treatment of diabetic kidney disease: landmark studies and ... · 2 chronic kidney disease is a...
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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