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What is the Impact of PRIME in

Clinical Practice of Diabetic


Nephropathy patient ?

Harsinen Sanusi
Division of Endocrinology &
Metabolic Department of Internal
Medicine Faculty of Medicine
Hasanuddin University Dr Wahidin
Sudirohusodo Hospital Makassar

East Indonesia Endo–Metabolism Up date 27-28 May 2006


The Diabetes Epidemic
• 151 million patients with diabetes, 221
million estimated by 2010
• 2.1% of worldwide population
• 97% are Type 2 DM patients
• Diabetic nephropathy  ESRD
• ESRD  high risk Cardio Vascular Death
• 65% of people with diabetes die of CVD
• Complications of diabetes include
– Coronary artery disease
– Peripheral vascular disease
– Diabetic nephropathy
– Stroke
Pathogenesis Of
Diabetic Nephropathy
Multifactorial
Genetic
Metabolic Factor
Haemodynamic Factors
Metabolic Hemodynamic
Glucose Flow/pressure
Advanced glycation Renin Angiotensin
Oxidative stress

Intracelellular signalling molecules

Growth Factors & Cytokines

Diabetic Complications

Cooper,ME Diabetologis 2001;44:1957


DIABETES MELLITUS HYPERTENSION

MICROALBUMINURIA

Glycemic control Blood pressure control

End Stage Renal


Disease
Natural History of Type 2 Diabetic
Nephropathy
Clinical type 2 diabetes
Functional changes*

Structural changes†

Rising blood pressure


Microalbuminuria

Proteinuria

Rising serum creatinine levels


End-stage ginjal disease

Cardiovascular death

Onset of 2 5 10 20 30
diabetes
Years
* Kidney size ↑, GFR ↑.

GBM thickening ↑, mesangial ekspansion ↑, microvascular changes
+/-.
Normal urinary
albumin
secretion

Microalbuminuria 40%

50%
Proteinuria (5-10 years)

20%
(20 year)

End Stage
Renal Disease
(ESRD)
Death
Risk Factors for Cardiovascular Disease
Association with type 2 Diabetes

Specific Non Specific


Microalbuminuria Hypertension
Glycated LDL Lipids
Glycated HDL Decreased HDL
Hypertriglyceridemia
Obesity
Small dense LDL
Renal failure
Cardiac autonomic neuropathy
Endothelial dysfunction
Altered fibrinolysis and
thrombosis

Felig P, Froshman LA. Endocrinology and Metabolism 2001;909


Diabetic Nephropathy
(ADA 2006)

Parameter Urine AER Urine AER Albumen


(µg/min) (mg/24 h) urine/creat
mg/gr

Normal <20 <30 <30


Microalbuminuria 20-199 30-299 30-299
Macroalbuminuria > 200 >300 >300

Diabetes care 2006;29 Suppl:S4-S42


Albuminuria Predicts Stroke and
CHD Events in Type 2 Diabetes
A: U-Prot <150 mg/L B: U-Prot 150–300 mg/L C: U-Prot >300 mg/L

1. 40
0 P<0.001
0.
9 30
Survival 0.8 A
curves B Incidence
for CV 0.7 (%) 20
mortality
0.6
C 10
0. Overall: P<0.001
5
0 0
0 10 20 30 40 50 60 70 80 90 Stroke CHD
Months events
U-Prot, urinary protein concentration.
Miettinen H et al. Stroke. 1996;27:2033–2039.
Albuminuria and Mortality in
NIDDM
1 Normoalbuminuria
n=191
0.9 Microalbuminuria
Survival

0.8 n=86
Macroalbuminuria

0.7
* n=51
0.6
*p<0.05: normo. vs. micro. and macroalbuminuria

0.5
0 1 2 3 4 5 6

Years

Gall MA, et al. Diabetes. 1995;44:1303-9


ESRD in type 2 diabetes mellitus
30

25

Cumulativ 20
e
incidence 15
of ESRD
(%) 10

0 2 4 6 8 10 12 14 16 18 20
Years from diagnosis of persistent proteinuria

Humphrey et al. Ann Int Med 1989;111:788-


796.
Screening for microalbuminuria is very
important for the following reasons:
Microalbuminuria has a prevalence rate
of 30% - 40% in patients with diabetes.
Microalbuminuria progresses within 5 to
10 years to overt proteinuria in 50% of
patients with type 2 diabetes.
Microalbuminuria is an indicator of
vascular injury.
Coexistence of Hipertension in
Diabetes
The bad companions...
Hipertensi is associated with
a doubling of the presence of

