Hypertension in the Metabolic Syndrome

1
Hypertension in the Metabolic Syndrome

• Thomas D. Giles, M.D.
• LSU Medical School
• New Orleans, LA

2
More Than 80 of Hypertensive Patients Have
Additional Comorbidities
Men
Women

• Comorbidities
• Obesity
• Glucose intolerance
• Hyperinsulinemia
• Reduced HDL-C
• Elevated LDL-C
• Elevated TG
• LVH

One 26
Two 25
Two 24
One 27
Three 20
Three 22
None 17
None 19
Four 12
Four 8
gt50 have 2 or more comorbidities
HDL-C, high-density lipoprotein cholesterol
LDL-C, low-density lipoprotein cholesterol LVH,
left ventricular hypertrophy TG,
triglycerides.Kannel WB. Am J Hypertens.
2000133S-10S.
3
Diabetes, Obesity, and the Metabolic Syndrome Are
Prevalent ComorbiditiesAmong Hypertensive
Patients

• Hypertension is usually accompanied by other CV
  risk factors, including obesity, glucose
  intolerance, hyperinsulinemia, high LDL-C, and
  LVH
• Assessment of CV risk in the hypertensive patient
  is based upon the presence of other CV risk
  factors in addition to BP levels

Kannel WB. Am J Hypertens. 2000133S-10S.
Diabetes and Cardiovascular Disease Review.
2002Issue 2. International Obesity Task Force
Web site. www.obesite.chaire.ulaval.ca/iotf.htm Ca
meron AJ et al. Endocrinol Metab Clin North Am.
200433351-375. Guidelines Committee. J
Hypertens. 2003211011-1053.
4
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5
Metabolic Syndrome A Cluster of Disturbances

• Abdominal obesity
• Atherogenic dyslipidemia
• Elevated blood pressure
• Insulin resistance glucose intolerance
• Atherothrombotic factors
• Proinflammatory factors

Expert Panel. JAMA. 20012852486-2497.
6
Diagnosis of the Metabolic Syndrome
Presence of 3 of the following
Waist circumference Men Women Triglycerides HDL-
C Men Women BP Fasting glucose
gt40 inchesgt35 inches 150 mg/dL lt40 mg/dLlt50
mg/dL 130/85 mm Hg 110 mg/dL
Expert Panel. JAMA. 20012852486-2497.
7
Metabolic Syndrome Definitions Compared
Parameter WHO NCEP AACE/ACE
SBP (mm Hg) gt160 130 130
DBP (mm Hg) gt90 85 85
Triglycerides, mg/dL (mmol/L) 150 (1.7) 150 (1.7) 150 (1.7)
HDL cholesterol, mg/dL (mmol/L) Men Women lt35 (0.9) lt39 (1.0) lt40 (1.04) lt50 (1.29) lt40 (1.04) lt50 (1.29)
BMI 30 kg/m2
Waist circumference, inches (cm) Men Women gt40 inches (102) gt35 inches (88)
Waist-hip ratio Men Women gt0.9 gt0.85
Fasting glucose, mg/dL (mmol/L) 110 (6.1) or diabetes 110 (6.1) or diabetes 110-125 (6.1-6.9)
2-hour glucose (mmol/L) 140 (7.8) or diabetes 140-300 (7.8-16.7)
Microalbuminuria (UAE) 20 µg/min
BMI, body mass index HDL, high-density
lipoprotein UAE, urinary albumin
excretion. Expert Panel. JAMA. 20012852486-2497.
Einhorn D et al. Endocr Pract. 20039237-252.
Alberti KG et al. Diabet Med. 199815539-553.
8
Metabolic Syndrome
9
Role of Abdominal Adipocytes in Insulin
Resistance and Heart Disease
Abdominal Adipocytes
Liver
?Adipocytokines Fatty Acids
Insulin Resistance
Metabolic Syndrome
Heart Disease
10
Visceral AdiposityThe Critical Adipose Depot
11
The Fat Cell Is More Than a Bag of Fat
Lactate
Cholesterolester Transfer Protein (CETP)
Prostaglandin
Angiotensinogen
Phospholipid Transfer Protein (PLTP)
Prostacyclin
Fat Cell
Monobutyrin
Leptin
Free Fatty Acids
Adiponectin
Plasminogen Activator Inhibitor (PAI-1)
Galectin-12
TNF-a
Adipsin (ASP) (complement 3aD)
IL-6
Lipoprotein Lipase (LPL)
Adapted from Bray GA. Contemp Diagn Obes. 1998.
12
Fat Cell Products and Hypertension
áVisceral Fat Stores
â Hepatic Insulin Clearance
á Portal FFA
á Plasma Insulin
Vascular Constriction
á Renal Na Reabsorption
Angiotensin II
Angiotensinogen
Angiotensin I
Hypertension
Bray GA. Contemp Diagn Obes. 1998.
13
Etiology of Insulin Resistance
? Circulating FFA
Lipoatrophy, adipokines
Weight gain, obesity
Insulin Resistance
The subnormal biologic response to agiven
concentration of insulin
Physical inactivity
Genetics
Aging
Adipokines cytokines secreted by adipose tissue.
14
Pathways Insulin Resistance Syndrome and Type 2
Diabetes
Insulin Resistance
Compensatory hyperinsulinemia
Inadequate insulin response
Type 2 Diabetes
Insulin Resistance Syndrome
CVD
Retinopathy Nephropathy Neuropathy
Hypertension Stroke PCOS NAFLD
NAFLD, nonalcoholic fatty liver disease PCOS,
polycystic ovary syndrome. Einhorn D et al.
Endocr Pract. 20039237-252.
15
Hypertension

