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Diabetes Symposium Primary prevention of diabetic nephropathy: pharmacological intervention

Diabetes Symposium Primary prevention of diabetic nephropathy: pharmacological intervention Piero Ruggenenti Mario Negri Institute for Pharmacological Research Unit of Nefrology and Dialysis, Azienda Ospedaliera Ospedali Riuniti , Bergamo,Italy Malaga, October 10 2005.

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Diabetes Symposium Primary prevention of diabetic nephropathy: pharmacological intervention

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  1. Diabetes Symposium Primary prevention of diabetic nephropathy: pharmacological intervention Piero Ruggenenti Mario Negri Institute for Pharmacological Research Unit of Nefrology and Dialysis, Azienda Ospedaliera Ospedali Riuniti, Bergamo,Italy Malaga, October 10 2005

  2. PROJECTED CHANGES OF ISCHEMIC HEART DISEASE MORTALITY WORLDWIDE (1990 to 2020) 5000 Deaths (x 1000) DEVELOPING COUNTRIES 4500 4000 3500 3000 2500 DEVELOPED COUNTRIES 2000 1500 1000 500 0 1990 2020 Yusuf et al. Circulation 2001 Cardiovascular diseases are the fastest growing cause of death in developing countries and by the year 2020 they would take the lead

  3. - Diabetes - High Blood Pressure - Chronic Renal Disease

  4. 2000 2030 THE GLOBAL BURDEN OF DIABETES (2000-2030) 52.4 42.3 30.7 18.6 33.8 80.9 16.7 71% 127% 22.8 102% 28.3 255% 9.1 32.9 211% 18.2 0.9 1.6 78% 81% * In million subjects World Developed Developing 2000 2030 154 m 370 m 55 m 84 m 99 m 286 m WHO, March 2003

  5. INCREASING DEATHS DUE TO DIABETES U.S. National Center for Health Statistics, 1999

  6. HALF-CENTURY’S EXPERIENCE IN DIABETES MELLITUS 90 Diabetic coma Cardiovascular complications 60 (%) 30 0 1910-20 1920-30 1930-40 1940-50 Joslin EP, B Med J, 1950

  7. PROTEINURIA IS AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE Cumulative incidence of CHD in type 1 diabetes Age adjusted cardiovascular mortality in PIMA indians 12 150 With proteinuria 10 125 8 100 CHD (%) Age- and sex-adjusted deaths (x 1000 person-year) 6 75 Without proteinuria 4 50 2 25 0 0 Proteinuric diabetics Healthy subjects Non proteinuric diabetics 12 14 16 18 20 22 24 0 Years of diabetes Juomilehto et al., Diabetologia, 1998 Nelson et al., Diabetes, 1988

  8. THE FACT 40 % of type 1 and of type 2 diabetics are at risk of overt nephropathy

  9. 80 60 1/Cr x 10 3(µmol/l) 40 20 0 0 10 20 30 40 50 Time(months) PROGRESSION OF RENAL FAILURE IN 9 DIABETICS Modified from Jones et al., Lancet, 1979

  10. GLOMERULAR HYPERTENSION Mechanical stress Podocyte proliferation * 1.2 1.0 0.8 Pg of Ang II per µg of cell lysate 0.6 0.4 Podocyte number 0.2 0 Control Stress Durvasula et al, Kidney Int, 2004 Scarring Pore dimension Riser et al., Am J Pathol, 1996

  11. 0.10 0.09 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0.00 Glomerular hypertension P GC 63 mmHg 53 mmHg Control Diabetic Pore radii distribution 0 10 20 30 40 50 60 Pore radius (Å) GLOMERULAR PERMEABILITY TO MACROMOLECULES Protein traffic

  12. 1 1 . 0 0 0 0 . 5 0 0 Angiotensin II 0 . 2 0 0 0.1 0 . 1 0 0 Diabetes Ficoll Fractional Clearance Fractional dextran clearance 0 . 0 5 0 0.01 Vehicle 0 . 0 2 0 0 . 0 1 0 Controls 0 . 0 0 5 0.001 2 0 3 0 4 0 5 0 24 28 32 36 40 44 48 52 56 60 ° Effective Molecular Radius(A) Effective Molecular Radius(A) Lapinski et al., J Am Soc Nephrol, 1996 A. Remuzzi et al., J Am Soc Nephrol, 1993

  13. PATHOPHYSIOLOGY OF PROGRESSIVE NEPHROPATHIES Renal injury Increased glomerular permeability to macromolecules Glomerular-capillary hypertension Reduction of nephron numbers Proteinuria Increased filtration of plasma proteins Excessive tubular reabsorption Nuclear signals for NF-kB-dependent and independent vasoactive and inflammatory genes. Corresponding protein products then released into interstitium Tubular cell transdifferentiation Fibroblast proliferation Fibrogenesis Renal scarring Remuzzi and Bertani, N Engl J Med,1998

