Increased Risk of Cancer with Anti-diabetes Drugs? Cons

Transcription

1 Increased Risk of Cancer with Anti-diabetes Drugs? Cons Inje University College of Medicine, Ilsanpaik Hospital, Department of Internal Medicine Dong-Jun Kim

2 Gastroenterology132: , 2007

3 IGF-1 System in the Development of Cancer in Diabetes Gastroenterology132: , 2007

4 C-peptide & Cancer Physician s Health Study J Natl Cancer Inst 96: , 2004

5 IGF-1 System in the Development of Cancer in Diabetes Cancer Epidemiol Biomarkers Prev 14: , 2005

6 Insulin Analogues & Cancer

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8 1. Allocation bias Human insulin group NPH insulin &/or RI Type 1 & type 2 diabetes Lower insulin secretion Limitations Insulin glargine group Insulin glargine only Type 2 diabetes only Higher insulin secretion Basal, basal plus, & basal bolus Basal only OHA 77.2% (SU 66.7%) OHA 92.1% (SU 79.8%) 2. No information of confounding factors (BMI, diabetes duration, smoking, and cancer type) 3. Large number of exclusion (participants who changed insulin type) 4. Unexplained effect of insulin glargine on reducing all-cause mortality

9 The four analyses published in Diabetologia Country and population Main allegations concerning Lantus Remarks Germany N=127,031 Lower risk of cancer in Lantus patients vs human insulin in crude analysis Higher risk only after debatable adjustment for insulin dose Short exposure to insulin No correction for BMI Sweden N=114,841 Scotland N=49,197 UK N=62,809 No increased risk of cancer overall Higher risk of breast cancer only in patients taking Lantus alone but not in patients taking Lantus plus other insulins Higher overall cancer rate in patients treated with Lantus alone, but not in patients treated with Lantus plus other insulins No evidence of increased risk of cancer with Lantus compared with human insulin Low number of breast cancers Demographic data different between patients groups; a strong possibility for an allocation bias Inconsistency in cancer findings among cohorts Differences between patient groups; patients treated with Lantus alone being older than other insulin users Allocation bias may explain findings Less heterogeneity between insulintreated patients than in the other analyses Hemkens, et al. Diabetologia 2009;52: Currie, et al. Diabetologia 2009;52: Jonasson, et al. Diabetologia 2009;52: Colhoun, SDRN Epidemiology Group. Diabetologia 2009;52:

10 Gastroenterology132: , 2007

11 Gastroenterology132: , 2007

12 GP database study in UK

13 The Hong Kong Diabetes Registry study 973 new insulin users vs matched nonusers 10.2 vs per 1000 person-years, P < Gastroenterology132: , Diabetes 59: ,

14 The Hong Kong Diabetes Registry study Limitations 1. Cancer development in the original cohort: 4.6% in insulin nonuser vs. 3.3% in insulin user 6.3% in insulin nonuser vs. 3.3% in insulin user in the analysis 2. More drop-out rate in insulin user 3. HbA1c in insulin users 8.1% vs. 7.1% in insulin nonuser vs per 1000 person-years in only 3 years after the initiation of insulin 5. No adjustment of BMI

15 Limitations of clinical studies about anti-diabetes drugs and cancer Retrospective observational study - diabetes, diabetes-related comorbidity, and treatment fully adjustment of confounding factors: impossible unavailable confounding factors allocation bias detection bias

16 Some considerations for clinical studies about anti-diabetes drugs and cancer Require longer duration of F/U RCT: impossible New development of cancer vs. growth of cancer foci Organ-specific mechanism of carcinogenesis site of cancer: general vs. organ-specific

17 Insulin and IGF-1 receptors Insulin binds to insulin receptor (preferentially) and with lower affinity to IGF-1 receptors Endogenous IGF-1 has a considerably higher affinity for IGF-1 receptor. Therefore IGF-1 receptors will be occupied by endogenous IGF-1 Overstimulation of IGF-1 has been linked to cell proliferation, fosters retinopathy and progression thereof Ins=insulin; Ins-R=insulin receptor; IGF-1=insulin-like growth factor-1; IGF1-R=insulin-like growth factor-1 receptor

18 Retinopathy progression (insulin glargine vs. NPH insulin) Diabetologia 52: , 2009 Gastroenterology132: , 2007

19 Cancer rates in the 5-year RCT (insulin glargine vs. NPH insulin) Insulin glargine (n=524) NPH insulin (n=503) Patients (%) RR (95% CI) 0.90 ( ) RR (95% CI) 0.63 ( ) All neoplasms Serious neoplasms Diabetologia 52:1971 3, 2009

