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Sowers Le Jacq Journals by mikesanye

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									 CVD RISK WITH METABOLIC
SYNROME and DIABETES

    James R. Sowers, M.D.
Professor of Medicine , Physiology and
            Pharmacology
Director, Diabetes and Cardiovascular
           Research Center
    University Of Missouri Medical
      Center,Columbia,Missouri
    Over the next 24 hours:
• 2200 diabetics will be newly-diagnosed
• 512 diabetics will die
• 66 diabetics will go blind
• 77 diabetics will be diagnosed with
  ESRD
• 153 diabetes-related amputationsi



                           Source: American Diabetes Association
                             Metabolic Syndrome:
                         Prevalence Increases With Age
                      47 million or 23% of US Adults Have Metabolic Syndrome
                 45
                 40                Men (n=4265)
                 35                Women (n=4559)
                 30
                 25
                 20
                 15
                 10
                  5
                  0
                          20-29            30-39        40-49       50-59   60-69   7
                                                                                    ?0
                                                            Age, yr
Adapted from: Ford ES, et al. JAMA. 2002;287:356-359.
What Causes the Rising
Incidence of Diabetics
   and the metabolic
 syndrome in the USA
and Other Countries?
     Is It Gluttony or Sloth??




      Jack in the Box          Average American
Bacon Ultimate Cheeseburger       child or teen
       1020 Calories          watches 3-4 hours TV
                                    per day
      71 grams of Fat
FRENCH(Freedom ?) FRIES

     20 Years Ago                       Today




      210 Calories                  610 Calories
                                   How many calories are
      2.4 ounces                    6.9 ounces
                                   in these fries?
         Calorie Difference: 400 Calories

     How to burn* 400 calories:

     Walk 2 hr 20 Minutes



         *Based on 130 pound person
Walking the dog
      Causes of Mortality in Patients With Diabetes



                    Pneumonia/
                    Influenza        Other
    Malignant
    Neoplasms                 4%       5%
                  13%
                                                                  55%
           13%
                             10%


Diabetes

            STROKE                                    Heart Disease

           Diabetes in America.. NIH No. 95-1468. 1995:233-257.
          CV Events in People With Diabetes:
       Framingham Heart Study – 30-y Follow-up
                                   Men                   10
                                                                           9
                                   Women

                                                    11
      Risk
      ratio                 30            19
                       38                                             9               6
                                     20                                                    3*



                    Total CVD        CHD          Cardiac        Intermittent        Stroke
                                                  failure        claudication
                                  Age-adjusted annual rate/1,000

                                                              P < .001 for all values except *P < .05
Wilson PWF, Kannel WB. In: Ruderman N et al, eds.
Hyperglycemia, Diabetes, and Vascular Disease. Oxford; 1992.
    Changing Rate of Stroke

• Stroke rates are not falling
• Incidence level or increasing
    Similar to CHF and atrial fibrillation
• May be due to increased DIABETES rates
• Increasing number of elderly with advanced
  vascular disease
• Increasing incidence + aging population =
  20%-40% increase in the number of strokes/y
 Adverse Prognostic Implications of
 Cardiovascular Metabolic Syndrome
 Population-based observational study in 1209 men
                     Metabolic syndrome present                                     Metabolic syndrome absent

                          Coronary heart                        Cardiovascular
                         disease mortality                     disease mortality                      All-cause mortality
                20       RR (95% CI):               20         RR (95% CI):                  20       RR (95% CI):
                         3.77 (1.74-8.17)                      3.55 (1.96-6.43)                       2.43 (1.64-3.61)
   Cumulative
   Hazard (%)




                15                                  15                                       15

                10                                  10                                       10

                5                                   5                                         5

                0                                   0                                         0
                     0    2   4    6   8    10 12         0     2   4     6   8     10 12         0     2   4     6   8     10 12
No. at risk       Follow-up (years)                            Follow-up (years)                       Follow-up (years)
metabolic syndrome
         Yes  866     852   834     292                  866        852       834      292        866       852       834      292
          No  288     279   234     100                  288        279       234      100        288       279       234      100


Lakka H-M et al. JAMA. 2002;288:2709-2716.
JNC 7: CVD Risk Factors
 Hypertension*
 Cigarette smoking
 Obesity* (BMI >30 kg/m2)
 Physical inactivity
 Dyslipidemia*                               *Components of the metabolic syndrome.

