Angiotensin Receptor Blockers and Renoprotection in Diabetes

1. Angiotensin Receptor Blockers and Renoprotection in Diabetes Denise Hughes Laurienti November 6, 2001

2. Clinical Case A 54 y/o BF with DM, HTN and elevated protein/creatinine ratio on spot urine. She was started on an ACE I about 3 mo. ago. She returns today c/o dry cough for 2 months. She works as a telemarketer and can’t talk on phone without coughing. You suspect the ACE I. You want to know if switching her to an ARB would be appropriate.

3. Diabetes and Kidney Disease • Diabetes is the leading cause of ESRD in the US, Europe, and Japan • 40% of people with type II diabetes develop diabetic nephropathy • The risk of developing diabetic nephropathy is 10-20 times higher in patients with microalbuminuria (20-200 μg/min) compared to those with normoalbuminuria (<20 μg/min) • Diabetes accounted for 40% of patients with ESRD in the US between 1994 and 1998

4. Diabetes and Kidney Disease • 1st Stage – hyperfiltration • 2nd Stage – microalbuminuria • 3rd Stage – overt diabetic nephropathy • 4th Stage – advanced clinical nephropathy • 5th Stage – End-Stage Renal Disease

5. Development of Nephropathy • Normal Kidney – GBM prevents filtration of macromolecules such as albumin by charge and size barriers • In Diabetes – increased number of large pores and decreased heparan sulfate (major component of negative charge) allowing albumin to leak into urine

6. Development of Nephropathy Jamison, Wilkinson. Nephrology, 1997.

7. Screening for Microalbuminuria • Normal albumin excretion < 20 mg/day • Microalbuminuria 30-300 mg/day • Proteinuria does not show up on dipstick until protein excretion 300-500 mg/day • 24-hour urine collection is gold standard for detection of microalbuminuria • Microalbumin can be detected on urine sample if specified to lab (early morning sample ideal) • Protein/creatinine ratio is more accurate

8. Renin-Angiotensin System AngiotensinogenAng I Ang II Ang Receptorrenin ACE binds to • Angiotensinogen produced and released by the liver • Renin produced by JG cells in response to glomerular hypoperfusion or changes in lytes • ACE produced mainly in pulmonary vasculature endothelium • Angiotensin II binds to its specific receptors in heart, brain, adrenal glands, kidneys, and vascular smooth muscle wall

9. Renin-Angiotensin System • Alternate pathways in which Ang I is converted to Ang II independent of ACE. Enzymes that facilitate this include chymase, CAGE, and cathepsin G. • Angiotensinogen can be directly converted to Ang II by t-PA, cathepsin G, or tonin. Zitnay, Siragy. Mineral Electrolyte Metabolism. 1998.

10. Renin-Angiotensin System There are 2 types of receptors to which Angiotensin II binds, and the effects differ: AT-1 receptors: • causes vasoconstriction • salt and water retention • aldosterone release and subsequent hypokalemia • sympathetic activity • stimulation of cell growth, proliferation, and matrix formation

11. Renin-Angiotensin System AT-2 receptors: • Less understood • Expressed mainly in fetal tissue • Thought to oppose actions mediated by AT-1 receptors • Lead to vasodilation, anti-proliferation, cell differentiation, apoptosis, and tissue regeneration

12. Pathways of AT-1 receptors thought to lead to protein phosphorylation Pathways of AT-2 receptors thought to lead to protein dephosphorylation Renal-Angiotensin System de Gasparo et al. Pharmacology Toxicology, 1998.

