Type 2 Diabetes and Cancer
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Type 2 diabetes is associated with increased risk of certain cancers like liver, pancreas, endometrium, colorectal, breast and bladder cancers. The relationship is complex with factors like reverse causality, detection bias, shared risk factors between diabetes and cancer, and the effects of antidiabetic medications influencing cancer risk. Metformin appears to have a neutral or protective effect on cancer risk while insulin and sulfonylureas may increase risk, though data is still limited. Further research is needed to fully understand the relationship between diabetes, antidiabetic treatments and cancer.
Type 2 Diabetes and Cancer
- 1. Type 2 Diabetes and Cancer Dr. Manel Mata Family Physician. La Mina Primary Care Centre. Barcelona Family and Community Medicine Teaching Unit. Catalonian Institute of Health. DAP_Cat Group. Institut Universitari d’Investigació en Atenció Primaria IDIAP-Jordi Gol. Barcelona. Spain. RedGDPS (Spanish Network of Primary Care Groups for the Study of Diabetes). www.Redgdps.org
- 2. Type 2 Diabetes and Cancer Dr. Manel Mata Conflict of interest disclosure: Honoraria from ASTRA-ZENECA, BAYER, BOEHRINGER INGELHEIM, BMS, ESTEVE, GSK, LILLY, MENARINI, MERCK, MSD, NOVARTIS, NOVONORDISK, SANOFI and SERVIER for the participation in Advisory Boards and lectures about the treatment of diabetes.
- 3. • The relationship between diabetes and cancer • Does antidiabetic treatment have an influence on the risk of cancer ? Type 2 Diabetes and cancer
- 4. American Diabetes Association American Cancer Society Giovanucci E et al. Diabetes Care. 2010;33(7):1674-85. T2DM is associated with increased risk for some cancers (liver, pancreas, endometrium, colorectal, breast, bladder) and reduced risk for prostate
- 5. Garg SK et al. Diabetes, Obesity and Metabolism. 2014; 16: 97-110 Increased risk of cancer in diabetic patients Summary of cohorts and case control studies meta-analysis Liver 2.5 Pancreas 2.6 Endometrium 2.2 Breast 1.3 Prostate 0.9
- 6. Garg SK et al. Diabetes, Obesity and Metabolism. 2014;16:97-110 Men Women All 1.44 1.35 Liver 5.16 6.37 Pancreas 1.67 2.13 Breast -- 1.65 Prostate 1.30 -- Increased cancer mortality in diabetic patients
- 7. There are numerous considerations when assessing cancer risk between diabetics and non diabetics: • Some cancers of metabolically active organs, such liver and pancreas, may induce the onset of type 2 diabetes •The general pattern of an initial elevated peak in cancer risk at the time of diabetes onset, which is substantially higher than subsequent risk, suggests that many cancers are being diagnosed at or around the time of recognition of diabetes Johnson JA et al. Diabetologia 2012; 55:1607–18
- 8. Walker JJ et al. Lancet Diabetes Endocrinol 2013; 1: 132–39 Timing of exposure: reverse causality and detection bias Reports from two different population databases have shown an initial spike in the risk of most cancers immediately after the onset of diabetes, followed by a subsequent normalisation of risk 1. Investigation of early cancer symptoms leads to the diagnosis of diabetes (reverse causality) 2. Diagnosis of diabetes can lead to additional clinical investigations, resulting in the identification of cancers (bias in cancer detection) 3. Reverse causality and bias in cancer detection might also be present in the time of initiation for a new drug.
