Diabetes, Hypertension and the Metabolic Syndrome:

1
Diabetes, Hypertension and the Metabolic
Syndrome Is There Anything New? Thomas D.
Giles, M.D. New Orleans, LA

2
Numbers of persons with diabetes will more than
double by 2030
40
118 increase
30.3
30
US population with diabetes(millions)
20
13.9
10
0
2002
2030
Year
AHA. Heart Disease and Stroke Statistics2005
Update.Wild S et al. Diabetes Care.
2004271047-53.
3
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.
4
The Metabolic Syndrome and Insulin Resistance
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
Metabolic syndrome diagnosis ATP III emphasizes
clinical practice

• Risk factor Defining level
• Abdominal obesity (in) Waist Men gt40 Women gt35
  
• Triglycerides (mg/dL) 150
• HDL-C (mg/dL) Men lt40 Women lt50
• BP (mm Hg) 130/85
• Fasting glucose (mg/dL) 110 (ADA 100)

NCEP ATP III. JAMA. 20012852486-97.
7
Metabolic syndrome diagnosis IDF emphasizes
central obesity
International Diabetes Federation

• Central obesity
• Plus any 2 of the following

• Defined according to waist circumference
  (ethnic- and gender-specific)

• Plasma triglycerides gt150 mg/dL
• HDL-C lt40 mg/dL
• BP ?140/90 mm Hg
• Fasting glucose ?100 mg/dL or previously
  diagnosed type 2 diabetes

Or receiving specific treatment for this
abnormality
www.idf.org. Accessed August 2005.
8
IDF ethnic- and gender-specific criteria for
central obesity
Waist circumference (inches)
Men
Women

• European ?37 ?32
• Sub-Saharan African
• Middle Eastern
• South Asian ?35 ?32
• South/Central American
• Chinese ?35 ?32
• Japanese ?34 ?35

www.idf.org. Accessed August 2005.
9
Metabolic syndrome diagnosis WHO emphasizes
central role of insulin resistance

• Insulin resistance
• Type 2 diabetes, or
• Impaired fasting glucose, or
• If fasting glucose lt110 mg/dL, glucose uptake
  below lowest quartile

• Plus any 2 of the following
• Antihypertensive medication and/or BP 140/90 mm
  Hg
• Plasma triglycerides 150 mg/dL
• HDL-C lt35 mg/dL (men) or lt39 mg/dL (women)
• BMI gt30 kg/m2 and/or waist-hip ratio gt0.9 (men)
  gt0.85 (women)
• Urinary albumin excretion rate 20 µg/min or
  albumin-creatinine ratio 30 mg/g

Grundy SM et al. Circulation. 2004109433-8.Adap
ted from Alberti KG, Zimmet PZ. Diabet
Med.199815539-53.
10
Metabolic Syndrome
11
Other markers of insulin resistance

• Family history of type 2 diabetes or CAD
• Overactive sympathetic nervous system
• ?Uric acid

Cohn GS et al. Am J Hypertens. 2005181099-103.
12
Over half of patients referred to cardiologists
have insulin resistance syndrome
Cardiac rehabilitation
Acute MI
59
58
60
50
Patients withinsulin resistance syndrome ()
40
20
0
N 1912Savage, 2005
N 235 Milani, 2003
N 85 Curran, 2004
Savage PD et al. Am Heart J. 2005149627-31. Mila
ni RV, Lavie CJ. Am J Cardiol. 20039250-4. Curra
n PJ et al. J Am Coll Cardiol. 200443(suppl
A)249A.
13
Almost 70 of patients with first MI have IGT or
undiagnosed diabetes
N 181 consecutive patients admitted to CCU
66
70
Undiagnosed diabetes
31
50
Patients ()
30
Impaired glucose tolerance (IGT)
35
10
0
Glucose tolerance test results
Norhammar A et al. Lancet. 20023592140-4.
14
Diagnosis of diabetes, IFG, and IGT
Plasma glucose (mg/dL)
Fasting
2-hr postload
Casual
126 100 to 125 (ADA) gt110 to 126 (AACE)

• 200
• 140 to 199 (ADA)
• gt140 to lt200 (AACE)

