Cardiovascular Disease and the Patient with Diabetes and Metabolic Syndrome

1
Cardiovascular Disease and the Patient
with Diabetes and Metabolic Syndrome Nathan D.
Wong, PhD, FACC, FAHA Professor and
Director Heart Disease Prevention
Program Division of Cardiology University of
California, Irvine President, American Society
for Preventive Cardiology
2
Presenter Disclosure

• Dr. Wong has received research support through
  Bristol-Myers Squibb, Novartis, and Forest
  Laboratories through the University of
  California, Irvine

3
Presentation Objectives

• Review the epidemiology implicating metabolic
  syndrome and diabetes in cardiovascular risk
• Discuss the clinical trial evidence for the role
  of lifestyle management, glycemic, lipid, and
  blood pressure control.
• Address the ABCs of lifestyle and clinical
  management of metabolic syndrome and diabetes
  aimed to reduce cardiovascular disease risk.

4
Diagnosed Diabetes in the US 2008
CDC BRFSS Self-Reported Diabetes 8.2 Nationwide
http//apps.nccd.cdc.gov/brfss/list.asp?catDByr
2008qkey1363stateAll
5
Prevalence of physician-diagnosed diabetes in
Adults age 20 and older by race/ethnicity and sex
(NHANES 2005-2006). Source NCHS and NHLBI. NH
non-Hispanic.
6
The Continuum of CV Risk in Type 2 Diabetes
Adapted from American Diabetes Association.
Diabetes Care. 2003263160-3167. Tsao PS, et al.
Arterioscler Thromb Vasc Biol. 199818947-953. Hs
ueh WA, et al. Am J Med. 1998105(1A)4S-14S. Amer
ican Diabetes Association. Diabetes Care.
199821310-314.
7
Diagnostic Criteria for Metabolic Syndrome
Modified NCEP ATP III
3 Components Required for Diagnosis
AHA/NHLBI Scientific Statement Circulation 2005
112e285-e290.
8
IDF Criteria Abdominal Obesity and Waist
Circumference Thresholds

• AHA/NHLBI criteria 102 cm (40 in) in men, 88
  cm (35 in) in women
• Some US adults of non-Asian origin with marginal
  increases should benefit from lifestyle changes.
  Lower cutpoints ( 90 cm in men and 80 cm in
  women) for Asian Americans

Alberti KGMM et al. Lancet 20053661059-1062.
Grundy SM et al. Circulation 20051122735-2752.
9
Prevalence of the Metabolic Syndrome Among US
Adults NHANES 1988-1994
Age (years)
Ford E et al. JAMA. 2002(287)356.
1999-2002 Prevalence by IDF vs. NCEP Definitions
(Ford ES, Diabetes Care 2005 28 2745-9)
(unadjusted, age 20) NCEP 33.7 in men and
35.4 in women IDF 39.9 in men and 38.1
in women
10
Diabetes and CVD

• Atherosclerotic complications responsible for
• 80 of mortality among patients with diabetes
• 75 of cases due to coronary artery disease (CAD)
• Results in gt75 of all hospitalizations for
  diabetic complications
• 50 of patients with type 2 diabetes have
  preexisting CAD. (This number may be less now
  that more younger people are diagnosed with
  diabetes.) 
• 1/3 of patients presenting with myocardial
  infarction have undiagnosed diabetes mellitus

Lewis GF. Can J Cardiol. 199511(suppl
C)24C-28C Norhammar A, et.al. Lancet
20023592140-2144
11
Risk of Cardiovascular Events in Patients with
Diabetes Framingham Study
__________________________________________________
_______________

• Age-adjusted
• Biennial Rate Age-adjusted
• Per 1000 Risk Ratio
• Cardiovascular Event Men Women Men
  Women
• Coronary Disease 39 21 1.5 2.2
• Stroke 15 6 2.9 2.6
• Peripheral Artery Dis. 18 18 3.4
  6.4
• Cardiac Failure 23 21 4.4
  7.8
• All CVD Events 76 65
  2.2 3.7
• Subjects 35-64 36-year Follow-up
  Plt.001,Plt.0001