- 9. Cancer Incidence excluding 1st year aRR Liver 3.50 Pancreas 2.85 Colon 1.56 Breast 1.56 Bladder 0.53 Prostate 0.76 Kidney 0.25 Tayside (Scotland) DART MEMO database 9,577 newly diagnosed T2DM 1993–2004, 19,154 matched non-diabetic comparators National Cancer Register. No significant differences in Any cancer 1.05 (0.93-1.18) Ogunleye AA, Ogston SA, Morris AD, Evans JMM
- 10. Diabetes and Cancer share common risk factors • Non-modifiable: Aging, Male sex, Race/Ethnicity • Modifiable: Obesity Diet (high calories, red meat, processed foods...) Sedentarism Smoking habit Excessive alcohol consumption Giovannucci E, et al. Diabetes Care 2010; 33: 1674-85 The relationship between type 2 diabetes and cancer is consistent and reasonably strong. Johnson JA & Pollak M. Diabetologia. 2010;53:2086-8 American Diabetes Association American Cancer Society
- 11. Biological links between Diabetes and Cancer • Hyperinsulinemia • Hyperglycaemia • Chronic inflammation (citokines) • Insulin receptor/insulin-like growth factor I (IGF-I) Axis – Promotion of cell proliferation – Decreased apoptosis Giovannucci E et al. Diabetes Care 2010; 33: 1674-85 American Diabetes Association American Cancer Society
- 12. Garg SK et al. Diabetes, Obes and Metab. 2014; 16: 97-110 The accumulation of experimental and epidemiological evidence is more consistent with the hyperinsulinaemia hypothesis and less so with the hyperglycaemia hypothesis. Johnson JA & Pollak M. Diabetologia. 2010;53:2086-8
- 13. Obesity and Endometrial Cancer https://tginnovations.wordpress.com/2013/08/10/you-already-know-how-to-defeat-cancer/
- 14. • The relationship between diabetes and cancer • Does antidiabetic treatment have an influence on the risk of cancer ? Type 2 Diabetes and cancer
- 15. Antidiabetic drugs and cancer - Metformin neutral or protective Safety signals: - Sulfonylureas colon - Insulin pancreas, colon - Pioglitazone bladder - Sitagliptin and Exenatide pancreas - Dapagliflozin bladder
- 16. Although still limited, early evidence suggests that metformin is associated with a lower risk of cancer and that exogenous insulin is associated with an increased cancer risk. Further research is needed to clarify these issues and evaluate if insulin glargine is more strongly associated with cancer risk compared with other insulins. Giovanucci E et al. Diabetes Care. 2010;33(7):1674-85.
- 17. Considerations when comparing users vs non users: • Confounding by indication: the non-random allocation of all glucose-lowering therapies in observational studies • Accounting for total, and perhaps cumulative drug exposure • Immortal time bias: the period between cohort entry and date of first exposure, during which cancer has not occurred, is misclassified or excluded (not accounted for in the analysis) Johnson JA et al. Diabetologia 2012; 55:1607–18
- 18. Several observational studies indicate that T2D patients treated with metformin have a lower risk of cancer, but these should be interpreted with caution because of possible confounders, mostly notably confounding by indication. Smith U & Gale EAM. Diabetologia 2010; 53:1541–4 Data from Ranzomized Clinical Trials (meta-analysis) • Improving blood glucose control confers no benefit in cancer risk. • UKPDS 34 reported a not statistically significant 29% reduction in cancer mortality rates with metformin. Johnson JA & Bowker SL et al Diabetologia 2011; 54:25–31 Metformin and cancer
- 19. Metformin was associated with reduced risk (OR 0.38), while insulin (OR 4.99) and insulin secretagogues (OR 2.52) with increased risk of pancreatic cancer in diabetic patients. Li D et al. Gastroenterology 2009;137:482–8 Case-control study 2004 to 2008 973 pancreatic cancer (259 DM) 863 controls (109 DM. Texas (US)
- 20. Insulin (HR 1.26) and sulfonylureas (HR 1.38) were associated with increased cancer risk in comparison to metformin, but this differences disapeared after several adjustments Kowall B et al. Diabetes Care 2015 ; 38:59-65 SU and insulin vs metformin German database. N=22,556, 4.8 years
- 21. Sulfonylureas vs No SU ADOPT trial 1.17 (ns) 6 Cohort studies 1.19 (ns) 10 Case-control studies 1.05 (ns) Thakkar B et al. Metabolism 2013; 62:922-34
- 22. Metformin vs No Metformin ADOPT trial 1.01 (ns) 9 Cohort studies 0.85 (ns) 13 Case-control studies 0.71 (0.57-0.88) Thakkar B et al. Metabolism 2013; 62:922-34
- 23. Our results show that metformin may reduce cancer incidence and mortality in patients with diabetes. However, the reduction seems to be of modest magnitude and not affecting all populations equally. Gandini S et al. Cancer Prev Res 2014; 7(9); 867–85 47 studies (65,540 cancers) Metformin vs No Metformin 0.690.90 0.660.45
- 24. Provinciali N et al. Expert Opin. Drug Saf. 2015; 14(10):1573-1585 Metformin acts as a mitochondrial poison inhibiting complex 1of the mitochondrial respiratory chain. Mitochondrial ATP production is impaired, creating a state of energy restriction.
