Treatment of diabetic kidney disease: landmark studies and ... · 2 Chronic kidney disease is a...

Treatment of diabetic kidney disease: landmark studies and tribulations

Division of Nephrology, Department of Medicine, The University of Hong Kong

APSN/JSN Continuing Medical Education (CME) Course 2016, 16 Jun 2016

Sydney C.W. TANG

2

Chronic kidney disease is a global public health problem

10.8%11.5%

Levey AS, et al. JAMA2007

Zhang L, et al. Lancet2012

11.5 – 13.4%

White SL, et al. Am J Kidney Dis2010

Estimated CKD Burden: 8 – 16% worldwide (Jha V, et al. Lancet 2013)

3

Chronic kidney disease (CKD): an increasingly common cause of death: 1990 to 2013

a systematic analysis for the Global Burden of Disease Study

19 Chronic kidney disease

36 Chronic kidney disease

Top 50 Causes of death: 1990 2013

The number of people with type 2 diabetes is increasing in every country

The Diabetes Epidemic

387 million people have diabetes; by 2035 this will rise to 592 million

IDF Diabetes Atlas 2014

179 million people with diabetes are undiagnosedThe greatest number of people with diabetes are between 40 and 59 years of age

Outline• The burden of diabetic kidney disease in Asia• Landmark clinical trials on treatment and tribulations• Recent clinical trials

– Investigational– Novel

• Future perspectives

Japan• Population: 127 million

Imai et al. Clin Exp Nephrol 2010

No CGN CGN No nephropathy

nephropathy

90930.5%

94831.8%

50717.0%

61320.6%

No diabetes DiabetesN=2977

Chronic Kidney Disease Japan Cohort StudyCKD-JAC

Diabetic nephropathy

Chronic glomerulonephritis

Hypertensive nephrosclerosis

43.8%

18.8%

Causes of incipient dialysisJSDT

• China has a high prevalence of chronic kidney disease (CKD); an increasing prevalence of hypertension, obesity and type 2 diabetes mellitus, and an ageing population will exacerbate the burden of CKD

• The current leading cause of CKD in China is glomerular disease, followed by diabetic nephropathy, and hypertension; IgA nephropathy is the most common glomerular disease

DN

Taiwan

Treated ESRD mortality

Taiwan Society of Nephrology data

Other developed Asian Countries

ESRD Registry Committee, Korean Society of Nephrology

Singapore Renal Registry Annual Registry Report 1999-2013

What about in developing Asian Countries?

Phillippine Society of Nephrology21ST REPORT OF THE MALAYSIAN DIALYSIS AND TRANSPLANT REGISTRY 2013

Cambodia• So far, no reliable data on the incidence

and prevalence of ESRD & CKD in Cambodia

• In a recent study carried out in MoPoTsyo (an NGO Health Center in the Takeo province of Cambodia) :– Over one-half of Cambodians with DM had a

reduced eGFR (60 ml/min/1.73 m2)

CKD population in Sri Lanka

• Estimates only• >75% due to DM ,HT and CGN• DM alone 36%• Diabetic population in SL 12%= 2.5 million• by 2030- ? 5 million• DBN – 30% to 50% will develop CKD (all stages)

=0.81 million• Estimated prevalence of HT in SL= 2 million

The Indian CKD registry confirms the emergence of DN as the pre-eminent cause of CKD in the country as a whole

Nepal• No formal registry in Nepal in relation to CKD and ESRD. So, very

little is known about the pattern of the ESRD. • It is presumed that diabetes mellitus is the commonest cause

of ESRD, followed by CGN and hypertension. (Sharma et al. Journal of Nepal Medical Association 2001; Adhikary Land Simkhada R. Kathmandu Medical college Journal 2005)

• A single hospital based retrospective study from the capital city (Kathmandu) from 1990 to 1999 found that three most common causes of ESRD were Glomerulonephritis (36%), Diabetes mellitus (16.8%), and hypertension (13.7%). (Khakhurel S et al. Journal of Nepal Medical Association 2009).

