Presentation developed by the International Society on Hypertension in Blacks, Inc ISHIB Atlanta, GA

1

Hypertension in the Metabolic Syndrome Elijah
Saunders,M.D.,FACC,FACP Professor of
Medicine(Cardiology) Head,Section of
Hypertension University of Maryland School of
Medicine
2
National Cholesterol Education Program Clinical
Identification of the Metabolic Syndrome
RISK FACTOR DEFINING MEASURES Abdominal
obesity Waist circumference Men gt40
in (gt102 cm) Women gt35 in (gt88
cm) Triglycerides ³150 mg/dL HDL-C
Men lt40 mg/dL HDL-C Women lt50 mg/dL Blood
pressure ³130/³85 mm Hg Fasting
glucose ³110 mg/dL
³3 Risk factors comprise the metabolic syndrome.
ICD-9 Code 277.7
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA. 2001. 2852486-2497.
3
Prevalence of the Metabolic SyndromeAccording to
the NCEP DefinitionNHANES III by Sex and
Race/Ethnicity
of Subjects
Ford ES, et al. JAMA. 2002287356-9
4
Metabolic Syndrome and Obesity Therapeutic and
Practical Approaches
The INTERPLAY BETWEEN HEMODYNAMICS AND METABOLIC
SYNDROME IN THE GENESIS AND TREATMENT OF
HYPERTENSION
5
NHLBI Workshop on Metabolic Risk Factor
Clustering Syndrome
definite factors in the syndrome

• Elevated triglyceride
• Reduced HDL
• Abdominal obesity
• Hyperinsulinemia

6
Factor Clustering Syndrome
possible contributors

• Elevated uric acid
• Hypertension
• Elevated PAI-1
• Hyperdymnamic circulation
• Elevated Apo B
• Elevated small dense LDL
• Total and LDL-cholesterol not associated

7
Hypertension Lipid Connection in Diabetes
Hypertension
Dyslipidemia
Diabetes
Ang II
LDL-C
Endothelial Dysfunction
Atherosclerotic Vascular Disease
8
Adapted from Johnstone MT, et al. Circulation.
1993882510-2516
9
Obesity Augments Renal Sodium Reabsorption,
Expands Plasma Volume, and Centralizes Blood
Volume While Also Causing Salt-Sensitivity
OBESITY
? Tubular Flow
? RAS Activity
? SNS Tone
? NO
Rightward Shift of Pressure-Natriuresis Curve
Steady-state In-out Na Homeostasis _at_ Higher
Volume or Salt Sensitivity
10
Expansion of ECFV and Attenuation of BP Response
? Venous capacitance
Ad libitum Na intake
Diet
Drug
BP agent
? RenalNa retention

• Prevention of PV
• expansion during antihypertensive drug
• therapy is key to maintaining BP response

? BP
ExpandedECFV/PV

• ECFVextracellular fluid volume, PVplasma volume.

11
CV Mortality in Microalbuminuria and Proteinuria
1.0
0.8
Normoalbuminuria
0.6
Microalbuminuria
Proportion Surviving
0.4
0.2
Gross proteinuria
2
4
6
8
10
12
0
Years of Follow-up
Log-rank test P lt.001 Valmadrid CT et al. Arch
Intern Med. 20001601093-1100.
12
Microalbuminuria/Proteinuria Associated With
Increased Risk For CV Mortality in Type 2
Diabetics
Normalbuminuria
Microalbuminuria
Proteinuria
4
3.85
3
3.28
3.05
Relative Risk of Death
2.45
2.39
2
1.97
1
1
1
1
0
Death due to CHD
Death due to Stroke
Death due to All CV Causes
Heart disease, Ischemic heart disease, Heart
failure, and/or Cerebrovascular
disease Normoalbuminuria (n460) lt30mg/L
Microalbuminuria (n208) gt30mg/L Proteinuria
(n172) gt300mg/L) Adapted from Valmadrid CT et
al. Arch Intern Med. 20001601093-1100.
13
Cardiovascular Risk Factors Associated with
Microalbuminuria

