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
Natural history of type 2
diabetic nephropathy
Clinical type 2 diabetes
Functional changes*
Hypertension
Microalbuminuria  Macroproteinuria
Structural changes†
Decreasing GFR
ESRD
Cardiovascular death
Diagnosis
2 years
5 years
10 years
20 years
* Altered renal haemodynamics, glomerular hyperfiltration
† Glomerular basement membrane thickening , mesangial expansion , microvascular changes +/-
30
years
2
Incidence of cardiovascular events
(% of patients per year)
Increasing albuminuria indicates
increasing risk in type 2 diabetes
16
*
14
12
10
8
*
6
4
2
0
Normoalbuminuria
*P<0.05 versus normoalbuminuria
after adjusting for other risk markers
Microalbuminuria
Macroproteinuria
Gimeno Orna et al. Rev Clin Esp 2003
3
Reduced GFR* increases cardiovascular risk
Relative risk* in patients with
impaired GFR (95% CI)
6,0
5,0
4,0
3,0
2,0
Increased risk
1,0
0,0
Reduced risk
Major
cardiovascular
event
Myocardial
infarction
*Relative risk of GFR 60 mL/min/1.73m2
compared with GFR >60 mL/min/1.73m2
Stroke
Cardiovascular
mortality
Total
mortality
Ruilope et al. J Am Soc Nephrol 2001
4
Angiotensin II is central to the
pathophysiology of renal disease
Glomerular pressure injury
Oxidative stress
Inflammation
Angiotensin II
Hyperfiltration
Glomerular capillary
hypertension
Chronic kidney
disease
Cell and tissue
growth
Reduction in
nephron mass
Glomerulosclerosis
Brewster, Perazella. Am J Med 2004
5
Antihypertensive drug class
recommendations
Diuretic
b-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







ESH/ESC Guidelines. J Hypertens 2003
JNC 7. JAMA 2003
6
ACEIs 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
Lewis EJ, N Engl J Med 1993
GISEN group. Lancet 1997
Remuzzi et al. Ann.Intern.Med 2002
HOPE Study Investigators. Lancet 2000
Vivian et al. Ann Pharmacother 2001
Treatment Algorithms: Hypertension 3rd Edition. Datamonitor 2002. London UK
7
– 60% of patients in The Netherlands
ARBs 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 2001
Lewis 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 2002
National Kidney Foundation. Am J Kidney Dis 2004
8
ACEIs 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 2001
Thurman, Schrier. Am J Med 2003
Opie, Parving. Circulation 2002
9
Diabetics Exposed to Telmisartan And
enalaprIL
Telmisartan in type 2 diabetic nephropathy:
reducing long term decline in renal function though
RAS Blockade
Barnett et al. N Engl J Med 2004;351:1952–1961
Renoprotective and antihypertensive efficacy
of 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 2002
Hannedouche et al. J Renin Angiotensin Aldosterone Syst 2001
11
Estacio et al. Diabetes Care 2000
Study 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 Kingdom
Barnett et al. N Engl J Med 2004;351:1952–1961
12
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
Barnett et al. N Engl J Med 2004;351:1952–1961
13
GFR and cardiovascular outcomes
Estimated event rate (%)
70
60
50
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
40
30
20
10
0
Death from
CV causes
Reinfarction
* Median follow-up 24.7 months
CHF
Stroke
Resuscitation
Composite
end point
Anavekar et al. N Engl J Med 2004
14
Value 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 2002
Hostetter. N Engl J Med 2004
Go et al. N Engl J Med 2004
Anavekar et al. N Engl J Med 2004
MacIsaac et al. Diabetes Care 2004
15
Study design