 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)
                                                              JAMA 2003:289:2560
      Impaired Endothelium-Dependent Vasodilation in
             People at Risk for Type 2 Diabetes
                                 16
                                       13.7
   % Increase over baseline of
    brachial artery diameter




                                 12
                                                   10.5
                                                                  9.8
                                                                            8.4
                                 8



                                  4



                                  0
                                      Control   Relatives**      IGT      Diabetes

*C vs R, IGT, D                                    1st-Degree relatives
**1 or both parents
Caballero AE et al. Diabetes. 1999; 48: 1856-1862.
James Sowers. N Engl J Med. 2002.
Markers of Inflammation & Thrombosis
    Lumen       “Vulnerable” plaque
  Lumen
                                      Activated   Adipocytes   ,
                                      T-Lymphocytes, Macrophages


                                          Cytokines
        Endothelial Cell               TNF IL-1 IL6
            Activation
  ICAM, VCAM          PAI-1 
    selectins          t-PA 
                                                      Liver

                                                                      CRP
            Endothelial Cells                                         SAA
                                          Gabay C, NEJM 1999; 340: 448
                                          Libby P, Circulation 1999; 100: 1148
   CV (Metabolic) Risk Factors in Diabetics
   Linked to Vascular Dysfunction
  • Central obesity      • Microalbuminuria
  • Insulin resistance                    • coagulation/
  •  Triglycerides                         fibrinolysis
  •  HDL-C                               • Increased
                                            Inflamation
  • (Small Dense LDL
    particals)                            • (NASH)(fatty liver)
  • Absent nocturnal                      • ROS Generation
    drop in BP/HR                              CV Oxidative Stress/
                                           Impaired Endothelial Function
Sowers J, Haffner S: Hypertension 2002.
  CHD Mortality According to
  Risk-Factor Status
                           140
                                    Non-Diabetic
                           120      Diabetic

 CHD Death 100
  Rate* per
             80
   10,000
Person-Years 60
                             40

                             20

                              0
                                    None           One      Two   Three

                                                   Risk Factors
*Age adjusted
Stamler et al, Diabetes Care 1993
How can we reduce
  the CVD risk in
    persons with
  Cardiometabolic
    Syndrome@
 Diabetes Mellitus?
Strategies for Reducing
Macrovascular Complications
 Prevention proven by intervention
   • Dyslipidemia
   • Hypertension
   • Antiplatelet therapy


 Prevention suggested by epidemiology
   • Disorders of Thrombolysis
   • Endothelial disorders
   • Inflammation/Oxidative Stress
Association of SBP and CVD Death in Type 2
DiabetesCardiovascular Mortality Rate/10,000 Person-Yr.


                                                          250
                                                                   Non-diabetic
                                                          225
                                                                   Diabetic
                                                          200
                                                          175
                                                          150
                                                          125
                                                          100
                                                          75
                                                           50
                                                           25
                                                           0
                                                                < 120     120 -139   140 -159   160 -179   180 -199   > 200
                                                                        Systolic Blood Pressure (mm Hg)
Stamler J, et al. Diabetes Care. 1993;16:434-444.
Association of SBP and
CVD Death in Type 2 Diabetes
                                 250
                                        Non Diabetic
 Cardiovascular Mortality Rate




                                 225
                                        Diabetic
   per 10,000 Person-Years




                                 200
                                 175
                                 150
                                 125
                                 100
                                  75
                                  50
                                  25
                                   0
                                       <120    120–139   140–159   160–179   180–199   ≥200
                                                Systolic Blood Pressure (mmHg)
  Stamler J et al. Diabetes Care. 1993;16:434–444.
Tight BP Control vs Tight Glucose Control
                                                         Any DM                         Microvascular
                                       Stroke            End Point           DM Death   Complications
                             0


