastro.2008.09.004

Gastroenterology

Volume 135, Issue 6, December 2008, Pages 1914-1923.e1

https://doi.org/10.1053/j.gastro.2008.09.004 Get rights and content

Background & Aims

Thiazolidinedione ligands for peroxisome proliferator-activated receptor γ (PPARγ), are used to treat diabetes. PPARγ is highly expressed in the colon, and exposure to thiazolidinediones has been proposed to affect the risk for colorectal neoplasia. In vitro models suggest that thiazolidinediones have antineoplastic effects, whereas in vivo studies have produced mixed results: Some indicate an increased risk for intestinal tumors. This study examined the association between PPARγ-targeted therapies and the risk of colonic neoplasia in patients with diabetes.

Methods

We conducted 3 retrospective case-control studies nested within the cohort of diabetic patients who were cared for within the Kaiser Permanente of Northern California system from 1994 to 2005. Case subjects were those with colonic neoplasia identified at the time of colonoscopy (study 1), sigmoidoscopy (study 2), or at follow-up lower endoscopy (study 3). Controls had no neoplasia identified at the endoscopic examination. A minimum of 1 year of therapy was used to define medication exposure.

Results

Fourteen thousand eighty-six patients were included. Among patients undergoing colonoscopy, there was an inverse association between thiazolidinedione exposure and prevalence of neoplasia (adjusted odd ratio [OR], 0.73; 95% confidence interval [CI], 0.57–0.92); however, this was not evident among patients without anemia (adjusted OR, 0.97; 95% CI, 0.64–1.49). Significant associations between any or long-term thiazolidinedione use and colonic neoplasia were not observed among patients undergoing sigmoidoscopy or serial lower endoscopies.

Conclusions

These results indicate that thiazolidinedione therapy is not associated with an increased risk for colonic neoplasia.

Section snippets

Patients and Methods

We conducted 3 retrospective case-control studies nested within the cohort of diabetic patients cared for within the Kaiser Permanente health care system in Northern California (KPNC) during the period 1994 to 1996 and who continue to receive care between 1999 and 2005.

Results

Among the 62,465 patients with type 2 diabetes mellitus, 14,086 had undergone at least 1 lower endoscopy during the study period and met the other inclusion criteria. Cases and controls were relatively similar in all baseline characteristics and across the 3 case-control studies (Table 1). In each case-control study, there were slightly lower percentages of case subjects who were women (eg, 41% cases vs 49% controls in study 1) or users of prescription NSAIDs (eg, 12% cases vs 17% controls in

Discussion

Previous animal studies have suggested that exposure to TZDs can increase or decrease the risk of colonic neoplasia. Because patients with type 2 diabetes mellitus have an increased risk of colorectal cancer, it is important to determine whether the phenomena observed in animal models apply to humans. Two prior studies addressed this question in patients with diabetes. Koro et al did not observe an association between TZD therapy and colon cancer risk but lacked sufficient data to conduct a

