Complications in Type 1 Diabetes: Nephropathy

1. Complications in Type 1 Diabetes: Nephropathy Peter A. Gottlieb, MD Barbara Davis Center University of Colorado Health Sciences Center Denver, CO

2. Why do complications occur? • Insulin hypothesis • Glucose hypothesis • DCCT and many other studies support glucose hypothesis

3. EDIC: Long Term Benefit of Intensive Treatment • The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions • and Complications Research Group. N Engl J Med 2000;342:381-9.

4. EDIC: Long Term Benefit of Intensive Treatment • The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions • and Complications Research Group. N Engl J Med 2000;342:381-9.

5. EDIC: Long Term Benefit of Intensive Treatment - The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000;342:381-9.

6. Transient hyperglycemia leads to oxidative stress which increases complications • Testing of this hypothesis is needed to determine if this is indeed true

8. Diabetic Nephropathy: Pathogenesis • Increased intraglomerular pressure • Mesangial cell expansion • Reactive Oxygen Species (ROS) • Endothelial cell dysfunction • Increased Glomerular Basement Membrane Thickness and Interstitial Fibrosis

9. DETAIL Study: Head to Head Comparison of ACE vs. ARB in Type 2 DN • 5 yr, prospective, multicenter, randomized study in T2DM with HTN and early DN • 120 subjects onTelmisartan 40-80 mg/day vs. 130 subjects on Enalapril 10-20 mg/day • Primary endpoint: Change in GFR • Secondary endpoints: Change in albuminuria, BP, CR, other CV outcome measures

11. DETAIL:Baseline Characteristics

12. DETAIL: Equivalent Protection from ACE and ARB in Change GFR

13. DETAIL: Key Points • Use of ACE or ARB slows down loss of GFR in T2DM with nephropathy • Confirms previous shorter term studies • Additional protection seen for CV complications

14. ACE and ARB Lower Proteinuria better than ACE alone in T2DM • Small 24 week study with 26 pts demonstrated that combination therapy of Losartan with Enalapril reduced proteinura greater than increased dose of Enalapril alone • Blood pressure was similarly lowered in both groups • CRP levels were lowered in combined treatment group, unchanged in ACE alone • Other parameters measured were not significantly different between groups Igarashi, et al, Endocrine Journal, 2006, epub

15. Prevention and Treatment of Diabetic Nephropathy in T1DM • Periodic screening for microalbuminuria – timed overnight samples beginning at 5 years from diagnosis • Treatment of either microalbuminuria or HTN (to 120/80 or age-matched target) with ACE or ARB • Use ACE or ARB, ACE with ARB and Diuretics, then consider other therapies based on clinical considerations

16. How do complications occur? • Activation of Polyol Pathway • Accumulation of Advanced Glycosylation End Products • Protein Kinase C Pathway • Flux Through the Hexosamine Pathway • Oxygen Radicals and Enhanced Oxidative Stress • Altered Expression of Growth Factors and Vasoactive Mediators

17. Aldose Reductase and Polyol Pathway - Brownlee, M. Nature 2001 414:13 813-820.

18. AGE Pathway - Brownlee, M. Nature 2001 414:13 813-820.

19. How can we intervene? • Polyol Pathway – Sorbinil, Zenarestat • Advanced Glycosylation End Products – Aminoguanidine, sR RAGE • Protein Kinase C Pathway – Selective PKC inhibitors such as LY333531 • Flux through Hexamine – ? • Oxidative Stress – Vitamin C, Vitamin E, a lipoic acid • Altered Expression of Growth Factors – VEGF inhibitors

20. Effect of a-lipoic acid on experiemental diabetic retinopathy Lin, et al, Diabetologia, 2006, 49:1089-1096

21. Do they work? • Sorbinil, Zenarestat - Toxicity, Ineffective • Aminoguanidine, sR RAGE - ? • PKC inhibitors - LY333531 - Maybe • Flux through Hexamine – ? • Oxidative Stress – Vitamin C, Vitamin E, a lipoic acid – Small effect? • Altered Expression of Growth Factors – VEGF inhibitors - Unknown

22. Why have our best efforts not succeeded? • Toxicity • Drug Development – Efficacy • Need to target multiple pathways at once • Or something else?

23. Unified Theory of Complications - Brownlee, M. Nature 2001 414:13 813-820.

24. Inhibition of GAPDH Affects Multiple Complication Pathways - Du X, et al. J. Clin. Invest. 112:1049–1057 (2003).

25. New Therapeutic Approaches • Glyceraldehyde-3-phosphate and fructose-6-phosphate are major substrates for complication pathways • Benfotiamine, is a derivative of the B vitamin thiamine • Activates the thiamine dependent pentose phosphate enzyme transketolase which converts these compounds away from these pathways • Affecting this pathway changes substrate availability for polyol, hexosamine, diacylglycerol (PKC), AGE pathway and NF-kB signaling

26. MMF and ACE synergize to Reverse Experimental DN Wu, et al. Inflamm res. 2006. 192-199

27. MMF and ACE synergize to Reverse Experimental DN TGFb ED1 MCP-1 Wu, et al. Inflamm res. 2006. 192-199

28. Unified Theory of Complications Benfotiamine PARP inhibitors - Brownlee, M. Nature 2001 414:13 813-820.

29. New Therapeutic Approaches • Molecules which can affect GAPDH activity • Superoxide Dismutase • Poly(ADPribose)polymerase (PARP) inhibitors, PJ34

30. Summary • Tight control of blood sugars is the best means to prevent and reverse complications of diabetes • Reducing glycemic variability may also contribute to the development of complications and can be achieved with CGMS • Therapies such as PKC inhibitors which attack single pathways may be of benefit • New therapeutic approaches which can target multiple pathways simultaneously may offer the best chance to prevent complications

31. Thank you