                          –10 -
Reduction in Risk (%)




                          –20 -


                          –30 -

                                                              Tight Glucose Control
                          –40 -
                                                              Tight BP Control

                                                                 *P < 0.05
                          –50 -

                        UKPDS Group. BMJ. 1998:317;703–713.
                         HOT: Greatest Benefit at ≤80 mmHg
                           in Diabetes and Hypertension
                                          *
                                                          *P = 0.005
                                24.4
                         25
                                                           *
   1,000 Patient-Years




                         20                      18.6
       Events per




                         15
                                                                       11.9
                         10

                          5

                          0
                              ≤90 mmHg         ≤85 mmHg          ≤80 mmHg



Hansson L et al. Lancet. 1998;351:1755–1762.
                    Multiple Antihypertensive Agents
                    are Needed to Achieve Target BP
       Trial                   Target BP                    No. of antihypertensive agents
                                (mmHg)               1             2            3            4

   McFarlane1              BP 130/85

   ABCD                     DBP <75

   MDRD                     MAP <92

   HOT                      DBP <80

   AASK                     MAP <92

   UKPDS                    DBP <85

DBP=diastolic blood pressure; MAP=mean arterial pressure.
Bakris GL et al. Am J Kidney Dis. 2000;36:646–661.
1. McFarlane SI et al. Diabetes Care. 2002;25;718–723.
Key Points for Optimal Hypertension
Management

                                                    JNC 7   <130/80 mm Hg in
              <140/90
                                                     BP     diabetes or renal
              mm Hg                                 Goals        disease



                         JNC 7 recommends:
            If SBP >20 mm Hg, DBP >10 mm Hg over goal,
              consider initiating with 2-drug combination

JNC 7 Report. Hypertension. 2003;42(6):1206-1252.
                                                                                28
Diabetes: Most Common Cause of ESRD


    Primary Diagnosis for Patients Who Start Dialysis
                                                         Other        Glomerulonephritis
                                                              10%     13%                                No. of patients
                                  700                                                                    Projection
                                                                            Hypertension
                                               Diabetes                                                  95% CI
       No. of dialysis patients




                                  600                                           27%
                                                 50.1%
            (thousands)




                                  500
                                  400
                                  300                                                              520,240
                                                                                    281,355
                                  200
                                                                    243,524
                                  100                                                             r2=99.8%
                                   0
                                        1984   1988          1992    1996       2000       2004       2008
United States Renal Data System. Annual data report. 2000.
  CVD Risks that Cluster with
  Microalbuminuria
• Central obesity              • Absent nocturnal drop in BP/HR
• Insulin resistance           • Increased CV oxidative stress
• Low HDL cholesterol levels
                               • Impaired endothelial function
• High triglyceride levels
• Small dense LDL particles    • Abnormal coagulation/ fibrinolytic
• Systolic hypertension          profiles
• Salt sensitivity             • Left ventricular hypertrophy
• Elevated CRP & other
  inflammatory markers

                                 •Microalbuminuria
                                               Sowers and Haffner Hyp. 2002
 Proteinuria Is an Independent Risk Factor
 for All-cause Mortality in NIDDM
                                     1.0
           Probability of Survival


                                                                                           Normoalbuminuria
                                     0.9                                                       (n=191)

                                     0.8                                                   Microalbuminuria
                                                                                                (n=86)

                                     0.7
                                                                                           Macroalbuminuria
                                                                                                (n=51)
                                     0.6
                                               P<0.01 normoalbuminuria vs microalbuminuria and macroalbuminuria
                                               P<0.05 microalbuminuria vs macroalbuminuria
                                     0.5
                                           0        1       2       3       4       5       6
                                                                 Years
Gall MA et al. Diabetes. 1995;44:1303-1309.
  Metabolic Syndrome/CKD Defined
• Metabolic syndrome is defined as the
 presence of 3 or more of the following risk
 factors
  –   HTN
  –   low HDL-C
  –   high triglycerides
  –   elevated glucose
  –   abdominal obesity
• CKD is defined as estimated GFR below
  60 mL/min/1.73 m2, microalbuminuria(30
  mg/g creatinine )
                           Chen et al. Annals Intern Med. 2004;140:167-174.
Metabolic Syndrome and Chronic Kidney
Disease/Microalbuminuria in US Adults