__________________________________________________
_______________
12
Diabetes as a CHD Risk Equivalent Type 2 DM and
CHD 7-Year Incidence of Fatal/Nonfatal MI (East
West Study)
Plt0.001
Plt0.001
45.0
7-year incidence rate of MI
20.2
18.8
3.5
No Diabetes
Diabetes
CHDcoronary heart disease MImyocardial
infarction DMdiabetes mellitus
Haffner SM et al. N Engl J Med. 1998339229-234.
13
Cardiovascular Disease (CVD) and Total
Mortality U.S. Men and Women Ages 30-74
(Risk-factor adjusted Cox regression) NHANES II
Follow-Up (n6255)




















plt.05, plt.01, plt.0001 compared to none
Malik and Wong, et al., Circulation 2004 110
1245-1250.
14
Odds of CVD Stratified by CRP Levels in U.S.
Persons (Malik and Wong et al., Diabetes Care
2005 28 690-3)

Odds Rat io

• plt.05, plt.01, plt.0001 compared to no
  disease, low CRP
• CRP categories gt3 mg/l (High) and lt3 mg/L
  (Low)
• age, gender, and risk-factor adjusted logistic
  regression (n6497)

15
Example of Significant Coronary Calcification
from Multidetector CT (Siemens Sensation 64)
scanner
16
10-Year CHD Event Rates (per 1000 person years)
by Calcium Score by CAC Categories in Subjects
with Neither MetS nor DM, MetS only, or DM
Coronary Heart Disease
CHD events per 1000 person years
Diabetes MetS Neither MetS/DM
0 1-99 100-399 400
Coronary Artery Calcium Score
Malik and Wong et al. (AHA 2009)
17
Under-Treatment of Cardiovascular Risk Factors
Among U.S. Adults with Diabetes

• NHANES Survey 2001-2002, 532 (projected to 15.2
  million) or 7.3 of adults aged gt/18 years had
  diabetes
• 50.2 not at HbA1c goal lt7
• 64.6 not at LDL-C goal lt100 mg/dl
• 52.3 not at recommended HDL-C gt/40 (M), gt/50
  (F)
• 48.6 not at recommended triglycerides lt150 mg/dl
• 53 not at BP goal of lt130/80 mg/dl
• Overall, only 5 of men and 12 of women at goal
  for HbA1c, BP, and LDL-C simultaneously

Malik S, Wong ND et al. Diab Res Clin Pract
200777126-33.
18
Summary of Care ABC's for Providers
19
Summary of Care ABC's for Providers
20
A1c TargetAspirin Therapy

• A1c Target In persons with diabetes, glucose
  lowering to achieve normal to near normal plasma
  glucose, as defined by the HbA1clt7
• Aspirin Daily Patients with type 2 DM gt40 years
  of age or with prevalent CVD, OR those with
  metabolic syndrome without DM who are at
  intermediate or higher risk (e.g., gt10 10-year
  risk of CHD)

