Diabetologia (2015) 58:201–202 DOI 10.1007/s00125-014-3426-2
LETTER
Linking prediabetes and cancer: a complex issue Dario Giugliano & Maria Ida Maiorino & Katherine Esposito
Received: 17 September 2014 / Accepted: 19 September 2014 / Published online: 25 October 2014 # Springer-Verlag Berlin Heidelberg 2014
To the Editor: We read with interest the meta-analysis by Huang et al [1] on the association between prediabetes and risk of cancer. In this article, prediabetes was defined as being a general term referring to an intermediate stage between normoglycaemia and overt diabetes [1]. Based on the data obtained from 13 cohorts (as indicated in Fig. 2 of their paper), the authors concluded that prediabetes was associated with a 15% increased risk for the general population of developing cancer. Overall, the findings seem to be in line with the evidence of a positive association between diabetes and cancer [2]; as for other diabetic complications, including cardiovascular complications, the association seems to encompass both the diabetic and prediabetic states. Type 2 diabetes is associated with an increased risk of several cancer types, including postmenopausal breast, colorectal, endometrial, liver and pancreatic cancer, and non-Hodgkin’s lymphoma [2]. These associations seem to be independent of BMI. Furthermore, patients with pre-existing diabetes who develop cancer have increased short-term and long-term mortality compared with non-diabetic patients [3]. The evidence that diabetes is associated with an increased risk of both cancer incidence and mortality did not escape the attention of Huang et al [1], who carried out a subgroup analysis dividing the endpoints in terms of cancer mortality and incidence, with similar results (a 14% and 17% increase, respectively). As nine cohorts were included in the subgroup analysis of cancer mortality, compared with just one cohort for D. Giugliano (*) : M. I. Maiorino Department of Medical, Surgical, Neurological and Metabolic Sciences and Aging, Second University of Naples, Piazza L. Miraglia 2, 80138 Naples, Italy e-mail: [email protected] K. Esposito Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy
cancer incidence (Table 2 in [1]), the results of the metaanalysis apply to mortality from cancer and not to the incidence of cancer. So the modest, albeit significant, positive association between prediabetes and cancer should read prediabetes and mortality from cancer. The magnitude of the association between prediabetes and cancer mortality, a 14% increase in the meta-analysis of Huang et al [1], appears to be less than that reported in the literature for diabetic patients: in 23 studies comparing cancer patients with or without pre-existing diabetes, Barone et al [3] showed that diabetes was associated with an increased mortality (41% increase) compared with normoglycaemia across all cancer types. Subgroup analyses by type of cancer showed an increased risk of cancer of the endometrium (76% increase), breast (61% increase) and colorectum (32% increase). A recent meta-analysis [4] has demonstrated that the metabolic syndrome is associated with common cancers, including liver, colorectal and bladder cancer in men, and endometrial, pancreatic, postmenopausal breast and colorectal cancer in women. Interestingly, the risks of site-specific cancer in prediabetic individuals (pooled sexes) were highest for liver, endometrial and stomach/colorectal cancer. In individuals with no overt diabetes at baseline, the metabolic syndrome is a strong risk factor for future type 2 diabetes and may be considered to be a prediabetic state [5]. Evaluating the influence of any single component of metabolic syndrome on the risk of some common cancers may overcome, at least in part, the forced combination of multiple components in a single variable, and provide a rough estimate of the risk of cancer in individuals with dysglycaemia (a high fasting or postprandial glucose level). Pooling the data from 14 data sets from eight different prospective studies evaluating the association between metabolic syndrome and risk of cancer [6], the risk estimate for dysglycaemia, compared with normal glucose values, was 1.29 (RR; 95% CI 1.11, 1.49), which was highly comparable with the estimate (RR 1.30, 95% CI 1.20, 1.40) of
202
Larsson et al [7] obtained with diabetic patients by pooling nine cohorts and six case–control studies comprising 26,306 cases of colorectal cancer. The estimate of Huang et al [1] for stomach/colorectal cancer combined was slightly higher (1.55, 1.15, 2.09) but was the result of three cohorts (Fig. 4 in [1]), two of which underwent evaluation of the risk of mortality from cancer. The meta-analysis by Huang et al [1], pooling prospective studies that evaluated the risk of cancer in association with impaired fasting glucose and impaired glucose tolerance, concludes that prediabetes is associated with an increased risk of cancer, especially liver, endometrial and stomach/colorectal cancer. As such, this interpretation seems to go the right way in terms of the positive association between diabetes and the incidence and mortality of cancer. However, readers should be aware that: (1) ten studies included in the meta-analysis evaluated cancer mortality, five studies evaluated cancer incidence and one study evaluated both; (2) the subgroup analyses indicating associations at specific sites are biased by the small number of studies included (three studies for stomach/colorectal, three studies for liver, and only one study for endometrial cancer) and by mixing mortality (four studies) and incidence (three studies); and (3) last but not least, the effect seems sex specific, as it is not significant in women. Finally, most studies included in the meta-analysis based the diagnosis of prediabetes on a single elevated blood glucose level at baseline; hence, the occurrence of frank diabetes during the observational period was not taken into consideration, and neither was any glucose-lowering treatment included in the analyses. Although the idea is attractive and is supported by indirect evidence from individuals with the metabolic syndrome, the relationship between prediabetes and risk of cancer remains nebulous and needs to be substantiated by further studies prospectively evaluating the development of cancer in individuals who remain in their prediabetic state. In the meantime, as prediabetes can be slowed down or even reversed to regain
Diabetologia (2015) 58:201–202
a normal plasma glucose level by lifestyle interventions, sustained and bearable lifestyle changes can also help in the fight against cancer [8]. Duality of interest The authors declare that there is no duality of interest associated with this manuscript. Contribution statement DG drafted the article and approved the final version. MIM and KE contributed to the critical revision of the article and its final approval. DG is the guarantor of this work.
