EDUCATIONAL SLIDE MODULES - Boehringer Ingelheim

Diabetic kidney diseaseEDUCATIONAL SLIDE MODULES

Date of preparation: April 2016Version 1.0

Module content

Diabetic kidney disease

Current management

Consequences of diabetic kidney disease

Prevalence

Basic concepts and definitions

Diabetes complications and kidney disease

Diabetes is a leading cause of cardiovascular disease, kidney failure, blindness and lower-limb amputation1

29% of people with diabetes aged ≥40 years have

diabetic retinopathy3

16% of people aged >65 years with diabetes die of stroke4

60% of non-traumatic lower-limb amputations

occur in diabetes patients ≥20 years old3

50–80% of people with diabetes die of cardiovascular

disease2

44% of new kidney failure cases are

observed in patients with diabetes3

A significant unmet need exists to reduce complications of diabetes

1. International Diabetes Federation. IDF Diabetes Atlas. 7th edn. 2015. www.idf.org/diabetesatlas (accessed 22 Feb 2016); 2. WHO. 10 Facts about Diabetes: www.who.int/features/factfiles/diabetes/facts/en/index5.html (accessed 22 Feb 2016); 3. Adapted from: CDC 2014 National Diabetes Fact Sheet: www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf (accessed 22 Feb 2016); 4. American Heart Association. Statistical Fact Sheet. 2014 www.heart.org/idc/groups/heart-public/@wcm/@sop/@smd/documents/downloadable/ucm_462019.pdf (accessed 22 Feb 2016)

• Diabetes remains the most common reason for progression to end-stage renal disease in many parts of the world1−3

• DKD is a strong predictor of mortality in patients with diabetes4,5

• DKD occurs as a consequence of multiple pathogenic pathways in the diabetic kidney1

– Hyperglycaemia plays a major, but not exclusive, role

DKD, diabetic kidney disease; T2D, type 2 diabetes1. Toth-Manikowski S & Atta MG. J Diabetes Res 2015;2015:697010; 2. Stewart JH et al. Nephrology 2007;12:520; 3. Thomas MC et al. Nat Rev Nephrol 2016;12:73; 4. Reidy K et al. J Clin Invest 2014;124:2333; 5. USRDS. Am J Kidney Dis 2003;42:1; 6. National Kidney Foundation. 2015. www.kidney.org/atoz/content/diabetes (accessed 22 Feb 2016)

Patients with diabetes are at high risk of kidney disease

Up to 40% of those with T2D will eventually

suffer from kidney failure2,3,6

10–40%

Module content


Current management


Prevalence



GFR, glomerular filtration rate; SGLT2, sodium-glucose co-transporter-2 Adapted from Kurts C et al. Nat Rev Immunol 2013;13:738 and Cherney DZ et al. Circulation 2014;129:587

Basic anatomical concepts: the kidney,

Ureter


Basic anatomical concepts: the kidney, the nephron,

Ureter

Proximal convoluted tubule

Distal convoluted tubule

GlomerulusJuxtaglomerular apparatus

(macula densa)

SGLT2

Collecting duct

Loop of Henle

Basic anatomical concepts: the kidney, the nephron, the glomerulus

KeyFlow of bloodFlow of filtrate

Afferent arterioleVasoconstriction decreases GFR

Efferent arterioleVasoconstriction increases GFR

Bowman’s capsule

Proximal convoluted tubule


NO, nitric oxide; RAAS, renin–angiotensin–aldosterone systemBurke M et al. Curr Vasc Pharmacol 2014;12:845

The kidney auto-regulates glomerular filtration by modulating afferent and efferent arteriole tone

ProstaglandinsNO RAAS

Afferent arteriole Efferent arteriole

Flow of filtrate





Increased filtration

The renin–angiotensin–aldosterone system is the gatekeeper of systemic and glomerular blood pressure

Lungs

Vascular endothelial cells

Renal epithelial cells

ACE

Angiotensin IIAngiotensin I

Liver

Angiotensinogen

Adrenalgland

+

ACTH

Pituitary gland

Vasoconstriction

+Kidney

Aldosterone

Kidney

Renin

↓ Blood pressure

+

-

↑ Blood pressure

ACE, angiotensin-converting enzyme; ACTH, adrenocorticotropic hormoneAdapted from Zaman MA et al. Nat Rev Drug Discov 2005;1:621, Skandalakis JE et al. In Skandalakis’ Surgical Anatomy. 2006; Chapter 27. Available at http://ueu.co/accesssurgery-print-27/ (accessed 16 Mar 2016) and Bernstein KE et al. Pharmacol Rev 2013;65:1