21
Type 2 Diabetes A1C Predicts CHD
CHD Mortality Incidence () in 3.5 Years
All CHD Events Incidence () in 3.5 Years

12
25

10
20
8
15
6
10
4
5
2
0
0
Lowlt6
High gt7.9
Middle 6-7.9
Middle 6-7.9
High gt7.9
Lowlt6
A1Chemoglobin A1C Plt0.01 vs lowest
tertile Plt0.05 vs lowest tertile
Adapted with permission from Kuusisto J et al.
Diabetes. 199443960-967.
22
UKPDS Relative Risk Reduction for Intensive vs.
Less Intensive Glucose Control
P0.03
P0.05
P0.02
Plt0.01
relative risk reduction
Plt0.01
Over 10 years, HbA1c was 7.0 (6.2-8.2) in the
intensive group (n2,729) compared with 7.9
(6.9-8.8) in the conventional group (n1,138).
UKPDS Group. Lancet. 1998352837-853.
23
UKPDS Metformin Sub-Study CHD Events
n 411 951 342 411 342 Events 73 139 39 36 1
6
UKPDS 34, Lancet 352 854, 1998
24
Recent Trials Show No Reduction in CV Events with
More Intensive Glycemic Control
ACCORD Primary Outcome
ADVANCE Primary Outcome
Cumulative incidence ()
Patients with events ()
0 12 24 36 48
60
Months of follow-up
Number at Risk Intensive 5570 5369
5100 4867 4599 1883 Standard 5569
5342 5065 4808 4545 1921
Number at Risk Intensive 5128 4843 4390
2839 1337 475 448 Standard 5123
4827 4262 2702 1186 440 395
1ACCORD Study Group. N Engl J Med.
20083582545-2559. 2ADVANCE Collaborative Group.
N Engl J Med. 20083582560-2572.
25
Was Intensive Glycemic Control Harmful? A closer
look at ACCORD AND ADVANCE

• ACCORD was discontinued early due to increased
  total and CVD mortality in the intensive arm.
  Major hypoglycemia 3-fold higher too.
• And the VA Diabetes Trial did show severe
  hypoglycemia to be a powerful predictor of CVD
  events.
• But a more recent analysis of ACCORD just
  published (Diabetes Care, May 2010) showed deaths
  to be associated with unsuccessful intensive
  therapy where A1c remained high.
• However, in both ACCORD AND ADVANCE, the
  subgroups without macrovascular disease at
  baseline had an actual benefit in the primary
  endpoint.

26
2009 ADA/AHA/ACC Statement Recommendations

• Goal of A1clt7 remains reasonable
• for uncomplicated patients
• ACC/AHA Class I (A)
• and for those with macrovascular disease
• ADA Level B ACC/AHA Class IIb (A)
• Incremental microvascular benefit may be obtained
  from even lower goals
• ADA Level B ACC/AHA Class IIa (C)
• Less stringent goals may be appropriate for those
  with labile glucose control or with advanced
  micro- or macrovascular disease
• ADA Level C ACC/AHA Class IIa (C)

Circulation 2009 119 351-357
27
Summary of Care ABC's for Providers
28
Prevalence of Hypertension in Adults with
Diabetes NHANES III 1988-1994
with Hypertension
BP 130/85 or therapy for hypertension
Geiss LS, et al. Am J Prev Med. 20022242-48.
29
HTN Control Rate Remains Poor in US Adults with
MetS and DM from NHANES 2003-2004(Wong ND et
al., Arch Intern Med 2007)

• Only 35 of those with DM on treatment for HTN
  are controlled to a goal of lt130/80 mmHg
• Only 47 of those with MetS on treatment for HTN
  have a blood pressure of lt130/85 mmHg
• Thus, JNC-7 recommendations to begin with
  combination therapy to improve goal attainment
  should be adhered to, esp. if SBP/DBP exceeds
  20/10 mmHg from goal.

30
UKPDS Effects of Tight vs. Less-Tight Blood
Pressure Control
UK Prospective Diabetes Study Group. BMJ. 1998
317703-713.
31
HOT Trial Effect of BP Control on CV Event Rate
Patients without Diabetes
Patients with Diabetes
Major CV events per 1000 patient-years
Diastolic Blood Pressure goal
Hansson L et al. Lancet. 19983511755-1762.
32
ACCORD Effects of Intensive BP Control (NEJM
2010 362 1575-85)

• 4733 participants with type 2 DM randomly
  assigned to intensive therapy targeting a SBP
  lt120 mmHg vs. standard therapy targeting a
  SBPlt140 mmHg.
• Mean follow-up 4.7 years.
• SBP after 1 year was 119 vs. 133 mmHg.
• No difference in the primary endpoint of nonfatal
  MI, stroke, or CVD death (annual rate) 1.9 vs.
  2.1 (HR0.88), p0.20.
• Stroke annual rates significantly lower 0.32 vs.
  0.53, HR0.59, p0.01. Thus, overall benefit
  may be greater in populations with higher stroke
  risk.