Prospective, multicentre, randomized, double-blind, doubledummy, parallel-group, forced-titration, 5-year treatment
Micardis 80 mg*
Micardis 40 mg
Run-in
period
E
n=250
R
enalapril 10 mg
enalapril 20 mg*
1 month
1 month
*Optional dose-reduction to Micardis 40 mg or
enalapril 10 mg after 2 months
59 months
Barnett et al. N Engl J Med 2004;351:1952–1961
16
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
17
Exclusion 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
Barnett et al. N Engl J Med 2004;351:1952–1961
18
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 (ESRD, MI, CVA, CHF)
• All-cause mortality
• Safety
Barnett et al. N Engl J Med 2004;351:1952–1961
19
Statistical 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
Barnett et al. N Engl J Med 2004;351:1952–1961
20
Baseline patient characteristics*
Males, n (%)
Caucasians, n (%)
Age (years), mean ± SD
Body weight (kg), mean ± SD
BMI (kg/m2), mean ± SD
GFR (ml/min/1.73m2), mean ± SD
UAER (µg/min), median
Microalbuminuria, n (%)
Macroalbuminuria, n (%)
History of CVD, n (%)
Micardis
(n=120)
Enalapril
(n=130)
87 (73)
118 (98)
61.2 ± 8.5
90.6 ± 14.9
30.8 ± 4.4
91.4 ± 21.5
46.2
98 (82)
22 (18)
59 (49)
95 (73)
128 (98)
60.0 ± 9.1
90.6 ± 17.4
30.6 ± 5.1
94.3 ± 22.1
60.0
106 (82)
23 (18)
63 (49)
*All patients who were enrolled and received at least
one dose of study medication
Barnett et al. N Engl J Med 2004;351:1952–1961
21
Risk factors at baseline*
Micardis
(n=120)
Enalapril
(n=130)
Never smoked
41 (34.2)
47 (36.2)
Ex-smoker
54 (45.0)
55 (42.3)
Smoker
25 (20.8)
28 (21.5)
Non-drinker
29 (24.2)
35 (26.9)
Average consumption
90 (75.0)
94 (72.3)
1 (0.8)
1 (0.8)
Smoking history, n (%)
Alcohol history, n (%)
Excessive consumption
*All patients who were enrolled and received at lest
one dose of study medication
Barnett et al. N Engl J Med 2004;351:1952–1961
22
Duration of diagnosis at baseline*
Micardis
(n=120)
Enalapril
(n=130)
10.0 ± 8.3
8.7 ± 9.2
Median
8.0
5.5
Range
0–34
0–49
9.2 ± 6.6
9.1 ± 6.3
Median
8.0
8.0
Range
0–25
0–37
Hypertension (years)
Mean ± SD
Diabetes (years)
Mean ± SD
*All patients who were enrolled and received at least
one dose of study medication
Barnett et al. N Engl J Med 2004;351:1952–1961
23
Concomitant CV treatment
Medication
Micardis (n=120)
Prior* During†
Pts receiving therapy – no. (%)
104 (86.7)
ARB
0
ACEI (ex. enalapril‡)
75 (62.5)
Enalapril‡
16 (13.3)
Diuretics
25 (20.8)
β-blockers
22 (18.3)
Ca channel blockers
31 (25.8)
Other antihypertensives and heparin 14 (11.7)
Aspirin
21 (17.5)
Statins
14 (11.7)
102 (85.0)
0
2 (1.7)
2 (1.7)
63 (52.5)
46 (38.3)
54 (45.0)
42 (35.0)
44 (36.7)
51 (42.5)
Enalapril (n=130)
Prior*
During†
122 (93.8)
1 (0.8)
82 (63.1)
27 (20.8)
28 (21.5)
23 (17.7)
33 (25.4)
18 (13.8)
26 (20.0)
22 (16.9)
106 (81.5)
1 (0.8)
0
1 (0.8)
67 (51.5)
49 (37.7)
58 (44.6)
46 (35.4)
54 (41.5)
54 (41.5)
* 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
Barnett et al. N Engl J Med 2004;351:1952–1961
24
Patient disposition
250
Telmisartan
120
Enalapril
130
Randomized
20
Discontinued due to
adverse events
30
18
Discontinued for
administrative reasons
14
5-year
completers
82
62
103
38
5-year GFR
LOCF GFR
86
40
74
113
25
Barnett et al. N Engl J Med 2004;351:1952–1961
Primary endpoint: GFR after 5 years*
Total GFR
100
90
80
70
60
50
40
30
20
10
0
Change in GFR
Telmisartan
p=NS†
Enalapril
0
-5
-10
-15
-20
-25
Telmisartan
Baseline
-14.8
-17.9
p=NS†
Enalapril
After 5 years
* All patients, LOCF
† p = NS, telmisartan vs enalapril