Personal communication with Sharma S, Nepal Society of Nephrology

AJKD 2010

Key messages:Total screened: 11,394 participantsDecreased eGFR (60 mL/min/1.73 m2): 7.3%-14%Proteinuria on dipstick: 2.4%-10%Hypertension: 26%-36%Diabetes: 3%-8%Obesity (body mass index> 30 kg/m2): 2%-20%

Sharma SK, et al. AJKD 2010

40-50%

~60%

USRDS 2014 Report

DM: 43.5%

DN as the etiology of dialysis therapy

Outline• The burden of diabetic kidney disease in Asia• Landmark clinical trials on treatment and tribulations• Recent clinical trials

– Investigational– Novel

• Future perspectives

ARBACEiARB/ACEiARB/DRIMRA

ARB: RENAAL & IDNT

Lewis EJ, N Eng J Med 2001

Brenner B, et al. N Engl J Med 2001

Risk reduction, 28%P=0.002

Vilayur et al.Nat Rev Nephrol(2009)

End

sta

ge re

nal d

isea

se (%

)

ACE inhibitors in diabetic nephropathy

Strippoli GF, BMJ 2004

Mann JF, et al. Lancet 2008

ONTARGET – Renal composite

Mann JF, J Hypertens 2013

VA NEPHRON-D

VA-NEPHRON-D: Significantly increased SAE

Acute Kidney Injury Hyperkalemia

Fried L et al, . N Engl J Med November 2013

HR 1.7 (95% CI 1.3-2.2) HR 2.8 (95% CI 1.8-4.3)

Dual blockade in patients with DN

Catala-Lopez F, Rev Esp Cardiol 2013

ALTITUDE: Outcomes

Parving, N Eng J Med 2012 (ALTITUDE study)

Trial terminated in 2011 due to efficacy and safety concerns. Increased non-fatal stroke, hyperkalaemia. Despite lower urinary protein and lower BP

Aldo antagonist +ACEi/ARBVs ACEi /ARB alone

Aldo antagonist +ACEi/ARBVs ACEi /ARB alone

Aldo antagonist +ACEi/ARBVs ACEi /ARB alone

Proteinuria Change in GFR

Incidence of hyperkalaemia

Spironolactone

Eplerenone

Total

Navaneethan et al, Clinical JASN 2009

Aldosterone antagonists

What did the guidelines say?KDIGO 2012

Finerenone• Finerenone (BAY94-8862) is a novel

nonsteroidal MRA that has greater receptor selectivity than spironolactone and better receptor affinity than eplerenone in vitro

• Lower incidence of hyperkalemia than spironolactone. [Pitt B, et al. Eur Heart J 2013]

• May be able to address the unmet medical need of safely managing albuminuria without adversely affecting serum K in patients with type 2 DN

Inclusion: T2DM,UACR≥30mg/g, eGFR > 30 (30-45: on a non-K sparing diuretic); on an RAS blocker, serum potassium </= 4.8 mmol/L.

Primary outcome variable: UACR at day 90 vs at baseline

N = ~ 90+ / Rx group (1.25, 2.5, 7.5, 10, 15, 20 mg daily)N = 94 in matching control group

Change in Least Squares Mean UACR

Bakris G, et al. JAMA 2015

Weir MR. Nat Rev Nephrol Oct 13, 2015

Demographic Characteristics of Patients Treated With Placebo or Finerenone, 1.25-20mg/d

Bakris G, et al. JAMA 2015

Serial eGFR and serum K levels

Bakris G, et al. JAMA 2015

60% had eGFR >60 ml/min2/3 on loop/thiazideModest BP reduction

The role of glycemic control

Glomerulocentric view:Cellular mechanisms of diabetic glomerulosclerosis

Adapted from Masaon RM. J Am Soc Nephrol 2003

Diabetic substrates

The PTEC

Downstream events promulgated

Pathways / molecules

NK-B ()

PKC ()

ERK1/2 ()

p38 ()

CDK ()

STAT-1 ()

TLRs ()

ROS ()

Smad ()

KKS ()

Glucose

Proteins Glycated proteins

Growth factors AGEs Ang II

Cell cycle arrest, cell hypertrophy and senescence

Upregulated inflammatory chemokines/ cytokines

Secretion of

profibrotic cytokines and ECM proteins

EMT (debatable)

Tang SC & Lai KN: Nephrol Dial Transplant 2012

HR=0.35(CI 0.15–0.83)

p=0.017

Cum

ulat

ive

inci

denc

e (%

)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Follow-up (months)0 6 12 18 24 30 36 42 48 54 60 66