ECG signs of MI
Microalbuminuria LVH and a prior history
of overt CV events
Kaplan NM. In Ellenberg and Rifkin’s Diabetes
Mellitus: Theory and Practice, 5th ed. 1997.
30 31.7

25

20 21.3 20.1
Prevalensi (%)

15

10 9.6
7.5

5 5.8

Non Type 2 Normo Hiper Type Type2 DM+


diabetic DM 2 DM HPT
tensi tensi

Microalbuminuria in persons aged 50-75 years

Dis Manage Health outcomes 2000;7(5):267-88


JNC VI: Target Blood Pressure

Recommendations

Patient Population Target Pressure

Essential Hypertension <140/90 mmHg

Diabetes Mellitus <130/85 mmHg

Patients with Proteinuria* <125/75 mmHg


* > 1 g/24 hrs

Arch Intern Med 1997 57:2413-2446


Blood pressure lowering medications
should reduce both blood pressure +
proteinuria
Therapies that reduce both blood
pressure and proteinuria have been
known to reduce renal disease
progression and incidence of
ischemic heart disease
National Kidney Foundation Recommendations on Treatment of
HTN and Diabetes
AMERICAN DIABETES ASSOCIATION
(ADA) 2006

• Reduce the risk and/or slow the


progression of DN
Optimize Glucose control
Blood pressure control
• Reduce the risk of DN protein intake
(0,8 gr/kg).

Diabetes care 2006;29 Suppl:S4-S42


AMERICAN DIABETES ASSOCIATION
(ADA) 2006
• T2DM + Hypertension + microalbuminuria
 ACE inhibitors / ARBs  delay the
progression to macroalbuminuria
• T2DM + Hypertension + macroalbuminuria
and renal insufficiency (serum creatinine
>1.5 mg/dl) ARBs  delay the
progression of nephropathy
Diabetes care 2006;29 Suppl:S4-S42
Practice points
• The earliest sign of renal involvement in
diabetic patients  microalbuminuria
• In incipient DN+hypertension accelerate
development & progression of overt ND
• ARBs are effective in slowing the
progression of kidney disease with
microalbuminuria due T2DM

Akira YT Wu. In Medical Progress 2005;32: 270274.


A PRogram for Irbesartan Mortality
and Morbidity Evaluation
Time Course of Type 2 Diabetic
Renal Disease

PRIME

Prevention Protection

IRMA 2 IDNT
Microalbuminuria Proteinuria ESRD
Cardiovascular Morbidity and Mortality

Early Stage Late Stage End Stage

Kidney Disease
The IRbesartan MicroAlbuminuria
Type 2 Diabetes In Hypertensive Patients Study
IRMA II Objectives
• Randomized multi-site, double-blind, placebo-controlled study
to evaluate the renal protective effect of the angiotensin II
receptor antagonist irbesartan in hypertensive patients with
type 2 diabetes and microalbuminuria
Population
• 590 patients (30 to 70 years old)
– Type 2 diabetes
– Hypertension (a mean systolic BP >135 mmHg or a mean diastolic BP
>85 mmHg, or both, on 2 of 3 consecutive measurements)
– Persistent microalbuminuria
• Albumin excretion rate of 20 to 200 µ g/min in 2 of 3 samples
• Serum creatinine concentration of no more than 1.5 mg/dL for men
and 1.1 mg/dL for women
Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
IRMA 2
Study Design

• 590 pasien hipertensi, type 2 diabetes, microalbuminuria


(albumin excretion rate 20–200 µg/min)

Screening/Enrollment Double-blind Treatment


Control group*

Irbesartan 150 mg*

Irbesartan 300 mg*


Up to 5 weeks Follow-up: 2 years
* Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists,
and dihydropyridine calcium channel blockers) could be added to all groups to help achieve equal blood
pressure levels.
Parving H-H, et al. N Engl J Med 2001;345:870-878.
IRMA 2 Baseline Characteristics
Placebo Irbesartan Irbesartan
n=201 150 mg 300 mg
n=195 n=194
Mean age (yrs) 58.3 58.4 57.3
Male (%) 68.7 66.2 70.6
Mean Systolic BP (mmHg) 153 153 153
Mean Diastolic BP (mmHg) 90 90 91
Mean BMI (kg/m2) 30.3 29.9 30.0
Mean urinary albumin
excretion (µ g /min) 54.8 58.3 53.4
Mean serum creatinine (mg/dl)
Men 1.1 1.1 1.1
women 0.9 0.9 1.0
Mean glycosylated hemoglobin (%) 7.1 7.3 7.1