Diabetes Impaired fasting glucose
(IFG) Impaired glucose tolerance (IGT)
200
Following equivalent of 75 g anhydrous glucose
in water
ADA. Diabetes Care. 200528(suppl 1)S4-36.AACE.
Endocr Pract. 20039240-52.
15
Multidisciplinary consensus on managingmetabolic
syndrome
AHA / NHLBI / ADA

• Modify lifestyle (weight loss, physical activity)
• Assess risk
• Framingham Risk Score
• CRP (optional)
• Reduce risk factors (ATP III, JNC 7, ADA)
• Lipids, BP, thrombosis, glucose

There is growing interest in the possibility
that drugs that reduceinsulin resistance will
delay onset of type 2 diabetes and will
reduceCVD risk when the metabolic syndrome is
present.
Grundy SM et al. Circulation. 2004109551-6.
16
Role of obesity in insulin resistance
? Caloric intake Sedentarylifestyle Genetic
factors
? Free fatty acids ? Glucose ? Lipids
Oxidativestress Inflammation
VisceralObesity
Insulinresistance
Adapted from Wellen KE, Hotamisligil GS. J Clin
Invest. 20051151111-9.
17
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.
18
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

CI, confidence interval CRP, C-reactive protein
NA, not applicable OR, odds ratio.Age
adjusted. Niskanen L et al. Hypertension.
200444859-865.
19
Insulin resistance increases risk of target
organ damage in hypertension
N 354 with untreated hypertension
P 0.003
59
60
45
40
Patients ()
P 0.04
30
19
15
10
0
Microalbuminuria
LV hypertrophy
With insulin resistance syndrome
Leoncini G et al. J Intern Med. 2005257454-60.
Modified ATP III definition
20
Clinical manifestations of insulin resistance

• Type 2 diabetes and glycemic disorders
• Dyslipidemia
• Low HDL
• Small, dense LDL
• Hypertriglyceridemia
• Hypertension
• Endothelial dysfunction/inflammation (hsCRP)
• Impaired thrombolysis
• ? PAI-1

Insulin resistance Glucotoxicity Lipotoxicity ?
Adiponectin
VisceralObesity
Atherosclerosis
Courtesy of Selwyn AP, Weissman PN.
21
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

22
Potential role of PPAR activation in CV risk
reduction
Geneticbackground
Food intake excess
Physical inactivity
Obesity
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Inflammation
PPAR activation
Hypercoagulation
Hypertension
resistance
Atherosclerosis
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
23
The PPAR Family
24
PPAR activation Newest strategy in CV risk
reduction
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Inflammation
PPAR activation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
25
TRIPOD Evidence that insulin resistance causes
?-cell failure
N 266 Hispanic women with gestational diabetes
randomized to troglitazone 400 mg or placebo for
median 30 months

• PPAR? activation 55 relative risk reduction for
  new-onset diabetes (HR 0.45 0.250.83)
• Effect was most prominent in women with initial
  increase in insulin sensitivity and accompanying
  large reduction in insulin output
• Protection persisted 8 months after cessation of
  active treatment
• PPAR? activation associated with preserved
  ?-cell function

TRIPOD Troglitazone in Prevention of Diabetes
Buchanan TA et al. Diabetes. 2002512796-803.
26
DPP Improving insulin sensitivity/secretion
prevents diabetes
N 3234
Diabetes hazard rate (per 100 pyr)
pyr person years IGR insulin-to-glucose
ratio DPP Diabetes Prevention Program
DPP Research Group. Diabetes. 2005542404-14.
27
PPAR? activation blunts progression to diabetes
Diabetes Prevention Program
15
Placebo
Metformin 850 mg
10
Cumulative incidence ()
Lifestyle
Troglitazone400 mg
5
?75 vs placeboP lt 0.001
0
1.5
1.0
0.5
0.0
Years
237
1568
2343
n
739
DPP Research Group. Diabetes. 2005541150-6.
Terminated early after 1.5 years
28
CV implications of insulin resistance and PPAR?
activation
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Dyslipidemia
Inflammation
PPAR activation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
29
Importance of LDL particle density