 • Metabolic syndrome is a common risk factor for
   CVD
 • Cross sectional analysis of NHANES III
 • Patients greater than 20 years of age, CKD
   (n=6,217), microalbuminuria (n=6,125)
 • Metabolic syndrome as previously defined
 • CKD as previously defined

 Chen et al. Annals Intern Med. 2004;140:167-174.
Multivariate Odds Ratio for CKD or
Microalbuminuria Based on Presence of
Components of the Metabolic Syndrome
                 CKD                                 Microalbuminuria
  Components                RR                       Components     RR

           0, 1             1.0                           0, 1      1.0

             2              2.2                            2        1.2

             3              3.4                            3        1.6

             4              4.2                            4        2.5

             5              5.9                            5        3.2


  Chen et al. Annals Intern Med. 2004;140:167-174.
Greater Benefit on CV Events with
in Patients with Renal Insufficiency in HOPE .

         1.0
                                         *P<0.05
         0.8

         0.6                             *         *       *
                                                                           Renal insufficiency
         0.4                                                               (Cr >1.7 mg/dL)

                                                                           Without renal
         0.2                                                               insufficiency

         0.0
           Primary      MI      Stroke    CV        All    Hosp   Revasc
           outcome                       death     death    HF


Mann JE et al.Ann Intern Med 2001
Progression of Renal Disease


       Microalbuminuria


                Overt Proteinuria


                          Doubling of
                          Creatinine
 CV Events
   Death                        End Stage Renal
                                    Disease
BP(ACE/ARB)- Reduction for Renal Protection

   Hemodynamic Effects
     • Reduction in systemic BP
     • Reduction in glomerular capillary pressure
       because of efferent glomerular arteriolar dilation
     • Reduction in proteinuria

   Nonhemodynamic
     • Inhibition of macrophage/monocyte infiltration
     • Reduction in Inflammation
     • Reduction in Oxidative Stress
Biochemical Results(AllHAT)

                                     Chlorthalidone   Amlodipine       Lisinopril
Serum cholesterol- mg/dL
                  Baseline            216.1 (43.8)    216.5 (44.1)    215.6 (42.4)
                  4 Years             197.2 (42.1)    195.6 (41.0)*   195.0 (40.6)*
Serum potassium – mmol/L
                  Baseline              4.3 (0.7)       4.3 (0.7)      4.4 (0.7)*
                  4 Years               4.1 (0.7)      4.4 (0.7)*      4.5 (0.7)*

Estimated     GFR† – mL/min/1.73m              2


                  Baseline            77.6 (19.7)      78.0 (19.7)     77.7 (19.9)

                  4 Yrs
* p<.05 compared to chlorthalidone      70.0           75.1*           70.7 *
† Ann Intern Med. 1999;130:461-470
           Development of Diabetes in ALLHAT
                                     Chlorthal   Amlod   Lisinopril
   Total
            Base        123.5         123.1         122.9
            4 Year      126.3         123.7        121.5 *
   Among baseline nondiabetics with baseline <126
            Base      93.1 (11.7)   93.0 (11.4)   93.3 (11.8)
            4 Year      104.4         103.1        100.5 *
   Diabetes Incidence (follow-up fasting
   glucose  126 mg/dl
                     4 Yr            11.6%       9.8%*   8.1%*
*p<.05 compared to chlorthalidpone
VALUE: Incidence of New-onset Diabetes
                                               23% Risk Reduction With
                           18                         Valsartan
                           16                      P < 0.0001
                           14
      New-Onset Diabetes

       treatment group)
       (% of patients in




                           12
                           10
                                                                    16.4%
                           8
                                        13.1%
                           6
                           4
                           2
                           0
                                Valsartan-based Regimen    Amlodipine-based Regimen
                                        (n = 5094)                 (n = 5074)