• Insulin resistance
• Low HDL cholesterol and high TG levels
• Systolic hypertension
• Increased CV oxidative stress
• Impaired endothelial function
• Abnormal coagulation
• Central obesity salt sensitivity male sex
• Absent nocturnal drop in BP

Sowers J et al. Hypertension. 2001 371053-1059.
14
mm Hg Above JNC VI BP Goal in Metabolic Syndrome
Hypertensives
Systolic
Diastolic
Combined glucose and lipid abnormalities
(CGLA)TGs ? 150HDL-C lt40 (men) lt50
(women)Serum glucose ? 110BP ? 130/85
15
Time (days) to BP Control in Hypertensives With
CGLA versus No-CGLA

• CGLA hypertensives
• 79 attained SBP and 83 attained JNC VI DBP goal
• SBP goal attained with 4 drugs (versus 3 in
  non-CGLA HTN)
• DBP goal attained with 3.5 drugs in CGLA versus
  3.2 drugs in non-CGLA HTN
• Time to goal BP differences were p lt 0.016 for
  both contrasts

Billakanty S, Dudley A, Nasser S, Shafi T, Flack
JM. WSU Hypertension Ctr Data
16
Blood Pressure and Proteinuria Relationship
Albuminuria
Normal (n110)
Micro- (n41)
Macro- (n21)
P-value
Blood Pressure, mm Hg
162.5 99.3 23.9 10.0 79.2
168.3 102.4 30.0 13.2 71.8
178.1 99.3 42.6 12.0 47.7
0.01 0.50 0.002 0.44 lt0.001
Systolic blood pressure Diastolic blood
pressure Distance from JNC VI goal SBP DBP EGFR,
ml/min/1.73m2
Normal- (lt30 mg/g crea) Micro- (30-300 mg/g
crea) Macro- (gt300 mg/g crea).Duncan K, Ohmit
S, Ramappa P, et al. (manuscript in preparation).
17
Influence of Albuminuria on Systolic Blood
PressureResponse, WSU Hypertension Clinic
Albuminuria
MACRO
MICRO
NONE
mm Hg
After adjustment for age, sex, race, and baseline
BP level.
18
Differences in Selected Pretreatment
Characteristics Amongst Hypertensives with
Diabetes
BP lt 130 / 85, mm Hg
NO 35.5 1.45 63.4 607
YES 34.8 1.16 74.7 82.4
BMI, kg/m2 Crea, mg/dl EGFR, ml/min/1.73m2 Urine
Albumin/Crea, mg/g Crea
19
Metabolic Syndrome and Obesity Therapeutic and
Practical Approaches
In hypertension treatment prevention of the
volume expansion during drug treatment (e.g.,
ACEI,ARBs,Aldosterone antagonists) when sodium
intake is high and the forces augmenting renal
sodium reabsorption are also high (e.g.,
obesity,metabolic syndrome) are both absolutely
essential that is, if you want to control BP
20
Hypertension Treatment and Control Rates in the
U.S. Population by Race/Ethnicity, NHANES III 2000

Hajjar and Kotchen. JAMA 2003290199-206.
21
Minimum Therapeutic BP Goals JNC 7 Criteria

• Diabetes and/or renal insufficiency
• All other hypertensives

lt130/85 lt140/90
22
Hypertension Awareness, Treatment and Control
Rates Amongst Persons with Diabetes NHANES III

