Diabetics Exposed to Telmisartan And enalaprIL Telmisartan in type 2 diabetic nephropathy: reducing long term decline in renal function through RAS Blockade

Diabetics Exposed to Telmisartan And enalaprIL

Telmisartan in type 2 diabetic nephropathy:

reducing long term decline in renal function

through RAS Blockade

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

2

Natural history of type 2 diabetic nephropathy

Clinical type 2 diabetes

Diagnosis

Functional changes*

Structural changes†

2 years 5 years 10 years 20 years 30 years

Hypertension

Microalbuminuria Macroproteinuria

Decreasing GFR

ESRD

Cardiovascular death

* Altered renal haemodynamics, glomerular hyperfiltration† Glomerular basement membrane thickening , mesangial expansion , microvascular changes +/-

3

Increasing albuminuria indicates Increasing albuminuria indicates increasing risk in type 2 diabetesincreasing risk in type 2 diabetes

0

2

4

6

8

10

12

14

16

Normoalbuminuria Microalbuminuria Macroproteinuria

Inci

dence

of

card

iova

scula

r eve

nts

(% o

f patie

nts

per

year)

Gimeno Orna et al. Rev Clin Esp 2003

*

*P<0.05 versus normoalbuminuria after adjusting for other risk markers

*

4

0,0

1,0

2,0

3,0

4,0

5,0

6,0

Rel

ativ

e ris

k* in

pat

ient

s w

ith

impa

ired

GF

R (

95%

CI)

Reduced GFR* increases cardiovascular riskReduced GFR* increases cardiovascular risk

Ruilope et al. J Am Soc Nephrol 2001

Major cardiovascular

event

Myocardialinfarction

Stroke Cardiovascularmortality

Totalmortality

Increased risk

Reduced risk

*Relative risk of GFR 60 mL/min/1.73m2 compared with GFR >60 mL/min/1.73m2

5

Angiotensin II

Brewster, Perazella. Am J Med 2004

Glomerulosclerosis

HyperfiltrationGlomerular capillary

hypertension

Glomerular pressure injuryOxidative stress

Chronic kidney disease

Cell and tissuegrowth

Inflammation

Reduction in nephron mass

Angiotensin II is Angiotensin II is ccentral to the entral to the ppathophysiology of athophysiology of rrenal enal ddiseaseisease

6

Diuretic -blocker CCB ACEI ARB

Renal insufficiency ESH/ESC (loop)

Non-diabetic nephropathy ESH/ESC WHO/ISH

Type 1 diabetic nephropathy ESH/ESC WHO/ISH

Type 2 diabetic nephropathy ESH/ESC WHO/ISH

Proteinuria ESH/ESC

Diabetic microalbuminuria WHO/ISH

Chronic kidney disease JNC 7

Antihypertensive drug class Antihypertensive drug class recommendationsrecommendations

ESH/ESC Guidelines. J Hypertens 2003JNC 7. JAMA 2003

7

ACEIs in diabetic renal diseaseACEIs in diabetic renal disease

• ACEIs: proven to be effective in DM1 and nondiabetic kidney disease

• Micro-HOPE: confirmed that ACEIs reduce risk of overt proteinuria and CV events in DM2 patients

• Prior 2001, ACEIs considered first line therapy for diabetic patients with nephropathy

• Today, ACEI most commonly used antihypertensive class used to treat hypertensive diabetics, with usage ranging from

– 49% of patients in Japan

– 73% of patients in Germany

– 60% of patients in The NetherlandsLewis EJ, N Engl J Med 1993

GISEN group. Lancet 1997Remuzzi et al. Ann.Intern.Med 2002

HOPE Study Investigators. Lancet 2000Vivian et al. Ann Pharmacother 2001

Treatment Algorithms: Hypertension 3rd Edition. Datamonitor 2002. London UK

8

ARBs in diabetic renal diseaseARBs in diabetic renal disease

• In major clinical trials, ARBs have demonstrated effective renoprotection in type 2 diabetic nephropathy

– RENAAL (ARB vs placebo)

– IRMA 2 (ARB vs placebo)

