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RisKesDas 2007
Diabetic nephropathy is the leading cause of ESRD
Diabetes
160
Hypertension
Incidence per million population
140 Glomerulonephritis
Cystic kidney
120
100
80
60
40
20
0
1980 1985 1990 1995 2000
Year
Brewster, Perazella. Am J Med 2004; 116:263-272
The Continuum of Diseases
Diabetes Diabetes
Hypertension Increase Risk Hypertension
Hyperlipidemia Hyperlipidemia
Majority of Hypertensive Patients Not at SBP Goal of
<140 mm Hg: Goal Gap
14.0
12.0
10.0
Population 8.0
(millions)
6.0
73% NOT
4.0 MEETING
GOAL
2.0
0.0
91–100
131–140
231–240
141–150
151–160
161–170
171–180
181–190
241–250
121–130
111–120
221–230
191–200
201–210
101–110
81–90
211–220
SBP Range (mm Hg)
SBP = Systolic Blood Pressure
Adapted from Whyte JL et al. J Clin Hypertens. 2001;3:211-216.
JNC 7: CVD Risk Factors
• Hypertension*
• Cigarette smoking
• Obesity* (BMI >30 kg/m2)
• Physical inactivity
• Dyslipidemia*
• Diabetes mellitus*
• Microalbuminuria
• estimated GFR <60 ml/min
• Age (older than 55 for men, 65 for women)
• Family history of premature CVD
(men under age 55 or women under age 65)
*Components of the metabolic syndrome.
JAMA 2003:289:2560
Adapted from Dzau V, et al.
Am Heart J. 1991;2(4 pt
1):1244-1263.
Identifiable Causes of Hypertension
Sleep apnea
Drug-induced or related causes
Chronic kidney disease
Primary aldosteronism
Renovascular disease
Chronic steroid therapy and Cushing’s syndrome
Pheochromocytoma
Coarctation of the aorta
Thyroid or parathyroid disease
JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314
Causal Factors for Hypertension
Hypertension 2003;289:2560-2572.
Endothelial cells
Angiotensinogen Angiotensin II
Blood
vessel
Aldosteron
Angiotensin I ACE
Renin
Kininogen Angiotensinogen
kallikrein renin
endopeptides
BKB receptor
Ang (1 – 7)
Inactive
Vasodilation peptides
NO
ACE
prostaglandins
A (1-7)
EDHF receptor
Inactive
tPA AT1 AT2 AT3 AT4 Peptides
receptors receptors receptors receptors
Vasodilation
Antiproliferation
Oxidation Vasodilation ? Vascular
Vasoconstriction Antiproliferation integrity
Proliferation Apoptasis
Matrix Formation
PAI-1
Aldosterone Prolong stimulation
Secretion leads to deleterious
effects
Angiotensin II Plays a Central Role in Organ Damage
Atherosclerosis* Stroke
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction Hypertension
LV hypertrophy
A II Fibrosis
Remodeling Heart failure DEATH
Apoptosis MI
GFR
Proteinuria
Renal failure
Aldosterone release
Glomerular sclerosis
*preclinical data
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 9971008, Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37S44, Daugherty A et al J Clin
Invest 2000; 105(11): 16051612, Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19S24, Booz GW, Baker KM Heart Fail Rev 1998; 3: 125130,
Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999:
16821704, Anderson S Exp Nephrol 1996; 4(suppl 1): 3440, Fogo AB Am J Kidney Dis 2000; 35(2):179188 18
Algorithm for Treatment of Hypertension
Lifestyle Modifications
Stage 1 HTN (SBP 140–159 or Stage 2 HTN (SBP >160 or DBP Drug(s) for the compelling
DBP 90–99 mmHg) >100 mmHg) indications
Thiazide-type diuretics for most. 2-drug combination for most Other antihypertensive drugs
May consider ACEI, ARB, BB, (usually thiazide-type diuretic and (diuretics, ACEI, ARB, BB, CCB)
CCB, or combination. ACEI, or ARB, or BB, or CCB) as needed.
Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
Moderation of alcohol
2-4 mmHg
consumption
JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314
The Diabetes Epidemic
38.2
44.2
16% 81.8
25.0 156.1
39.7 91%
59%
18.2
35.9
13.6 97%
26.9
10.4 98%
19.7
1.1
88%
1.7
59%
350
300
Glucose
200
150
100 Fasting Glucose
50
Relative Function
250
200 Insulin Resistance
%
150
100
50 Insulin Level
Beta cell failure
0
-10 -5 0 5 10 15 20 25 30
Years of Diabetes
Adapted from R.M. Bergenstal, International Diabetes Center
Association of Systolic Blood Pressure (SBP) and CV
Death in Type 2 Diabetes
250
225 No diabetes
(deaths/10,000 person-years)
Diabetes
200
175
CV Mortality
150
125
100
75
50
25
0
120 120–139 140–159 160–179 180–199 200
Functional changes*
Structural changes*
Microalbuminuria
Proteinuria
Cadiovascular death
Onset of diabetes 2 5 10 20 30
Years
* Renal hemodynamics altered, glomerular hyperfiltration.
† Glomerular basement membrane thickening ,
Angiotensin II receptor
blockers
Activation Blockade
PPAR-γ Angiotensin
pathways pathways
Dyslipidemia Hypertension
Inhibition of
atherosclerosis
Kurtz TW, Pravenec M. J Hypertens 2004;22: 2253
• JNC 8 or the 2014 Evidence-Based Guideline for the Management
of High Blood Pressure in Adults was released in December
• James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for the management of
high blood pressure in adults: Report from the panel members appointed to the Eighth Joint
National Committee (JNC 8). JAMA 2014; DOI:10.1001/jama.2013.284427. Available at:
http://jama.jamanetwork.com/journal.aspx
Angiotensinogen Angiotensin II
Blood
vessel
Aldosteron
Angiotensin I ACE
Renin
Kininogen Angiotensinogen
kallikrein renin
endopeptides
BKB receptor
Ang (1 – 7)
Inactive
peptides
Ang II
Vasodilation
NO
ACE
prostaglandins
A (1-7)
EDHF receptor
Inactive
tPA AT1 AT2 AT3 AT4 Peptides
receptors receptors receptors receptors
Vasodilation
Antiproliferation
Oxidation Vasodilation ? Vascular
Vasoconstriction Antiproliferation Integrity
Proliferation Apoptasis
Matrix Formation
Aldosterone Prolong stimulation PAI-1
Secretion leads to deleterious
effects
AT1R-Blockade and Insulin Sensitivity
Irbesartan
increased
Glucose uptake
in skeletal
muscle
Placebo
n = 201
Irbesartan 150 mg
n = 195
Irbesartan 300 mg
n = 194
0
0 3 6 12 18 22 24
Follow-up (months)
RRR=70%
p<0.001
18 RRR=39%
p=0.08
16 14.9
14
Subjects with 12
Overt 9.7
10
Proteinuria
(%) 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: 870–8.
IRMA-2 Results: Irbesartan Normalizes Urinary Albumin
Excretion
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: 870–8.
IRMA-2: Early Use of Irbesartan is Renoprotective in Hypertensive
Type 2 Diabetes Patients with Microalbuminuria
Irbesartan*
Screening/Enrollment n = 579
Placebo*
n = 569
Up to 5 weeks
Amlodipine*
n = 567
Minimum follow-up:
approximately 2 years
(average 3 years)
* Adjunctive antihypertensive therapies (excluding ACE
inhibitors, angiotensin II receptor antagonists, and calcium
channel blockers) added to each arm to achieve equal
blood pressure reduction Lewis EJ et al. N Engl J Med 2001; 345: 851–860.
IDNT: Irbesartan Produces A Consistent Blood
Pressure Response
160 Irbesartan
Amlodipine
SBP Control
140
BP
(mm Hg) 120 Patients received 3.0 concomitant
antihypertensive agents in the irbesartan
and amlodipine groups, and 3.3
Mean concomitant agents in the control group.
100
DBP
80
0 6 12 18 24 30 36 42 48 54
Control
Subjects 40 n = 567
(%)
30
20
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.
IDNT Results: Irbesartan Significantly Reduces the
Time to ESRD
40
Irbesartan
n = 579
RRR 23%
n = 567
30 Control +
p=0.04
Subjects amlodipine
n = 569
(%)
20
10
0
0 6 12 18 24 30 36 42 48 54 60
Follow-up (months)
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Follow-up time (months)
Lewis EJ et al. N Engl J Med 2001; 345: 851–860.
SUMMARY
Lower is better and Earlier is better
Clinical benefits occur in patients with hypertension when BP
is lowered to optimal levels.