13. Mechanism of Action of ACE I and ARBs ACE I : • blocks conversion of Ang I to Ang II, so they diminish activity of AT-1 and AT-2 receptor subtypes • ACE is also a kininase so ACE I leads to increased kinin levels • Bradykinins cause vasodilation and lead to improved insulin sensitivity • Increased bradykinins cause common side effect of cough

14. Mechanism of Action of ACE I and ARBs ARBs: • Exhibit high affinity for AT-1 receptors and no effect on AT-2 receptors • AT-1 responsible for all of the deleterious actions of Ang II, so blocking it prevents vasoconstriction, salt and water retention, aldosterone release, and sympathetic activity • By blocking AT-1, some believe this will stimulate unopposed AT-2 leading to vasodilation

15. Evidence for ARBs and Renoprotection in Diabetes Three large RCTs looking at ARBs in patients with diabetes and their effectiveness at preventing nephropathy: • Renoprotective Effects of Irbesartan- irbesartan (2 different doses) vs. placebo • Irbesartan Diabetic Nephropathy Trial (IDNT)- irbesartan vs. amlodipine vs. placebo • Angiotensin II Antagonist Losartan Study (RENAAL)- losartan vs. placebo

16. Renoprotective Effect of Irbesartan Design: • randomized, double-blind, placebo controlled • 96 centers worldwide • Followed pts for 2 yrs • Parving HH, et al. The Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type II Diabetes. NEJM. 2001.

17. Renoprotective Effect of Irbesartan Patient Population: • Men and women age 30-70 • Type II diabetes • Hypertension- 2 of 3 blood pressure readings of SBP>135 and/or DBP>85 in one week • Persistent microalbuminuria- AER between 2 and 200 μg/min in 2 of 3 overnight urine specimens • SCr<1.6 mg/dl in men, <1.2 mg/dl in women • Exclusion of patients with nondiabetic renal disease, cancer, life expectancy<2yrs, or indication for ACE I

18. 1469 Patients 3 wk screening process -128 patients -643 patients excluded for medical reasons albuminuria/BP out of range -18 patients no albuminuria 590 patients left for randomization Placebo Irbesartan 150 mg QD Irbesartan 300 mg QD N=201 N=195 N=194 Renoprotective Effect of Irbesartan

19. Renoprotective Effect of Irbesartan • Primary Endpoint: progression to overt nephropathy (AER>200 μg/min and 30% higher than baseline on 2 consecutive visits) • Secondary Endpoint: change in level of albuminuria, change in creatinine clearance, or normalization of albuminuria (to <20 μg/min)

20. Renoprotective Effect of Irbesartan Results

21. Renoprotective Effect of Irbesartan

22. Renoprotective Effect of Irbesartan Kaplan-Meier Curve showing the Incidence of Progression to Diabetic Nephropathy Parving HH, et al. NEJM. Sept., 2001

23. Renoprotective Effect of Irbesartan Conclusions: • Irbesartan 300 mg QD reduced risk of progressing to overt nephropathy and greater reduction in AER • Irbesartan 300 mg QD led to normalization of albuminuria in more patients • No significant difference in decline in creatinine clearance between the 3 groups

24. Irbesartan Diabetic Nephropathy Trial (IDNT) Design: • Randomized, double-blind, placebo controlled • 210 clinical centers • Mean duration of F/U 2.6 years • 1715 patients • Lewis EJ, et al. Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy due to Type II Diabetes. NEJM. 2001

25. IDNT Patient Population: • Type II diabetic men and women age 30-70 • Hypertension SBP>135 and/or DBP>85 • Proteinuria >900 mg/24 hrs • Serum creatinine 1.0-3.0 mg/dl (women) and 1.2-3.0 mg/dl (men)

26. Primary Endpoint: Doubling SCr ESRD Death (any cause) Secondary Endpoint: Death (CV causes) MI CHF hospitalization CVA Above ankle amputation IDNT

27. IDNT - Results

28. IDNT - Results

29. IDNT - Results Patients in Irbesartan group had: • 23% lower rate of CHF than placebo • Increase in SCr 23% slower than placebo and 21% slower than amlodipine • 33% reduction of proteinuria compared to 6% in amlodipine group and 10% in placebo