20 Cancer rates with insulin glargine vs. comparators in controlled trials in the sanofi-aventis adverse-event database Database includes 31 RCTs with insulin glargine Glargine vs NPH: 20 studies Duration: Median ~6 months; six >6 months, one 5 yrs Combined study population 10,880 people Classification, n (%) Glargine: n = 5,657 exposure 4,711 person years Comparator: n = 5,223 exposure 4,524 person-years Insulin glargine (n = 5,657) Comparator (n = 5,223) Relative risk (95% CI) All cancers 45 (0.80) 46 (0.88) 0.90 ( ) Breast 4 (0.07) 6 (0.11) 0.62 ( ) Gastrointestinal (NOS) 6 (0.11) 4 (0.08) 1.38 ( ) Colon and rectum 6 (0.11) 10 (0.19) 0.55 ( ) Skin 12 (0.21)* 6 (0.11) 1.85 ( ) Melanoma 6 (0.11) 1 (0.02) Gastroenterology132: , 2007

21 Statement of Key regulatory and professional bodies FDA statement, 1 July 2009 The FDA recommends that patients should not stop taking their insulin therapy without consulting a physician since uncontrolled blood sugar level can have both immediate and long-term serious adverse effects EMEA statement, 29 June 2009 Patients being treated with insulin glargine are advised to continue their treatment as normal. At this time there is no recommendation that patients should change their current treatment ADA statement, 26 June 2009 Patients concerned about these studies or their insulin regimen should talk to their doctor and should not stop taking their insulin on the basis of the findings reported here EASD statement The EASD advises that patients do not stop taking insulin glargine based upon the information presented on this website. If you wish to have further information you should contact your doctor AACE statement The AACE does not recommend that the use of any insulin be changed IDF statement The International Diabetes Federation stresses that it is important that people needing insulin do not stop taking the drug. IDF cautioned that people with diabetes should see their doctor for advice before considering any change to their treatment AFFSAPS (French health safety agency) statement At present we are issuing no message about any dangers associated with Lantus Patients taking this medicine should continue their treatment FDA=Food and Drug Administration; EMEA=European Medicines Agency; ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; AACE=American Association of Clinical Endocrinologists; IDF=International Diabetes Federation; AFFSAPS=Agence Française de Sécurité Sanitaire des Produits de Santé

22 MET & Cancer

23 Anti-cancer effect of metformin on breast cancer cell lines Cell cycle 8: ,2009

24 Metformin & Cancer

25 Tayside, Scotland study Metformin & Cancer Adjusted RR 0.63, 95% CI ( ) Diabetes Care 32: , 2009

26 GP database study in UK Metformin & Cancer

27 Gastroenterology132: , 2007

28 Metformin & Breast Cancer GP database study in UK Diabetes care 33: , 2010

29 GP database study in Netherlands ZODIAC (Zwolle Outpatients Diabetes project Integrating Available Care) study n=1,353 F/U, 9.6 years Age, 68 years Gastroenterology132: , 2007 Diabetes care 33: ,2010

30 Meta-analysis of 11 studies Metformin & Cancer RR 0.69, 95% CI ( ) Cancer Prev Res 3(11): , 2010

31 J Clin Oncol 27: , 2009

32 Metformin & Cancer

33 Gastroenterology132: , 2007

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35 Further Considerations in MET in Oncology Candidate site: breast, colon, prostate, lung More important mechanism of action? Optimum compound and dosing regimen? Relevant predictive host or tumor biomarker? Similar result in non-diabetes? Off-patent drug but clue to identify patentable molecules Cancer Prev Res 3(9):1060-5, 2010 Gastroenterology132: , 2007

36 Gastroenterology132: , 2007

37 GLP-1-based treatment and Cancer Diabetes care 33: , 2010 Gastroenterology132: , 2007

38 Anti-diabetes drugs & Cancer Insulin SU DPP-4 inhibitor GLP-1 agonist vs. α-gi inhibitor MET TZD

39 In summary, Marked increase of diabetes population increased life expectancy of diabetes longer duration of anti-diabetes drug exposure long-term surveillance for cancer Risk benefit ratio

40 Thank you for your attention! Gastroenterology132: , 2007