• Stable GFR maintained by net 10 mmHg outward pressure

Renal auto-regulation keeps glomerular pressure and filtration rate stable

Glomerular blood hydrostatic pressure

(GBHP)

= 55 mmHg

Blood colloid osmotic pressure (BCOP)

= 30 mmHg

Net filtration pressure (NFP)= GBHP – BCOP – CHP

= 55 – 30 – 15

= 10 mmHg

Capsular hydrostatic pressure (CHP)

= 15 mmHg

GFR, glomerular filtration rate. Adapted from Tandon OP. In Synopsis of human physiology – Part two. Ch 5, 1998; 2nd edn and Burke et al. Current Vascular Pharmacology 2014;12:845



(GBHP)

= 55 mmHg


= 30 mmHg


= 55 – 30 – 15

= 10 mmHg


= 15 mmHg


• Glomerular hypertension leads to glomerular barotrauma



= 30 mmHg


= 55 – 30 – 15

= 10 mmHg


= 15 mmHg


(GBHP)

= 65 mmHg

Increasing pressure by 10 mmHg





= 30 mmHg


= 15 mmHg


(GBHP)

= 65 mmHgNet filtration pressure (NFP)

= GBHP – BCOP – CHP= 65 – 30 – 15

= 20 mmHgDouble net filtration pressure






= 30 mmHg


= 15 mmHg


(GBHP)

= 65 mmHgNet filtration pressure (NFP)

= GBHP – BCOP – CHP= 65 – 30 – 15

= 20 mmHgDouble net filtration pressure

Doubling of net filtration pressure

Increased GFR




Typical pattern of kidney damage in T2D patients

Glomerulus from a patient with near-normal renal structure

Glomerulus from a patient with typical diabetic nephropathology

Minimal mesangial expansion Diffuse mesangial expansion

Advanced arteriolar hyalinosis

Mild interstitial fibrosis

T2D, type 2 diabetesFioretto P et al. Diabetologia 1996;39:1569Photographs courtesy of Dr Fioretto

Definitions of kidney disease

The terms DKD and DN are often used interchangeably; both ultimately lead to CKD1–3

Chronic kidney disease (CKD): abnormalities of kidney structure or function, present for >3 months, with implications for health1

Diabetic kidney disease (DKD): refers to kidney disease that is specific to diabetes; based primarily on the presence of elevated albumin in the urine2

Diabetic nephropathy (DN): damage to the kidney caused by diabetes; kidney biopsy may help for definitive diagnosis2,3

1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1; 2. National Kidney Foundation. KDOQI™ Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007;49:S1-S180; 3. Haneda M et al. J Diabetes Invest 2015;6:242

• eGFR is generally reduced after widespread structural damage to the kidney • It is categorised as follows:

Estimated glomerular filtration rate is the most commonly used index of renal function

Kidney failure

<15

Normal

≥90

Mildlydecreased

60–89

Mildly to moderately decreased

45–59

Moderately to severely decreased

30–44

Severelydecreased

15–29

eGFR (ml/min/1.73 m2)

eGFR, estimated glomerular filtration rateKidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1

• Albuminuria indicates increased glomerular permeability• Albuminuria can be categorised according to urine albumin-to-creatinine ratio or

to 24 h urine albumin excretion, as follows:

Albuminuria is a key marker of kidney damage

UACR (mg/g)

24 h UAE (mg/24 h)

Macroalbuminuria/severely increased*

>300

>300

Microalbuminuria/moderately increased*

30–300

30–300

Normal to mildly increased

<30

<30

*Note that KDIGO 2012 guidelines recommend avoiding the terms microalbuminuria and macroalbuminuriaUACR, urine albumin-to-creatinine ratio; UAE, urine albumin excretionKidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1

eGFR category Description eGFR

(ml/min/1.73 m2)G1 Normal or high ≥90G2 Mildly decreased 60–89G3a Mildly to moderately decreased 45–59G3b Moderately to severely decreased 30–44G4 Severely decreased 15–29G5 Kidney failure <15

Stages of CKD are classified according to eGFR and degree of albuminuria

CKD

Albuminuriacategory Description

UACR (approx. equivalent)mg/g mg/mmol

A1 Normal to mildly increased <30 <3A2 Moderately increased 30–300 3–30A3 Severely increased >300 >30

CKD

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratioKidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1

Albuminuria stages, description and range (mg/g)

A1 A2 A3Normal to mildly

increasedModeratelyincreased

Severely increased

<30 30–300 >300

GFR

cat

egor

ies,

des

crip

tion

and

rang

e (m

l/min

/1.7

3 m

2 ) G1 Normal or high ≥90

G2 Mild decrease 60–89

G3a Mild–moderate decrease 45–59

G3b Moderate–severe decrease 30–44

G4 Severe decrease 15–29

G5 Kidney failure <15

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rateKidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1

eGFR and albuminuria categories indicate CKD prognosis

Green: low CKD risk (if no other markers of kidney disease, no CKD); yellow: moderately increased risk; orange: high risk; red, very high risk.