- 25. Provinciali N et al. Expert Opin. Drug Saf. 2015; 14(10):1573-1585 Epidemiologic data support the conclusion that metformin has beneficial anticancer effects in diabetics or subjects with high BMI or insulin resistance. Thus far, the evidence from clinical trials stems largely from modulation of biomarkers in a direction consistent with benefit, that is, decreased proliferation or increased apoptosis, in breast and endometrial cancers. Multiple trials are ongoing and should inform the field as to whether this potential anti-cancer agent truly has benefit.
- 27. Bowker SL et al. Diabetes Care 2006; 29(2):254-8 10.309 T2DM starting sulfonylurea, metformin or insulin monotherapy Saskatchewan database (Canada) 1991-1996. Mean follow-up: 5,4 years (range 1-9) Adjusted HR by age, sex and commorbidity (Chronic Disease Score) Greater cancer mortality with sulfonylureas (1.3) and insulin (1.9) in comparison to Metformin
- 28. Currie C et al. J Clin Endocrinol Metab 2013; 98: 668–77 UK General Practice Research Database, 2000–2010 84,622 T2DM patients Conclusions: Exogenous insulin therapy was associated with an increased risk of diabetes-related complications, cancer (OR 1.81), and all-cause mortality (OR 2.2). Differences in baseline characteristics between treatment groups should be considered when interpreting these results.
- 29. Men Women Increased mortality in diabetic patients with cancer (greater in those treated with insulin) Conclusions/interpretation: More intensive diabetes treatment reflects a larger degree of comorbidity at the time of cancer diagnosis and a poorer survival noDM DM no Med DM+OHA DM+INS RR 6.5 426,129 patients with incident cancer, (42,205 with diabetes prior to cancer diagnosis) DM+INS RR 5 Ranc K et al. Diabetologia 2014; 57:927-34
- 30. The link beetween exogenous insulin and cancer: Insulin has affinity for the IGF-1 receptors expressed by tumor cells Increased insulin, IGF-1, and IGF-2 signaling through the insulin receptor and IGF-1 receptor can induce tumorigenesis by up-regulating the insulin receptor and IGF-1 receptor signaling pathways Gallagher EJ et al. Endocr Pract. 2010;16(5):864-873.
- 31. 2009 Insulin Glargine and cancer
- 32. Diabetologia, 26 june 2009 Five original papers and one editorial about cancer and glargine
- 33. ORIGIN Glargine vs. Standard Care • 1st CV Composite: HR = 1.02 (0.94, 1.11) • 2nd CV Composite: HR = 1.04 (0.97, 1.11) • Death: HR = 0.98 (0.90, 1.08) • Microvascular Composite: HR = 0.97 (0.90, 1.05) • Cancer: HR = 1.00 (0.88, 1.13) • Conversion IFG/IGT to DM: HR = 0.72 (0.58, 0.91) P=0.006 N=12,537; 573 sites; 40 countries; Median Follow-up: 6.2 years The ORIGIN trial Investigators. 10.1056/NEJMoa1203858 en NEJM.org Outcome Reduction with Initial Glargine INtervention
- 34. Owens DR. Diabetes Care 2012; 35:2426-8 On the basis of the findings from epidemiological studies and the latest pharmacokinetic data the chapter on whether insulin glargine per se is an independent risk factor for cancer should now be closed.
- 35. 17.9.10 FDA alert 9.6.11 Withdrawal in France and Germany 15.6.11 FDA Warning 21.7.11 EMA Warning ………. 5.12.14 Observational study of 6 population databases (5,9 M patients-year): No increase 2010 Pioglitazone and bladder cancer
- 36. N= 1,491,060, 40-79 year-old T2DM on antidiabetic treatment, 155,535 on Pioglitazone. Follow-up 42 months (2006-2009) 175 bladder cancer cases in Pio users vs 1,841 in nonPio users 49.4 vs 42.8 per 100,000 person-years (aRR 1.22) HR Any exposure 1.22 Exposure >24 months 1.36 Cumulative dose >28,000 mg 1.75 EMA 21/07/11 • The benefits outweigh the risks in those patients responding well to pioglitazone • After three to six months of treatment, discontinue pioglitazone in patients not having sufficient benefit • Discontinue treatment with pioglitazone in those patients who have, or have had, bladder cancer, include those who are awaiting investigation of haematuria. Neumann A et al. Diabetologia 2012; 55:1953-62
- 37. Observational study of 6 population databases (5.9 M patient-years) 3,248 incident bladder cancer cases RR (95% CI)* Pioglitazone Men 1.01 (0.97-1.06) Women 1.04 (0.97-1.11) Rosiglitazone Men 1.01 (0.98-1.03) Women 1.00 (0.94-1.07) *adjusted for age, calendar year, diabetes duration, smoking and any ever use of the drug There was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men (HR 1.01) or in women (RR 1.04) after adjustment for age, calendar year, diabetes duration, smoking, and any ever use of pioglitazone. Levin D. Diabetologia. 2015 Mar;58(3):493-504. Diabet Med. 2015;32(3):305-13.