33
Scientific Statements Diabetes, CV Disease and
Hypertension

• JNC VII Report on Diabetic Hypertension
• BP goal (lt130/80 mm Hg)
• Commonly requiring combinations of 2 drugs
• ACEIs, CCBs, Thiazide-diuretics, ?-blockers, and
  ARBs shown to reduce CVD/CVA risk
• ACEIs/ARBs reduce progression of diabetic
  nephropathy and reduce albuminuria
• ARBS reduce progression of macroalbuminuria

Grundy SM, et al. Circulation. 19991001134-1146.
Chobanian AV, et al. JAMA. 20032892560-2572.
34
Summary of Care ABC's for Providers
35
LDL-C as a Predictor of CAD in Patients with
Diabetes
Hazard ratio
LDL-C quartile mean
LDLlow-density lipoprotein cholesterol
CADcoronary artery disease.
Adapted with permission from Howard BV et al.
Arterioscler Thromb Vasc Biol. 200020830-835.
36
CARDS Primary Endpoint
Relative Risk Reduction 37 (95 CI 17-52)
15
P 0.001
Placebo 127 events
10
Cumulative Hazard ()
Atorvastatin 83 events
5
0
0
1
2
3
4
4.75
Years
651
1022
1306
1351
Placebo
1410
305
328
694
1074
1361
1392
Atorva
1428
Colhoun HM et al. Lancet 2004364685-96.
37
HPS Substudy First Major Vascular Event by
LDL-C and Prior Diabetes Status
Simvastatin(10,269)
Placebo(10,267)
Rate ratio (95 CI)
LDL-C anddiabetes status
Statin better
Placebo better
lt116 mg/dL
With diabetes
191 (15.7)
252 (20.9)
No diabetes
407 (18.8)
504 (22.9)
³116 mg/dL
With diabetes
410 (23.3)
496 (27.9)
No diabetes
1,025 (20.0)
1,333 (26.2)
24 reduction(Plt0.0001)
All patients
2,033 (19.8)
2,585 (25.2)
0.4
0.6
0.8
1.0
1.2
1.4
HPS Collaborative Group. Lancet.
20033612005-2016.
38
Reducing CVD Risk with Statin Therapy in Patients
with Diabetes

• Number needed to treat to prevent 1 major CVD
  event
• From HPS and 4S
• Without coronary disease 14
• With coronary disease 4
• From meta-analysis
• Without vascular disease 39
• With vascular disease 19

HPS Collaborative Group. Lancet.
20033612005-2016. Pyorala K, et al. Diabetes
Care. 199720614-620 Kearney PM
Lancet2008371227-239
39
Lipid Goals for Persons with Metabolic Syndrome
and DM (Grundy et al., 2005)

• LDL-C targets, ATP III guidelines
• High Risk CHD, CHD risk equivalents (incl. DM
  or gt20 10-year risk) lt100 mg/dL (option lt70
  mg/dl if CVD present)
• Moderately High Risk (10-20) 2 RF lt130 mg/dL,
  option lt100 mg/dL
• Moderate Risk (2 RF, lt10) lt130 mg/dL
• -- Low Risk 0-1 RF lt160 mg/dL
• HDL-C gt40 mg/dL (men)
• gt50 mg/dL (women)
• TG lt150 mg/dL

40
Specific Dyslipidemias Elevated Triglycerides

• Non-HDL Secondary Target
• Non-HDL TC HDL
• Non-HDL secondary target of therapy when serum
  triglycerides are ?200 mg/dL (esp. 200-499 mg/dl)
• Non-HDL goal LDL goal 30 mg/dL

41
Specific Dyslipidemias Low HDL Cholesterol

• Management of Low HDL
• LDL is primary target of therapy
• Weight reduction and increased physical activity
  (if the metabolic syndrome is present)
• Non-HDL is secondary target of therapy (if
  triglycerides ?200 mg/dL)
• Consider nicotinic acid or fibrates (for patients
  with CHD or CHD risk equivalents)