– IDNT (ARB vs amlodipine)

• Both ACEIs and ARBS are recommended for diabetic hypertension and for the treatment of renal disease in the medical literature and guidelines

Parving et al. N Engl J Med 2001; Brenner et al. N Engl J Med 2001Lewis et al. N Engl J Med 2001; ESH/ESC Guidelines. J Hypertens 2003

JNC 7. JAMA 2003; Johnson. Intern Med J 2004 American Diabetes Association. Diabetes Care 2004

National Kidney Foundation. Am J Kidney Dis 2002National Kidney Foundation. Am J Kidney Dis 2004

9

ACEIs vs ARBsACEIs vs ARBs

• ACEI and ARBs block RAS by different mechanisms that may have clinical significance

• Prior to DETAIL, no direct clinical comparisons of the two most effective renoprotective therapies (ACEIs and ARBs)

• The need for such a comparative study has been a recognized gap in evidence-based medicine

• DETAIL is the first trial to address this gap

Hostetter. N Engl J Med 2001Thurman, Schrier. Am J Med 2003

Opie, Parving. Circulation 2002

DDiabetics iabetics EExposed to xposed to TTelmisartan elmisartan AAnd nd

enaenallapraprILIL

Telmisartan in type 2 diabetic nephropathy:

reducing long term decline in renal function though

RAS Blockade


11

Renoprotective and antihypertensive efficacy Renoprotective and antihypertensive efficacy of enalapril and telmisartanof enalapril and telmisartan

• Micardis and enalapril: comparable antihypertensive efficacy

– Lower incidence of adverse events with Micardis

• Micardis and enalapril reduce proteinuria similarly in patients with moderate renal failure

– Fewer adverse events with Micardis

• Micardis shown to reduce microalbuminuria and proteinuria

• Enalapril stabilized GFR decline in normotensive type 2 diabetics over 5 years Lacourcière et al. Kidney Int 2000

Amerena et al. J Int Med Res 2002Hannedouche et al. J Renin Angiotensin Aldosterone Syst 2001

Estacio et al. Diabetes Care 2000

12

Study overviewStudy overview

• Investigator-led, with independent steering committee

• Enrolment initiated in August 1997

• Last patient completed 5-year follow-up in 1Q 2004

• 39 centres in 6 countries:

– Denmark

– Finland

– The Netherlands

– Norway

– Sweden

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

13

Objectives

To compare long-term changes in GFR in patients with

type 2 diabetes + hypertension + albuminuria using:

– ACEI enalapril 10–20 mg

or

– ARB Micardis 40–80 mg


14

GFR and cardiovascular outcomes GFR and cardiovascular outcomes

0

10

20

30

40

50

60

70

Death fromCV causes

Reinfarction CHF Stroke Resus-citation

Compositeend point

Est

ima

ted

eve

nt r

ate

(%

)

* Median follow-up 24.7 months Anavekar et al. N Engl J Med 2004

GFR ≥ 75.0 ml/min/1.73 m2

GFR 60.0–74.9 ml/min/1.73 m2

GFR 45.0–59.9 ml/min/1.73m2

GFR <45 ml/min/1.73 m2

15

Value of GFRValue of GFR

• Best overall index of renal function and a powerful predictor of cardiovascular disease

• Albuminuria weakly correlates with GFR

• Accurate GFR assessment only possible using direct measurement

• No previous study of renoprotection with ARBs used direct measurement of GFR to estimate impact on renal function as primary endpoint

National Kidney Foundation. Am J Kidney Dis 2002Hostetter. N Engl J Med 2004Go et al. N Engl J Med 2004

Anavekar et al. N Engl J Med 2004MacIsaac et al. Diabetes Care 2004

16

Study designStudy design

Prospective, multicentre, randomized, double-blind, double-dummy, parallel-group, forced-titration, 5-year treatment

E R

Run-inperiod

n=250

Micardis 40 mgMicardis 80 mg*

enalapril 10 mg enalapril 20 mg*

*Optional dose-reduction to Micardis 40 mg or enalapril 10 mg after 2 months

59 months1 month 1 month


17

Inclusion criteria Inclusion criteria

• Male or female, 35–80 years

• Type 2 diabetes

• ACEI for 3 months (ACEI tolerant)