StandardIntensive

HbA1c 6.5%HbA1c 7.3%

ADVANCE:New or worsening nephropathy

Standard

Intensive

Placebo

Per-Ind

1.02

0.820.84

0.680.6

0.8

1.0

1.2

Annual event rate %Hazard ratios

P for interaction=0.93

All participants 19% (2 to 34)

Placebo 20% (-4 to 39)

Per-Ind 18% (-9 to 39)

Relative riskreduction (95% CI)

FavoursIntensive

FavoursStandard

Hazard ratio

0.5 1.0 2.0

BP arm

Glucose arm

All participants 18% (-1 to 32)

Standard 18% (-7 to 37)

Intensive 17% (-12 to 38)

Hazard ratio0.5 1.0 2.0

Relative riskreduction (95% CI)

FavoursPer-Ind

FavoursPlacebo

0.820.84

RRR 33%, P=0.005

BPGlucose

Perkovic, J Am Soc Nephrol. 2009

Role of statin in diabetic patients with nephropathy

0 1 2 3 4 5 Years of follow-up

0

5

10

15

20

25 P

ropo

rtion

suf

ferin

g ev

ent (

%)

Risk ratio 0.83 (0.74–0.94) Logrank 2P=0.0022 Placebo

Eze/simv

SHARP :CV events

Baigent, et al. Lancet 2011

SHARP- subgroup analyses

Baigent, et al. Lancet 2011

Statins in CKD- meta analysisRisk of CV events by kidney function

Statin better PBO better

Hou et al. Eur Heart J (2013) 34 (24): 1772-1774

Albuminuria reduction in patients with diabetic kidney disease

Adapted from: UKPDS 64. Kidney Int 2003; 63: 225-32

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

S-creat. >175 μmol/l or ESKD

2.0%

2.8%

2.3%

Annual transition rate in T2DM

1.4%

3.0%

4.6%

19.2%

Annual risk of all-cause death in T2DM

Stages of nephropathy in diabetes

Activation of inflammatory and fibrogenic pathways in proximal tubular epithelial cells by ultrafiltered proteins

Glomerular compartment

Tubulointersitial compartment

Glomerular filtration barrier

Activation of inflammatory and fibrogenic pathways in proximal tubular epithelial cells by ultrafiltered proteins

Inflammation and T cell

recruitment

Accumulation of fibroblasts

Fibrosis

Lai KN, et al. Kidney Int 2007

Reduction in albuminuria and protection from renal endpoint - RENAAL

De Zeeuw, Kidney Int, 2004

Meta-analysis of 1.2 M subjects from 21 studies

Medline and EMBASE 1950 – 2014Mean FU > 1,000 patient-yrs Reported ESRD outcomes with longitud UACR measured21 trials with 78,342 pts and 4,183 ESRD events

for each 30% reduction in albuminuria, the riskof ESRD decreased by 23.7%(95% confidence interval, 11.4% to 34.2%; P=0.001)

Outline• The burden of diabetic kidney disease in Asia• Landmark clinical trials on treatment and tribulations• Recent clinical trials

– Investigational– Novel

• Future perspectives

The Chemokine and Cytokine storm in the diabetic kidney

Tang SC, et al. JASN 2006

Tang SC, et al. Contrib Nephrol 2011

Tang SC, et al. NDT 2013

e.g. CCL2

Primary Endpoint

UACR changes from baseline during 52 weeks were –2% for placebo (95% CI–11% to 9%), –18% for 5 mg CCX140-B (–26% to –8%), and –11% for 10 mg CCX140-B (–20% to –1%).

Primary endpoint: UACR over timePrimary endpoint: UACR over time

UACR is reduced by 36% and 44% in the 0.75 mg and 1.25 mg groups compared to a 2% increase in the placebo group

Time, Weeks

% G

eom

etric

Mea

n C

hang

e

-60

-40

-20

0

20

0 2 4 6 8 10 12 30-Days off

p<0.001 for both doses vs. placebo (repeated measures analysis 12 weeks)

Placebo

0.75 mg atrasentan

1.25 mg atrasentan

De Zeeuw, et al. JASN 2014

Change in UACR and eGFR

Change in UACR from baseline to thelast measurement during treatment

Renal glucose handling in humansIn “normal” individuals: Approximately 900mmol (180g) of  glucose is filtered by the kidneys daily.1