• GFR is not easy to measure directly in clinical practice1

• Instead, it is estimated from equations using serum creatinine level, age, race, sex and body size:

– MDRD formula: estimates glomerular filtration rate (eGFR)2

– CKD-EPI equation: developed to provide a more precise eGFR than the MDRD formula in the higher range of GFR2,3

– Cockcroft–Gault formula: estimates creatinine clearance (eCrCl)4

• GFR is considered the best overall index of renal function5

– UACR evaluation may be more relevant in specific clinical contexts; both should be used in clinical assessment6

Measuring renal function

CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; UACR, urine albumin-to-creatinine ratio1. Levey AS et al. Ann Intern Med 2009;150:604; 2. Levey AS et al. Ann Intern Med 1999;130:461; 3. Levey AS et al. Ann Intern Med 2006;145:247; 4. Cockcroft DW & Gault MH. Nephron 1976;16:31; 5. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1; 6. Polkinghorne KR et al. Clin Biochem Rev 2014;35:67

Module content


Current management


Prevalence



*p-value for trend: 0.003eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio

De Boer IH et al. JAMA 2011;305:2532

Prevalent cases of diabetic kidney disease in the United States*

Diabetic kidney disease is common

0

2

4

6

8

1988–1994 1999–2004 2005–2008

Prev

alen

t cas

es, i

n m

illio

ns, ±

95%

CI

All diabetic kidney diseasePersistent albuminuria only(UACR ≥30 mg/g)Impaired eGFR only (<60 ml/min/1.73 m2)Albuminuria and impaired eGFR

18% prevalence increase

34% prevalence increase

CKD, chronic kidney disease; DKD, diabetic kidney diseaseUnited States Renal Data System. Annual Data Report, 2015 www.usrds.org/adr.aspx (accessed 22 Feb 2016)

Point prevalence from a 5% sample of US Medicare patients

Proportion of diabetes patients with kidney disease has increased

2.7%

97%

1996

13.8%

86,2%

2013 Diabetes + CKD

All diabetes

Patients with diabetes = 3,844,800Patients with DKD = 103,660

Patients with diabetes = 7,164,020Patients with DKD = 986,560

CKD, chronic kidney disease; T2D, type 2 diabetesChan JC et al. Am J Med 2014;127:616

Late-onset diabetes accelerates the occurrence of diabetic kidney disease

Duration of diabetes (year)

Cum

ulat

ive

inci

denc

e of

CK

D (%

)

Young-onset T2D

0

100

Late-onset T2D80

60

40

20

0

10 30 50 70604020

Improved diabetes care has been associated with reduced CV outcomes, but not renal complications

Year

0

50

100

150

1990 2000 2010

Even

ts p

er 1

0,00

0 ad

ult

popu

latio

n w

ith d

iabe

tes

MI Stroke ESRD

CV, cardiovascular; ESRD, end-stage renal disease; MI, myocardial infarctionAdapted from Gregg EW et al. N Engl J Med 2014;370:1514

CKD, chronic kidney disease*Austria, Belgium, Denmark, Finland, Greece, Iceland, Italy, Netherlands, Norway, Spain, Sweden, UKKainz A et al. Nephrol Dial Transplant 2015;30:iv1113 (Supplementary data)

Projection of CKD in patients with diabetes in 12 European countries*

Prevalence of diabetic kidney disease is projected to increase even further

Estim

ated

rela

tive

prev

alen

ce

rate

(per

mill

ion

popu

latio

n)

0

20.000

40.000

60.000

80.000

100.000

120.000

140.000

160.000

180.000

200.000

2010 2015 2020 20250

2.000

4.000

6.000

8.000

10.000

12.000

14.000

2010 2015 2020 2025

Year Year

CKD stage 3

CKD stage 4

CKD stage 5

Module content


Current management


Prevalence



• Markers of DKD (declining eGFR and worsening albuminuria)are associated with:

CV, cardiovascular; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rateKDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2013;3:1

Diabetic kidney disease has serious consequences

Increasedmortality

Impairedcognition

Renal events

CV eventsCV death

Percentages indicate absolute excess mortality above the reference group (individuals with no diabetes or kidney disease)*No diabetes and no kidney disease; GFR, glomerular filtration rate; T2D, type 2 diabetesAfkarian M et al. J Am Soc Nephrol 2013;24:302