  14. P GC 63 mmHg 53 mmHg ** 400 * 300 Urinary protein excre tion (mg/24 h) 200 Diabetes + Losartan 100 Diabetes 0 0 4 8 12 months Angiotensin II receptor blocker by limiting urinary protein traffic - through a reduction in dimension of large unselective pores - also reduced tubulointerstitial and glomerulosclerosis injury Remuzzi et al., J Am Soc Nephrol, 1993

  15. wo CLINICAL AND KIDNEY FUNCTIONAL PARAMETERS Basal Enalapril SBP (mmHg) DBP (mmHg) GFR (ml/min/1.73sqm) RPF (ml/min/1.73sqm) FF (%) Urinary protein excretion (g/24h) Albumin fractional clearance (x10-5) IgG fractional clearance (x10-5) 152 ± 19 83 ± 9 23 ± 11 366 ± 164 7.0 ± 3.5 3.0 ± 1.9 455 ± 394 138 ± 156 149 ± 14 81 ± 6 24 ± 12 357 ± 212 7.2 ± 3.0 2.2 ± 1.3 248 ± 355 * 78 ± 131 ** * p < 0.05 Basal vs.Enalapril; ** p < 0.01 Basal vs. Enalapril wox 10 -3 u (Å) 60 6.0 55 5.0 50 4.0 45 3.0 40 2.0 35 1.0 30 0 Control Diabetes Enalapril Control Diabetes Enalapril u mean size of membrane pores filtrate volume fraction that would pass through the shunts if plasma protein were absent Remuzzi A et al., J Nephrol, 1993

  16. 0 Captopril Conventional therapy 25 50 75 100 0 1 2 3 4 ACE-I IS BETTER THAN CONVENTIONAL THERAPY IN TYPE 1 DIABETES % with Doubling of Baseline Creatinine Baseline creatinine > 1.5 mg/dl • 2 – • 0 – • - 2 – • - 4 – • 6 – • 8 – • 40 – • - 20 – • 0 – • - 20 – • 40 – • 60 – P <.001 Decrease in Mean Blood Pressure (mm Hg) % Reduction in Proteinuria NS Lewis et al. N Engl J Med. 1993;329:1456-1462.

  17. 0 Losartan Conventional therapy 25 50 75 100 0 1 2 3 4 RENAAL: ARB IS BETTER THAN CONVENTIONAL THERAPY IN TYPE 2 DIABETIC NEPHROPATHY % with Doubling of Baseline Creatinine + ESRD + death • + 2 – • 0 – • - 2 – • - 4 – • 6 – • 8 – • 9 – • 10 – • + 40 – • + 20 – • 0 – • - 20 – • 40 – • 60 – p <.001 + 19 Decrease in Mean Blood Pressure (mm Hg) % Reduction in Proteinuria -9.2 -9.6 - 45 NS Brenner et al, N Engl J Med., 2001.

  18. In diabetic renal disease a major achievement has been already to limit progression from macroalbuminuria to the need of dialysis 1 -

  19. RENAAL Secondary Composite Endpoint and Components Losartann=751 n 89 50 47 90 Placebon=762 n 127 68 50 79 % RiskLosartan vs placebo - 32 - 28 - 5 +12 Heart Failure MI Stroke CV Death

  20. HAZARD RATIO OF RENAL AND CARDIOVASCULAR EVENTS ACCORDING TO 6 MONTHS REDUCTION IN PROTEIN/CREATININE RATIO Hazard ratio (95 % C.I.) ESRD CV events Heart failure Increased risk Decreased risk 1 0.8 1.2 0.4 0.6 0.2 RENAAL Study group, 2002

  21. HAZARD RATIO FOR CARDIOVASCULAR EVENTS ACCORDING TO TREATMENT AND RESIDUAL (6 MONTHS) PROTEINURIA 1.05 CV Endpoint 1.04 Losartan Placebo 1.03 1.02 1.01 1 2.0 3.0 4.1 ≥ 5.2 <0.4 Hazard ratio relative to lowest proteinuria Protein/creatinine ratio at 6 months (g/g) RENAAL study group, 2002

  22. AT1 blockade Angiotensin II AT2 overstimulation • BP reduction • vasodilation • antigrowth and antitrophic effects • cardiovascular fibrosis • Inhibition of coronary angiogenesis Akishita et al., Circulation, 2000 Silvestre et al., Circ Res, 2002 Any disruption of angiogenesis that may arise from stimulation of AT2 receptors in the context of AT1 blockade could have serious implications in ischemic tissues such as a diseased myocardium or in lower limbs affected with peripheral arterial disease