Barnett. Presented at ESC 2004
26
GFR change from baseline (LOCF)
10
Enalapril
Micardis
Change in GFR
(ml/min/1.73 m2)
5
0
-5
-10
-15
-20
-25
0
3
2
1
4
5
Year
Number of
Enalapril
patients assessed Telmisartan
(carried forward)
103 (0)
86 (0)
110 (22)
99 (23)
113 (23)
102 (21)
113 (30)
102 (31)
113 (39)
103 (41)
Barnett et al. N Engl J Med 2004;351:1952–1961
27
Yearly change in GFR*
Baseline to
Year 1
Year 1 to
Year 2
Year 2 to
Year 3
Year 3 to
Year 4
Year 4 to
Year 5
2
Change in GFR
(ml/min/1.73 m2)
0
-2
-4
-6
-8
Telmisartan
Enalapril
-10
* Patients in the study and with data for each yearly timepoint
Barnett. Presented at ESC 2004
28
Systolic and diastolic BP*
155
90
Enalapril
Micardis
Enalapril
Micardis
Diastolic BP (mmHg)
Systolic BP (mmHg)
150
145
140
85
80
75
135
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Year
* All patients, LOCF
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Year
Barnett et al. N Engl J Med 2004;351:1952–1961
29
Secondary endpoints at 5 years*
Endpoint
Micardis
enalapril
Difference
P
+8.84
+8.84
0.00
NS
n
116
128
UAER – ratio‡
1.03
0.99
1.04
NS*
n
115
125
Mean change
serum creatinine (µmol/l)
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.
Barnett et al. N Engl J Med 2004;351:1952–1961
30
Safety*
Micardis
Enalapril
115 (95.8)
61 (50.8)
20 (16.6)
2 (1.6)
6 (5.0)
1 (0.8)
6 (5.0)
2 (1.7)
9 (7.5)
9 (7.5)
6 (5.0)
3 (2.5)
130 (100.0)
57 (43.8)
30 (23.1)
0
(0.0)
6
(4.6)
3
(2.3)
6
(4.6)
2
(1.5)
7
(5.4)
6
(4.6)
6
(4.6)
2
(1.5)
n
Total AEs over 5 years
Serious AEs
Discontinuation due to AE
Due to worsening of study disease
Due to worsening of other disease
Due to cough
CVA
Creatinine ≥200 µmol/l)
CHF
Non-fatal MI
Deaths
Due to CV event
AE= Adverse event; *All patients who were enrolled
and received at least one dose of study medication
%
n
%
Barnett et al. N Engl J Med 2004;351:1952–1961
31
Discussion – 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 2002
Parving et al. Semin Nephrol 2004
Brenner. Kidney Int 2003
32
Micardis: stabilisatie nierfunctie
90
GFR (ml/min/1.73 m2)
80
70
60
50
40
No Treatment
Ageing
30
20
Threshold for ESRD
10
0
Baseline
1
2
3
Year
* All patients, LOCF
4
5
Barnett et al. N Engl J Med 2004;351:1952–1961
Parving et al . Semin. Nephrol. 2004
33
Micardis: stabilisatie nierfunctie
90
GFR (ml/min/1.73 m2)
80
70
60
50
Micardis
No Treatment
Ageing
40
30
20
Threshold for ESRD
10
0
Baseline
1
2
3
Year
* All patients, LOCF
4
5
Barnett et al. N Engl J Med 2004;351:1952–1961
Parving et al . Semin. Nephrol. 2004
34
Renoprotective effects of ARBs:
GFR decline in DETAIL, IRMA 2, IDNT and RENAAL
RENAAL*
IRMA2†
IDNT†
DETAIL†
3.4 years
2 years
2.6 years
5 years
Losartan 100 mg
Irbesartan 300 mg
Irbesartan 300 mg
Micardis 80 mg
GFR decline
(ml/min/1.73m2/year)
0
-1
-2
-3
-4
-5
-6
* Median
† Mean
-3,7
-4,4
-5,7
-5,5
Parving et al. N Engl J Med 2001; Brenner et al. N Engl J Med 2001
Lewis et al. N Engl J Med 2001; Barnett et al. N Engl J Med 2004;351:1952–1961
35
Discussion – 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 2000
Lewis et al. N Engl J Med 2001
Brenner et al. N Engl J Med 2001
HOPE Investigators. Lancet 2000
36
Discussion – 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 2002
Hannedouche, et al. J Renin Angiotensin Aldosterone Syst 2001
37
Summary
• 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%)
38
Conclusions
• 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 earlystage nephropathy
39