In animal models,  ~90% reabsorbed in the S1 and S2 

segments of the proximal tubule via SGLT2.2

Remainder reclaimed in the S3 segment1,3

Minimal glucose is excreted by the kidney In hyperglycaemic individuals: glucose reabsorption by the kidney effectively doubles

1Am J Physiol Renal Physiol 2001;280:F10–8; 2Kidney Int Suppl 2007;106:S27‐35; 3J Inherit Metab Dis 2000;23:237–246; 

Renal glucose handling in humans

600

400

200

00 200 400 600 800

Rate of glucose filtration /

reabsorptio

n /excretio

n(m

g/min)

Plasma glucose (mg/dL)

Tm

Reabsorbed

Filtered Excreted

Threshold

Tm

Enhanced renal tubular glucose reabsorption contributes to hyperglycaemia in T2DM

– Hyperglycaemia results in increased glucose filtered at the glomerulus and glucose reabsorption operates at the transport maximum (i.e. if normal glucose is 5 mM/L glucose and Tm is 10 mM/L glucose then twice the amount of glucose is reabsorbed if BSL is 10 mM/L or above)

– SGLT2 and GLUT transporter numbers are increased, thus Tm is increased

Enhanced renal tubular glucose reabsorption contributes to hyperfiltration in diabetes

– Reduced Na+ delivery to the distal nephron

– Leading to activation of the macula densa within the JG apparatus to adjust the tone of the afferent glomerular arterioles to increase glomerular filtration (tubuloglomerular feedback mechanism)

– Hyperfiltration in the early stages of diabetic nephropathy delivers more glucose to the tubule and hence more ‘available’ to be reabsorbed

Guyton & Hall. Textbook Of Physiology, 11th Edition 2006

Renal corpuscle:The structure on the left in blue and pink is the renal corpuscle. The structure on the right is the renal tubule. The blue structure (A) is the Bowman's capsule (2 and 3). The pink structure is the glomerulus with its capillaries. At the left, blood flows from the afferent arteriole (9), through the capillaries (10), and out the efferent arteriole (11). The mesangium is the pink structure inside the glomerulus between the capillaries (5a) and extending outside the glomerulus (5b). Macula densa is #7.

160

110

60

20

6

5

4

3

2

1

0 5 10 15 20 25 30

Pathophysiology of type 2 diabetes: deterioration over 20 years

Urin

e pr

otei

n ex

cret

ion

(g/2

4 h)

GFR

(ml/m

in)

Years after diabetes onset

Hyperfiltration

GFR

ESRD

Onset ofdiabetes

Primaryprevention

Secondaryprevention

Tertiaryprevention

Onsetnephropathy

Williams ME. Am J Nephrol 2005;25:77–94.

GlomerulomegalyRenal hypertrophy

Key inclusion and exclusion criteria

• Key inclusion criteria– Adults with type 2 diabetes– BMI ≤45 kg/m2

– HbA1c 7–10%* – Established cardiovascular disease

• Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease

• Key exclusion criteria– eGFR <30 mL/min/1.73m2 (MDRD)

LDL cholesterol, mg/dL 84.9 (35.3) 86.3 (36.7) 85.5 (35.2)eGFR, mL/min/1.73m2 (MDRD) 73.8 (21.1) 74.3 (21.8) 74.0 (21.4)≥90 mL/min/1.73m2 488 (20.9%) 519 (22.1%) 531 (22.7%)60 to <90 mL/min/1.73m2 1238 (53.1%) 1221 (52.1%) 1204 (51.4%)<60 mL/min/1.73m2 607 (26.0%) 605 (25.8%) 607 (25.9%)

Placebo (n=2333)

Empagliflozin10 mg

(n=2345)

Empagliflozin25 mg

(n=2342)HbA1c, % 8.08 (0.84) 8.07 (0.86) 8.06 (0.84)Time since diagnosis of type 2 diabetes, years≤5 423 (18.1) 406 (17.3) 434 (18.6)>5 to 10 571 (24.5) 585 (24.9) 590 (25.2)>10 1339 (57.4) 1354 (57.7) 1318 (56.3)

Baseline characteristics

Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug.