• Hyperinsulinemia can enhance renal sodium
  reabsorption and vascular reactivity
• Angiotensinogen from fat cells can increase
  angiotensin II and thus blood pressure
• Both systolic and diastolic blood pressure
  increase with increasing body mass index

16
Inflammation, Abdominal Obesity, and Smoking as
Predictors of Hypertension

• Odds ratio for developing hypertension during
  11-year follow-up in 379 middle-age normotensive
  men

Risk factor Baseline value Reference value OR (95 CI) P
CRP concentration 3.0-9.99 mg/L 0.1-0.99 mg/L 3.55 (1.74-7.23) lt0.001
Cigarettes/day 20 NA 2.38 (1.39-4.08) 0.001
Waist girth gt88.5 cm lt82.5 cm 2.32 (1.34-4.04) 0.003
CI, confidence interval CRP, C-reactive protein
NA, not applicable OR, odds ratio.Age
adjusted. Niskanen L et al. Hypertension.
200444859-865.
17
Rise in Circulating Inflammatory Markers in
Prehypertension

• Increase,
• prehypertensive vs normotensive Marker ()
  P
• CRP 31 lt0.01
• TNF-a 32 lt0.05
• Amyloid-a 9 lt0.05
• Homocysteine 6 lt0.01
• White blood cell count 10 lt0.05

