new therapeutic interventions in the management of dn ... · diabetes and ckd are present rs x 2.2...
Post on 07-Oct-2020
0 Views
Preview:
TRANSCRIPT
New therapeutic interventions in the management of DN
Christoph Wanner MD Mandaluyong City
April 25 2014
Kidney Disease: Improving Global Outcomes
April 23-26, 2014 | Manila, Philippines PSN 34th Annual Convention
Because…… All recent trials failed to improve CV and renal outcomes in patients with type 2 diabetes mellitus
But ……. More than 50.000 patients are currently in clinical trials that will report renal outcome data from 2015 onwards
Disappointment & Hope
Kidney Disease: Improving Global Outcomes
Kidney International 2014 in press
KDIGO Controversies Conference on Diabetic Kidney Disease, March 2012, New Delhi, India
Diabetic Kidney Disease – A clinical update from KDIGO
Kidney Disease: Improving Global Outcomes
Objectives
Global picture Diabetes complica1on Recent advances in treatment
Established Strategies New Treatments Poten1al future Interven1ons
Kidney Disease: Improving Global Outcomes
Global picture and the Asian-Pacific region
Kidney Disease: Improving Global Outcomes
The diabetes epidemic: global projections for 2013–2035
The Diabetes Atlas, 6th ed. IDF 2013
2011: 382 million
2035: 592 million
↑55%
Kidney Disease: Improving Global Outcomes
Estimated national prevalence of diabetes mellitus in selected Asia-Pacific region countries
www.idf.org/atlasmap/atlasmap
9.6
7.6
10 8.9
5.6
9.8
6.4
10.1
12.3 13
8.2
11.3 11.4
6.7
13.1
8.3
12.2
15.3
0 2 4 6 8
10 12 14 16 18 20
Nat
iona
l pre
vale
nce
(%)
2013 2035
Kidney Disease: Improving Global Outcomes Kidney International Supplements 2012; 2:163–171
Diabetes complications
Kidney Disease: Improving Global Outcomes
0
5
10
15
20
25
30
AMI CVA/TIA PVD Death
T2DM + / CKD + T2DM + / CKD –
Cardiovascular risk is greatest when both diabetes and CKD are present
Inci
denc
e pe
r 100
pat
ient
-yea
rs
x 2.2
x 2.1
x 1.7 x 2.5
Foley RN, et al. J Am Soc Nephrol. 2005;16:489–495
Among patients with diabetes and CKD, the rate of cardiovascular events is more than twice that among patients with diabetes only
Kidney Disease: Improving Global Outcomes
Impact of nephropathy on risk of death
UKPDS 64. Kidney International 2003; 63: 225–232
No nephropathy
Microalbuminuria
⇓ 2.0%
Macroalbuminuria
⇓ 2.8%
ESRD
⇓ 2.3%
1%
3%
5%
19%
DEATH
Annual Risk
Kidney Disease: Improving Global Outcomes
Diabetic nephropathy
• Leading cause of ESRD ~ 30-50% of new cases
• Increasing prevalence globally
• Approximately one-third of all patients
• More common in Hispanics, Blacks and Native Americans
• High cardiovascular morbidity and mortality
• Cause incompletely understood and…. No cure
Kidney Disease: Improving Global Outcomes
New therapeutic interventions in the management of DN
Established New Future potential Strategies Treatments Interventions
Prevention of obesity Bardoxolone Atrasentan
Glycemic control Aleglitazar SGLT2 Inhibitors
BP control Double RAAS-B DPP4 Inhibitors
RAAS blockade/inhibition CCR2 Inhibition
Low salt
ONTARGET ALTITUDE VA-NephronD
Kidney Disease: Improving Global Outcomes
