new therapeutic interventions in the management of dn ... · diabetes and ckd are present rs x 2.2...

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 International 2014 in press

KDIGO Controversies Conference on Diabetic Kidney Disease, March 2012, New Delhi, India

Diabetic Kidney Disease – A clinical update from KDIGO


Objectives

Global picture Diabetes complica1on Recent advances in treatment

Established Strategies New Treatments Poten1al future Interven1ons


Global picture and the Asian-Pacific region


The diabetes epidemic: global projections for 2013–2035

The Diabetes Atlas, 6th ed. IDF 2013

2011: 382 million

2035: 592 million

↑55%


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


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


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


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



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


Approaches to improving outcomes related to DKD

Kidney International 2014 in press


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


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


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%


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


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


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.


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







RAAS blockade/inhibition CCR2 Inhibition

Low salt


All failed !


Recent advances in treatment

Kidney Disease: Improving Global Outcomes N Engl J Med 2013;369:2492-2503


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 AleRenal







RAAS blockade/inhibition CCRX Inhibition (Spiegelmer)

Low salt



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


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


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


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


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


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





Glycemic control Aleglitazar DPP4 Inhibitors

BP control Double RAAS-B SGLT2 Inhibitors

RAAS blockade/inhibition CCRX Inhibition (Spiegelmer)

Low salt



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


April 23-26, 2014 | Manila, Philipines PSN 34th Annual Convention

Thank you ☺

new therapeutic interventions in the management of dn ... · diabetes and ckd are present rs x 2.2...

Documents