Prevention And Treatment of Diabetic Nephropathy - … · · 2018-03-29Prevention And Treatment...

Prevention And Treatment of Diabetic Nephropathy

MOH Clinical Practice Guidelines 3/2006

Dr Stephen Chew Tec Huan

Prevention

• Tight glucose control reduces the development of diabetic nephropathy

Progression Of Complications In Type 1 Diabetics With Intensive And Conventional Treatment

(DCCT) - Primary Prevention

Complications Conventional Therapy

Intensive Therapy

Risk Reduction

Rate/100 patient-year % (95% CI)

Urinary Alb (mg/24hr)

>40 3.4 2.2 34 (2-56)

>300 0.3 0.2 44 (-124-86)

Clinical Nephropathy at 5 years

9.8 3.1 69 (24-87)

The Diabetes Control And Complications Trial Research Group, NEJM 1993

Progression Of Complications In Type 1 Diabetics With Intensive And Conventional Treatment

(DCCT) -Secondary Prevention

Complications Conventional Therapy

Intensive Therapy

Risk Reduction

Rate/100 patient-year % (95% CI)

Urinary Alb (mg/24hr)

>40 5.7 3.6 43 (21-58)

>300 1.4 0.6 56 (18-76)

Clinical Nephropathy at 5 years

16.1 7.0 57 (29-73)

The Diabetes Control And Complications Trial Research Group, NEJM 1993

UKPDS• Prospective randomized trial in type II

diabetics• Selected newly diagnosed Type II DM with

little or no prexisting renal complications• Compared the effect of intensive therapy and

conventional therapy on development of complications.

UKPDS• Patients on the intensive therapy arm were

treated with a sulphonylurea, or if needed insulin was added, to keep fasting blood glucose <7mmo/l

• Conventional therapy was started with diet, and a sulphonylurea added to keep fasting blood glucose <15mmol/l.

• Patients followed up 10 years

Effect of Intensive Therapy And Conventional Therapy On Renal End Points At Nine Years In

Type 2 DM with Normoalbuminuria

Intensive (FG <7)

Conventional (FG<15) p

RR for intensive (99% CI)

Microalbuminuria 19.2 25.4 <0.001 0.76 (0.62-0.91)

Proteinuria 4.4 6.5 0.02 0.67 (0.42-1.07)

Doubling of serum creatinine 0.91 3.52 <0.01 0.26

(0.07-0.91)

UK Prospective Diabetes Study Group, Lancet 1998

Prevention

• Blood pressure control reduces the development of microvascular disease in diabetics

Tight BP control reduces microvascular events

Tight : 144/82 mm Hg achievedLess: 154/72 mmHg achieved

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group UK Prospective Diabetes Study Group, BMJ 1998;317:703-713

Tight BP control reduces microvascular events

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group UK Prospective Diabetes Study Group, BMJ 1998;317:703-713

Tight Blood Pressure Control Confers CV Benefits in Diabetic Patients

-50

-40

-30

-20

-10

0

Tight glucose control(FPG < 107 mg/dL)

Tight BP control(150/85 mmHg)

StrokeAny DMendpoint DM death

Microvascularcomplications

*

** *

Red

uctio

n in

Ris

k (%

)

DM=diabetes mellitusFPG=fasting plasma glucose*P<0.05.

The benefits of lowering BP in the UKPDS were greater than those achieved through glycemic control

UKPDS 35. BMJ. 2000;321:405-412; UKPDS 38. BMJ. 1998;317:703-713.

Screening

• Screening for albuminuria should begin 5 years after the diagnosis of type 1 diabetes

• It should be done immediately after the diagnosis of type 2 diabetes.