HbA1c

229422962296

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

227222722280

218822182212

213321502152

211321552150

206321082115

200820722080

196720582044

174118051842

145615201540

124112971327

110911641190

96210061043

705749795

420488498

151170195

12 28 52 94 10880 12266 1360 150 164 178 192 20640

80

Weight

228522902283

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

191518931891

221522382226

213821742178

159816731678

123912981335

425483489

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

81

28 52 1080 164 22012

Systolic blood pressure

82

232223222323

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

223522502247

220322352221

216121932197

213321742169

207321252129

202420952102

197420722066

177118531878

149215561571

127413271351

112611891212

98110341070

735790842

450518528

171199216

Placebo

Empagliflozin 10 mgEmpagliflozin 25 mg

16 28 52 94 10880 12266 1360 150 164 178 192 20640

3-point MACEEmpagliflozin 10 mg

HR 0.85(95% CI 0.72, 1.01)

p=0.0668

Empagliflozin 25 mgHR 0.86

(95% CI 0.73, 1.02)p=0.0865

Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio

CV death

HR 0.62(95% CI 0.49, 0.77)

p<0.0001

Cumulative incidence function. HR, hazard ratio

Hospitalisation for heart failure

HR 0.65(95% CI 0.50, 0.85)

p=0.0017

Cumulative incidence function. HR, hazard ratio

All-cause mortality

HR 0.68(95% CI 0.57, 0.82)

p<0.0001

Kaplan-Meier estimate. HR, hazard ratio

Adverse events consistent with genital infection

Rate = per100 patient-years

Placebo (n=2333)

Empagliflozin 10 mg

(n=2345)

Empagliflozin 25 mg

(n=2342)

n (%) Rate n (%) Rate n (%) Rate

Events consistent with genital infection

42 (1.8%)

0.73 153 (6.5%)

2.66 148 (6.3%)

2.55

Serious events 3 (0.1%)

0.05 5 (0.2%)

0.08 4 (0.2%)

0.07

Events leading to discontinuation

2 (0.1%)

0.03 19 (0.8%)

0.32 14 (0.6%)

0.23

By sex

Male 25(1.5%)

0.60 89 (5.4%)

2.16 77 (4.6%)

1.78

Female 17(2.6%)

1.09 64(9.2%)

3.93 71(10.8%)

4.81

eGFR over time

• Empa (10 or 25 mg daily) dropped eGFR by around 4 ml/min (from 74 to 70 – 71) over the initial 4 weeks, which became stable over the 4-year treatment period

• The placebo group pursued a steady decline in eGFR from 74 to 67 ml/min at the end of the trial

89

90

Worsening nephopathy

Doubling of sCr, initiation of RRT or death from renal disease

N with event Empa

N with event Placebo

HR P

New onset or worsening of nephropathy

525/4124 388/2061 0.61 <0.0001

New onset albuminuria

459/4091 330/2033 0.62 <0.0001

2x sCr 70/4645 60/2323 0.56 0.0009RRT 13/4687 14/2333 0.45 0.0409

92

FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin

and dapagliflozin – 14 Jun 2016

• From March 2013, when canagliflozin was approved, to October 2015, FDA received reports of 101 confirmable cases of AKI, some requiring hospitalization/dialysis, with canagliflozin or dapagliflozin use.

• In half of the cases, AKI occurred within 1 month of starting the drug, and most patients improved after stopping it.

• Some cases occurred in patients who were younger than 65 years. Some patients were dehydrated, had low BP, or were taking other medicines that can affect the kidneys.

http://www.fda.gov/Drugs/DrugSafety/ucm505860.htm

Recommendations from FDA

• Consider factors that may predispose patients to AKI prior to starting SGLT2i, e.g. decreased blood volume; CKD; CHF; and taking other medications such as diuretics, ACE, ARBs, and NSAIDs.

• Assess kidney function prior to starting SGLT2i and monitor periodically thereafter.

• If AKI occurs, promptly discontinue the drug and treat the kidney impairment.

Evidence based treatments in people with diabetic nephropathy

1. Risk factor modification / Patient education 2. RAS blockade

• ARB or ACEI• DRI: no evidence• MRA: possibly the newer compounds

3. BP lowering4. Glycaemic control5. Lipid lowering6. Novel approaches for albuminuria reduction

• ET antagonist: short term: albuminuria; 4-year trial ongoing• CCR2 inhibition: initial data encouraging• VDR activator: cost

7. SGLT2 inhibition: CV events; ? renoprotective

Fernandez-Fernandez B, et al. Nat Rev Nephrol 2014

Into the future

DPP4iSGLT2iETARi?TCM