New Clinical Studies in Diabetic Kidney Disease

Sang Youb Han, MD, PhD

Division of Nephrology,

Inje University Ilsan-Paik Hospital

Contents

• Recent clinical data

• New therapeutic targets

• Remaining issues

Recent Clinical Data

• New issues: Normoalbuminuric DKD, eGFR • Target blood glucose level • Optimal BP • Nocturnal BP • Normoalbuminura to microalbuminuira • Remission of microalbuminuira • Optimal dose of RAS blockade • ACE inhibitor vs. ARB • Combination of ACE inhibitor and ARB • ARB + renin inhibitor • MR blockade

Recent Clinical Data

• Normoalbuminuric DKD • Target blood glucose level • Optimal BP • Nocturnal BP • Normoalbuminura to microalbuminuira • Remission of microalbuminuira • Optimal dose of RAS blockade • ACE inhibitor vs. ARB • Combination of ACE inhibitor and ARB • ARB + renin inhibitor • MR blockade

Normo Micro

• BENEDICT (N Engl J Med 2004)

: T2D, HTN, >3 yrs

: trandolapril (6.0%) vs. verapamil (11.9%) vs. combination(5.7%) vs. placebo(10%)

• ROADMAP (N Engl J Med 2011)

: T2DM, HTN, 3.2yrs

: olmesartan(8.2%) vs. control (9.8%)

: fatal cardiovascular events (0.7% vs. 0.1%, P=0.01)

• T1DM, normotensive for 5 yrs (Mauer, N Engl J Med 2009)

: renal biopsy & albuminuria

: losartan or enelapril - not effective

Kidney Bx in T2DM

• T2DM, normo & microalbuminuric, 169 Pima Indian

• losartan > 5 yrs

• Normo: no effective

• Micro: effective

Weil, Diabetes Care 2013

Combination of ACE Inhibitor and ARB

• CALM II: candesartan + lisinopril Andersen, Diabetes Care 2005

• ONTARGET: telmisartan + ramipril

• Lisinopril + irbesartan

• VA-NEPHRON: losartan + lisinopril – early termination

• Ongoing study: VALID: benazapril + valsartan

Mann, Lancet, 2008

Juarez, Am J Kidney Dis 2013

RR for Primary Renal Outcome in Subgroups: ONTARGET

• 132 T2 DKD, CKD 2-3

• UPCR>300mg/gCr

• Lisinopril vs. irbesartan

• equipotent half dose

• eGFR: 49±21

• PCR: 1.32

• F/U 3.2 yrs

• No benefit

• Similar adverse effects

Juarez, Am J Kidney Dis 2013

VA-NEPHRON

• T2DM, 1448 • Losartan + Lisinopril • UACR > 300, eGFR 30-90

• Primary end point : eGFR (ml/min/1.73 m2) changes : eGFR ≥ 60 : ≥30, eGRF < 60 : ≥50% : ESRD or death

• Safety outcomes: mortality, hyperkalemia, AKI

• Early termination: 2013.2

Fried, N Engl J Med 2013

Direct Renin inhibitor: Aliskiren

• Aliskiren (Persson, Kidney Int 2008)

: reduction of BP and albuminuria

• Aliskiren + ARB

1) AVOID, Parving, N Engl J Med 2008

2) Persson, Diabetes Care 2009

3) Persson, Clin J Am Soc Nephrol 2011

4) ALTITUDE: early termination

AVOID

• Aliskiren + Losartan

vs. Losartan

• T2DM, 599 pts

• ACR: 300-3500 mg/gCr

• eGFR > 30 ml/min/BSA

• Primary outcome

: ACR reduction at 6 Mo

Parving, N Engl J Med 2008

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-

Renal Endpoints )

• Double-blind study, 8561 T2DM with RAAS blockade

• Aliskiren 300 mg once daily vs. or placebo

• Doubling of s-Cr or ESRD: similar

• 14% reduction in albuminuria

• Early termination d/t safety issue

: hyperK ≥6 mmol/L (8.8% vs. 5.6%)

: reported hypotension (12.1% vs. 8.0%)

: ischemic stroke

Parving, N Engl J Med 2012

MR blockade

• SPR vs. placebo(Schjoedt, Kidney Int 2005) : DM 1, RAS blockade : 30% (CI, 17-41) reduction in albuminuria

• SPR vs. placebo(Schjoedt, Diabetes Care 2005)

: DM 2, RAS blockade : 33%(CI, 25-41) reduction in albuminuria

• SPR vs. losartan(Mehdi, J Am Soc Nephrol 2009)

: 81 DM 2, lisinopril : reduction of ACR: SPR(34.0%) vs. losartan(16.8%) : hyperK

Mehdi, J Am Soc Nephrol 2009

New Therapeutic Targets

• Rho kinase inhibition • AGE inhibitor: thiamine, pyridoxamine • Inhibitor of fibrosis: TGF-β, CTGF, PDGF-pirfenidione, tranilast • PKC inhibitor: ruboxistaurin • JAK 1/2 inhibitor: CKD 3-4, macroalubminuria • Anti-oxidant, anti-inflammatory drugs: pentoxifyllin • Nitric oxide: NADPH oxidase inhibitor • Glycosaminoglycan: sulodoxide • Endothelin antagonist: atrasentan, avosentan • PPAR-α, γ • Vitamin D analgue