- 38. 2013 Incretins and pancreas cancer
- 39. Butler P & Gale E Nauck M Diabetes Care Publish Ahead of Print, published online May 6, 2013 To date, the FDA has not seen a convincing signal between the use of GLP-1 or DPP-4 agents and pancretic cancer, but it continues to monitor new findings and carefully evaluates them. JUNE 2013
- 40. Incretins and Pancreatic Ductal Adenocarcinoma One study of eight necropsies (7 sitagliptin and 1 exenatide) described enlargement of the pancreas, chronic inflammation and dysplasia (premalignant) that might favor the long term appearance of ductal cancer Butler AE et al. Diabetes 2013; 62: 2595-604 Plausible model: Stimulation of GLP1 receptors might proliferate exocrine ducts accelerating dysplasia in patients with a chronic low-grade pancreatic inflammation Butler A & Gale E, Diabetes Care. published online May 6, 2013 The FDA and the EMA agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data. Egan AG et al. NEJM 2014; 370(9) Pub Online 27 february 2014
- 41. TECOS (Sitagliptin)3 Placebo n=7,339 Sitagliptin n=7,332 p value Pancreatic cancer 14 (0.2%) 9 (0.1%) 0.32 DPP4 inhibitors in the cardiovascular outcomes trials Pancreas cancer SAVOR TIMI53 (Saxagliptin)2 Placebo (N=8,212) Saxagliptin (N=8,280) p value Cancer (%) 4.4 4.0 0.15 Pancreatic Cancer, n (%) 12 (0.1) 5 (0.06) 0.095 EXAMINE (Alogliptin)1 No pancreatic cancer cases in both arms 1. White et al. NEJM 2013 2. Scirica et al. NEJM 2013 3. Green et al. NEJM 2015
- 42. http://professional.diabetes.org/Presentations_Details.aspx?session=4740 ELIXA study lixisenatide vs placebo Pancreatic neoplasm during the study n (%) Placebo N=3032 Lixisenatide N=3031 Events adjudicated as malignant by PSAC Patients with events Related Possibly related Unlikely related Not related 9 (0.3) 0 2 (<0.1) 3 (<0.1) 4 (0.1) 3 (<0.1) 0 0 2 (<0.1) 1 (<0.1) Events adjudicated as benign by PSAC Patients with events 0 1 (<0.1) Events with insufficient documentation Patients with events 1 (<0.1) 1 (<0.1) PSAC, Pancreatic Safety Assessment Committee
- 43. Dapagliflozin and bladder cancer
- 44. Malignancy (continued) *Incidence rate ratio = 1.047 (95% CI: 0.702, 1.579) DAPA=dapagliflozin Johnsson K et al. Diabetologia 2012;55(Suppl1)743-P SGLT2 inhibitors (Dapagliflozin) and risk of cancer EMA 12/11/12 A causal relationship between dapagliflozin and bladder cancer is unlikely. As a precautionary measure, dapagliflozin is not recommended for use in patients concomitantly treated with pioglitazone. RR 5.4
- 45. Messages to take home • T2DM is associated with an increased incidence and mortality for some cancers. •Epidemiologic data support the conclusion that metformin has beneficial anticancer effects in diabetics or subjects with high BMI or insulin resistance. Multiple trials are ongoing and should inform the field as to whether this potential anti-cancer agent truly has benefit. • Some safety signals have emerged from clinical trials or observational studies: Further research is needed to clarify these issues. • Cancer risk should not be a major factor in choosing between available diabetes therapies. Only for selected patients at high risk for cancer or recurrences may require careful consideration.
- 46. “Prevention avoids the labour of being sick” Thomas Adams, 1618 Diabetes and Cancer: What can we do?
- 47. Thanks for your attention manelmatacases@gmail.com