Aware
On Treatment
lt 130 / 85
lt140 / 90
Controlled
Geiss LS, et al. Am J Prev Med 2002 22(1) 42-48.
23
ISHIB Recommended Goal BP Levels
mm Hg
Control
lt 130 / 80 lt 140 / 90 lt 130 / 80 lt 130 / 80
Diabetes Non-diabetic kidney disease
(proteinuria lt1 g/d) Non-diabetic kidney disease
(proteinuria ?1 g/d) High-risk1 hypertensives
Adapted from Douglas JG et al. Arch Intern Med
2003163525-541. 1 history of CVD event, stroke,
TIA, evidence of target-organ damage (e.g., LVH,
microalbuminuria), CHD, or high-risk for CHD
(e.g., metabolic syndrome)
24
Systolic Blood Pressure is Less Often Controlled
Than Diastolic Blood Pressure Framingham Heart
Study (1990-95)N1959 HypertensivesAverage
Age66 years 54 Women
All Hypertensives
Hypertensives on Treatment (N1189, 60.7)

Controlled to Goal
SBP
DBP
Both
SBP
DBP
Both
Lloyd-Jones DM, Evans JC, Larsen, MG, et al.
Hypertension 200036(4)594-599.
25
Management of HTNNew England VA Study (N800)

• If DBP ?90 mm Hg and SBP ?155 mm Hg, medications
  ? 26 of time
• If DBP ?90 mm Hg and SBP ?165 mm Hg,medications
  ? 22 of time
• Patients with poorly controlled BP seen more
  often
• Patients who received more therapy achieved
  better control

Berlowitz et al. N Engl J Med. 19983391957.
26
Important Clinical Barriers to BP Control

• Suboptimal drug combinations
• Physiologic
• obesity/metabolic syndrome
• proteinuria
• excess dietary sodium
• ETOH
• Secondary hypertension
• sleep apnea
• renal parenchymal disease
• mineralocorticoid hypertension
• renovascular hypertension

• Overuse of monotherapy
• Polypharmacy
• Perceived side effects
• Misuse of diuretics
• Concurrent medications
• NSAIDs (low GFR)
• cyclosporine
• sympathomimetics

27
HOT Significant Benefit From Intensive
Antihypertensive Treatment in Diabetes
25
20
15
P.005 for trend
Major CV Events/1000 Patient-yrs in
Hypertensive Patients with Diabetes
10
5
0
?90
?85
?80
Target DBP (mm Hg)
Defined as fatal and nonfatal MI, fatal and
nonfatal stroke, and all other CV death.
Adapted from Hansson L et al. Lancet.
19983511755-1762.
28
Consensus Statement Management of High BP in
African Americans
Patient with elevated BP
Uncomplicated hypertensionGoal BP lt140/90 mm Hg
Diabetes/nondiabetic renal disease with
proteinuria gt1 g/24 hGoal BP lt130/80 mm Hg
If BP lt155/100 mm Hg, monotherapy
If BP ?155/100 mmHg, combination therapy
If BP lt145/90 mm Hg, monotherapy or combination
therapy including a RAS blocker
If BP ?145/90 mm Hg, combination therapy
including a RAS blocker
Not at BP goal?Intensify lifestyle changes AND
Not at BP goal?Intensify lifestyle changes AND
Add a 2nd agent from a different class
orincrease dose
Increase doseor add a 3rd agentfrom a different
class
Add a 2nd agent from a different class
orincrease dose
Increase doseor add a 3rd agentfrom a different
class
RAS, renin-angiotensin system. Preferable BP
goal for patients with renal disease with
proteinuria gt1 g/24 h is lt125/75 mm Hg. Initiate
monotherapy at the recommended starting dose with
an agent from any of the following classes
diuretics, beta blockers,calcium channel
blockers (CCBs), angiotensin-converting enzyme
(ACE) inhibitors, or angiotensin II receptor
blockers (ARBs). To achieve BP goals more
expeditiously, initiate low-dose combination
therapy with any of the following combinations
beta blocker/diuretic,ACE inhibitor/diuretic,
ACE inhibitor/CCB, or ARB/diuretic. Consider
specific clinical indications when selecting
agents. Douglas J et al. Arch Intern Med.
200316525-541.
29
Relative Risk of New Diabetes
Unadjusted Hazard Ratios with 95 CI
Verapamil SR Strategy
HR
CI confidence interval HR hazard ratio
30
Background Antihypertensive Medicine and Risk of
Diabetes
31
IRMA 2 Clinical Outcome Measures

