1. Diabetes in Cancerland Edwin Gale

2. This Meeting Thanks to: The Steno team The Danish Cancer Society The EASD

3. Questions We Want to Answer Background: The Diabetologia papers drew attention to the issue of cancer and diabetes But also revealed how little we knew… And drew attention to the pitfalls of reaching conclusions about cancer risk

4. ADA/ACS Consensus 1. Is there a meaningful association between diabetes and cancer incidence or prognosis? 2. What risk factors are common to both diabetes and cancer? 3. What are possible biologic risks between diabetes and cancer risk? 4. Do diabetes treatments influence risk of cancer or cancer progression?

5. The Consortium Arose from the desire of some of the groups to establish core methodologies, and (where possible) to pool data and work together on major unanswered questions.

6. A number of issues relating to diabetes and cancer have recently become the focus of considerable interest and controversy, and form the basis for a recent call for research applications from the EASD/EFSD. Three questions appear central to this debate: What is the mechanistic basis for the epidemiological association between diabetes and cancer? Does choice of therapy for diabetes influence cancer risk? If so, how and why? Why does cancer have a worse prognosis in people with diabetes, and could this be overcome?

7. Although some pointers can be derived from controlled clinical trials, much research in this area will inevitably take the form of descriptive studies. The limitations of this approach are well established, but descriptive studies have an essential role in hypothesis generation, and may potentially form the basis for future clinical trials. We believe that collaboration is a key element of future work in this area, and that this should bring together those with expertise in basic science, oncology, diabetes therapy, epidemiology, and statistical modelling. Oversight of this activity would be entrusted to a Steering Committee, whose membership would be drawn from non-participants in the study groups.

8. A central aim of such a consortium would be to optimise methodology for descriptive studies, to develop joint work- programmes, and (where possible) to analyse data derived from different databases in parallel. Participants in the consortium are invited to exchange and discuss protocols, and to meet in regular workshop groups to discuss methodology and share analysis of their research findings. Although the EASD initiative would form the focus for such an interaction, participation in the collaboration would potentially be open to other groups with shared interests and activities. A key criterion for participation in the consortium is the contribution and sharing of novel data and/or methodologies to address the central questions outlined above.

9. Aims 1. To meet one another and discuss resources available and work in progress 2. To provide a workshop for discussion of shared methodologies 3. To outline some of the major unanswered questions 4. To explore the feasibility of joint analysis of these questions

10. So, What are the Questions?

11. DiabetesCancer Glucose Obesity Insulin

12. DiabetesCancer Glucose Obesity Insulin Diabetes therapy

13. DiabetesCancer Glucose Obesity Insulin Diabetes therapy

14. Hyperglycaemia? Obesity? Insulin/resistance? Diabetes therapy?

15. Question One To what extent are the excess cancer risks associated with diabetes due to non-glycaemic risk factors (obesity, insulin resistance, etc)?

16. Question Two (a) What is the influence of hyperglycaemia upon cancer development? (b) What is the influence of hyperglycaemia upon cancer progression? If so, which cancers?

17. Question Three (a) What is the role of endogenous hyperinsulinaemia upon cancer development? (b) What is the role of exogenous hyperinsulinaemia upon cancer development? If so, which cancers? & Does insulin formulation matter?

18. Cancer Risk vs Insulin dose insulin dose Adjusted HR Currie et al submitted

19. Question Four Can a beneficial effect of metformin upon cancer risk be confirmed? If so, which cancers?

20. Question Five What, if any, are the effects of other diabetes therapies? TZDs Sulfonylureas GLP-1 agonists DPP-4 antagonists

21. Question Six Do people with diabetes have a higher cancer mortality? If so, is this tumour specific?

22. Six Questions 1. Is the increased cancer risk with diabetes secondary to other associated features? 2. What is the role of hyperglycaemia? 3. What is the role of hyperinsulinaemia? 4. Is metformin protective? 5. What other agents should be examined? 6. Does diabetes affect cancer mortality?

23. Problems worthy of attack Show their worth by fighting back Piet Hein