42
ACCORD Lipid Study Results (NEJM 2010 362
1563-74)

• 5518 patients with type 2 DM treated with open
  label simvastatin randomly assigned to
  fenofibrate or placebo and followed for 4.7
  years.
• Annual rate of primary outcome of nonfatal MI,
  stroke or CVD death 2.2 in fenofibrate group vs.
  1.6 in placebo group (HR0.91, p0.33).
• Pre-specified subgroup analyses showed possible
  benefit in men vs. women and those with high
  triglycerides and low HDL-C.
• Results support statin therapy alone to reduce
  CVD risk in high risk type 2 DM patients.

43
Summary of Care ABC's for Providers
44
Smoking Cessation

• What you do does matter. Physicians who intervene
  influence cigarette smoking behavior.
• How do you get your patients to quit smoking?
• Identify i.e. in vitals signs
• Interventions as brief as 3 minutes can
  significantly increase quit rates
• Dose dependent changes in behavior
• 5-10 may quit within 1 year with MD advice alone
  
• Smoking cessation aids

45
EFFICACY OF SMOKING CESSATION INTERVENTIONS (1
YEAR QUIT RATES)

• ACUPUNCTURE ----
• HYPNOSIS ----
• PHYSICIAN ADVICE 6
• SELF-HELP METHODS 14
• NICOTINE PATCH 11-15
• PHYSICIAN ADVICE/SELF-HELP PAMPHLETS 22
• AVERSIVE SMOKING (RAPID PUFFING) 25
• PHARMACOTHERAPY/BEHAVIORAL THERAPY 25
• BEHAVIORAL STRATEGIES (GROUP PROG.) 40

46
The 5 As for Effective Smoking Intervention

• ASK about smoking
• ADVISE to quit
• ASSESS willingness to make a quit attempt
• ASSIST if ready - offer therapy and consultation
  for quit plan and if not, then offer help when
  ready
• ARRANGE follow up visits

47
Summary of Care ABC's for Providers
48
CHD Mortality Rates(by Degree of Glucose
Tolerance)
Incidence rate/1000
Indicates patients known to have diabetes prior
to the study. CHDcoronary heart disease
NGTnormal glucose tolerance IGTimpaired
glucose tolerance
Adapted with permission from Eschwege E et al.
Horm Metab Res Suppl. 19851541-46.
49
Most Cardiovascular Patients Have Abnormal
Glucose Metabolism
GAMI n 164
EHS n 1920
CHS n 2263
18
27
31
35
37
37
36
45
34
Prediabetes
Type 2 Diabetes
Normoglycemia
GAMI Glucose Tolerance in Patients with Acute
Myocardial Infarction study EHS Euro Heart
Survey CHS China Heart Survey
Anselmino M, et al. Rev Cardiovasc Med.
2008929-38.
50
Diabetes Prevention Program Protocol Design
51
Diabetes Prevention Program Reduction in
Diabetes Incidence
52
Benefit of Comprehensive, Intensive Management
STENO 2 Study
Primary End PointCV events ()
60

• Treatment Goals
• Intensive TLC
• HgbA1c lt6.5
• Cholesterol lt175
• Triglycerides lt150
• BP lt130/80

Conventional Therapy
50
n 80
Intensive Therapy
40
30
20
n 80
10
0
0
12
24
36
48
60
72
84
96
Months of Follow Up
Gaede, P. et al, NEJM 2003348390-393
53
Summary of Care ABC's for Providers
54
Metabolic Syndrome Lifestyle Management Obesity
/ Physical Activity

• Obesity / weight management low fat high
  fiber diet resulting in 500-1000 calorie
  reduction per day to provide a 7-10 reduction on
  body weight over 6-12 mos, ideal goal BMI lt25
• Physical activity at least 30, pref. 60 min
  moderate intensity on most or all days of the
  week as appropriate to individual