CRP, C-reactive protein TNF-a, tumor necrosis
factor-a.Chrysohoou C et al. Am J Hypertens.
200417568-573.
18
Mortality Is Strongly Associated With Systolic BP
in Men With Type 2 Diabetes
250
Nondiabetic
Diabetic
200
CV
mortality
150
rate/
10,000
100
person
-
yrs
50
0
lt120
120
-
139
140
159
160
-
179
180-189
?200
-
SBP (mm Hg)
SBP, systolic blood pressure.Stamler J et al.
Diabetes Care. 199316434-444.
19
CHD Risk Based on Major Risk Factors
37
40
35
27
30
25
Men Women
Estimated 10-year rate ()
25
20
20
13
15
8
10
5
5
5
0
A
C
D
B
Risk factors Blood pressure (mm
Hg) 120/80 140/90 140/90 140/90 Total cholesterol
(mg/dL) 200 240 240 240 HDL cholesterol
(mg/dL) 50 50 40 40 Diabetes No No
Yes Yes Cigarettes No No No Yes
Wilson PWF et al. Circulation. 1998971837-1847.
American Heart Association. Heart Disease and
Stroke Statistics - 2004 Update.
20
Use of Markers for Prediction of Risk for MI
Among Healthy Middle-Aged Men
Lipoprotein(a)
Total homocysteine
TC
Fibrinogen
tPA antigen
TCHDL-C
hs-CRP
hs-CRP TCHDL-C
0
1.0
2.0
4.0
6.0
Relative risk for future MI
hs-CRP, high-sensitivity C-reactive protein MI,
myocardial infarction TC, total
cholesterol.Values based on men in the top
compared with the bottom quartile for each
marker.Ridker PM. Ann Intern Med.
1999130933-937.
21
Clinical Management of the Metabolic Syndrome
Screening

• Standard part of initial adult patient assessment
• Include measurement of waist circumference in
  physical exam
• Labs
• fasting glucose
• full fasting lipid profile
• Assess global risk of CHD
• Future may include other risk factors, eg,
  C-reactive protein, fibrinogen, and small,
  dense LDL

Wong ND. Prev Cardiol. 2005847-54.
22
Clinical Management of the Metabolic Syndrome
Main Goals

• Prevention of type 2 diabetes
• Prevention of cardiovascular disease

23
Clinical Management of the Metabolic Syndrome
NCEP Recommendations

• Primary management of the metabolic syndrome
  should be to reverse its root causes
• overweight/obesity
• physical inactivity
• In addition, lipid and nonlipid risk factors
  associated with the metabolic syndrome should be
  appropriately treated
• hypertension
• prothrombic state
• dyslipidemia

NCEP, National Cholesterol Education Program.
Expert Panel. Circulation. 20021063143-3421.
24
Clinical Management of the Metabolic Syndrome
Approaches

• Therapeutic lifestyle changes
• dietary restriction of calories, simple
  carbohydrates and saturated fats
• increased dietary fiber
• regular aerobic exercise
• weight loss
• Pharmacologic therapy
• statins
• fibrates
• ACE inhibitors/ARBs
• other agents?
• What is the evidence?

25
Clinical Management of the Metabolic Syndrome
Approaches

• Therapeutic lifestyle changes
• dietary restriction of calories, simple
  carbohydrates and saturated fats
• increased dietary fiber
• regular aerobic exercise
• weight loss
• Pharmacologic therapy
• statins
• fibrates
• ACE inhibitors/ARBs
• other agents?
• What is the evidence?

26
Lifestyle Interventions and Risk of Diabetes
Diabetes Prevention Program
70
58
60
50
Reduced incidence of diabetes ()
40
31
30
20
10
0
Lifestyle modification
Metformin
N3234 nondiabetic individuals.Diabetes
Prevention Program Research Group. N Engl J Med.
2002346393-403.
27
Prevention of Diabetes Through Lifestyle Changes
Among Individuals With IGT Finnish Diabetes
Prevention Study
1.0
Intervention group
0.9
0.8
Cumulative probability ofremaining free of
diabetes
0.7
Control group
0.6
Relative risk 0.4 (Plt0.001)
0.5
0.4
0
1
2
3
4
5
6
Year
IGT, impaired glucose tolerance.Tuomilehto J et
al. N Engl J Med. 20013441343-1350.
28
ALLHAT Incidence of New-Onset Diabetes at 4
Years
P ?.001
P .04
11.6
9.8
8.1