Julius S, et al. Lancet. 2004;363:2022-2031.
HOPE/HOPE-TOO: Development of diabetes
                                        New Diabetes - All Patients
          0.12
                                                                 HOPE Study Ends
                         Ramipril

          0.10           Placebo

          0.08

 Hazard   0.06

          0.04

          0.02                                                 ALL: RR: 0.69, CI: (0.57-0.83)

                                                               CONT: RR: 0.70, CI: (0.57-0.86)
          0.0
                 Years       1      2          3         4          5         6          7

                                        Bosch J. European Society of Cardiology C 2003. Vienna, Austria
 LIFE: New-Onset Diabetes
                             0.10                 Intention-to-Treat
                             0.09

                             0.08        Atenolol (N=3979)
                                         Losartan (N=4019)
                             0.07
            End Point Rate




                             0.06

                             0.05

                             0.04

                             0.03

                             0.02
                                                  Adjusted Risk Reduction   25%, P<.001
                             0.01                 Unadjusted Risk Reduction 25%, P<.001
              0.00
      Study Month 0                 6   12   18    24   30   36   42   48   54   60   66


Dahlöf. 2002.
Prevention of Type 2 Diabetes by Inhibition of the
RAS
Results
•    Study                     Treatment        Control               RR (fixed) 95% CI       RR (fixed) 95% CI
ALLHAT 2002   119/5840 302/9733                                                       .66    [0.53, 0.81]
ALPINE 2003    1/196    8/196                                                         0.13   [0.02, 0.97]
CAPP 1999      227/5184 280/5229                                                      0.09   [ 0.70, 1.03]
CHARM 2003    163/2715 202/2721                                                       0.01   [0.66, 0.97]
HOPE           102/2837 155/2883                                                      0.69   [0.52, 0.85]
LIFE 2002      241/4006 319/3592                                                      0.75   [0.64, 0.88]
SCOPE 2003     99/2160  125/2170                                                      0.81   [0.62, 1.06]
SOLVD 2003     9/153    31/138                                                        0.26   [0.13, 0.53]
STOP-HTN-2 1999 99/1969 97/1961                                                       0.95   [0.72, 1.26]
Total (95% CI)      25060        29023                                                0.78 [0.72, 0.84]
Total events 1158 (Treatment), 1609 (Control)
Test for heterogeneity Chi2 =22.39, df = 8 (p = 0.004),
P = 64.3%
Test for overall effect Z = 6.73 (p < 0.00001)

                                                 0.1      0.2   0.5   1    2    5    10
                                              Favors Treatment            Favors Control
Scheen A. Diabetes 2004;53(S2);A169.
DREAM         NAVIGATOR

                     • Valsartan
        RSG   PBO    • Nateglinide 2#2


 RAM   RSG    PBO
       RAM    RAM
       1000   1000

 PBO   RSG    PBO
       PBO    PBO
       1000   1000
Steno-2: Multifactorial Intervention on Macro and
Microvascular Outcomes

   160 patients with type 2 diabetes/microalbuminuria
                 60               Conventional therapy                             Relative Risk
                                                                     Variable         (95% CI)   P
 Composite CVD




                 50
  outcome* (%)




                           53% risk reduction                        Nephropathy         0.39    0.003
                 40              P=0.01                                              (0.17-0.87)
                 30                                                  Retinopathy         0.42       0.02
                 20                                                                  (0.21-0.86)
                                           Intensive therapy†        Autonomic           0.37    0.002
                 10                                                  Neuropathy      (0.18-0.79)
                  0                                                  Perpheral           1.09       0.66
                      0    12 24 36 48 60 72 84 96                   Neuropathy      (0.54-2.22)
                             Follow-up (months)
    No. at risk                                                                                        0.0   0.5    1.0   1.5   2.0   2.5
Conventional          80    72   70   63    59   50   44   41   13
                                                                                                    Intensive             Conventional
      Intensive       80    78   74   71    66   63   61   59   19                                                        therapy better
                                                                                                   therapy better

