The 2019 Royal Pharmaceutical Society / UCL School of Pharmacy New Year Lecture

1. The 2019 Royal Pharmaceutical Society/ UCL School of Pharmacy New Year Lecture

2. The Prevention and Treatment of DiabetesDr Elizabeth RobertsonDirector of Research, Diabetes UK Human Islets of Langerhans Morgan & Richardson, Diabetologia, 2018

3. What is diabetes?

4. What is diabetes? • There are two main types of diabetes • Type 1 - where the pancreas does not produce any insulin • Type 2 - where the pancreas does not produce enough insulin - or the body's cells do not react to insulin

5. Type 1 diabetes: causes “What once seemed like a single autoimmune disorder, with roots in T-cell mediated attack of insulin-producing β cells, is now recognised to result from a complex interplay between environmental factors and microbiome, genome, metabolism, and immune systems that vary between individual cases.” DeMeglio et al Lancet 2018

6. Type 1 diabetes: stages Greenbaum et al Diabetes 2018

7. Progression of Type 1 diabetes • Slow progressors – develop islet autoantibodies early in childhood but can take up to 10 years for a Type 1 diagnosis • Late starters – develop islet autoantibodies as teenagers or adults and progress rapidly to a Type 1 diagnosis • WHY? Long et al Diabetalogia 2018

8. Type 2 diabetes risk factors

9. Heterogeneity of diabetes Insulin resistance Age at diagnosis B-cell function HbA1c BMI Cluster 1: Severe autoimmune diabetes (SAID) Cluster 2: Severe insulin-deficient diabetes (SIDD) Cluster 3: Severe insulin-resistant diabetes (SIRD) Cluster 4: Mild obesity-related diabetes (MOD) Cluster 5: Mild age-related diabetes (MARD) E. Ahlqvist et al Lancet D&E 2018

10. Misdiagnosis of diabetes? Incidence of genetically defined Type 1 and Type 2 diabetes in the first six decades of life. Thomas et al, Lancet D&E, 2018

11. The crisis we’re facing

12. Scale of the UK diabetes crisis

13. Scale of the UK diabetes crisis

14. Diabetes around the world Diabetes around the world Total number of adults (millions) with diabetes (20-79 years)

15. Diabetes: A global emergency Number of people with diabetes worldwide and per region in 2017 and 2045 (20-79 years) Scale of the global diabetes crisis Number of people with diabetes worldwide and per region in 2017 and 2045 (20-79 yrs)

16. Inpatient care in the UK

17. Inpatient care in the UK

18. Investment in diabetes research in the UK

19. European diabetes research 2002-15 • UK biggest contributor to European diabetes research • Overall decline in European diabetes research from 45% of the world output to 33% Begum et al Diabetic Medicine 2017

20. How we can tackle the growing crisis

21. Current treatment and prevention strategies

22. Role for Chemoprevention in Type 2? Colhoun et al, The Lancet 2004

23. Trends in rates of all-cause mortality among populations with diagnosed Type 2 diabetes Gregg et al, Lancet D&E, 2016

24. Need for more targeted use of existing and new Type 2 drugs Metformin DPP4 SGLT2 PIO SU NICE Type 2 diabetes guidelines £36 £43 £4 £16 Curtis HJ, et al .Diabetes Obes Metab. 2018

25. Type 2 remission: DiRECT • Profs Lean (Glasgow) and Taylor (Newcastle) trialling a low-calorie diet weight management programme for Type 2 remission • Builds on successful Diabetes UK funded research • 800 cals a day for 8-20 weeks followed by weight management programme = not a quick fix! • But can it work long term as part of routine GP care?