Chlorthalidone
Amlodipine
Lisinopril
43.2 lower onset of new diabetes with
lisinopril compared to chlorthalidone (P ?.001 at
4 y). ALLHAT Officers and Coordinators. JAMA.
20022882981-2997.
29
CHARM-PreservedDevelopment of New-Onset Diabetes
Number of cases HR Candesartan Plac
ebo (CI) P value
47 77 0.60 0.005 (0.41-0.86)
N3025.CI, confidence interval HR, hazard
ratio. Yusuf S et al. Lancet. 2003362777-781.
30
Effects of ACE Inhibition on the Development of
Diabetes HOPE
6
5.4
5
3.6
4
Diabetesincidence ()
3
2
1
0
Ramipril
Placebo
Relative risk, 0.66 95 confidence interval,
0.51-0.85 Plt.001. Yusuf S et al. JAMA.
20012861882-1885.
31
Chinese Prevention Trial Lifestyle Intervention,
Acarbose, and Metformin Reduce Risk of Diabetes

• 43 decrease in RR with diet exercise
• 88 decrease in RR with acarbose
• 77 decrease in RR with metformin

P .09
P .0002
P .0001
Data from Yang W et al. Chin J Endocrinol Metab.
200117131-136.
32
LIFEMajor Endpoints
7
Change inrelativerisk()
-10
-11
-13


-25
-25
Primary endpoint
CVmortality
Stroke
MI
Total mortality
New-onset diabetes
P0.021 P0.001, losartan vs atenolol. Dahlöf
B et al. Lancet. 2002359995-1003.
33
Clinical Management of the Metabolic Syndrome
Approaches

• Therapeutic lifestyle changes
• dietary restriction of calories, simple
  carbohydrates and saturated fats
• increased dietary fiber
• regular aerobic exercise
• weight loss
• Pharmacologic therapy
• statins
• fibrates
• ACE inhibitors/ARBs
• other agents?
• What is the evidence?

34
Statin Therapy in CHD PatientsA Meta-Analysis
0
-10
-16
Rate()
-20
-23
-25
All-cause mortality CHD mortality CHD mortality
or nonfatal MI
-30
-40
25 studies in meta-analysis N65,511.CHD,
coronary heart disease MI, myocardial
infarction.Wilt TJ et al. Arch Intern Med.
20041641427-1436.
35
Statin Therapy in Patients With Diabetes
AFCAPS/ TexCAPS
4S
LIPID
0
-10
-20
? in risk of major acute coronary event
-30
-40
Total
Diabetic
-50
-60
Downs JR et al. JAMA. 19982791615-1622 4S
Study Group. Lancet. 19943441383-1389 LIPID
Study Group. Lancet. 20023591379-1387.
36
Dyslipidemia in Metabolic Syndrome

• Low HDL
• High TG
• Average to low LDL
• Atherogenic lipoprotein particles
• VLDL Remnants with apo CIII

37
Anti-Atherogenic Effects of HDL
HDL
Inhibition of monocyte- adhesion
mono- cyte
HDL
HDL
LDL
Endothelium
LDL
Cholesterol- efflux
Inhibition of LDL-oxidation
Ox LDL
macro- phage
foam cell
HDL
38
Gemfibrozil Effect on Lipids VA-HIT
Placebo Gemfibrozil
200
35
34
150
33
LDL cholesterol(mg/dL)
HDL cholesterol(mg/dL)
100
32
50
31
0
30
0
1
2
3
4
5
0
1
2
3
4
5
Year
Year
200
200
150
150
Total cholesterol(mg/dL)
Triglycerides(mg/dL)
100
100
50
50
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Year
Year
VA-HIT, Veterans Affairs Cooperative Studies
Program High-Density Lipoprotein Cholesterol
Intervention Trial. Rubins HB et al. N Engl J
Med. 1999341410-418.
39
Gemfibrozil Effect on Fatal and Nonfatal CHD
Events VA-HIT
25
Placebo
20
15
Cumulativeincidence()
Gemfibrozil
10
5
0
2
0
1
3
4
5
6
Year
Rubins HB et al. N Engl J Med. 1999341410-418.
40
Fenofibrate Versus Atorvastatin in Patients With
Low HDL-C (lt40 mg/dL)
Randomized, Double-Blind Comparative Trial
Atorvastatin 10 mg (12 weeks) n68
15.2
Fenofibrate 200 mg (12 weeks) n57
5.6
Baseline HDL-C
Absolute Change in HDL-C, mg/dL
Twice as many patients taking fenofibrate
achieved an HDL-C of 40 mg/dL compared with
patients taking atorvastatin.
Després J-P, et al. J Intern Med.
2002251490-499.
41
The PPAR Family
42
Effects of Weight Loss (10Kg) on Systemic
Hemodynamics
Mean Arterial Pressure
Total Peripheral Resistance
Heart Rate
Cardiac Output
Percent
NS
- 5
-10