References 1. Huang Y, Cai X, Qiu M et al (2014) Prediabetes and the risk of cancer: a meta-analysis. Diabetologia 57:2261–2269 2. Renehan A, Smith U, Kirkman MS (2010) Linking diabetes and cancer: a consensus on complexity. Lancet 375:2201–2202 3. Barone BB, Yeh HC, Snyder CF et al (2008) Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300:2754–2764 4. Esposito K, Chiodini P, Colao A, Lenzi A, Giugliano D (2012) Metabolic syndrome and risk of cancer: a systematic review and meta-analysis. Diabetes Care 35:2402–2411 5. Alberti KGMM, Eckel RH, Grundy SM et al (2009) International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–1645 6. Esposito K, Chiodini P, Capuano A et al (2013) Colorectal cancer association with metabolic syndrome and its components: a systematic review with meta-analysis. Endocrine 44:634–647 7. Larsson SC, Orsini N, Wolk A (2005) Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 97:1679–1687 8. Esposito k, Ciardiello F, Giugliano D (2014) Unhealthy diets: a common soil for the association of metabolic syndrome and cancer. Endocrine 46:39–42
LETTER
Linking prediabetes and cancer: a complex issue Dario Giugliano & Maria Ida Maiorino & Katherine Esposito
Received: 17 September 2014 / Accepted: 19 September 2014 / Published online: 25 October 2014 # Springer-Verlag Berlin Heidelberg 2014
To the Editor: We read with interest the meta-analysis by Huang et al [1] on the association between prediabetes and risk of cancer. In this article, prediabetes was defined as being a general term referring to an intermediate stage between normoglycaemia and overt diabetes [1]. Based on the data obtained from 13 cohorts (as indicated in Fig. 2 of their paper), the authors concluded that prediabetes was associated with a 15% increased risk for the general population of developing cancer. Overall, the findings seem to be in line with the evidence of a positive association between diabetes and cancer [2]; as for other diabetic complications, including cardiovascular complications, the association seems to encompass both the diabetic and prediabetic states. Type 2 diabetes is associated with an increased risk of several cancer types, including postmenopausal breast, colorectal, endometrial, liver and pancreatic cancer, and non-Hodgkin’s lymphoma [2]. These associations seem to be independent of BMI. Furthermore, patients with pre-existing diabetes who develop cancer have increased short-term and long-term mortality compared with non-diabetic patients [3]. The evidence that diabetes is associated with an increased risk of both cancer incidence and mortality did not escape the attention of Huang et al [1], who carried out a subgroup analysis dividing the endpoints in terms of cancer mortality and incidence, with similar results (a 14% and 17% increase, respectively). As nine cohorts were included in the subgroup analysis of cancer mortality, compared with just one cohort for D. Giugliano (*) : M. I. Maiorino Department of Medical, Surgical, Neurological and Metabolic Sciences and Aging, Second University of Naples, Piazza L. Miraglia 2, 80138 Naples, Italy e-mail: [email protected] K. Esposito Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy
cancer incidence (Table 2 in [1]), the results of the metaanalysis apply to mortality from cancer and not to the incidence of cancer. So the modest, albeit significant, positive association between prediabetes and cancer should read prediabetes and mortality from cancer. The magnitude of the association between prediabetes and cancer mortality, a 14% increase in the meta-analysis of Huang et al [1], appears to be less than that reported in the literature for diabetic patients: in 23 studies comparing cancer patients with or without pre-existing diabetes, Barone et al [3] showed that diabetes was associated with an increased mortality (41% increase) compared with normoglycaemia across all cancer types. Subgroup analyses by type of cancer showed an increased risk of cancer of the endometrium (76% increase), breast (61% increase) and colorectum (32% increase). A recent meta-analysis [4] has demonstrated that the metabolic syndrome is associated with common cancers, including liver, colorectal and bladder cancer in men, and endometrial, pancreatic, postmenopausal breast and colorectal cancer in women. Interestingly, the risks of site-specific cancer in prediabetic individuals (pooled sexes) were highest for liver, endometrial and stomach/colorectal cancer. In individuals with no overt diabetes at baseline, the