• Screening for albuminuria should be done annually

ABNORMAL ALBUMIN EXCRETION

Timed(ug/min)

24 hour(mg/day)

Alb/Cr(mg/gm)

Normal <20 <30 <30

Microalbuminuria 20-200 30-300 30-300

Macroalbuminuria >200 >300 >300

Microalbuminuria needs to be persistent over 6 months

Screening

• Serum creatinine should be done annually• and the GFR estimated

– Cockcroft – Gault equation (Age/weight/cr)– MDRD formula (Age, creatinine)

Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus

• 3rd NHNES; > 40 yrs, T2 DM; Survey• 13% of type 2 DM with CRI (MDRD)

– DR 28%– Microalbuminuria 45%– Macroalbuminuria 19%

• 30% of CRI with neither DR nor albuminuria

Kramer HJ et al; JAMA 2003; 289; 3273-77

Detection of Microalbuminuria

Impact of Blood Pressure Reduction on Mortality in Diabetes

TrialConventional

careIntensive

careRisk

reductionP-value

UKPDS 154/87 144/82 32%

66%

0.019

HOT 144/85 140/81 0.016

Mortality endpoints are:UK Prospective Diabetes Study (UKPDS) – “diabetes related deaths”Hypertension Optimal Treatment (HOT) Study – “cardiovascular deaths” in diabetics

Turner RC, et al. BMJ. 1998;317:703-713. Hansson L, et al. Lancet. 1998;351:1755–1762.

Drug choices in the non-albuminurichypertensive diabetic patient

• Blood pressure control reduces cardiovascular events

• Initial drug choices include– Angotensin converting enzyme inhibitors– Angiotensin receptor blockers– Beta blockers– Diuretics– Calcium channel blockers

ABCD: Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and

type 2 diabetes.• 470 hypertensive diabetics DBP> 90• 2 x 2;

– nislodipine vs enalapril; – Intensive versus moderate

• 5 year follow up• Intensive BP 132/78 vs Mod 138/76• Results

– GFR decline no difference– Normo to Micro: 25% vs 18 % (p 0.20 ns)– Micro to Macro: 16 % vs 25% (p 0.28 ns)

Estacio RO et al; Diabetes Care 2000; 23; Suppl 2 B 54-64

Blood Pressure Target

• The blood pressure target in all diabetics should be less than 130/80

• Diabetics with proteinuria in excess of 1 gram should attempt to achieve values of less than 125/75 mm Hg

MAP (mmHg)

95

125

105

45

GFR (ml/min/1.73m2)

1250

250

Albuminuria (ug/min)

COURSE OF GFR, ALBUMINURIA, MEAN ARTERIAL BLOOD PRESSURE IN 9 IDDM PATIENTS TREATED WITH ANTIHYPERTENSIVES

years90

Parving HH et al; Am J Kidney Dis. 1993 Jul;22(1):188-95

Slide SourceHypertensionOnline

www.hypertensiononline.org

Meta Analysis: Lower Mean BP Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in Results in Slower Rates of Decline in GFR in Diabetics and NonGFR in Diabetics and Non--DiabeticsDiabetics

9595 9898 101101 104104 107107 110110 113113 116116 119119

r = 0.69; P < 0.05

MAP (mmHg)

GFR

(mL/

min

/yea

r)

130/85 140/90

UntreatedHTN

00

--22

--44

--66

--88

--1010

--1212

--1414 Parving HH, et al. Br Med J. 1989.Moschio G, et al. N Engl J Med. 1996.Viberti GC, et al. JAMA. 1993. Bakris GL, et al. Kidney Int. 1996.Klahr S, et al. N Eng J. Med 1994. Bakris GL. Hypertension. 1997.Hebert L, et al. Kidney Int. 1994. The GISEN Group. Lancet. 1997.Lebovitz H, et al. Kidney Int. 1994.

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.Reprinted by permission, Harcourt Inc.