*The differences between the treatment groups were not statistically significant

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


IRMA 2
Control SeSBP
Blood Pressure Response Irbesartan 150 mg
160 SeSBP
150 Irbesartan 300 mg
SeSBP
140
Mean SeSBP 130 Control SeDBP
and SeDBP 120 Irbesartan 150 mg
(mm Hg) SeDBP
110
Irbesartan 300 mg
100 SeDBP
90
80
70
0
0 3 6 9 12 15 18 21 24 27
Months
Concomitant antihypertensive agents received by 56% of patients in the
control group, 45% in the irbesartan 150 mg group, and 43% in the
irbesartan 300 mg group.
Parving H-H, et al. N Engl J Med 2001;345:870-878.
IRMA 2 Primary Endpoint
Time to Overt Proteinuria

20
Control
Irbesartan 150 mg
15 Irbesartan 300 mg
Subjects
(%)
10

0
0 3 6 12 18 22 24
Follow-up (mo)

Parving H-H, et al. N Engl J Med 2001;345:870-


878.
IRMA 2 Primary Endpoint
Development of Overt Proteinuria
RRR=70%
P<0.001
18 RRR=39%
P=0.08
16 14.9
14
Subjects 12
(%) 10 9.7
8
6 5.2
4
2
0
Control 150 mg 300 mg
(n=201) (n=195) (n=194)
Irbesartan
Parving H-H, et al. N Engl J Med 2001;345:870-878.
IRMA 2
Normalization of Urinary Albumin Excretion Rate
45 P=0.006
40
35 34
30
Subjects 24
25
(%) 21
20
15
10
5
0
Control 150 mg 300 mg
(n=201) (n=195) (n=194)
Irbesartan
Parving H-H, et al. N Engl J Med 2001;345:870-878.
Conclusion IRMA 2
• Irbesartan is renoprotective, independent of
its blood pressure-lowering effects
– 70% risk reduction in the progression from
microalbuminuria to overt diabetic nephropathy with
irbesartan 300 mg
– Regression to normoalbuminuria was more frequent
with irbesartan 300 mg

• Irbesartan is safe and well tolerated


– Fewer non-fatal CV events, serious AEs, and
discontinuations due to AEs in the irbesartan groups
Parving H-H, et al. N Engl J Med 2001;345:870-878.
Time Course of Type 2 Diabetic
Renal Disease

PRIME

Prevention Protection

IRMA 2 IDNT
Microalbuminuria Proteinuria ESRD

Cardiovascular Morbidity and Mortality

Early Stage Late Stage End Stage

Kidney
Disease
IDNT
Study Design
• 1,715 pasien hipertensi, diabetes type 2, dan
proteinuria ≥ 900 mg/hari, creatinine 1.0-3.0 mg/dl

Screening/Enrollment Double-blind Treatment


Irbesartan*

Control group*
Up to 5 weeks
Amlodipine*
* Adjunctive antihypertensive therapies (excluding
ACE Minimum follow-up:
inhibitors, angiotensin II receptor antagonists, approximately 2 years
and
calcium channel blockers) could be added to all (average follow-up 2.6 years)
groups to help achieve equal blood pressure
levels.

Lewis EJ et al. N Engl J Med 2001;345:851-860.


IDNT Baseline Characteristics*
Irbesartan Amlodipine Placebo
Group Group Group
n=579 n=567 n=569
Mean age (yrs) 59.3 59.1 58.3
Male (%) 65 63 71
Mean Systolic BP (mmHg) 160 159 158
Mean Diastolic BP (mmHg) 87 87 87
Mean BMI (kg/m2) 31.0 30.9 30.5
Median urinary albumin
excretion (g/24hr) 1.9 1.9 1.9
Mean serum creatinine (mg/dl) 1.67 1.65 1.69
Mean glycosylated hemoglobin (%) 8.1 8.2 8.2

*The differences between the treatment groups were not statistically significant,
except for the smaller number of females in the placebo group (P=0.02)

Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.