Mortality is more frequent in T2D patients with kidney disease than in those without

Stan

dard

ised

10-

year

cum

ulat

ive

inci

denc

e of

mor

talit

y (9

5% C

I)

4.1%

17.8%

23.9%

47.0%

7.7%

0

10

20

30

40

50

60

70

No kidneydisease

Albuminuria Impaired GFR Albuminuria &impaired GFR

No diabetes, nokidney disease

Excess mortality

Increased mortality

Risk of renal events* increases as renal function declines

eGFR ≥90

eGFR 60–89

eGFR <60

0

5

10

15

20

25

MacroMicro

Normo

Ris

k of

rena

l eve

nt* (

HR

)

10,640 patients with available data

Average follow-up4.3 years

Baseline UACR

Baseline eGFR

*Renal events defined as: death as a result of kidney disease, requirement for dialysis or transplantation, or doubling of serum creatinine to >200 μmol/l eGFR in ml/min/1.73 m2

eGFR, estimated glomerular filtration rate; HR, hazard ratio; UACR, urine albumin-to-creatinine ratioNinomiya T et al. J Am Soc Nephrol 2009;20:1813

Renal events

• Renal and cardiac systems are inextricably linked; acute or chronic disorder of one can induce dysfunction in the other1

• Elderly patients with CKD are more likely to die of heart disease than advance to ESRD and dialysis2

Kidney disease is associated with significant impairment of cardiac function

Organ damage/dysfunction

Renal and cardiac systems should be considered together

CKD, chronic kidney disease; CV, cardiovascular; ESRD, end-stage renal disease1. Ronco C et al. J Am Coll Cardiol 2008;52:1527; 2. Dalrymple L et al. J Gen Intern Med 2011;26:379

CV events

Cardiorenal connection:

Haemodynamic control:

Kidney failure or heart failure results in a vicious cycle, affecting both organs

Nitric oxide/reactive oxygen species imbalanceSympathetic nervous system activation

Renin-angiotensin system activation Inflammation

Nitric oxide/reactive oxygen species imbalanceSympathetic nervous system activation

Renin-angiotensin system activation Inflammation

Kidneyfailure

Heart failure

Pressure natriuresis

Increased blood pressure

Increased peripheral resistance

Total body autoregulation

Increased cardiac output

Volume expansion

Cardiovascular damageBongartz L et al. Eur Heart J 2005;26:11

<1010–29

30–299≥3000

2

4

6

8

10

12

14

UACR (mg/g)eGFR (ml/min/1.73 m2)

Risk of CV death increases as renal function declines

Low eGFR and high UACR are independent predictors of CV mortality

Adj

uste

d H

R105,872 patients

730,577 person-years

CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; UACR, urine albumin-to-creatinine ratioMatsushita K et al. Lancet 2010;375:2073

CV death

Declining eGFR is a risk factor for CV death and all-cause mortality

All-cause mortality Cardiovascular mortality

6015

1.5

4

2

1

8

45 75 90 105 12030

Adj

uste

d H

R (9

5% C

I)

eGFR ml/min/1.73 m2eGFR ml/min/1.73 m2

1.5

4

2

1

8

15 45 60 75 90 105 12030

Adj

uste

d H

R (9

5% C

I)

CKD CKD

HRs adjusted for age, sex, race, smoking, history of cardiovascular disease, diabetes, serum total cholesterol concentration, body mass index and albuminuriaCKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratioMahmoodi BK et al. Lancet 2012;380:1649

347,256 hypertensive individuals2,970,318 patient-years

CV death/ all-cause mortality

Adj

uste

d H

R (9

5% C

I)Increasing UACR is a risk factor for CV death and all-cause mortality

UACR (mg/g)

Adj

uste

d H

R (9

5% C

I)

0.5

1

2

4

8

2.5 5 10 30 300 1000

UACR (mg/g)

2.5 5 10 30 300 10000.5

1

2

4

8

HRs adjusted for age, sex, race, smoking, history of cardiovascular disease, diabetes, serum total cholesterol concentration, body mass index and eGFR splinesCKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; UACR, urine albumin-to-creatinine ratioMahmoodi BK et al. Lancet 2012;380:1649

All-cause mortality Cardiovascular mortality

CKD CKD

347,256 hypertensive individuals2,970,318 patient-years

CV death/ all-cause mortality

Impaired renal function can be a stronger predictor of mortality than history of MI

History of MI RR (95% CI) p-value

No

Yes 0.0367

eGFR (ml/min)