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

• Normal gross renal morphology 12 months

• UAER 11–999 µg/min

• Serum creatinine 140 µmol/l; HbA1C <12%

• GFR 70 ml/min/1.73 m2 (iohexol clearance)Barnett et al. N Engl J Med 2004;351:1952–1961

18

Exclusion criteriaExclusion criteria

• Any condition (other than CVD) that could affect long-term survival of patient

• Renal dysfunction not due to diabetes

• Single kidney or known renal artery stenosis

• NYHA functional class II–IV

• Hypersensitivity to study drugs

• History of angioedema


19

OutcomesOutcomes

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 (ESRD, MI, CVA, CHF)

• All-cause mortality

• Safety


20

Statistical analysisStatistical analysis

• Non-inferiority study

• Power calculation:

– Assume 25% drop-out rate per year

– SD of difference between treatment arms in change in GFR assumed to be 12 ml/min (estimate from literature)

– Micardis judged to be non-inferior if lower bound of confidence interval for Micardis-enalapril five-year cumulative difference <10 ml/min/1.73 m2


21

Micardis Enalapril(n=120) (n=130)

Males, n (%) 87 (73) 95 (73)

Caucasians, n (%) 118 (98) 128 (98)

Age (years), mean ± SD 61.2 ± 8.5 60.0 ± 9.1

Body weight (kg), mean ± SD 90.6 ± 14.9 90.6 ± 17.4

BMI (kg/m2), mean ± SD 30.8 ± 4.4 30.6 ± 5.1

GFR (ml/min/1.73m2), mean ± SD 91.4 ± 21.5 94.3 ± 22.1

UAER (µg/min), median 46.2 60.0

Microalbuminuria, n (%) 98 (82) 106 (82)

Macroalbuminuria, n (%) 22 (18) 23 (18)

History of CVD, n (%) 59 (49) 63 (49)

Baseline patient characteristics*


*All patients who were enrolled and received at least one dose of study medication

22


Smoking history, n (%)

Never smoked 41 (34.2) 47 (36.2)

Ex-smoker 54 (45.0) 55 (42.3)

Smoker 25 (20.8) 28 (21.5)

Alcohol history, n (%)

Non-drinker 29 (24.2) 35 (26.9)

Average consumption 90 (75.0) 94 (72.3)

Excessive consumption 1 (0.8) 1 (0.8)

Risk factors at baseline*Risk factors at baseline*


*All patients who were enrolled and received at lest one dose of study medication

23


Hypertension (years)

Mean ± SD 10.0 ± 8.3 8.7 ± 9.2 Median 8.0 5.5

Range 0–34 0–49

Diabetes (years)

Mean ± SD 9.2 ± 6.6 9.1 ± 6.3 Median 8.0 8.0

Range 0–25 0–37

Duration of diagnosis at baseline*Duration of diagnosis at baseline*


*All patients who were enrolled and received at least one dose of study medication

24

Micardis (n=120) Enalapril (n=130)Medication Prior* During† Prior* During†

Pts receiving therapy – no. (%) 104 (86.7) 102 (85.0) 122 (93.8) 106 (81.5)

ARB 0 0 1 (0.8) 1 (0.8)

ACEI (ex. enalapril‡) 75 (62.5) 2 (1.7) 82 (63.1) 0

Enalapril‡ 16 (13.3) 2 (1.7) 27 (20.8) 1 (0.8)

Diuretics 25 (20.8) 63 (52.5) 28 (21.5) 67 (51.5)

β-blockers 22 (18.3) 46 (38.3) 23 (17.7) 49 (37.7)

Ca channel blockers 31 (25.8) 54 (45.0) 33 (25.4) 58 (44.6)

Other antihypertensives and heparin 14 (11.7) 42 (35.0) 18 (13.8) 46 (35.4)

Aspirin 21 (17.5) 44 (36.7) 26 (20.0) 54 (41.5)