  23. A META-ANALYSIS OF 47 TRIALS OF 8,305 PATIENTS WITH DIABETIC NEPHROPATHY RANDOMIZED TO ACEi OR ARB THERAPY vs PLACEBO All cause mortality Relative Risk (95% C.I.) Patients ACEi 4,805 ARB 3,329 Increased risk Decreased risk 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 Strippoli et al., J Am Soc Nephrol, 2003

  24. ANGIOTENSIN RECEPTOR BLOCKADE VS ACE-I IN TYPE 2 DIABETES AND NEPHROPHATY A 5-years, randomized trial Enalapril (n = 130) Telmisartan (n = 120) DGFR(ml/min/1.73 sqm) CV events(%) (fatal//non fatal) -14.9 21 -17.9 27 “These findings support the clinical equivalence of AII-RA and ACE-I in persons with type 2 diabetes and nephropathy” Barnett et al., N Engl J Med, 2004 However: - more progression and events on telmisartan - statistics ?

  25. ANNUAL MORTALITY AND ESRD IN SUBJECTS WITH TYPE 2 DIABETES AND NEPHROPATHY 25 ° (%) 20 15 RENAAL UKPDS ? 10 * 5 0 ESRD Mortality Estimate from the ° UKPDS and the *RENAAL studies Adler et al., Kidney Int, 2003

  26. RISK OF CARDIOVASCULAR EVENTS ACCORDING TO RENAL OR CORONARY ARTERY DISEASE R.R. (95 % C.I.) Renal insufficiency and albuminuria Coronary artery disease 0.5 1 1.25 1.5 2.0 2.5 Increased risk

  27. EVIDENCE THAT ACE-I HAS A DIFFERENT EFFECT ON GLOMERULAR INJURY ACCORDING TO THE DIFFERENT PHASE OF THE DISEASE AT WHICH THE TREATMENT IS STARTED Diabetes 200 300 * Diabetes 160 ACEi 200 Proteinuria (mg/24h) Proteinuria (mg/24h) 200 120 ACEi * Diabetes + ACEi 80 100 Diabetes + ACEi 40 0 0 0 20-24 24-28 28-32 0 3 1 - 3 3 3 5 - 3 7 3 9 - 4 1 Time (weeks) Time (weeks) Perico et al., J Am Soc Nephrol, 1994

  28. RENAAL IDNT IRMA 2 Normoalbuminuria Micro Macro ESRD UAE µg/min < 20 20 - 200 > 200 18 0 25 13 Duration of diabetes (years)

  29. EFFECT OF ANGIOTENSIN II ANTAGONISM ON PROGRESSION TO MACROALBUMINURIA IN SUBJECTS WITH TYPE 2 DIABETES AND MICROALBUMINURIA 20 Placebo 15 Incidence of macroalbuminuria (%) 10 Irbesartan 5 0 12 0 3 18 22 6 24 Months of follow-up Parving et al., N Engl J Med, 2001

  30. The second important step was to reduce the number of patients who progress from microalbuminuria to overt nephropathy 2 -

  31. THE ASSOCIATION OF MICROALBUMINURIA AND MORTALITY IN TYPE 2 DIABETES An overview of 2.138 patients of 8 clinical trials from 1992 to 1995 R.R. (95 % C.I.) Micro worse 0.5 1 4 16 64 256

  32. Preventing nephropathy is more important than retarding progression

  33. IRMA 2 RENAAL IDNT BENEDICT Normoalbuminuria Micro Macro ESRD UAE µg/min < 20 20 - 200 > 200 18 0 25 13 Duration of diabetes (years)

  34. The BENEDICT trial 6.500 pazienti studiati 1.200 hanno preso parte allo studio

  35. PRIMARY AIM To assess whether microalbuminuria can be prevented in people with type 2 diabetes and normal urinary albumin excretion

  36. Inclusion criteria Type 2 diabetes mellitus Arterial hypertension Normoalbuminuria Serum creatinine WHO criteria Age ≥ 40 yrs Duration < 25 years HbA1c < 11 % Systolic BP > 130 mmHg and/or Diastolic BP > 85 mmHg and/or need for antihypertensive agents UAE < 20 µg/min (in at least 2 of 3 consecutive overnight urine collections) < 1.5 mg/dl The BENEDICT group, CCT 2003 Ruggenenti et al., N Engl J Med, 2004

  37. E F F E C T S O F E N A L A P R I L ( 1 0 m g / d a y ) I N N O N - O B E S E S U B J E C T S W I T H T Y P E 2 D I A B E T E S , N O R M A L B L O O D P R E S S U R E A N D N O R M O A L B U M I N U R I A * 40 30 UAE (mg/24 h) 20 10 0 110 * 105 ) Placebo (n=79) Mean Blood Pressure mmHg 100 Enalapril (n=77) ( 95 90 0 1 2 3 4 5 6 Years Ravid et al., Ann Intern Med 1998 * p < 0.05 vs. enalapril