>76 –

76–59 0.1749

58–44 0.0001

<44 0.0000

0,1 1 10

Risk of all-cause mortality in patients with chronic heart failureN=1906, of whom 394 (20.7%) with diabetes

eGFR, estimated glomerular filtration rate; MI, myocardial infarction; RR, risk ratioHillege HL et al. Circulation 2000;102:203

• Albuminuria is significantly associated with poor performance of verbal memory, executive function and processing speed

• The effect of albuminuria on performance was equivalent to an additional ~3.5 years of age at baseline

Albuminuria is correlated with impaired cognition in T2D

ACCORD-MIND study OR for performance in the lowest tertile (95% CI)

DSST p-value

Model 4 0.001

Model 3 0.001

Model 2 0.001

Model 1 <0.001

Unadjusted <0.001

RAVLT

Model 4 0.006

Model 3 0.006

Model 2 0.003

Model 1 0.002

Unadjusted <0.001

0,5 1 2 4

Model 1 + history of CVD, including stroke

Model 2 + diabetes duration and HbA1c

Model 3 + hyperlipidaemia, hypertension, alcohol consumption, current smoking status, BMI, depression

BMI, body mass index; CVD, cardiovascular disease; DSST, digit symbol substitution test; HbA1c, glycated haemoglobin; OR, odd ratio; RAVLT, Rey auditory verbal learning test; T2D, type 2 diabetesMurray AM et al. Diabetes Care 2011;34:1827

Impaired cognition

Adjusted by age, gender, race, education

Module content


Current management


Prevalence



The aim of treatment:to prevent the complications of diabetes

Microvascular complications

Diabetic retinopathy


Diabetic neuropathy

Diabetes

Macrovascular complications

Limb amputation Coronary heart

diseaseStroke

Myocardial infarctionPeripheral artery

disease

Adapted from Grobbee DE. Metabolism 2003;52:24

A multifactorial intervention strategy is recommended in DKD

Glucose

BP

Lipids

ACEi/ ARB

HbA1c target individualised, but generally ~7%1

Target of <130/80 mmHg2

Use ACEi or ARBs when albumin excretion ≥30 mg/g1

Lipid-lowering recommended to reduce risk of atherosclerotic events; statins not recommended in patients on haemodialysis1

ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; DKD, diabetic kidney disease; HbA1c, glycated haemoglobin1. National Kidney Foundation. Am J Kidney Dis 2012;60:850; 2. NICE. Clinical guideline: Type 2 diabetes (CG87), May 2009

Intensive glucose control reduces risk of microalbuminuria

Heterogeneity: χ2=16.71, df=6 (p=0.01); Test for overall effect: Z=2.60 (p=0.009)

Coca SG et al. Arch Intern Med 2012;172:761

0.01 0.1 1 10 100

Favours intensive Favours standard

Total (95% CI) 0.86 (0.76, 0.96)

0.88 (0.80, 0.96)

0.26 (0.13, 0.52)0.74 (0.51, 1.07)1.00 (0.77, 1.30)0.88 (0.75, 1.04)0.44 (0.16, 1.17)0.92 (0.86, 0.98)

VADT Feasibility Trial

ACCORD

VADTUKPDS 34UKPDS 33KumamotoADVANCE

Risk ratioM–H, random (95% CI)Study or subgroup

Glucose

Intensive glucose control reduces risk of macroalbuminuria

Heterogeneity: χ2=16.71, df=6 (p=0.01); Test for overall effect: Z=2.60 (p=0.009)

Coca SG et al. Arch Intern Med 2012;172:761

Glucose

0.72 (0.60, 0.86)

VADT Feasibility Trial

VADT

UKPDS 33

Kumamoto

Risk ratioM–H, random (95% CI)Study or subgroup

0.01 0.1 1 10 100

0.74 (0.65, 0.85)

0.35 (0.11, 1.13)

0.56 (0.33, 0.96)

0.90 (0.60, 1.35)

0.11 (0.01, 1.94)

0.79 (0.67, 0.93)

Total (95% CI)

ACCORD

ADVANCE

Favours intensive Favours standard

HR 0.54 95% CI 0.34; 0.85

p=0.007

2

Patie

nts

with

end

-sta

ge

rena

l dis

ease

* (%

)

1

04 6 10

Follow-up (years)

2 80

*Defined as requirement for renal-replacement therapyHR, hazard ratioZoungas S et al. N Engl J Med 2014;371:1392

ADVANCE-ON study

Intensive glucose control associated with significantly reduced risk of ESRD

Standard control

Intensive control

No. at riskIntensive 5571 5402 5186 4124 3764 2811Standard 5569 5400 5173 4041 3681 2683