IDNT Average Systolic, Mean Arterial and
Diastolic Blood Pressures
160
150 Systolic
140
Blood pressure (mmHg)

130
120 Irbesartan
110 Mean Arterial Pressure Amlodipine
(P=0.001 for both treatment groups compared to Placebo
100
placebo for visits after baseline)
90
80
Diastolic
70

0 6 12 18 24 30 36 42 48 54
Months of Follow-up
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
©2001 Massachusetts Medical Society. All rights reserved.
IDNT Primary Endpoint :Time to Doubling of Serum
Creatinine, ESRD, or Death

70
Irbesartan
RRR 23%
60 P=0.006
RRR 20%
Amlodipine P=0.02
50 P=NS

Control
Subjects
(%) 40

30

20
Primary Composite
10
end point
0
0 6 12 18 24 30 36 42 48 54 60
Lewis EJ et al. N Engl J Med 2001;345:851-860. Follow-up (mo)
IDNT : Primary Endpoint
Primary Endpoint = Doubling Creatinine, ESRD, orall cause mortality
50
-23%
Composite

-20% (p=0.006)
Patients Reaching Primary

(p=0.02)
40
Outcome (%)

30

20

10

0
Placebo Irbesartan Amlodipine
(n=569) (n=579) (n=567)

Lewis EJ et al. N Engl J Med 2001;345:851-860.


IDNT
Doubling Serum Creatinine
70

Irbesartan
60 RRR 37%
P<0.001 RRR 33%
Amlodipine P=0.003
50 P=NS

Subject 40 Control
s (%)
30

20

10

0
0 6 12 18 24 30 36 42 48 54 60

Lewis EJ et al. N Engl J Med 2001;345:851-860. Follow-up (mo)


IDNT
Time to ESRD
40

Irbesartan
RRR 23%
30 Control +
P=0.04

Subjects amlodipine
(%)
20

10

0
0 6 12 18 24 30 36 42 48 54 60
Follow-up (mo)
Data on file, Bristol-Myers Squibb and Sanofi-
Synthelabo.
IDNT
Time to CHF
30
Irbesartan
RRR 37%
P<0.001
Amlodipin RRR 23%
P=0.15
e
20
Subjects Control
(%)

10

0
0 6 12 18 24 30 36 42 48 54 60

Follow-up (mo)
Lewis EJ et al. N Engl J Med 2001;345:851-860.
Data on file, Bristol-Myers Squibb and Sanofi-
Synthelabo.
IDNT
Summary
Irbesartan successfully reduced the risk of
progression of renal disease and total mortality,
independent of its blood pressure-lowering
effects
– 20% reduction in the primary endpoint vs. control
– 23% reduction vs. amlodipine, despite similar BP
reduction

Irbesartan was generally safe and well


tolerated

Lewis EJ et al. N Engl J Med 2001;345:851-860.


PRIME
Conclusions
• PRIME is a comprehensive morbidity and/or
mortality program in hypertensive patients with type
2 diabetes
– In IRMA 2, irbesartan prevents or slows the
progression to overt nephropathy in early stage
diabetic renal disease
– In IDNT, irbesartan protects against further renal
disease progression and death in later stages of
diabetic renal disease
• The renoprotective effects of irbesartan are above
and beyond its effect on systemic blood pressure
Parving H-H, et al. N Engl J Med 2001;345:870-878.
Lewis EJ et al. N Engl J Med 2001;345:851-860.
PRIME
Clinical Impact
• Treating 10 hypertensive patients with type 2
diabetes and microalbuminuria with irbesartan 300
mg for 2 years would prevent one patient from
developing overt diabetic nephropathy within 2
years
• Treating 15 hypertensive patients with type 2
diabetes and proteinuria with irbesartan for 3 years
would prevent one patient from developing a
doubling of serum creatinine, ESRD or death within
3 years
Summary
• The earliest sign of renal involvement
in diabetic patients  Microalbuminuria
• 90 % Incipient diabetic nephropathy 
Hypertension
• Hypertension accelerate develop &
progression diabetic nephropathy.
Summary
• Irbesartan  diabetic hypertension +
microalbuminuria (early intervention) –
overt nephropathy (late intervention):
Incidence ESRD decrease
Prolong of life
Saving of money
…leads to adult obesity
Discussion
In many tipe-2 diabetes mellitus patients (>50%),
microalbuminuria does not represent a real incipient
diabetic nephropathy, but only the presence of an
increased CV risk.