Approaches to improving outcomes related to DKD
Kidney International 2014 in press
Kidney Disease: Improving Global Outcomes
ACE inhibitors and angiotensin receptor blockers slow pro- gression of kidney disease in hypertensive type 2 diabetics
2000
20
2
200
Alb
umin
uria
(µg/
min
)
40%
60% A1 Normoalbuminuria
A3 Overt nephropathy
A2 Albuminuria
Time (years)
IDNT
RENAAL
IRMA 2
Δ GFR 2-20:10
Δ GFR 1-3
Δ GFR 1 BENEDICT
ROADMAP
Clinical Trials
Alb
umin
uria
(µg/
min
)
2000
200
20
2
Kidney Disease: Improving Global Outcomes
Glycemic control in diabetes: a brief history of intervention trials
1960 1970 1980 1990 2000 2010
UGDP
Oxford Steno Kroc
Dallas Oslo ACCORD
VADT
ADVANCE
UKPDS
DCCT
UKPDS
EDIC
VACS
Kumamoto
BARI -2D
PROactive
RECORD
SDIS
ADA Standards of Care 1989
Kidney Disease: Improving Global Outcomes
Cumulative incidence of macroalbuminuria by diabetes duration – Typ 1 DM
Ian H. de Boer, ASN 2013
Cumulative incidence at 25 yrs’ duration of diabetes: • Conv 17% • Int 6%
Kidney Disease: Improving Global Outcomes
New Patients on RRT 1965-2010 in Austria Primary renal Diagnosis
0
200
400
600
800
1000
1200
1400
1965
1967
1969
1971
1973
1975
1977
1979
1981
1983
1985
1987
1989
1991
1993
1995
1997
1999
2001
2003
2005
2007
2009
Vascular
T2DM
T1DM
Others
Interst N
Hereditary
GN
Small kidneys
ÖDTR: www.nephro.at
Kidney Disease: Improving Global Outcomes
Oral Antidiabetics and Kidney Function
60 - 30 <30 <15; Hemodialysis >60
Metformin
Pioglitazon
Acarbose
Repaglinid
Gliclazid Dose reduction
Glimepirid
Linagliptin
Avogaro & Schernthaner Acta Diab 2013
Saxagliptin Dose reduction
Sitagliptin
Vildagliptin
Dose reduction
Gliquidon
Dapagliflozin
Dose reduction
Kidney Disease: Improving Global Outcomes
Salpeter et al. Cochrane Database Syst Rev 2010: CD002967 KDIGO: Kidney International 2014
The use of Metformin
A Cochrane review (347 trials & cohort studies) found no cases of lac1c acidosis; half of the studies included CKD pa1ents.
MeLormin use should be re-‐evaluated when GFR <45 ml/min/1.73m² (max 1000 mg) and stopped when <30 ml/min/1.73m²
The major precipita1ng factor is an abrupt loss of tubular secre1on. Such a loss does not occur in stable CKD, but in AKI or rapid volume deple1on associated with an intercurrent illness. Pa1ents with CKD should be alerted to withhold meLormin if they experience intercurrent illness that could lead to rapid volume deple1on.
Kidney Disease: Improving Global Outcomes
Potential clinical signals of concern with therapies for T2DM? Another dimension in the complexity (cardiotoxicity)?
UGDP 1969 Tolbutamide CV death <0.05
Meta analysis 2005 Muraglitazar CVD <0.03
Meta analysis 2007 Rosiglitazone CVD <0.043
ACCORD 2008 Intensive control Death <0.04
Kidney Disease: Improving Global Outcomes
New therapeutic interventions in the management of DN
Established New Future potential Strategies Treatments Interventions
Prevention of obesity Bardoxolone Atrasentan
Glycemic control Aleglitazar SGLT2 Inhibitors
BP control Double RAAS-B DPP4 Inhibitors
RAAS blockade/inhibition CCR2 Inhibition
Low salt
ONTARGET ALTITUDE VA-NephronD
All failed !