• In insulin resistance, LDL-C levels are similar
  or only slightly elevated vs general population
• However, atherogenicity of LDL particles varies
  according to density More dense more
  atherogenic
• Proportion of small, dense LDL particles greater
  in patients with insulin resistance or diabetes
  vs general population

Miranda PJ et al. Am Heart J. 200514933-45.
30
Greater atherogenicity of small, dense LDL vs
normal LDL
Susceptible to oxidation Binds to arterial
wallPenetrates arterial wall Toxic to
endothelial cells Promotes PAI-1 production by
endothelial cellsPromotes thromboxane production
by endothelial cellsAccumulates Ca2 in vascular
smooth muscle cellsBinds to LDL scavenger
receptor
Adapted from Sniderman AD et al. Ann Intern Med.
2001135447-59.
31
CV implications of insulin resistance and PPAR?
activation
Hyperinsulinemia
Hyperglycemia
Insulin
Inflammation
Dyslipidemia
Inflammation
PPAR activation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
32
Adipokines An overview
Atherogenic
Antiatherogenic

• Adiponectin

• CRP
• IL-6
• PAI-1
• Angiotensinogen
• Leptin
• Resistin
• MCP-1

Lau DCW et al. Am J Physiol Heart Circ Physiol.
2005288H2031-41. Wellen KE, Hotamisligil GS. J
Clin Invest. 20051151111-9.
33
Adiponectin associated with decreased risk of MI
N 18,225 men 6-year follow-up
1.2
1.0
0.8
Relative
0.6
risk
0.4
0.2
0.0
1
2
3
4
5
Quintile of
adiponectin
(95 CI)
7.9
12.6
16.5
21.1
29.2

g/mL
m
Adjusted relative risk (P lt 0.001)
Lipid-adjusted

relative risk (P lt 0.02)
Pischon
T et al.
JAMA
. 20042911730-7.
34
Contrasting roles of CRP and PPAR? on
inflammation and insulin resistance
Adipose tissue
? IL-6
Liver
? CRP
PPAR?
? Glucose
Insulin resistance
Lau DCW et al. Am J Physiol Heart Circ Physiol.
2005288H2031-41.
35
Direct relationship of CRP to metabolic syndrome

• Womens Health Study N 14,719

8
6
Median CRP(mg/L)
4
2
0
0
1
2
3
4
5
Components of the metabolic syndrome (n)
n 4086 3884 3152 2292
1135 170
Ridker PM et al. Circulation. 2003107391-7.
Modified ATP III definition
36
PPAR? activation decreases CRP in patients with
diabetes
N 357 26 weeks
Rosiglitazone 4 mg
Rosiglitazone 8 mg
Placebo
0
10
Mean change from baseline()
20
30
40
P lt 0.05
50
27
P lt 0.05
22
Haffner SM et al. Circulation. 2002106679-84.
37
Benefits of combined insulin sensitizer therapy
Effects on CRP, PAl-1, and MMP-9
Weeks 824
MMP-9
30

22.2
20
10
?Baseline()
CRP
PAl-1
0
0.56
10
9.8
14.35

20
P 0.046
30
26.9
32.76
P 0.026
40
P lt 0.001
Metformin 2 g (n 70)
Metformin 1 g rosiglitazone 8 mg (n 57)
Weissman PN et al. Diabetes. 200453(suppl 2)A28.
NS vs baseline
38
PPAR? activation improves renal endothelial
function and reduces proteinuria
N 19 with type 2 diabetes with/without
microalbuminuria
P lt 0.05
P lt 0.05
140
133
120
Treatment with rosiglitazone was followed by 60
reductions in albuminuria and proteinuria in
diabetic patients with microalbuminuria.
119
120
103
100
GFR(mL/min)
80
60
40
20
0
Placebo
Rosiglitazone
Nateglinide
Rosiglitazone
Microalbuminuria
No microalbuminuria
Pistrosch F et al. Diabetes. 2005542206-11.
39
Thiazolidinediones in patients with type 2
diabetes and HF
AHA/ADA consensus statement summary

• NYHA class I/II HF Thiazolidinediones may be
  used cautiously, with initiation of treatment at
  the lowest dose and gradual dose escalation
• Allow more time than usual to achieve target A1C
• NYHA class III/IV HF Thiazolidinediones should
  not be used at this time

