Improving CVD outcomes in DM

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					Improving Cardiovascular
Outcomes in People with
   Diabetes Mellitus
  David C.W. Lau, MD, PhD, FRCPC
         Departments of Medicine
    Biochemistry and Molecular Biology
Julia McFarlane Diabetes Research Centre
           University of Calgary
              403-220-2261
        Email: dcwlau@ucalgary.ca
                 Objectives
• Recognize the increased cardiovascular disease
  risk in people with diabetes
• Review current data on CVD prevention and
  protection in people with diabetes
• Identify and address gaps in screening and
  managing patients at risk for cardiovascular
  disease
• Discuss the updated evidence-based CDA
  guidelines on the treatment and prevention of
  macrovascular complications
• Understand the implications of treating to target
  in clinical practice
MRFIT: Impact of Diabetes
on Cardiovascular Mortality
 140

              No Diabetes (N=342,815)           125
 120
              Diabetes (N=5,163)                      *   Risk factors:
 100                                                  •   Smoking
                                      91              •   Hypertension
  80                                                  •   Hyper-
                                                          cholesterolemia
  60                        59
                                           47
  40

                 31              22
  20
             6         12
   0
              None          1         2     All 3
                 Number of risk factors*
       From J Stamler, et al. Diabetes Care 16:434-444, 1993
       Cardiovascular Events in
          Type 2 Diabetes
Incidence (%) at 7 years of Fatal and Nonfatal MIs
                                      45
 45     No Diabetes (N=1059)
 40                                   40
 35     Type 2 Diabetes (N=1373)      35
 30                                   30
 25                                   25
 20                                   20
 15                                   15
 10                                   10
  5                                    5
  0                                    0
      AMI Stroke CV death                  AMI Stroke CV death

      No prior AMI                            Prior AMI
          From SM Haffner, et al. NEJM 339:229-234, 1998
             OASIS Study: Total Mortality
             0.25
                       Diabetes/+CVD (N=1148)
                                                          RR = 2.88 (2.37-3.49)
                       Diabetes/-CVD (N=569)
             0.20      No Diabetes/+CVD (N=3503)
                       No Diabetes/-CVD (N=2796)
Event rate




             0.15                                         RR=1.99 (1.52-2.60)


             0.10                                         RR=1.71 (1.44-2.04)

             0.05
                                                          RR=1.00

              0.0

                         3       6       9      12     15      18        21   24
                                         Months
                    K Malmberg, et al. Circulation 102:1014–1019, 2000
Mortality Rates 1980-1996
   140          Diabetes
                Cancer
                Cardiovascular Disease
   120          Stroke


   100


    80


    60
         1980     1984      1998     1992      1996
                           Year
   From McKinlay et al. Lancet 2000; 356:757
Coronary Heart Disease, 2000
             35

                        General Population
             30         Diabetes Population


             25
   Percent




             20


             15


             10


             5


             0
                  <10   10 - 19 20 - 29 30 - 39 40 - 49 50 - 59 60 - 69 70 - 79   80+

                                                 Age
  Relationship between Glycemic
  Control in Diabetes and CHD?
• Is glycemic control important in
  retarding CHD?
• What have we learned from the
  United Kingdom Prospective Diabetes
  Study in type 2 diabetes?
• What should the glycemic targets be?
UKPDS: Long-term Glycemic Control
                      Cross-sectional, median values
              9

                       Conventional
              8
  HbA1c (%)




                                             Intensive
              7


                                         6.2% upper limit of normal range
              6
              0
                  0      3         6         9        12                15
                             Years from randomisation
                                       From UKPDS, Lancet 352:837-853, 1998
    UKPDS: Glucose Control Study
             Summary
The intensive glucose control policy maintained a
lower HbA1c by mean 0.9 % over a median follow up
of 10 years from diagnosis of type 2 diabetes with
reduction in risk of:
12% for any diabetes related endpt          p=0.029
25% for microvascular endpoints             p=0.0099
16% for myocardial infarction               p=0.052
24% for cataract extraction                 p=0.046
21% for retinopathy at twelve years         p=0.015
33% for albuminuria at twelve years         p=0.000054

            From UKPDS, Lancet 352:837-853, 1998
HgbA1c and Diabetes End Points




  Adapted from UKPDS 35, Stratton et al., BMJ 321:405-412, 2000
           The Problem

• Macrovascular complications are
  usually SILENT until much advanced
• Therefore the need for regular
  screening is of paramount importance
• Prevention and treatment should be
  emphasized
     Improving Outcomes of
   Macrovascular Complications
• Blood glucose control alone is not
  sufficient in diabetes
• Need to recognize role of
   Hypertension
   Dyslipidemia
   Insulin resistance
UK Prospective Diabetes Study