Kidney Disease: Improving Global Outcomes
Recent advances in treatment
Kidney Disease: Improving Global Outcomes N Engl J Med 2013;369:2492-2503
Kidney Disease: Improving Global Outcomes N Engl J Med 2013;369:2492-2503
Kidney Disease: Improving Global Outcomes
Heart failure and death
N Engl J Med 2013;369:2492-2503
Kidney Disease: Improving Global Outcomes NEJM 2013;369:1892-‐1903
Kidney Disease: Improving Global Outcomes NEJM 2013;369:1892-‐1903
Kidney Disease: Improving Global Outcomes
Kidney Disease: Improving Global Outcomes AleRenal
Kidney Disease: Improving Global Outcomes
New therapeutic interventions in the management of DN
Established New Future potential Strategies Treatments Interventions
Prevention of obesity Bardoxolone Atrasentan
Glycemic control Aleglitazar SGLT2 Inhibitors
BP control Double RAAS-B DPP4 Inhibitors
RAAS blockade/inhibition CCRX Inhibition (Spiegelmer)
Low salt
ONTARGET ALTITUDE VA-NephronD
Kidney Disease: Improving Global Outcomes
Kidney Disease: Improving Global Outcomes
Each of these trials was controversial in some respects
Mathews D; ADA 2010 & update
EXAMINE
SAVOR
Glycemic outcome trials in type 2 diabetes
CAROLINA
CARMELINA
Kidney Disease: Improving Global Outcomes
SAVOR-TIMI 53: study design
Duration Event driven (n=1040)
Median duration: 2.1 yr LFU 0.2% W/C 2.4%
N Engl J Med 2013;369:1317-1312
Kidney Disease: Improving Global Outcomes
SAVOR-TIMI 53: primary endpoint
The primary endpoint (CV death, nonfatal MI, nonfatal stroke)
The upper limit of the 95% CI was <1.3 but not <1.0 Therefore, saxagliptin met the non-inferiority criterion (did not increase the risk of CV events versus placebo) but did not demonstrate superiority (did not reduce the risk for CV events versus placebo)
NEJM 2013;369:1317-2
Kidney Disease: Improving Global Outcomes
EXAMINE: study design
Alogliptin versus placebo, in addition to standard of care, in subjects with type 2 diabetes mellitus, HbA1c 6.5–11.0%, and acute coronary syndrome (within 15-90 days prior to randomization)
N Engl J Med. 2013;369:1327-1335
Kidney Disease: Improving Global Outcomes
EXAMINE: primary endpoint
The upper limit of the HR was <1.3, which was the pre-specified safety boundary based on the FDA’s 2008 guidance for evaluating CV safety of new antidiabetes drugs Therefore, alogliptin met the non-inferiority criterion (did not increase the risk of CV events versus placebo) However, as the limit was not <1.0, alogliptin did not demonstrate superiority (did not reduce the risk for CV events versus placebo)
The primary endpoint (CV death, nonfatal MI, nonfatal stroke) occurred in 11.3% of alogliptin patients and 11.8% of placebo patients; hazard ratio=0.96 (one-sided repeated CI bound, 1.16)
N Engl J Med. 2013;369:1327-1335
Kidney Disease: Improving Global Outcomes
Each of these trials was controversial in some respects
Mathews D; ADA 2010 & update
EXAMINE
SAVOR
Glycemic outcome trials in type 2 diabetes
CAROLINA
CARMELINA
Kidney Disease: Improving Global Outcomes
New therapeutic interventions in the management of DN
Established New Future potential Strategies Treatments Interventions
Prevention of obesity Bardoxolone Atrasentan
Glycemic control Aleglitazar DPP4 Inhibitors
BP control Double RAAS-B SGLT2 Inhibitors
RAAS blockade/inhibition CCRX Inhibition (Spiegelmer)
Low salt
ONTARGET ALTITUDE VA-NephronD
Kidney Disease: Improving Global Outcomes
Summary
• Worldwide epidemic of type 2 diabetes • Aggressive multi-risk factor intervention including tight
glycemic control improves outcomes – Microvascular – Macrovascular (not so much)
• Guidelines recommend tighter control of glycemia, but ... • Renal endpoints critically important for newer therapies • Regulatory agencies establish guidance for safety
Kidney Disease: Improving Global Outcomes
April 23-26, 2014 | Manila, Philipines PSN 34th Annual Convention
Thank you ☺
top related