Treatment of irbesartan should be considered as an


integral component of the overall therapy required for
CV protection.
Table 2. Several principles applicable to clinical practice can be derived
from studies of irbesartan, in patients with diabetes (1)

• Patients with type 2 diabetes should be screened for


microalbuminuria at the time of diabetes diagnosis
and annually thereafter as per ADA guidelines
• Screening for microalbuminuria is very important for the
following reasons:
• Microalbuminuria has a prevalence rate of 30 to 40% in patients with
diabetes.
• Microalbuminuria is an indicator of vascular injury.
• Microalbuminuria progresses within 5 to 10 years to overt proteinuria in
50% of patients with type 2 diabetes.
• Progression to overt proteinuria can be reduced by 70% with 300mg of
irbesartan.
Table 2. Several principles applicable to clinical practice can be derived
from studies of irbesartan, in patients with diabetes (2)

• Irbesartan has already proven effective for the treatment of


hypertension in patients with type 2 diabetes. Irbesartan has
been shown to be effective as a treatment for patients with renal
disease as well.
• The PRIME studies have increased the knowledge of how best
to treat diabetic nephropathy or with microalbuminuria while
optimally treating hypertension. Recall that IDNT, irbesartan
achieved a 23% risk reduction compared with amlodipine on the
primary endpoint; the composite of :
• time to a doubling of the baseline serum creatinine level (DSC),
• the onset of ESRD,
• death from any cause.
Table 2. Several principles applicable to clinical practice can be derived
from studies of irbesartan, in patients with diabetes (3)

• Irbesartan has demonstrated therapeutic value at any stage of


renal disease in patients with diabetes.
• Clinicians should routinely consider treatment with irbesartan when
patients present with diabetic nephropathy or with microalbuminuria.
• Irbesartan should be used by clinicians as first-line option in the
treatment of diabetic nephropathy.
• AIIRAs are safe and well-tolerated therapy the treatment of
diabetic nephropathy, and irbesartan has been shown to have
superior efficacy and persistence as compared to other AIIRAs.
• Irbesartan, in the treatment of diabetic nephropathy, was
independent of blood pressure lowering.
Table 2. Several principles applicable to clinical practice can be derived
from studies of irbesartan, in patients with diabetes (4)

• Irbesartan, in the treatment of diabetic nephropathy, was


independent of blood pressure lowering.
• AIIRAs, such as irbesartan, have value beyond being an anti-
hypertensive.
• The AIIRA, irbesartan could be used in the treatment of diabetic
nephropathy regardless of any concomitant hypertension.
• The PRIME studies highlight the discrepancy between
recommendations and reality in diabetic nephropathy treatment.
• AIIRAs may help to combat the growing trend that shows
diabetic nephropathy to be on the increase, globally.
• The PRIME results have important health economic implications
implying that increased AIIRA use will bring massive savings to
society-cost savings of $ 2.5 billion within 3 years.
FERDINANDO C. SASSO, et al., Diabetes Care 25:1909–1913, 2002
OBJECTIVE—

• ACE-is delay the progression from incipient to overt


diabetic nephropathy and reduce albumin excretion
rate (AER), independently of blood pressure.

• A-II type 1 receptor antagonists produce similar


effects on MAU and mean arterial pressure.

• The aim of this study was to evaluate the effect of


irbesartan on MAU and blood pressure in
hypertensive and normotensive type 2 diabetic
patients.
RESEARCH DESIGN AND METHODS—

• Sixty-four MAU hypertensive (group 1) and 60 MAU


normotensive (group 2) type 2 diabetic male
patients, matched for age, BMI, HbA1c, and
diabetes duration, were enrolled.

• Each group was divided into two subgroups


receiving either irbesartan (150 mg b.i.d. orally) or
placebo for 60 days.

• After 15 days of washout, irbesartan was given to


the subgroups who had received the placebo, and
vice versa, in a randomized double-blind crossover
study.
ADA Guidelines
Patients with type 2 diabetes
should be screened for
microalbumin uria at the time of
diabetes diagnosis and
annually thereafter
The 24-h mean systolic BP in Diabetic patients
In hypertensive,
was significantly reduced (P<0.01) at the end of irbesartan:
• Subgroup 1, irbesartan 15 mmHg, placebo 1 mmHg,
• Subgroup 2, irbesartan 12 mmHg, placebo 2 mmHg.