metabolic syndrome is a strong risk factor for future type 2 diabetes and may be considered to be a prediabetic state [5]. Evaluating the influence of any single component of metabolic syndrome on the risk of some common cancers may overcome, at least in part, the forced combination of multiple components in a single variable, and provide a rough estimate of the risk of cancer in individuals with dysglycaemia (a high fasting or postprandial glucose level). Pooling the data from 14 data sets from eight different prospective studies evaluating the association between metabolic syndrome and risk of cancer [6], the risk estimate for dysglycaemia, compared with normal glucose values, was 1.29 (RR; 95% CI 1.11, 1.49), which was highly comparable with the estimate (RR 1.30, 95% CI 1.20, 1.40) of
202
Larsson et al [7] obtained with diabetic patients by pooling nine cohorts and six case–control studies comprising 26,306 cases of colorectal cancer. The estimate of Huang et al [1] for stomach/colorectal cancer combined was slightly higher (1.55, 1.15, 2.09) but was the result of three cohorts (Fig. 4 in [1]), two of which underwent evaluation of the risk of mortality from cancer. The meta-analysis by Huang et al [1], pooling prospective studies that evaluated the risk of cancer in association with impaired fasting glucose and impaired glucose tolerance, concludes that prediabetes is associated with an increased risk of cancer, especially liver, endometrial and stomach/colorectal cancer. As such, this interpretation seems to go the right way in terms of the positive association between diabetes and the incidence and mortality of cancer. However, readers should be aware that: (1) ten studies included in the meta-analysis evaluated cancer mortality, five studies evaluated cancer incidence and one study evaluated both; (2) the subgroup analyses indicating associations at specific sites are biased by the small number of studies included (three studies for stomach/colorectal, three studies for liver, and only one study for endometrial cancer) and by mixing mortality (four studies) and incidence (three studies); and (3) last but not least, the effect seems sex specific, as it is not significant in women. Finally, most studies included in the meta-analysis based the diagnosis of prediabetes on a single elevated blood glucose level at baseline; hence, the occurrence of frank diabetes during the observational period was not taken into consideration, and neither was any glucose-lowering treatment included in the analyses. Although the idea is attractive and is supported by indirect evidence from individuals with the metabolic syndrome, the relationship between prediabetes and risk of cancer remains nebulous and needs to be substantiated by further studies prospectively evaluating the development of cancer in individuals who remain in their prediabetic state. In the meantime, as prediabetes can be slowed down or even reversed to regain
Diabetologia (2015) 58:201–202
a normal plasma glucose level by lifestyle interventions, sustained and bearable lifestyle changes can also help in the fight against cancer [8]. Duality of interest The authors declare that there is no duality of interest associated with this manuscript. Contribution statement DG drafted the article and approved the final version. MIM and KE contributed to the critical revision of the article and its final approval. DG is the guarantor of this work.
References 1. Huang Y, Cai X, Qiu M et al (2014) Prediabetes and the risk of cancer: a meta-analysis. Diabetologia 57:2261–2269 2. Renehan A, Smith U, Kirkman MS (2010) Linking diabetes and cancer: a consensus on complexity. Lancet 375:2201–2202 3. Barone BB, Yeh HC, Snyder CF et al (2008) Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300:2754–2764 4. Esposito K, Chiodini P, Colao A, Lenzi A, Giugliano D (2012) Metabolic syndrome and risk of cancer: a systematic review and meta-analysis. Diabetes Care 35:2402–2411 5. Alberti KGMM, Eckel RH, Grundy SM et al (2009) International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–1645 6. Esposito K, Chiodini P, Capuano A et al (2013) Colorectal cancer association with metabolic syndrome and its components: a systematic review with meta-analysis. Endocrine 44:634–647 7. Larsson SC, Orsini N, Wolk A (2005) Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 97:1679–1687 8. Esposito k, Ciardiello F, Giugliano D (2014) Unhealthy diets: a common soil for the association of metabolic syndrome and cancer. Endocrine 46:39–42