Statins 14 (11.7) 51 (42.5) 22 (16.9) 54 (41.5)

Concomitant CV treatmentConcomitant CV treatment

* Concomitant medication received for a minimum of 6 consecutive months by any patient who was enrolled and received at least one dose of study medication

† LOCF dataset‡ Patients had to have received an ACEI for ≥3 months prior to enrolment


25

Patient dispositionPatient disposition

Enalapril130

82 86

Telmisartan120

Randomized

250

Discontinued for administrative reasons

Discontinued due toadverse events20

18

30

14

5-year completers

62

103

74

113

5-year GFR

LOCF GFR


38 40

26

Primary endpoint: GFR after 5 years*Primary endpoint: GFR after 5 years*

0

10

20

30

40

50

60

70

80

90

100

Telmisartan Enalapril

Total GFR

* All patients, LOCF† p = NS, telmisartan vs enalapril

p=NS†

-17.9

-14.8

-25

-20

-15

-10

-5

0

Telmisartan Enalapril

Change in GFR

p=NS†

Barnett. Presented at ESC 2004

Baseline After 5 years

27

-25

-20

-15

-10

-5

0

5

10

0 1 2 3 4 5

GFR change from baseline (LOCF) GFR change from baseline (LOCF)

Year

Enalapril

Micardis

Number of Enalaprilpatients assessed Telmisartan(carried forward)

113 (39)103 (41)

103 (0)86 (0)

110 (22)99 (23)

113 (23)102 (21)

113 (30)102 (31)


Cha

nge

in G

FR

(ml/m

in/1

.73

m2 )

28

Yearly change in GFR*Yearly change in GFR*

-10

-8

-6

-4

-2

0

2

Baseline toYear 1

Year 1 toYear 2

Year 2 toYear 3

Year 3 toYear 4

Year 4 toYear 5

TelmisartanEnalapril

Cha

nge

in G

FR

(ml/m

in/1

.73

m2 )

* Patients in the study and with data for each yearly timepoint Barnett. Presented at ESC 2004

29

Systolic and diastolic BP* Systolic and diastolic BP*

Dia

sto

lic B

P (

mm

Hg

)

Year

90

85

80

75

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

Sys

tolic

BP

(m

mH

g)

Year

EnalaprilMicardis

155

150

140

135

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

145

Barnett et al. N Engl J Med 2004;351:1952–1961 * All patients, LOCF

EnalaprilMicardis

30

Secondary endpoints at 5 years*Secondary endpoints at 5 years*

Endpoint Micardis enalapril Difference P

Mean change +8.84 +8.84 0.00 NS serum creatinine (µmol/l)n 116 128

UAER – ratio‡ 1.03 0.99 1.04 NS*n 115 125

UAER=urinary albumin excretion rates; NS=not significant; * All patients, LOCF† Determined from the logarithm of the individual change from baseline‡ Ratio of treatment differences.


31

Safety*Safety*

n % n %

Total AEs over 5 years 115 (95.8) 130 (100.0)Serious AEs 61 (50.8) 57 (43.8)Discontinuation due to AE 20 (16.6) 30 (23.1) Due to worsening of study disease 2 (1.6) 0 (0.0)

Due to worsening of other disease 6 (5.0) 6 (4.6) Due to cough 1 (0.8) 3 (2.3)

CVA 6 (5.0) 6 (4.6)Creatinine ≥200 µmol/l) 2 (1.7) 2 (1.5)CHF 9 (7.5) 7 (5.4)Non-fatal MI 9 (7.5) 6 (4.6)Deaths 6 (5.0) 6 (4.6)

Due to CV event 3 (2.5) 2 (1.5)

Micardis Enalapril


AE= Adverse event; *All patients who were enrolled and received at least one dose of study medication

32

Discussion – GFRDiscussion – GFR

• Age-related decline of GFR in healthy individuals is ~1 ml/min/1.73m2/year (NHANES III)

• In diabetics with proteinuria without intervention, declines at 10–12 ml/min/1.73m2/year