Glucose

• Risk of severe hypoglycaemia is increased in patients with kidney disease1

– Hypoglycaemia is associated with increased risk of CV events2

Kidney disease complicates glucose control

0123456789

10

--

+-

-+

++

Ris

k fo

r sev

ere

hypo

glyc

aem

ia1

(inci

denc

e ra

te ra

tio)

CKDDiabetes

CKD, chronic kidney disease; CV, cardiovascular1. Moen MF et al. Clin J Am Soc Nephrol 2009;4:1121; 2. Sanon VP et al. Clin Cardiol 2014;37:499

Glucose

In the ADVANCE-BP study, rate of all renal events* significantly associated with achieved systolic BP levels (p<0.0001 for trend)

*New-onset microalbuminuria or nephropathy, doubling of serum creatinine to >200 μmol/l, or ESRD BP, blood pressure; ESRD, end-stage renal disease; T2D, type 2 diabetesde Galan B et al. J Am Soc Nephrol 2009;20:883

Lower blood pressure is associated with lower frequency of renal events in T2D

Ann

ual p

atie

nt e

vent

rate

(%)

Achieved systolic BP (mmHg)

100 110 120 130 140 150 160 1704

5

6

7

8

910

Median systolic BP (mmHg)No. of person years

106 116 125 135 144 154 1681431 4266 8974 11983 9138 4942 3470

BP

ACE inhibitors slow progression of albuminuriaand renal function decline in patients with T2D

*p=0.047 vs placebo; †p=0.042 vs placeboACE, angiotensin-converting enzyme; CrCl, creatinine clearance; SD, standard deviation; T2D, type 2 diabetes Ravid M et al. Ann Intern Med 1998;128:982

ACEi/ARB

Follow-up (years)

10

20

30

0

40

Albuminuria

Mea

n al

bum

in e

xcre

tion,

mg/

24 h

(±SD

)

0 1 3 652 4

Placebo

Enalapril

p=0.001

Renal function (CrCl)

Mea

n C

rCl,

ml/s

(±SD

)

Follow-up (years)

1.6

1.7

1.8

1.5

2.0

0 1 3 652 4

1.9

Placebo

Enalapril

*†

ARBs have demonstrated beneficial impact on markers of kidney disease

Impact on serum creatinine levels1 Impact on microalbuminuria2

Hyp

erte

nsiv

e pa

tient

s w

ith

mic

roal

bum

inur

ia(%

)

0 6 12 18 24 36 480

5

10

15

20

30 42

25Placebo

Olmesartan

HR 0.7595% CI 0.61, 0.92

p=0.0068*

HR 0.7195% CI 0.54, 0.92

p=0.009

Placebo

Irbesartan

Patie

nts

with

dou

bllin

g of

BL

sCR

(%)

0 6 12 18 24 36 54

10

20

30

60

030 42 48

40

50

70

*Exploratory p-valueARB, angiotensin receptor blocker; BL sCR, baseline serum creatinine; HR, hazard ratio1. Lewis et al. N Engl J Med 2001;345:851; 2. Menne J et al. J Hypertens 2012;30:811

ACEi/ARB

Follow-up (months) Follow-up (months)

0,5

Variable p-valueCoronary events

Non-fatal MI 0.12CHD death 0.95Subtotal 0.37

Non-haemorrhagic strokeIschaemic 0.0073Unknown type 0.85Subtotal 0.01

Revascularisation proceduresCoronary 0.0027Non-coronary 0.36Subtotal 0.0036

Any major atherosclerotic event

0.0021

• In the SHARP study, simvastatin plus ezetimibe reduced the risk of any major atherosclerotic event by 17% (p=0.0021) in patients with advanced CKD1

– However, the combination has not shown renal protection in this population2

• Statin effects on renal parameters have been inconsistent3

– Recommended by guidelines to reduce major atherosclerotic events in patients with CKD and diabetes4

– Initiation not recommended in patients on dialysis4

CHD, coronary heart disease; CKD, chronic kidney disease; MI, myocardial infarction1. Baigent C et al. Lancet 2011;377:2181; 2. Haynes R et al. J Am Soc Nephrol 2014;25:1825; 3. Fellström B et al. Curr Med Res Opin 2009;25:271; 4. National Kidney Foundation. Am J Kidney Dis 2012;60:850

Statins can help to reduce cardiovascularrisk in patients with CKD

SHARP3 (CKD patients N=9270, 2094 with diabetes)

21

Lipids

Favours simvastin + ezetimibe Favours placebo

Attaining multiple treatment targets is associated with lower risk of ESRD and related death in T2D