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Antidiabetic drugs and risk of cancer
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Citation Excerpt :
A minimum of a year-therapy was considered as medication exposure. The results proved no association between TZDs therapy and colonic neoplasia (overall OR = 0.73, 95% CI = 0.57–0.92, patients without anemia OR = 0.97, 95% CI = 0.64–1.49 [74]. In other study, carried out by Lai et al. [53], 19,000 patients with newly diagnosed diabetes were exposed to metformin, TZDs or alpha glucosidase inhibitors.
Antidiabetic drugs are an important group of medications used worldwide. They differ from each other in the mechanisms of lowering blood glucose as well as in adverse effects that may affect the course of the treatment and its efficacy. In recent years, new drugs have been discovered in order to improve the maintenance of proper blood glucose level and to reduce unwanted effects of these drugs. Their growing administration is related to the increasing incidence of diabetes observed in all countries in the world. Epidemiological data indicate that diabetes increases the risk of cancer, as well as the risk of death linked with neoplasms. It is still unknown whether this is an effect of antidiabetic drugs or just the effect of diabetes itself. In recent years there have been numerous investigations and meta-analyzes, based on both comparative and cohort studies trying to establish the relationship between antidiabetic pharmacotherapy and the incidence and mortality due to cancer. According to their findings, most of antidiabetic drugs increase the risk of cancer while only few of them show antitumor properties. Different mechanisms of action of glucose-lowering drugs may be responsible for these effects. However, most of the published studies concerning the influence of these drugs on cancer incidence were designed with some limitations and differed from each other in the approach.
In this review, we discuss the association between antidiabetic drugs used in monotherapy or polytherapy and cancer risk, and consider potential mechanisms responsible for the observed effects.
Positive and negative effects of glitazones in carcinogenesis: Experimental models vs. clinical practice
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Data on glitazone use and cancer risk in diabetic patients are controversial. Some studies found neither higher nor lower risk of cancer in glitazone users [51,81,88,107]. A retrospective analysis showed that the incidence of lung cancer was 33% lower compared to non-users [60], but the duration of glitazone use was not considered, the participants were almost exclusively men, and the study was not able to account for smoking history, which complicates data interpretation.
Diabetes increases cancer risk, which may be modulated by careful choice of treatment. Experimental reports showed efficacy of glitazones in various in vitro and in vivo models of carcinogenesis, but procarcinogenic effects in some models were reported too, and, similarly, data on cancer incidence in glitazone users are inconsistent. This review summarizes oncostatic effects of glitazones in preclinical and clinical studies and brings a brief summary of their impact on cancer risk in diabetic patients, with a focus on the association between pioglitazone use and bladder cancer.
Thiazolidinedione use and cancer incidence in type 2 diabetes: A systematic review and meta-analysis
2012, Diabetes and Metabolism
Citation Excerpt :
In this previous review, we observed an increased risk of bladder cancer associated with TZD use (pooled RR: 1.15, 95%CI 1.04–1.26), which in subgroup analyses was significantly associated with pioglitazone use, but not rosiglitazone use, suggesting that TZD analogues may differ in their association with any given cancer [15]. Aside from the recent focus on bladder cancer, a number of studies report on TZD use and other cancers in people with type 2 diabetes [16–19]. Therefore, our objective was to systematically gather, summarize and appraise evidence from randomized controlled trials (RCTs), cohort and case-control studies to explore the effects of TZDs on the risk of overall and site-specific cancers in people with type 2 diabetes.
Evidence suggests thiazolidinediones (TZDs) may modify the relationship between type 2 diabetes and cancer incidence. We aimed to summarize data from randomized controlled trials (RCTs) and observational studies to examine risk of overall and site-specific cancers with TZD use in individuals with type 2 diabetes.
We searched 12 key biomedical databases and seven grey literature sources up to June 2011, without language restrictions. We performed separate meta-analyses according to cancer site and study design, comparing ever-use to never-use of TZDs, and pioglitazone alone.
The search yielded 1338 unique citations; we included four RCT, seven cohort and nine nested case-control studies, contributing data from 2.5 million people. Estimates from observational studies suggested any TZD use was associated with a decreased risk of colorectal (pooled RR: 0.93, 95%CI 0.87–1.00, P = 0.04, I² = 30%), lung (pooled RR: 0.91, 95%CI 0.84–0.98, P = 0.02, heterogeneity (I²) = 35%) and breast (pooled RR: 0.89, 95%CI 0.81–0.98, P = 0.02, I² = 44%) cancer. Risk of overall cancer with TZD use was not significantly modified in RCTs (pooled RR: 0.92, 95%CI 0.79–1.07, P = 0.26, I² = 0%) or observational studies (pooled OR: 0.95, 95%CI 0.78–1.16, P = 0.63, I² = 70%). Pioglitazone use was, however, associated with a decreased risk of overall cancer (colorectal, lung, breast, prostate and renal sub-sites combined) in observational studies (pooled RR: 0.95, 95%CI 0.91–0.99, P = 0.009, I² = 0%).
Our findings suggest that use of TZDs is associated with a modest but significantly decreased risk of lung, colorectal and breast cancers. Results were limited by the paucity of studies designed to answer our research question. Further evaluation of TZD use, cancer risk factors and potential confounders is required.
Certaines données suggèrent que les thiazolidinediones (TZDs) pourraient modifier les relations diabète type 2 (DT2) et cancer. Nous avons passé en revue les résultats provenant des essais contrôlés randomisés (ECR) et des études observationnelles afin d’examiner l’association éventuelle entre le risque de cancer, global et par site-spécifique, avec l’utilisation des TZDs chez les patients atteints de DT2.
La recherche bibliographique a été fondée sur 12 bases de données biomédicales et sept sources de littérature grise jusqu’à juin 2011, sans restriction de langue. Les méta-analyses ont été réalisées par site de cancer et par type d’étude, en fonction ou non de la prise de TZDs.
La recherche bibliographique a donné 1338 citations uniques ; nous avons inclus quatre ECR, sept études de cohorte et neuf études cas-témoins, soit les données de 2,5 millions de patients. Les estimations provenant d’études observationnelles suggèrent que la prise de TZDs est associée à une diminution du risque de cancer colorectal (RR combiné : 0,93, IC à 95 % 0,87–1,00, P = 0,04, I² = 30 %), de cancer du poumon (RR combiné : 0,91, IC 95 % 0,84–0,98, P = 0,02, hétérogénéité (I²) = 35 %) et de cancer du sein (RR combiné : 0,89, IC 95 % 0,81–0,98, P = 0,02, I² = 44 %). Il n’y avait pas de modification significative du risque total de cancer global par la prise de TZDs en ECR (RR combiné : 0,92, IC 95 % 0,79–1,07, P = 0,26, I² = 0 %) ou en études d’observation (OR combiné : 0,95, IC 95 % 0,78–1,16, P = 0,63, I² = 70 %). La prise de pioglitazone était cependant associée à une réduction du risque global de cancer (dont cancer colorectal, du poumon, du sein, de la prostate, et du rein combiné) dans les études observationnelles (RR combiné : 0,95, IC 95 % 0,91–0,99, P = 0,009, I² = 0 %).
Nos résultats suggèrent que la prise des TZD est associée à une diminution modeste mais significative du risque de cancers pulmonaire, colorectal et mammaire. Ces résultats sont limités par la rareté des études qui visent à répondre à la question posée dans cette étude. Il est nécessaire d’évaluer de manière plus poussée, les effets de la prise des TZDs, les facteurs de risque de cancer et les facteurs de confusion potentiels.
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Citation Excerpt :
We observed a decreased cancer risk in diabetic women with effective medications compared with those without. An effective medical intervention for type 2 diabetes can decrease colon cancer risks [37,38], but we have not found similar reports in endometrial cancer in the English literature by now. A recent epidemiological investigation suggested a protective role of regular physical activity, a common way to control overweight/obesity and diabetes mellitus, on cancer risk [39].
To investigate the association between insulin-resistance-related conditions (comprising the metabolic syndrome) and endometrial cancer risk in Chinese women.
We conducted a large case-control study including 942 endometrial cancers and 1721 controls on a Chinese population. The relative endometrial cancer risks from various factors were calculated by the х² test. Menopausal status and BMI were applied as potential confounders to analyze the joint effects with other factors.
We found that overweight/obesity, hypertension, diabetes mellitus and glucose metabolic disturbance were all associated with endometrial cancer risk. Effective medication on diabetes can significantly decrease cancer risk (uncontrolled diabetes: RR = 5.563, 95% CI = 2.406–12.859, p < 0.001; controlled diabetes: RR = 1.331, 95% CI = 0.529–3.352, p > 0.05) as compared with normal controls. Serum lipids were also found to be linked to endometrial cancer risk: positive correlations were present with total serum cholesterol, triglycerides, low-density lipoprotein cholesterol and dyslipidaemia, while a negative correlation was found with high-density lipoprotein cholesterol. We also observed an elevated risk for type I endometrial cancer (OR = 1.839, 95% CI = 1.539–2.197, p < 0.001) in women with BMI ≥ 24.58 versus those with BMI < 24.58, but not for type II cancer (OR = 1.092, 95% CI = 0.969–1.231, p > 0.05).
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: The authors disclose the following: Supported by NIH grant CA102599. Drs Lewis, Habel, Ferrara, and Quesenberry have received research funding from Takeda. Dr Lewis has received research support from GlaxoSmithKline. Drs Habel and Ferrara have received research support from Eli Lilly. Dr Habel has also received research support from Merck.