In normotensive,
• Subgroup 1, irbesartan 6 mmHg, placebo 3 mmHg,
• Subgroup 2, irbesartan 1 mmHg, placebo 3 mmHg.

The 24-h mean diastolic BP in Diabetic patients


In hypertensive,
was significantly reduced (P<0.01) at the end of irbesartan:
• Subgroup 1, irbesartan 6 mmHg, placebo 1 mmHg,
• Subgroup 2, irbesartan 7 mmHg, placebo 1 mmHg.

In normotensive,
• Subgroup 1, irbesartan 1 mmHg, placebo 1 mmHg,
• Subgroup 2, irbesartan 1 mmHg, placebo 0 mmHg.
Figure 2—AER in the two subgroups of normotensive (A) and hypertensive (B)
diabetic subjects. *P<0.01.
RESULTS—
Of the 124 patients were randomized. AER was significantly reduced (P<0.01)
in :
• Hypertensive
• in subgroup 1, irbesartan 36 g/min, placebo 5 g/min,
• in subgroup 2, irbesartan 35 g/min, placebo 3 g/min.
• Normotensive
• in subgroup 1, irbesartan 31 g/min, placebo 2 g/min,
• in subgroup 2, irbesartan 40 g/min, placebo 5 g/min.
RESULTS—

• In MAU hypertensive type 2 diabetic subjects,


irbesartan reduced 24-h mean systolic and diastolic
pressure and AER.
• In MAU normotensive type 2 diabetic patients,
irbesartan reduced AER.

CONCLUSIONS—

• These results indicate the beneficial effects of


irbesartan on AER in type 2 diabetic subjects,
independently of its antihypertensive effects.
Irbesartan, selective blockade of the A-II type 1
receptor :
• Comparable to ACE-Is in lowering BP and MAU.
• The beneficial effect :
• of blocking A-II generated by non–ACE pathways
• without altering either bradykinin metabolism
• the potential beneficial effects of AT2 receptor
stimulation.
• AT2 receptor stimulation causes
vasodilatation, inhibits cell proliferation, and
promotes cell differentiation through
production of : bradykinin, NO, and cGMP.
Irbesartan, selective blockade of the A-II type 1
receptor :
• Has double antiproliferative effect, both direct AT1
receptor– mediated and indirect AT2 receptor–
mediated AT1-RAs could protect against mesangial
expansion.
• Moreover, irbesartan seems to decrease AER even
in a prehypertensive phase.
• The effect of irbesartan on MAU, even in
normotensive type 2 diabetic subjects, suggests that
the nephroprotection brought about by AT1-RA
could be caused by the direct action on renal
hemodynamics and glomerular morphology.
Potential Impact of IRBESARTAN on
“Real Life Clinical Practice”

• IDNT was powered for renal primary endpoints


• IDNT was not powered for composite CV secondary endpoint or its
components
• Compared to amlodipine or other antihypertensive therapies, irbesartan was
shown to provide superior renoprotection and comparable
cardiovascular protection benefits
• The renoprotective benefits, shown to be independent of blood pressure,
were statistically significantly superior to either amlodipine based or
“placebo” treatments,
• Irbesartan is the clear choice as the treatment of greatest benefit in type 2
hypertensive diabetics
Selecting an appropriate
drug is more important
than lowering blood
pressure per se.

Thank you
Impact of Blood Pressure Reduction
on Mortality in Diabetes
Trial Conventional Intensive Risk P-value
care care reduction
UKPDS 154/87 144/82 32% 0.019

HOT 144/85 140/81 66% 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.
Chronic Renal Disease:
Initial Treatment Recommendations

Renal Insufficiency
Clcr <60 mL/min ≥ 130/80
CrSerum >1.4 mg/dL*
ACE Inhibitor
or ARB
Microalbuminuria Start
(only Abnormality) ≥ 130/80 And
Titrate
To Maximum
Proteinuria Tolerable
Dose

Diabetes Mellitus
*for women, CRSerum >1.2 mg/dL
PRIME
Objectives
• IRMA 2
– To determine whether irbesartan can prevent or slow
the progression from microalbuminuria to overt
nephropathy in patients at an early stage of type 2
diabetic renal disease

• IDNT
– To compare the effects of irbesartan, amlodipine, and
a control group on renal disease progression, total
mortality, and cardiovascular morbidity in patients at a
later stage of type 2 diabetic renal disease