26. DiRECT hypothesis • Too much fat within the liver and pancreas • prevents normal insulin action • prevents normal insulin secretion • Both defects are reversible by substantial weight loss • Individuals have different levels of tolerance of fat within the liver and pancreas

27. Two initial small scale studies 11 and 30 participants 100% 0%

28. DiRECT first year results Overall: 46% remission at 12 months Remissions by weight-loss category at 12 months Lean et al, Lancet 2017

29. Responders and non-responders Taylor et al, Cell Metabolism, 2018

30. Health economic costs of DiRECT Components of one-year cost: DiRECT intervention vs. control Lean et al, Lancet D & E 2018

31. NHS Diabetes Prevention Programme (NDPP) • 100% coverage of England • 280,000 referrals, 159,600 attended initial assessment • 52% of participants attended 8 sessions or more (out of 13 sessions)* • Mean weight change for completers -3.2kg (-3.1 to -3.4kg)* * Data to March 2018

33. Type 2 prevention plans: Scotland, Wales & Northern Ireland A Healthier Future: Type 2 diabetes prevention, early detection and intervention: framework Diabetes Strategic Framework NHS Diabetes Prevention Programme Diabetes National Services Framework

34. NHS long term plan (published Jan 7th 2019) • Prevention of Type 2 • doubling enrolment to NDPP over next 5 years including new digital option • 200,000 people • Remission of Type 2 • test an NHS programme supporting low calorie diets and weight management for obese people with Type 2 diabetes • 5,000 people www.longtermplan.nhs.uk

35. A vaccine for Type 1? A peptide immunotherapyrelies on injecting small protein fragments (or peptides) to ‘retrain’ the immune system and stop it attacking the pancreas, potentially preventing or slowing down Type 1 diabetes

36. Proinsulin peptide immunotherapy is safe Ali et al, Science Translational Medicine, 2017

37. Environmental factors? Coxsackie B virus Gale, Diapedia, 2014 D.Hober, Discovery Medicine, 2010 Laitinen et al, Diabetes, 2014

38. Prevention of Type 1? Progression to diabetes in children with confirmed autoantibodies (N = 577) Ab+, antibody positive GP, general population FDR, first degree relative Steck et al, Diabetes Care, 2015

39. Looking to the future

40. World-leading UCL diabetes research Professor Lucy Walker

41. T cells attack the pancreatic islets and destroy the beta cells Islet of Langerhans T T T Brown: insulin Blue: T cells

42. T cells responding to islet antigen have a gene signature of Follicular Helper T cells 4 of the top 20 most significantly upregulated genes are Tfh genes Follicular helper T cell (Tfh)

43. Can follicular helper T cells be used as an early indication of the autoimmune response in Type 1 diabetes? • People with Type 1 have a gene signature of follicular helper T cells in their blood • design new strategies to halt this type of damage? • interfere with cell development? Follicular helper T cell (Tfh)

44. The Future… • Artificial pancreas • Microbiome • AI diagnostics • Stem cell therapy • Islet implants • Psychological interventions • Social interventions • And more…

45. Artificial Pancreas Professor Roman Hovorka, University of Cambridge, has led the world in artificial pancreas research • People living with diabetes • #wearenotwaiting • Open Artificial Pancreas System • #OpenAPS

46. Role of the Microbiome? Pollak, Diabelalogia, 2017

47. The future of precision medicine in diabetes? • in vivo imaging of beta cell mass and function • postprandial glucose indices models • virtual imaging of patients using digital data • genetic risk scores Roden, Cobellini, Rich, Kovatchev, ADA 2018

48. Genetic risk scores Grubb et al, Diabetes Care 2018

49. Diabetes is a complex condition and therefore needs a personalisedapproach to prevention, diagnosis, treatment and care linked to population scale interventions. • The importance of translating research into practice–remission of Type 2 diabetes - an example where pharmacists could play a key role? • Strengthof diabetes research in the UK and the need for more investment

50. ‘Overcoming diabetes’ Professor David Taylor “if governments, health care providers and the wider public maintain the confidence and integrity of purpose required to keep investing in public health measures and effective new treatments, and to act on the evidence available about the societal and personal actions needed to protect health, diabetes and its consequences will not be major causes of death or disability by 2050s.”