• Primary outcome
• Time to occurrence of overt proteinuria
• (UAER gt200 ?g/min)
• Secondary outcomes
• Change in UAER
• Regression to normoalbuminuria (UAER lt20
  ?g/min)
• Change in creatinine clearance
• Clotting factors and lipid profile

UAER, urinary albumin excretion rate. Parving H-H
et al. N Engl J Med. 2001345870-878.
32
IRMA 2 Normalization of UAER
P.006
34
24
21
Patients ()
Control(n201)
150 mg/d (n195)
300 mg/d (n194)
UAER, urinary albumin excretion rate.
Control defined as placebo. Normoalbuminuria
defined as UAER of lt20 ?g/min. Adjunctive
antihypertensive therapies (excluding ACE
inhibitors, ARBs, and dihydropyridine CCBs)
could be added to all groups to help achieve
target BP levels. Parving H-H et al. N Engl J
Med. 2001345870-878.
Irbesartan
33
IRMA 2 Summary

• The renal benefits of irbesartan are independent
  of its BP-lowering effects1
• 70 risk reduction in the progression from
  microalbuminuria to overt diabetic
  nephropathywith irbesartan 300 mg/d vs control
  (Plt.001)1
• More frequent restoration of
  normoalbuminuria with
• Irbesartan 300 mg/d vs control (P.006)1
• Irbesartan is safe and well tolerated2
• Fewer nonfatal CV events, serious AEs, and
  
• discontinuations due to AEs in the
  irbesartan groups2

AE, adverse event. 1. Parving H-H et al. N
Engl J Med. 2001345870-878. 2. Data on file,
Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.
34
Optimal Utilization of Diuretics

• Usually necessary to use when gt 2 non-diuretic
  drugs have been prescribed
• Monitor potassium closely if potassium sparing
  diuretics are used in persons taking ACEI, ARBs,
  potassium supplements
• In refractory, overweight patients with preserved
  kidney function consider adding an aldosterone
  antagonist as second diuretic
• Must know the level of kidney function
• EGFR lt mid 40s use loop diuretic or metolazone
• if furosemide used, needs to be dosed at least
  twice daily
• conventional thiazide doses are likely to be
  ineffective though higher doses 50 - 100 mg/d may
  work
• EGFR gt mid 40s use thiazide diuretic (can use
  metolazone)
• loop diuretics not as effective as thiazides in
  this setting

35
Suggested Therapeutic Approach to Hypertension in
the Metabolic Syndrome

• Most patients will need more than one drug and
  combination therapy should be considered
  initially
• Use low-dose diuretics or avoid diuretics and
  betablockers(except for compelling
  indications)when BP control can be achieved,in
  regimens with 2 or less drugs

36
Suggested Therapeutic Approach(contd)

• When diuretics are necessary to control BP
• Consider aldosterone antagonists if renal
  function is preserved or hyperkalemia is not a
  problem
• Use renin angiotensin system blockers(ACEIs,ARBs
  ) to blunt hypokalemia,glucose intolerance,and
  dysmetabolism

37
SUMMARY
Hypertension is more than just elevated blood
pressure. Markers of this vascular abnormality
can be found in early childhood. During
adolescence, the acquisition of adiposity results
in the association of hypertension with multiple
risks factors(metabolic syndrome) for CAD.
Jamerson 2001
38
Conclusions

• The frequent association between hypertension and
  multiple risk for CVD is more than a chance
  finding.
• Metabolic Syndrome 60 more common than
  diabetes
• Subjects with metabolic syndrome but without DM
  deserves special attention