 Does tight blood pressure
 control reduce morbidity
 and mortality in Type 2
 diabetes?
UKPDS: Blood Pressure Control Study
 In 1148 patients with Type 2 diabetes a
   tight blood pressure control policy
   which achieved blood pressure of 144 /
   82 mmHg gave reduced risk for:
 Any diabetes-related endpt   24%   p=0.0046
 Diabetes-related deaths      32%   p=0.019
 Stroke                       44%   p=0.013
 Microvascular disease        37%   p=0.0092
 Heart failure                56%   p=0.0043
 Retinopathy progression      34%   p=0.0038
 Deterioration of vision      47%   p=0.0036
BP and Diabetes End Points




Adapted from UKPDS 36, Adler et al., BMJ 321:412-419, 2000
CVD Outcomes in Elderly with DM
   and Systolic Hypertension
                   Syst-Eur                 SHEP

 BP (mmHg)          8.6/3.9             9.8/2.2
 Mortality           64%                  26%
 CVD events          68%                  34%
 Strokes             86%                  22%
 CHD events           58%                  56%

              Syst-Eur Trial, NEJM 340:677-684, 1999
              SHEP, JAMA 265:352-364, 1991
              Curb et al, JAMA 276:1886-1892, 1996
How Do ACE Inhibitors  CVD?

               • Endothelial
                 dysfunction is an
                 early and common
                 manifestation of
 Endothelium     atherosclerotic
                 CVD
               • ACE inhibitors
                 improve endothelial
                 dysfunction
                       HOPE: Cardiovascular Benefits of
                        Ramipril in People with Diabetes
                                                                                0.16
                                Primary Outcome                                           All Mortality
                     0.2
                                  Placebo

                                  Ramipril
                                                                                0.08
Kaplan-Meier rates




                     0.1

                                                   RR=0.75 (0.64-0.88)                                        RR=0.76 (0.63-0.92)
                                                    p=0.0004                                                   p=0.004
                       0                                                          0
                            0        400          800     1200        1600            0      400            800     1200    1600


                     0.16                                  0.08                                  0.12
                                MI                                    Stroke                                CV Death

                     0.08                                  0.04                                  0.06



                                      RR=0.78 (0.64-0.94)                    RR=0.67 (0.5-0.9)                     RR=0.63 (0.49-0.79)
                                       p=0.01             0
                                                                              p=0.0074              0
                                                                                                                    p=0.001
                       0
                            0              1000         2000      0            1000          2000       0            1000           2000

                                                        Duration of follow-up (days)
       Diabetes Mellitus:
    Number Needed to Treat


15 high risk people with diabetes
would have to be treated with
ramipril for 4.5 years to prevent
1 from having an MI, stroke, CV
death, hospitalization for CHF,
revascularization, overt
nephropathy, laser therapy or
renal failure
          HOPE-DM Summary
• In people with diabetes at risk for
  CVD, addition of ramipril to other
  effective therapies prevents:
   CV death, strokes and MI
   Total mortality
   Revascularization
   Diabetic nephropathy
• The benefit is independent of the
  effect on BP
• The only adverse event is a 5% excess
  of cough
     EUROPA: Primary Endpoint
         % CV death, MI or cardiac arrest
14

12       RRR: 20%                             Placebo
         p = 0.0003
10
                                              Perindopril
8

6

4

2

0
     0    1      2        3        4       5 Years

         Placebo annual event rate: 2.4%
Heart Protection Study:
      Objectives
To assess the effects of simvastatin 40
mg daily and of antioxidant vitamin
supplementation (600 mg vitamin E, 250
mg vitamin C, 20 mg beta-carotene
daily) on total mortality and cause-
specific mortality in a wide range of
patients at high risk of CHD

        Adapted from Eur Heart J 1999; 20:725-41
          HPS: Patient Population


        CHD                     20,536                     Hypertension
   n=13,379 (65%)              Subjects                    n=8,455 (41%)


  with MI      no MI                                     with CHD     no CHD
8,510 (41%) 4,869 (24%)                                 5,595 (27%) 2,860 (14%)



         CVD                        PVD                     Diabetes
     n=3,280 (16%)             n=6,748 (33%)               n=5,963 (29%)


  with CHD    no CHD    with CHD    no CHD     with CHD     no CHD
 1,458 (7%) 1,822 (9%) 4,042 (20%)2,706 (13%) 1,978 (10%) 3,985 (19%)

                          Eur Heart J 20:725-41, 1999
           Simvastatin: Vascular
          Events by Prior Disease
Baseline feature     Statin     Placebo Risk ratio and 95% CI
                   (n=10,269) (n=10,267)
    Previous MI     1,007      1,255
  Other CHD (not MI)452         597
    No prior CHD
       CVD            182        215
       PVD            332       427
      Diabetes        279       369

  ALL PATIENTS      2,042     2,606                24% SE 2.6 reduction
                    (19.9%)   (25.4%)                  (2P<0.00001)

