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 cant 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 (lt20 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 lt 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 Receptor
  renin 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
Renal-Angiotensin System

• Pathways of AT-1 receptors thought to lead to
  protein phosphorylation

• Pathways of AT-2 receptors thought to lead to
  protein dephosphorylation

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
  SBPgt135 and/or DBPgt85 in one week
• Persistent microalbuminuria- AER between 2 and
  200 µg/min in 2 of 3 overnight urine specimens
• SCrlt1.6 mg/dl in men, lt1.2 mg/dl in women
• Exclusion of patients with nondiabetic renal
  disease, cancer, life expectancylt2yrs, or
  indication for ACE I

18
Renoprotective Effect of Irbesartan
19
Renoprotective Effect of Irbesartan

• Primary Endpoint progression to overt
  nephropathy (AERgt200 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 lt20 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 SBPgt135 and/or DBPgt85
• Proteinuria gt900 mg/24 hrs
• Serum creatinine 1.0-3.0 mg/dl (women) and
  1.2-3.0 mg/dl (men)

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IDNT

• Primary Endpoint
• Doubling SCr
• ESRD
• Death (any cause)

• Secondary Endpoint
• Death (CV causes)
• MI
• CHF hospitalization
• CVA
• Above ankle amputation

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 (P0.002)

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 gt 300 or AERgt0.5 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
RENALL

• Primary Endpoint
• Doubling of SCr
• ESRD
• Death

• Secondary Endpoint
• MI
• Stroke
• Hospitalization for CHF or USA
• Vascular intervention
• Death from CV cause

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
  (Plt0.001)

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 gt age 17
• Average age 50s in all groups
• Type II Diabetes
• AER 20-300 µg/min, GFR gt 60 ml/min
• SBPlt160 mmHg
• Excluded-brittle DM, hypotension, DBPgt95

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 didnt 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