• In DETAIL, the initial steep decline stabilized by Micardis and enalapril to ≈2 ml/min/1.73m2/year after Year 3

National Kidney Foundation. Am J Kidney Dis 2002Parving et al. Semin Nephrol 2004

Brenner. Kidney Int 2003

33

Micardis: stabilisatie nierfunctie Micardis: stabilisatie nierfunctie

0

10

20

30

40

50

60

70

80

90

Baseline 1 2 3 4 5

Year

No TreatmentAgeing

GF

R (

ml/m

in/1

.73

m2 )

Threshold for ESRD

* All patients, LOCFBarnett et al. N Engl J Med 2004;351:1952–1961

Parving et al . Semin. Nephrol. 2004

34

Micardis: stabilisatie nierfunctieMicardis: stabilisatie nierfunctie

0

10

20

30

40

50

60

70

80

90

Baseline 1 2 3 4 5

Year

MicardisNo TreatmentAgeing

GF

R (

ml/m

in/1

.73

m2 )

Threshold for ESRD

* All patients, LOCFBarnett et al. N Engl J Med 2004;351:1952–1961

Parving et al . Semin. Nephrol. 2004

35

-4,4

-5,7 -5,5

-3,7

-6

-5

-4

-3

-2

-1

0

Losartan 100 mg Irbesartan 300 mg Irbesartan 300 mg Micardis 80 mg

Renoprotective effects of ARBs: Renoprotective effects of ARBs: GFR decline in DETAIL, IRMA 2, IDNT and RENAALGFR decline in DETAIL, IRMA 2, IDNT and RENAAL

RENAAL*

GF

R d

ecl

ine

(m

l/min

/1.7

3m2/y

ea

r)

IDNT† DETAIL†

* Median† Mean

Parving et al. N Engl J Med 2001; Brenner et al. N Engl J Med 2001Lewis et al. N Engl J Med 2001; Barnett et al. N Engl J Med 2004;351:1952–1961

IRMA2†

3.4 years 2 years 2.6 years 5 years

36

Discussion – mortalityDiscussion – mortality

• Over 5 years, expected mortality rate in older type 2 diabetics is ~35% (micro) and ~50% (macro)

• ARBs reduce ESRD, but not yet demonstrated significant reductions of CV endpoints in type 2 diabetes with nephropathy (IDNT, RENAAL)

• ACEIs reduce CVD in type 2 diabetes (HOPE), but not yet demonstrated in nephropathy

• In DETAIL, there were only 6 deaths (~5%) in each group, half of which were due to CV events

Valmadrid et al. Arch Intern Med 2000Lewis et al. N Engl J Med 2001

Brenner et al. N Engl J Med 2001HOPE Investigators. Lancet 2000

37

Discussion – safetyDiscussion – safety

• DETAIL inclusion criteria required all patients to be tolerant of ACEIs

• Therefore, no major differences in adverse events between Micardis and enalapril were anticipated

• Nevertheless, there were fewer withdrawals due to adverse events with Micardis

• This is in line with previous studies, in which Micardis showed a safety profile superior to enalapril

Amerena, et al. J Int Med Res 2002Hannedouche, et al. J Renin Angiotensin Aldosterone Syst 2001

38

SummarySummary

• First long-term study in patients with hypertension and early-stage type 2 diabetic nephropathy to compare ARBs and ACEIs

• Using GFR, the most reliable indicator of kidney function and important predictor of cardio vascular disease

• Micardis is comparable to enalapril in reducing GFR decline and providing renoprotection in patients with type 2 diabetes and nephropathy

• Very low mortality rate (5%)

39

ConclusionsConclusions

• Results in accord with the proven renoprotective profile of ARBs and ACEIs

• Consistent with emerging data supporting clinical equivalence of angiotensin-II–blockers and ACEIs in various states of high cardiovascular risk.

• Micardis is therefore a valid choice for first-line treatment of hypertensive patients with type 2 diabetes and early-stage nephropathy

Documents

Diabetics Exposed to Telmisartan And enalaprIL Telmisartan in type 2 diabetic nephropathy: reducing long term decline in renal function through RAS Blockade