Alicic, Am J Kidney Dis 2014

Prevalence of vit D deficiency & 2’ hyperparathyroidism by GFR intervals

Levin, Kidney Int 2007

Link btw Vit D and RAAS

Plum, Nature Rev Drug Disc 2010

Vit D analogue: VITAL

• 281 DM(2) with RAS blockade

• 11–339 mg/mmol

• eGFR : 15–90 mL/min/BSA

• 1 μg & 2 μg paricalcitol

• Primary end points

: UACR at 24 wks

• Adverse events: similar

De Zeeuw, Lancet 2010

Glycosaminoglycans: Sulodexide

• DiNAS: 223 T2DM, ACR 20-300mg/g, CKD 2

• 50, 100, 200 mg

• 74% reduction after 4 Mo

• SUN-micro: 1056 T2DM, ACR 35-200mg/g, Cr<1.5mg/dL

• 200 mg + maximal dose of RAS blockade for 4 Mo

• SUN-macro: 2240 T2DM, proteinuria >900mg/d

• 200 mg + With maximal dose of RAS blockade for 24 Mo

• Early termination

Gamabaro, J Am Soc Nephrol 2002 Lewis, Am J Kidney Dis 2011 Packham, J Am Soc Nephrol 2012

Phosphodiesterase inhibitor: Pentoxifyllin

McCormick, Am J Kidney Dis 2008

Anti-Oxidant: Bardoxolone • Phase IIb

• 227 DM(2), eGFR 20 - 45 ml/min/BSA

• Bardoxolone methyl

• Primary outcome: change in eGFR at 24 weeks

• Secondary outcome change in eGFR at 52 wks

Pergola, N Engl J Med 2011

BEACON Bardoxolone Methyl in Patients With CKD and T2DM

• 2185 T2DM, CKD 4 • bardoxolone methyl 20 mg • Primary composite outcome : ESRD or death from CV causes

• 2012.10 : early termination • side effect : muscle spasm, hypomagnesaemia, nausea • Poor adherence : 81%-42%-25%(25-75-150 mg) at 52 wk

Zeewu, N Engl J Med 2013

Zeewu, N Engl J Med 2013

AGE inhibitor : Vitamin B derivatives

• Alkhalaf, Diabetes Care 2010 – DM(2), UAE : 15-300 mg/24 h(+ RAS blockade), 12 wks

– benfotiamine (900 mg/day) (n = 39) vs. placebo (n = 43)

– no difference

• House, JAMA 2010 – type 1 or 2 diabetes, 36 Mo

– radionuclide GFR: vit-B, 16.5 vs. Cont 10.7 , p= .02

– composite outcome: B-vitamin (HR, 2.0; 1.0-4.0)

– P-total homocysteine(umol/L) : 2.2 vs. 2.6, P < .001

Endotheline Receptor Antagonist

• Mann, J Am Soc Nephrol 2010

– 1392 DM(2), 4 Mo, RAS blokade + avosentan 25 & 50 mg/d

– significantly reduction of ACR: 44.3, 49.3, 9.7%(placebo)

– adverse events: fluid overload and CHF

– Early termination

• Kohan, J Am Soc Nephrol 2011

– 89 DM(2), eGFR > 20 ml/min/BSA, UACR 100-3000 mg/gCr

– significant reduction of ACR

– Peripheral edema

– 9% (placebo) vs. 14, 18, 46%(0.25, 0.5, 1.75 mg atrasentan)

ETRA: atresentan

• 211 T2DM • UACR 300-3500, eGFR 30-75 ml/min per 1.73 m2 • multinational, double-blind studies • placebo (n=50) vs. 0.75 (n=78) vs. 1.25 mg (n=83)

+ max. dose of RAS blockade • 12 weeks

• Reduced albuminuria • improved BP and lipid • Increase in weight, decrease in Hb

Zeeuw, J Am Soc Nephrol 2014

Albuminuria & BP

Zeeuw. J Am Soc Nephrol 2014

Pirfenidone • 77 T2DM, albuminuria(+), eGFR: 20 -75 ml/m/BSA • Double-blind, placebo-controlled • 1200 or 2400 mg + RAAS inhibition

Sharma, J Am Soc Nephrol 2011

Viable Candidates

• PKC inhibitor: ruboxistaurin, phase III (stop)

• Anti-CTGF Ab: phase II (stop)

• JAK ½ inhibitor: phase II

Remaining but Important Issues

• Acute kidney injury

: contrast, NSAIDs, heart failure, hypoglycemia,

DM foot, hospitalizations , surgical interventions,

UTI, Postinfectious glomerulonephritis

• Ischemic nephropathy, peripheral artery dz

• Smoking

• Diet: low salt, low protein

• Exercise, weight control

Kelly, Am J Nephrol 2010

Association btw 24-h U-Na excretion and All-cause Mortality in T1DM

• FinnDiane study

• 1998-2002

• 2,807 T1DM

• 150±20 mmol/d

• 10 f/u

Thomas, Diabetes Care 2011

Lambers Heerspink, Kidney Int 2012

eGFR decline

Summary & Conclusion

• Primary prevention with RAS blockade : NO

• Combination of RAS blockade: NO

• Mineralocorticoid blocker: Yes

• New drugs: vit D analogue, pentoxifyllin, ETRA

• Individualized therapeutic strategy

• Multifactorial & non-pharmacological intervention