  38. EFFECTS OF CALCIUM ANTAGONIST SUBCLASSES ON MARKERS OF NEPHROPATHY PROGRESSION A systematic review of randomized trials of dCCBs and ndCCBs in hypertensive adults with proteinuria MAP Proteinuria 10 10 ndCCBs ndCCBs dCCBs dCCBs 0 0 0 Change vs. basal (%) -10 -10 -20 -20 -30 -30 p < 0.01 Bakris et al., Kidney Int 2004

  39. THE EFFECT OF 6 MONTH TREATMENT WITH TRANDOLAPRIL AND ITS FIXED-DOSE COMBINATION WITH VERAPAMIL ON PROTEINURIA IN 60 NORMOTENSIVE ADULTS WITH TYPE 2 DIABETES p < 0.05 p < 0.01 p < 0.001 100 1.5 80 1.0 60 Proteinuria (g/24 hours) DGFR (ml/min) 40 0.5 20 0 0 pre post pre post pre post pre post Trandolapril Trandolapril VeraTran VeraTran Rubio-Guerra et al., Diabetes Care, 2004

  40. -6 -5 -4 -3 -2 -1 0 Study design TREATMENT PERIOD RUN-IN RAS inhibitors withdrawal Trandolapril (2mg/d) ndCCBs withdrawal Verapamil S.R. (240 mg/d) Randomisation Trandolapril (2mg/d) plus Verapamil S.R. (180 mg/d) Placebo 0 6 12 18 24 30 36 months weeks Overnight UAE Blood pressure and routine laboratory tests

  41. Placebo (30 events) 15 10 Cumulative Incidence of Microalbuminuria(%) 5 Trandolapril plus verapamil (17 events) A.F. (95 % C.I.) = 0.39 (0.19 - 0.80) p = 0.01 0 0 6 12 18 24 30 36 42 48 Follow-up (months) No. at Risk Trandolapril plus Verapamil Placebo 300 300 249 229 232 214 217 203 210 187 201 176 192 164 162 136 115 89

  42. Placebo (30 events) 15 10 Cumulative incidence of microalbuminuria (%) 5 Trandolapril (18 events) A.F. (95 % C.I.) = 0.47 (0.26 - 0.83) p = 0.01 0 0 6 12 18 24 30 36 42 48 Follow-up(months) No. at Risk Trandolapril Placebo 301 300 254 229 237 214 224 203 207 187 198 176 188 164 149 136 104 89

  43. 0 6 12 18 24 30 36 42 48 Follow-up(months) Verapamil (36 events) 15 Placebo (30 events) 10 Cumulative incidence of microalbuminuria (%) 5 0 No. at Risk Verapamil Placebo 303 300 234 229 210 214 202 203 189 187 181 176 174 164 134 136 98 89

  44. ADVERSE EVENTS Trandolapril plus verapamil Trandolapril Verapamil Placebo N=301 N=303 N=300 N=300 Fatal Cardiovascular Non Fatal Cardiovascular 4 1 80 12 2 1 67 13 2 0 67 11 5 3 70 12

  45. COST-EFFECTIVENESS OF RAS INHIBITION IN TYPE 2 DIABETES MODELED OVER 25 YEARS ESRD Per patient costs 25 30 ? ? 25 20 20 Cumulative incidence (%) 15 15 U.S. $ (x 1,000) RENAAL RENAAL IRMA-2 10 IRMA-2 10 Normo BENEDICT Normo BENEDICT 5 5 Macro Macro Macro Macro Micro Micro 0 0 RAS-inhibition Placebo RAS-inhibition Placebo Palmer et al., Diabetes Care, 2004

  46. Chronic Disease Outreach Program in Australia Tiwi Islands Wadeye Borroloola Broome Naiuyu Bega, Kalgoorlie Soweto, South Africa Chennai, India

  47. Conventional Perindopril 20 15 ESRD Death Events per 100 persons/years 10 5 0 1990 1995 2000 A cost effectiveness analysis estimate savings of $ 800,000 AUS to $ 4,1 million at 2 years in cost of dialysis avoided or delayed Hoy et al., J Am Soc Nephrol,2003

  48. Armenia Moldova Nepal China Cuba Maroco India Nicaragua Philippines Nigeria Indonesia Bolivia Australia South Africa Paraguay Established programs Programs in development

  49. A new agenda for kidney doctors will be for the future preventing nephropathy with the final aim to limit cardiovascular events and death 3 -

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