Mean glomerular filtration rate (GFR) decline and achieved follow-up blood pressure in study B*

Peterson, J. C. et. al. Ann Intern Med 1995;123:754-762* GFR 13-24; n = 255

Mean glomerular filtration rate (GFR) decline and achieved follow-up blood pressure in study A*

Peterson, J. C. et. al. Ann Intern Med 1995;123:754-762* GFR 22-55ml/min; n = 585

Combination Therapy Needed to Achieve Target SBP Goals

Number of BP Medications

Trial/SBP Achieved

1 2 3 4

UKPDS (144 mm Hg)

RENAAL(141 mm Hg)

ALLHAT (138 mm Hg)

IDNT (138 mm Hg)

HOT (138 mm Hg)

INVEST (133 mm Hg)

ABCD (132 mm Hg)

MDRD (132 mm Hg)

AASK (128 mm Hg)

Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

Drug choices in early nephropathy

• The initial therapy of choice should include and ACE inhibitor or an ARB

Drug Choices in Type 1 diabetics with overt nephropathy

• In the presence of overt nephropathy in type 1 diabetes, there is evidence that an ACE inhbitor can retard the progression of otherwise progressive renal disease

ACE-I Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes

% with doubling of

baseline creatinine

100

75

50

25

0

0 1 2 3 4

Baseline creatinine >1.5 mg/dL & overt proteinuria

Captopriln=207

Placebon=202

P<.001

Years of follow-up

Placebo BP achieved 129-136/80-84;Captopril BP achieved 128/134/77-82

50%

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.Collaborative Study Group Trial

Drug choices in type 2 diabetics with overt nephropathy

• In type 2 diabetes with overt nephropathy, either an ACE inhibitor or an ARB may be used to retard the progression of renal disease.

Long-Term Benefits of ACE Inhibition in Normotensive Type 2 Diabetics With Microalbuminuria

Years

Pro

tein

uria

(mg/2

4 h

)

460

420

380

340

300

260

220

180

140

100

60

20

0 1 2 3 4 5

Placebo (n=45)

Enalapril

Per

centa

ge

of

initia

l va

lue

100/c

reat

inin

e

Years0 1 2 3 4 5

75

Placebo

Enalapril (n=49)

* ** *** ***

*

* ††

*p<0.05; **p<0.01; †p<0.02; ***p<0.005

110

105

100

95

90

85

80

Ravid et al. Ann Intern med. 1993; 118(8):577-581

0

5

10

15

20

25

30

Irbesartan Amlodipine Placebo0

5

10

15

20

25

30

Losartan Placebo

Dou

blin

g of

seru

m c

reat

inin

e co

ncen

trat

ion

(% o

f pat

ient

s)

RENAAL IDNTp = 0.003 rr 20%

p < 0.001 rr 23%p = 0.006 rr 25%

ARBs Can Reduce Diabetic Renal Disease Progression

n = 1715; 2.6 years n = 1513; 3.45 yearsBrenner et al. N Engl J Med 2001;345:861–869; Lewis et al. N Engl J Med 2001;345:851–860

IRMA II Irbesartan vs Placebo Primary Endpoint at 2 Years

Progression toNephropathy

Total # of

Patients n %

Placebo 201 30 14.9 - - - -

UnadjustedRisk

Reduction

PValue†

Adjusted*Risk

Reduction

PValue†

300 mg Irbesartan 194 10 <0.001

19

5.2 70%

0.08

68%

44%

<0.001

150 mg Irbesartan 195 9.7 39% 0.05

† For irbesartan vs placebo (the significance level for the primary endpoint was

0.025)

*Hazard ratios were adjusted for baseline level of microalbuminuria and blood pressure achieved during the study Parving HH, et al. N Engl J Med. 2001;345(12):870-878.

IRMA II Change in Urinary Albumin Excretion*

-50

-40

-30

-20

-10

0

10

20

% c

han

ge i

n u

rin

ary

alb

um

in e

xcr

eti

on

0 3 6 12 18 22 24Months of Follow-up

150 mg of irbesartan

300 mg of irbesartan

Placebo

*P<0.001 for difference between both irbesartan groups and placebo

Parving HH, et al. N Engl J Med. 2001;345(12):870-878.