Nesto RW et al. Circulation. 20031082941-8.
40
Mortality benefit with combined
insulin-sensitizing therapy
8872 acute MI patients, mean age 76.4 years,
discharged on glucose-lowering medication
No insulin sensitizer (n 6641)Thiazolidinedione
s (n 1273) Metformin (n 819) TZD MET (n
139)
1.00
0.95
Proportion of patientssurviving
0.90
48 Relativerisk reduction
0.85
0.80
0
50
200
250
300
350
100
150
Days from discharge
Inzucchi SE et al. Diabetes Care. 2005281680-9.
41
PROactive Study design
Objective Assess the effects of pioglitazone
on reducing macrovascular events in type 2
diabetes Design Randomized double-blind,
controlled outcome Population N 5238 with
type 2 diabetes and history of macrovascular
disease Treatment Pioglitazone (up to 45 mg)
or placebo Primary outcome Composite of
all-cause mortality, MI, ACS, coronary or
peripheral revascularization, amputation,
stroke Secondary outcomes Individual
components of primary outcome, CV
mortality Follow-up 4 years
Charbonnel B et al. Diabetes Care.
2004271647-53. Dormandy JA et al. Lancet.
20053661279-89.
42
PROactive Baseline CV history

Dormandy JA et al. Lancet. 20053661279-89.
43
PROactive Reduction in primary outcome
All-cause mortality, MI, ACS, coronary or
peripheral revascularization, amputation, stroke
25
10 Relative risk reduction HR 0.90
(0.801.02)P 0.095
Placebo(572 events)
20
Pioglitazone(514 events)
15
Proportionof events()
10
5
0
6
0
12
18
24
30
36
Time from randomization
Number at risk
Pioglitazone
2488
2373
2302
2218
2146
348
Placebo
2530
2413
2317
2215
2122
345
Dormandy JA et al. Lancet. 20053661279-89.
Unadjusted
44
HPS and CARDS Benefits of lowering LDL-C in
diabetes
Event rate ()
? LDL-C(mg/dL)
Statin better
Placebo better
Placebo
Statin
P
HPS
0.73
34.8
lt0.0001 0.0003 0.001
12.6 13.5 9.0
9.4 9.3 5.8
All diabetes
0.67
34.8
Diabetes, no CVD
0.63
46.4
CARDS
0.5
0.7
0.9
1
1.7
Relative risk
Statin vs placebo HPS Heart Protection
Study CARDS Collaborative Atorvastatin Diabetes
Study
HPS Collaborative Group. Lancet.
20033612005-16.Colhoun HM et al. Lancet.
2004364685-96.
45
ASCOT-LLA Atorvastatin reduces CV events in
patients with diabetes and hypertension
N 2532, baseline LDL-C 128 mg/dL
14.0
Placebo
12.0
23 Risk reduction P 0.036
10.0
8.0

6.0
Atorvastatin 10 mg
4.0
2.0
HR 0.77 (0.610.98)
0.0
Years
0.5
0.0
1.0
1.5
2.0
2.5
3.0
3.5
Number at risk
1231
1258
1209
1191
1171
1065
699
370
Placebo
1237
1274
1219
1200
1175
1058
714
375
Atorvastatin
Nonfatal MI, CV mortality, UA, stable angina,
arrhythmias, stroke, TIA, PAD, retinal vascular
thrombosis, revascularization ASCOT-LLA
Anglo-Scandinavian Cardiac Outcomes TrialLipid
Lowering Arm
Sever PS et al. Diabetes Care. 2005281151-7.
46
Steno-2 supports aggressive multifactorial
intervention in type 2 diabetes

• Objective Target-driven, long-term,
  intensified intervention aimed at multiple
  risk factors compared with conventional
  therapy
• Design N 160 patients with type 2 diabetes
  and microalbuminuria
• Intensive treatment targets BP lt130/80 mm Hg
• A1C lt6.5
• Total-C lt175 mg/dL
• Triglycerides lt150 mg/dL

Gæde P et al. N Engl J Med. 2003348383-93.
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
ABCs of coronary prevention
Adapted from Cohen JD. Lancet. 2001357972-3.