-15
P lt 0.01
pre-weight loss
vs.
P lt 0.001
Ann. Int. Med. 1983 98315.
43
Systolic Hypertension in the Elderly Program
(SHEP) Influence of Diabetes on Cardiovascular
Event Rates
35
Active treatment
RR .66, 95 Cl .46 - .94
Placebo
30
25
20
5-Year Cumulative Event Rates for All Major
Cardiovascular Events ()
RR .66, 95 Cl .55 - .79
15
10
5
0
Diabetes
Nondiabetes
RR, relative risk Cl, confidence interval. Curb
JD, et al. JAMA. 19962761886-1892.
44
Mortality and Morbidity in Non-Diabetic Patients
SHEP
SYST-EUR
SHEP
SYST-EUR
-15
Rate in Placebo Group
Mortality
21.6
21.8
-34
-18
CV Endpoints
35.8
28.9
-30
-38
Stroke
15.0
12.3
-19
-39
12.4
15.2
Coronary
-22
-50
Active Better
Placebo Better
50
0
-100
Number of endpoints / 1000 patient years
45
Tight BP Control vs. Tight Glucose Control
Any DM
Microvascular
Stroke
End Point
DM Death

Complications
0 -
-10 -
-20 -
Reduction in Risk ()
-30 -
Tight Glucose Control
-40 -
Tight BP Control
P lt 0.05
-50 -
UKPDS. BMJ. 1998317703-712.
46
Hypertension and DiabetesReduction in Total
Mortality
Captopril (UKPDS) Atenolol (UKPDS) Diuretic (
SHEP) Nitrendipine (Syst-Eur) Nitrendipine
(Syst-China)
0
20
40
60
80
100
47
Multiple Risk Factor Intervention The Steno-2
Study
Intensive therapy
Conventional therapy
80
P0.01
P0.21
70
P0.019
60
50
P0.001
Patients()
40
30
20
P0.06
10
0
Cholesterollt175 mg/dL
Triglycerideslt150 mg/dL
SBPlt130 mm Hg
Glycosylatedhemoglobinlt6.5
DBPlt80 mm Hg
Gaede P et al. N Engl J Med. 2003348383-393.
48
Multiple Risk Factor Intervention The Steno-2
Study
60
P0.007
50
Conventional therapy
40
Primarycomposite endpoint ()
30
20
Intensive therapy
10
0
96
84
72
60
48
36
24
12
0
Follow-up (months)
Gaede P et al. N Engl J Med. 2003348383-393.
49
Summary Hypertension in the Metabolic Syndrome

• The metabolic syndrome predicts the development
  of both diabetes and CVD
• Adolescents and adults (particularly those who
  are overweight or obese) should be assessed for
  metabolic syndrome
• Lifestyle interventions have been shown to
  prevent (or delay the onset) of diabetes in
  individuals with impaired glucose tolerance

50
Summary Hypertension in the Metabolic Syndrome
(contd)

• Initial therapy for the metabolic syndrome should
  be dietary and exercise interventions
• Conventional CV risk factors should also be
  identified and treated in persons with metabolic
  syndrome
• Hypertension, in particular, should be treated
  aggressively.