~60%risk reduction

Predefined protocol and targetsHbA1c <7%

BP <130/80mmHgLDL-C <2.6 mM (100 mg/dl)

Triglyceride <2 mM (177 mg/dl)Persistence with RAS inhibitors

Prim

ary

com

posi

te e

ndpo

int*

(%)

<3 treatment targets attained

0.00

Months of follow-up

50

≥3 treatment targets attained

40

30

20

10

0

5.00 10.00 15.00 20.00 25.00

RR 0.4395% CI 0.21, 0.86

*Death and/or ESRD, defined as the need for dialysis, or plasma creatinine level 500 µmol/lBP, blood pressure; ESRD, end-stage renal disease; HbA1c, glycated haemoglobin; LDL-C, Low-density lipoprotein cholesterol; RAS, renin-angiotensin system; RR, risk ratioChan JC et al Diabetes Care 2009;32:977

Steno-2 study: randomised controlled trial of intensified vs conventional multifactorial treatment in patients with T2D and microalbuminuria

Intensified multifactorial intervention helps achievement of treatment goals

Patients reaching treatment goal at 8 years (%)1

Intensified treatment (i.e. strict goals; n=67)Conventional treatment (i.e. goals indicated by DMA; n=63)

HbA1c<6.5%

Cholesterol<4.5 mmol/l

Triglycerides<1.7 mmol/l

Diastolic BP<80 mmHg

0

20

40

60

80

Patie

nts

(%)

p=0.06

p<0.001

p=0.19

p=0.001

p=0.21

100

Systolic BP<130 mmHg

HbA1c<6.5%

Cholesterol<4.5 mmol/l

Triglycerides<1.7 mmol/l

Diastolic BP<80 mmHg

Systolic BP<130 mmHg

p=0.31

p=0.35 p=0.005

p=0.27

p=0.14

0

20

40

60

80

Patie

nts

(%)

100

Patients reaching treatment goal at 13 years (%)2

Treatment goals Treatment goals

Intensified treatment (i.e. strict goals; n=55)Conventional treatment (i.e. goals indicated by DMA; n=38)

BP, blood pressure; DMA, Danish Medical Association; HbA1c, glycated haemoglobin1. Gaede P et al. N Engl J Med 2003;348:383; 2. Gaede P et al. N Engl J Med 2008;358:580


CV, cardiovascular; HR, hazard ratio; MI, myocardial infarctionGaede P et al. N Engl J Med 2008;358:580

Intensified multifactorial intervention reduces CV risk

*Death from CV causes, non-fatal MI, coronary-artery bypass grafting, percutaneous coronary intervention, non-fatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease

Intensive therapy 80 72 65 61 56 50 47 31

Conventional therapy 80 70 60 46 38 29 25 14

Patients at risk

Conventional

Intensive

0

10

20

30

40

50

60

70

80

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Cum

ulat

ive

inci

denc

e (%

)

Years of follow-up

Risk for composite CV endpoint*

HR 0.4195% CI 0.25, 0.67

p<0.001

0,1 1 10

VariableRelative risk

p-value HR (95% CI)(95% Cl)

Nephropathy 0.39 (0.17, 0.87) 0.003

Retinopathy 0.42 (0.21, 0.86) 0.02

Autonomic neuropathy 0.37 (0.18, 0.79) 0.002

Peripheral neuropathy 1.09 (0.54, 2.22) 0.66


HR, hazard ratioGaede P et al. N Engl J Med 2003;348:383

Intensified multifactorial intervention reduces risk of microvascular events

n=80 for each group; average follow-up 7.8 years Favours intensive therapy

Favours conventional therapy

Diabetic kidney disease: summary

Kidney disease is a common complication of diabetes• Up to 40% of patients with T2D will eventually suffer from

kidney failure

Albuminuria (marker of kidney damage) and reduced eGFR are key criteria in the diagnosis of DKD

Impaired renal function is associated with increased CV and mortality risk

Intensive multifactorial treatment is effective in reducing CV and renal outcomes, but many patients still experience disease progression

CV, cardiovascular; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate

Back-up slides

Diabetes is the leading cause of end-stage renal disease in the US

0

10.000

20.000

30.000

40.000

50.000

60.000

Num

ber o

f pat

ient

s w

ith E

SRD

Year

Diabetes

Hypertension

Glomerulonephritis

Cystic kidney disease

ESRD, end-stage renal diseaseUS Renal Data System. Annual data report 2014. www.usrds.org/adr.aspx (accessed 22 Feb 2016)

High background prevalence of renal impairment, especially in elderly individuals – US study