 *CV death, MI, stroke, revascularization, amputation
 †Total
      fat intake <30%, >30% min excersise 3-5 x weekly, ACE inhibitor, ASA, BP
 <130/80 mm Hg, total-C <175 , TG <150 mg/dL, A1c < 6.5%
 N Engl J Med. 2003;348:383–1393.
 Prevention of CVD in Diabetes

 No Smoking
 ASA
 Lipid Control (Statin) +
  LDL <70, HDL >45-50, TG <150 mg/dl
  (HMG CoA Reductase Inhibitors)
 Blood Pressure <130/80 mm Hg
 Glycemic Control: A1C<7%
 Dash Diet and increased Aerobic
  Excercise
Metabolic factors associated with
   CVD in postprandial state
                   Endotheial Dysfunction

                    Platelet activation
                   Fibrinolytic resistance


                    coagulability
                   Postprandial Glycemia
                   Postprandial lipemia
                                                 Ins/IGF-1
                                                  receptor



                      Glucose
                                           PO4
                     Transport                                  MAP
               AKT                                             kinase

         (-)                           IRS-1

                                       P13-K
Na-K ATPase
NOS gene / expression &
incresed glucose transport       (-)ROS?
                                                 (+)
                                     Ang II
                                                         Mitogenesis,
                                                         hypertrophy &
                                                         remodeling
                  VA-HIT: Increasing HDL-C
                  Reduces Risk of CV Death
                   25
                                                                        RRR 22%
                   20                                  Placebo          (95% CI, 7-34; P=.006)



   Cumulative      15
    incidence                                             Gemfibrozil
       (%)         10

                     5

                     0
                         0      1       2          3       4      5     6
                                              Year

Rubins HB et al. N Engl J Med. 1999;341:410-418.
II - SUPEROXIDE PRODUCTION IN HUMAN VASCULATURE.

            Human Internal Mammary Arteries incubated with Angiotensin II



       1500



       1000                               *
 02-




                                        p< 0.01



           500

                           N = 11      N = 11     N = 15

       .     0
                        CONTROL       Ang II       Ang II +
                                                    ARB
                                                              Circ. 2000;101:2206-2212
    Role of the NADPH oxidase and p47phox in
    Ang II-induced Generation of ROS.

          O2             O2•-
                  e-
                                                    Ang II
                  Gp91                       AT1R
                  NOX    p22
NAD(P)H
                         p47 Rac
          NADP
                         p67?          Rac

                 p47
                                P67?
CV Risk Factors in Diabetic and Cardiometabolic-
Syndrome-Linked Vascular Dysfunction
 • Central obesity                • Microalbuminuria
 • Insulin resistance             • Impaired Endothelial
 •  LDL-C                          Mediated Vasodilation
 •  Triglycerides                • Abnormal coagulation /
 •  HDL-C                          fibrinolytic profiles
 • Small Dense LDL particles      • RAS-Mediated ROS
 • Absent nocturnal drop in BP      Inflammation
   and heart rate                    – LVH,CHF,Stroke
 • Non-Alcoholic Fatty Liver
   (NASH)

      CV Oxidative Stress / Impaired Endothelial Function
 How Do Statins
 inhibitors reduce
      Stroke?
Are there non-lipid
lowering Effects of
      Statins
Summary
• Patients with diabetes/ dyslipidemia have a high risk
  of CVD, and should be treated aggressively- - LDL< 70mg/dl.
• In clinical trials:
   – HPS results showed significant benefit from lipid-
     lowering, including nephropathy(All LDL levels)
   – CARDS Benefits in diabetic patients striking-
     Stroke Reduction 48% with Atorvastatin Rx
   – ASCOT LLA: incidence of nonfatal MI and fatal
     CHD lower by 36% in atorvastatin group
   – STENO-2: intensive intervention aimed at multiple
     risk factors in patients with type 2 diabetes and
     microalbuminuria reduced the risk
     of CV and microvascular events by 50%

								
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