                                    0.4 0.6 0.8 1.0 1.2 1.4
    Lancet 360:7-22, 2002
                                    Statin better Statin worse
       CDA Lipid Guidelines
• People with diabetes should be treated to
  achieve the following target lipid goals
  [Grade B, Level 2):
• High risk
   LDL-C 2.5 mmol/L
   TC/HDL-C ratio ≤ 4
• Low to moderate risk
   LDL-C 3 mmol/L
   TC/HDL-C ratio ≤ 5
 Benefit of a Multifactorial Approach
     to Diabetes Care: Steno 2
• 160 patients randomized to either conventional
  care by family doc +/- specialist or intensive
  multidisciplinary care at the Steno Diabetes Clinic
• 8 years of follow-up
• Intervention Group
    Behavioral and drug therapies aimed at achieving targets
     in glycemia, lipids, blood pressure and microalbuminuria
    Multidisciplinary care every 3 months
    ASA and ACE inhibitors (independent of BP) given for
     vascular protection
• Control Group
    Conventional diabetes care aimed at achieving clinical
     practice guideline targets
            From P Gaede, et al. NEJM 348:383-393, 2003
From Gaede et al, NEJM 348:383, 2003
            Steno 2:
Effect on BP, Lipids and Glycemia
                                                                         Intensive
                                                                         therapy
  80
                P<0.001                                 P=0.21           Conventional
                                                                         therapy

  60                           P=0.19
                                           P=0.001
  40

  20 P=0.06

   0   Glycosylated Cholesterol Triglycerides Systolic BP Diastolic BP
       Hemoglobin < 4.49 mmol/L <1.69 mmol/L<130 mm Hg <80 mm Hg
       <6.5%


           From P Gaede et al, NEJM 348:383-393, 2003
   Steno 2: Effects of Intensive
 Therapy on Combined CV Outcomes
                 60
                           P=0.007
                 50
                                  Conventional therapy
Primary          40
composite                         Intensive therapy
endpoints 30
                 20

                 10

                 0
                     0      12    24 36 48 60 72                 84    96
  No. at Risk                     Months of Follow-up
  Conventional        80     72    70    63    59     50   44   41    13

  Intensive Rx        80     78    74    71    66     63   61   59    19

                From P Gaede, et al. NEJM 348:383-393, 2003
   Optimizing Diabetes Care:
 Number Needed to Treat (NNT)
• NNT = 1/absolute risk reduction (AAR)
• AAR = Event rate (control) – event rate
  (treatment)
• Microvascular complications
   UKPDS ( blood glucose)                    39.2
   UKPDS ( blood pressure)                   12.2
   Steno ( BG, BP, lipid and UAE)             1.5
• Major CHD
   HOT study                                  16
   4S study                                    5
   CARE study                                 12
• Screening for breast cancer                  1000
            From P Gaede et al, NEJM 348:383-393, 2003
UKPDS: Priorities for and Benefits of
    CVD Reduction in Diabetes

•   LDL-C
•   HDL-C
•   A1C
•   Systolic BP
•   Smoking cessation


    Adapted from RC Turner, et al. UKPDS, BMJ 316:823-828, 1998
        CDA Clinical Practice Guidelines
             Macrovascular Complications,
             Dyslipidemia and Hypertension

Approximately 80% of people with diabetes
 mellitus will die as a result of vascular event
   To reduce this excessive risk, all coronary risk
    factors must be addressed and treated aggressively
2003 CDA Recommendation
 The 1st priority in the prevention of diabetes
 complications should be reduction in CV risk by
 vascular protection through a comprehensive
 multifaceted approach…

 CDA Clinical Practice Guidelines. Can J Diabetes 27(suppl 2):S58-S63, 2003
CDA Clinical Practice Guidelines

  Priority for CVD Risk Reduction

                Vascular Protection


             Blood Pressure Control


                   Renal Protection
  Adapted from CDA CPG. Can J Diabetes 27(suppl 2):S58-S63, 2003
      2003 CDA Guidelines:
     Cardiovascular Protection
                                       In all patients
 1. Vascular Protection                •   ACE inhibitor
                                       •   ASA
                                       •   Lipid Control (statin)
2. Hypertension Control                •   BP Control
                                       •   Also as required:
                                            Glycemic control
3. Control of Nephropathy
                                            Lifestyle
                                            Smoking cessation


    Adapted from CDA CPG. Can J Diabetes 27(suppl 2):S58-S63, 2003
         2003 CDA guidelines:
    Important Messages for the Management
            of People with Diabetes
• Vascular protection is the first priority
• Aggressive multifactorial diabetes care  CV risk
      Secondary Prevention

Drugs:
 Statins (cholesterol lowering)
 ACE inhibitors ( blood pressure)
 Aspirin (blood thinner)
 Beta Blockers ( blood pressure)
The SuperPill
Guidelines on Vascular Protection:
 Translation to Clinical Practice
• Lifestyle modification
      body weight
     Regular physical activity 150’/week  4h/week
•   ACEI
•    Cholesterol - statins
•    Blood pressure – ACEI/ARB + others
•    Hyperglycemia – OHA ± insulin
•   Low dose ECASA
•   Smoking cessation
Thank you

Questions?

				
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