IRMA II Incidence of Progression to Diabetic Nephropathy

0

5

10

15

20

Inci

den

ce o

f D

iab

eti

c N

ep

hro

path

y (

%)

0 3 6 12 18 22 24

201 201 164 154 139

195 195 167 161 148

129

142

36

45

Placebo (n)Irbesartan 150 mg (n)Irbesartan 300 mg

Months of Follow-up

194 180 172 159 150 49194

Placebo 150 mg ofirbesartan

300 mg ofirbesartan

P<0.001 for difference between 300 mg irbesartan group and placebo

Parving HH, et al. N Engl J Med. 2001;345(12):870-878.

5.2%

9.7%

14.9%

Drug Choices in type 2 diabetics with early nephropathy

• Both an ARB and ACE inhibitor demonstrate similar benefit in reducing a decline in the GFR

Inclusion criteria

• 250 patientsInclusion criteria• Male or female, 35–80 years• Type 2 diabetes (onset >40 years) on diet ± OHA

or insulin• ACE inhibitor for ≥3 months (ACE inhibitor

tolerant)• Mild-to-moderate hypertension (BP ≤180/95

mmHg)• Normal gross renal morphology ≤12 months

Barnett et al. N Engl J Med 2004;351:1952–1961.

Outcomes

Primary endpoint

• Change in GFR after 5 years

Secondary endpoints• Changes in GFR after 1, 2, 3 and 4 years• Changes in UAER and serum creatinine after 1, 2,

3, 4 and 5 years• Incidence of clinical events

– (end-stage renal disease, myocardial infarction,b l id i h f il )


ARB vs ACE inhibitors in type 2 diabetes and incipient nephropathy

Total GFR

0102030405060708090

100

Telmisartan Enalapril

*All patients, LOCF; 250 patients; 5 years follow up†p = NS, telmisartan vs enalapril

p = NS†

-17.9-14.8

-25

-20

-15

-10

-5

0Telmisartan Enalapril

Change in GFR

p = NS†

Baseline After 5 years

ml/

min

/1.7

3m

2

ml/

min

/1.7

3m

2


Problems of use of ACE inhibitors

• Hyperkalaemia• Acute renal failure with underlying bilateral

renal artery stenosis

Slide SourceHypertensionOnline

www.hypertensiononline.org

125

140

155

170

Baseline 1 Month 5.6 Yrs Month offACE-I

+Clonidine

SB

P (

mm

Hg)

Impact of ACEImpact of ACE--I on BP and GFR:I on BP and GFR:Acute and Chronic EffectsAcute and Chronic Effects

60

65

70

75

80

85

90

Baseline 1 Month 5.6 Yrs Month offACE-I

+Clonidine

*P<0.05 compared to baseline

Bakris GL, Weir MR. Arch Intern Med. 2000;160(5):685-93.©American Medical Association

GFR

ml/

min

/1.7

3m

2

*

* *

*

*

Recommended Practices

• The serum creatinine and potassium should be checked within 4 weeks of initiation of treatment to detect any rise in the serum creatinine of hyperkalaemia

The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal

diseases: a meta-analysis.

• Jan 1996 to Dec 1994• 5 studies IDDM; 5 studies non DM CRF• End points: Death and reduce GFR decline

FU (mths) Study Size ORIDDM 9 to 35 108 0.56 [0.44 -0.77]Non DM 18 to 36 1413 0.67 [0.50-0.89]

Pedrini MT et al; Ann Intern med 1996; 124: 627-32

Other measures: low protein diet

• Type 1 diabetics with overt nephropathy should be maintained on a low protein diet of 0.8gram / kg/ day of protein

Clinical Targets

• Therapy should aim to reduce albuminuriaas much as possible, and its is reasonable to aim for a urinary protein levels to less than 1 gram per day or at least 50% of the pre treatment value

Recommended nephrology consultation

• Decline in renal function• Difficulties in hyperkalaemia• Atypical features eg haematuria, casts, renal

bruits• Difficult blood pressure control• Heavy proteinuria (in excess of 3 gm/day)• Absence of retinopathy

Summary