View full text

Clinical—Alimentary TractThiazolidinedione Therapy Is Not Associated With Increased Colonic Neoplasia Risk in Patients With Diabetes Mellitus

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients and Methods

Results

Discussion

Gastroenterology

Gastroenterology

Diabetes mellitus and risk of colorectal cancer: a meta-analysis

J Natl Cancer Inst

Increased blood glucose and insulin, body size, and incident colorectal cancer

J Natl Cancer Inst

Insulin resistance, apoptosis, and colorectal adenoma risk

Cancer Epidemiol Biomarkers Prev

The nuclear eicosanoid receptor, PPARγ, is aberrantly expressed in colonic cancers

Carcinogenesis

Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice

Nat Med

Activators of the nuclear receptor PPARγ enhance colon polyp formation

Nat Med

Differentiation and reversal of malignant changes in colon cancer through PPARγ

Nat Med

The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus

Coron Artery Dis

Choice of treatment affects plasma levels of insulin-like growth factor-binding protein-1 in noninsulin-dependent diabetes mellitus

J Clin Endocrinol Metab

Biology of PPAR γ in cancer: a critical review on existing lacunae

Curr Mol Med

Ligands for peroxisome proliferator-activated receptors α and γ inhibit chemically induced colitis and formation of aberrant crypt foci in rats

Cancer Res

APC-dependent suppression of colon carcinogenesis by PPARγ

Proc Natl Acad Sci U S A

Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands

Cancer Res

Cancer risks in thiazolidinedione users compared to other anti-diabetic agents

Pharmacoepidemiol Drug Saf

Clinical—Alimentary Tract
Thiazolidinedione Therapy Is Not Associated With Increased Colonic Neoplasia Risk in Patients With Diabetes Mellitus

Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APC^Min/+ mice