Grundy SM, Hansen B, Smith SC, et al. Clinical
management of metabolic syndrome. Report of the
American Heart Association / National Heart,
Lung, and Blood Institute / American Diabetes
Association Conference on Scientific Issues
Related to Management. Circulation 2004 109
551-556
55
(No Transcript)
56
Physical Inactivity A Call to Arms
10,000 Steps Daily
30 minutes most days
57
Physical Activity Recommendations

• Aerobic exercise a minimum of 30 minutes, 5 times
  weekly
• Optimal physical activity is at least 30 minutes
  daily
• Resistance exercise training using free weights
  or machines 2 days a week in the absence of
  contraindications

58
Summary of Care ABC's for Providers
59
ADA Nutritional Guidelines

• Patients with pre-diabetes should receive
  individualized Medical Nutrition Therapy (MNT)
• Weight loss recommended for all overweight or
  obese individuals who have or are at risk for
  diabetes
• Physical activity and behavior modification
  effective for weight loss and maintenance
• Fiber 14 g/1000 kcal intake
• Saturated fat 7 with minimal
  trans fat

60
Therapeutic Lifestyle ChangesNutrient
Composition of TLC Diet

• Nutrient Recommended Intake
• Saturated fat Less than 7 of total calories
• Polyunsaturated fat Up to 10 of total calories
• Monounsaturated fat Up to 20 of total calories
• Total fat 2535 of total calories
• Carbohydrate 5060 of total calories
• Fiber 2030 grams per day
• Protein Approximately 15 of total
  calories
• Cholesterol Less than 200 mg/day
• Total calories (energy) Balance energy intake and
  expenditure to maintain desirable body
  weight/ prevent weight gain

61
Effect of Mediterranean-Style Diet in the
Metabolic Syndrome

• 180 pts with metabolic syndrome randomized to
  Mediterranean-style vs. prudent diet for 2 years
• Those in intervention group lost more weight
  (-4kg) than those in the control group (0.6kg)
  (plt0.01), and significant reductions in CRP and
  Il-6

Esposito K et al. JAMA 2004 292(12) 1440-6.
62
Conclusions

• Metabolic syndrome and diabetes are associated
  with increased levels of atherosclerosis and
  cardiovascular disease event risk
• Lifestyle measures focusing on weight reduction,
  dietary, and physical activity guidance are
  crucial in initial management.

63
Conclusions (cont.)

• Clinical management emphasizes achievement of BP
  and lipid goals, glycemic control, and
  antiplatelet therapy.
• Multidisciplinary programs including primary care
  physicians, specialists (endocrinologists and
  cardiologists), dietitians, and exercise
  specialists are key for the successful management
  of these conditions.

64
Thank you for your attention! Now Published from
Informa Healthcare
For more information visit our website at
www.heart.uci.edu
65
Question 1

• Which of the following statements is true?
• Diabetes prevalence is higher in African
  Americans and Hispanics compared to Caucasians
• The prevalence of diabetes is approaching the
  prevalence of obesity
• The impact of diabetes on CVD is similar in men
  and women
• All of the above

66
Question 2

• What are the recommended target levels for LDL-C
  and BP for most uncomplicated patients with DM?
• LDL-C lt100 mg/dl and 120/80 mmHg
• LDL-C lt100 mg/dl and 130/80 mmHg
• LDL-C lt70 mg/dl and 140/90 mmHg
• None of the above

67
Question 3

• Diabetes has been considered a CHD risk
  equivalent because
• Nearly all persons with CHD also have diabetes
• Persons with diabetes have a similar risk of
  developing CHD than those who already have CHD
  (e.g., myocardial infarction)
• Both a and b

68
Question 4

• Recent large clinical trials such as ACCORD and
  ADVANCE suggest
• Aggressive glycemic control significantly reduces
  the risk of future CVD events in high risk
  persons with diabetes
• The HbA1c target should be set closer to 6 than
  the conventional target of lt7
• A less stringent goal than lt7 for HbA1c might be
  considered in more complicated patients with
  diabetes (e.g., those difficult to control, with
  known macrovascular disease, or with
  long-standing diabetes)