30. IDNT - Results Adverse Events: Overall, irbesartan group had lower rate of adverse events/1000 days (P=0.002)

31. IDNT -Conclusions • Irbesartan assoc. with slowing of progression to nephropathy (decreased time to doubling of creatinine) • Results independent of blood pressure • Irbesartan assoc. with 23% lower rate of CHF • Lower adverse events in irbesartan group (but higher rate of hyperkalemia)

32. IDNT - Limitations • Bristol Myer Squibb performed data handling • Amlodipine used as comparison instead of diltiazem or verapamil • Patients in placebo group required more non-study antihypertensives, so more likely to receive B-blockers (United Kingdom Prospective Diabetic Study)

33. Angiotensin II Antagonist Losartan Study (RENAAL) Design: • Randomized, double-blind, placebo controlled • 250 centers in 28 countries • Followed 1513 patients for a mean of 3.4 years • Brenner BM, et al. Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type II Diabetes and Nephropathy. NEJM. 2001

34. RENALL Patient Population: • Men and women age 31-70 • Type II diabetes • Nephropathy (alb/Cr ratio > 300 or AER>0.5 g/day on 24° urine) • SCr 1.3-3.0 mg/dl • Excluded-type I DM, nondiabetic renal dz, MI or CABG in last month, CVA or PTCA w/in 6 months, TIA in last year, or CHF

35. Primary Endpoint: Doubling of SCr ESRD Death Secondary Endpoint: MI Stroke Hospitalization for CHF or USA Vascular intervention Death from CV cause RENALL

36. RENALL - Results

37. RENALL – Results Patients in the losartan group had a reduction in proteinuria of 35%, while the patients in the placebo group had an increase in proteinuria (P=<0.001) Brenner et al. NEJM. 2001.

38. RENALL – Conclusions • Losartan has renoprotective effects by reducing risk of doubling creatinine AND by reducing progression to ESRD • Losartan reduces episodes of CHF • Effects reported as independent of blood pressure

39. ACE I versus ARBs Design: • Randomized, double-blind, placebo controlled • 4 centers in Canada • 122 patients followed for 52 weeks • Muirhead N, et al. The Effects of Valsartan and Captopril on Reducing Microalbuminuria in Patients with Type II Diabetes: A Placebo Controlled Trial. Current Therapeutic Research. 1999.

40. ACE I versus ARBs Patient Population: • Males and females > age 17 • Average age 50’s in all groups • Type II Diabetes • AER 20-300 μg/min, GFR > 60 ml/min • SBP<160 mmHg • Excluded-brittle DM, hypotension, DBP>95

41. ACE I versus ARBs

42. ACE I versus ARBs Results: Primary Endpoint- Overt Nephropathy Secondary Endpoint- Change in GFR Most common adverse experience- cough (captopril)

43. ACE I versus ARBs

44. ACE I versus ARBs Conclusions: • Patients in valsartan and captopril groups less likely to reach endpoint • No statistically significant difference between the valsartan and captopril groups

45. ACE I versus ARBs Limitations: • Small study population size • Differences among the groups • Lower AER initially in the captopril group • Short follow-up period

46. Final Conclusions Need for more evidence: • Unfortunate that these studies didn’t have ACE I as a treatment arm • HOPE and MICRO-HOPE show that ACE inhibitors reduce risk of CV events in patients with diabetes and one other risk factor for CV disease

47. Final Conclusions ARBs in heart failure: • ELITE II and Val-HeFT • Ongoing trials Dickstein. Current Controlled Trials in Cardiovascular Medicine. 2001.

48. Final Conclusions • ARBs are renoprotective in patients with diabetes • ARBs reduce risk of progression to overt nephropathy, rise in creatinine and ESRD • More evidence comparing ARBs and ACE I, and ARBs in diabetic patients at risk for CV disease is needed • ACE inhibitors still first line

49. Acknowledgments Special Thanks to: Dr. Pirouz Daeihagh Dr. Paul J. Laurienti