Coresh J et al. JAMA 2007;298:2038

Risk of kidney disease increases with age

0

5

10

15

20

25

30

35

40

45

50

20–39 40–59 60–69 ≥70

Prev

alen

ce, %

Age group, years

1988–19941999–2004

Time of survey

ADVANCE: observational analyses examining the association between albuminuria and eGFR at baseline or during follow-up and the risk for CV events and renal events in T2D

Albuminuria and reduced eGFR are associated with increased risk of CV events

eGFR ≥90

eGFR 60–89

eGFR <60

0

1

2

3

4

MacroMicro

Normo

Ris

k of

CV

even

t* (H

R)



Baseline UACRBaseline eGFR

*CV events defined as: CV death, non-fatal myocardial infarction or nonfatal stroke. eGFR in ml/min/1.73 m2

CV, cardiovascular; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratioNinomiya T et al. J Am Soc Nephrol 2009;20:1813

ADVANCE: Observational analyses examining the association between albuminuria and eGFR at baseline or during follow-up and the risk for CV events and renal events in T2D

Albuminuria and reduced eGFR are associated with increased risk of CV death

eGFR ≥90

eGFR 60–89

eGFR <60

0

1

2

3

4

5

6

MacroMicro

Normo

Ris

k of

CV

deat

h (H

R)

eGFR in ml/min/1.73 m2

CV, cardiovascular; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratioNinomiya T et al. J Am Soc Nephrol 2009;20:1813

Baseline UACRBaseline eGFR



HR calculated using lowest normal albuminuria as reference; CV, cardiovascular; HR, hazard ratio1. Solomon SD et al. Circulation 2007;116:2687; 2. Stehouwer C et al. Kidney Int 2004;92:S42

Proportion of patients with T2D in each category (%)

CV mortality risk increases with increasing albuminuria in patients with stable coronary disease

1 0,89 0,991,35

1,891,68

0

0,5

1

1,5

2

2,5

3

3,5

4

Lowest normal(<5.0 mg/g)

Low normal (5.0–6.5 mg/g)

Medium normal (6.6–9.4 mg/g)

High normal (9.5–16.9 mg/g)

Low-to-medium microalbuminuria

(17.0–125.0 mg/g)

Highmicroalbuminuria tomacroalbuminuria

(>125.0 mg/g)

Adj

uste

d H

R1

Microalbuminuria may represent an early marker of vascular endothelial dysfunction2

7,2 10,6 15,2 19,2 28,344,6

Albuminuria

Declining eGFR is associated with mortality and ESRD in diabetes

ESRD and eGFRMortality and eGFR

00.5

1248

163264

Adj

uste

d H

R ±

95%

CI

15 30 45 60

eGFR (ml/min per 1.73 m2)

15 30 45 60 75 90 105 1200

1

1.52

4

8

Adj

uste

d H

R ±

95%

CI

eGFR (ml/min per 1.73 m2)

Cardiovascular mortality

Includes data from participants with type 1 and type 2 diabetes

0

1

1.52

4

8

Adj

uste

d H

R ±

95%

CI

All-cause mortalityNo diabetes, 95% CIDiabetes, 95% CI

15 30 45 60 75 90 105 120eGFR (ml/min per 1.73 m2)

HRs adjusted for age, sex, race, smoking, history of cardiovascular disease, serum total cholesterol concentration, body-mass index and albuminuria

eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio. Fox CS et al. Lancet 2012;380:1662

Increasing UACR is associated with mortality and ESRD in diabetes

3000

Adj

uste

d H

R ±

95%

CI

00.5

1248

163264

10 20 100030030UACR (mg/g)

No diabetes, 95% CIDiabetes, 95% CI

No diabetes, 95% CIDiabetes, 95% CI

0

1

1.52

4

8All-cause mortality

2.5 5 10 30 300 1000UACR (mg/g)

2.5 5 10 30 300 10000

1

1.52

4

8

UACR (mg/g)

Cardiovascular mortality

ESRD, end-stage renal disease; HR, hazard ratio; UACR, urine albumin-to-creatine ratio. Fox CS et al. Lancet 2012;380:1662

HRs adjusted for age, sex, race, smoking, history of cardiovascular disease, serum total cholesterol concentration, body-mass index and albuminuria

Includes data from participants with type 1 and type 2 diabetes

Mortality and UACR ESRD and UACR

Adj

uste

d H

R ±

95%

CI

Adj

uste

d H

R ±

95%

CI

EDUCATIONAL SLIDE MODULES - Boehringer Ingelheim

Documents

Transcript of EDUCATIONAL SLIDE MODULES - Boehringer Ingelheim