Transcript Metabolic Syndrome, Diabetes and Cardiovascular Diseases

Metabolic Syndrome, Diabetes and
Cardiovascular Diseases
Jacques Genest MD
Cardiovascular Genetics Laboratory
McGill University Health Center
Disclosure J. Genest MD
Advisory Board, Speaker’s Bureau, Consultant, Grants
 AstraZeneca
 Merck Frosst
 Schering Plough
 Pfizer
 Novartis
 Biotech: Resverlogix
Stock ownership: none
CVD Prevention: Guiding Principles
Target Adults for Screening
(unless compelling reason)
Determine Cardiovascular Risk
Institute Lifestyle Changes
Treat according to Level of Risk
Genest J et al. Can J Cardiol 2009 Oct;[in press].
Metabolic Syndrome
• Association of several metabolic
abnormalities
• Uniform classification remains elusive
• International Diabetes Federation
classification
• Higher long-term risk than FRS estimates
• Measuring hsCRP may help stratify risk
C
Metabolic Syndrome:
Meta-analysis of Cardiovascular Risk
Motillo S, Eisenberg M. 2009 Unpublished
Classification of the Metabolic Syndrome
(Harmonized definition -2009)
• Central obesity:
 Europids Men >94 cm Women >80 cm







South Asians Men 90 cm Women 80 cm
Chinese
Men 90 cm Women 80 cm
Japanese
Men 90 cm Women 80 cm
Ethnic south and central Americans: Use South Asian recommendations
First Nations use South Asian recommendations until more specific data are
available.
Sub-Saharan African: Use European data until more specific data are available
Eastern Mediterranean and middle east (Arab) populations: Use European data
• With these factors:




3/5
Plasma triglycerides >1.7 mmol/l
HDL cholesterol Men <1.03 mmol/l Women <1.3 mmol/l
Blood pressure >130/85 mm Hg (or treatment for hypertension)
Fasting plasma glucose >5.6 mmol/l
Alberti K. Circulation 2009;120:1640
Guiding Principles
Target Adults for Screening
(unless compelling reason)
Determine Cardiovascular Risk
Institute Lifestyle Changes
Treat according to Level of Risk
Genest J et al. Can J Cardiol 2009 Oct;[in press].
Risk Assessment
CV risk assessment remains imperfect
• Framingham Risk Score (CVD) [FRS may
underestimate risk in some patients]
• Reynolds Risk Score (CVD) [RRS web-based,
includes family history and hsCRP]
We now recommend Cardiovascular Risk (Total CVD)
assessment, not only CAD. As CHEP and CDA do.
Diabetes and CV Disease
♦ Raging Global Epidemic
♦ A Major Risk Factor for CV Disease
♦ Worsens CV Outcomes in Diabetes
Rx Targets may be Misleading
Diabetes: the growing global
burden
Prevalence estimates of diabetes mellitus 2025
1
No data
< 2%
2–5%
5–8%
8–11%
11 –14%
14–17%
> 17%
IDF:2
• Diabetes currently affects 246 million people worldwide
• It is expected to affect 380 million by 2025
1Adapted
from IDF. E-Atlas. Available at: www.eatlas.idf.org (accessed 05.03.07).
third edition © International Diabetes Federation, 2006.
2Diabetes Atlas,
Complications of Diabetes
Stroke
Diabetic
Retinopathy
Leading cause
of blindness
in adults
2- to 4-fold increase in
cardiovascular
mortality and stroke
Cardiovascular
Disease
8/10 individuals with
diabetes die from CV
events
Diabetic
Nephropathy
Leading cause of
end-stage renal
disease
Diabetic
Neuropathy
Leading cause of
non-traumatic lower
extremity amputations
Adjusted cummulative incidence
Lifetime Risk for CHD
Men
0.7
Women
0.7
0.6
0.6
0.5
0.5
0.4
0.4
30%
0.3
0.3
0.2
0.2
0.1
0.1
0
0
50
60
70
80
90
16%
50
60
70
80
90
Attained Age
Lloyd Jones et al
Circ 2006;113:791
Diabetes & Lifetime Risk for CHD
Adjusted cummulative incidence
Diabetic
Non Diabetic
Men
0.7
67%
Women
0.7
0.6
0.6
0.5
0.5
0.3
0.3
0.2
0.2
0.1
0.1
0
0
57%
Diabetes confers the highest lifetime risk for CHD of
0.4
0.4
any
single risk factor
30%
50
60
70
80
90
.
16%
50
60
70
80
90
Attained Age
Lloyd Jones et al
Circ 2006;113:791
Increased Risk of Cardiovascular Events Over 7 Years in Patients
With Type 2 Diabetes
Myocardial
Infarction
Stroke
CV Death
Nondiabetic –MI (n=1,304)
Diabetic –MI (n=890)
Nondiabetic +MI (n=69)
P<0.001*
Diabetic +MI (169)
P<0.001*
P<0.001*
CV = cardiovascular; -MI = no prior myocardial infarction; +MI = prior myocardial infarction
*For diabetes vs. no diabetes and prior MI vs. no prior MI
Haffner SM, et al. N Engl J Med. 1998;339:229–234.
MRFIT: Diabetes Amplifies Risk from Other Risk Factors
No Diabetes
Diabetes
125
91
*TC > 200 mg/dL
SBP > 120 mm Hg
Current smoker
59
47
31
22
12
6
0
1
2
No. of Additional RFs*
Stamler J et al. Diabetes Care 1993;16:434-444.
3
Identification of Individuals at High Risk of
Coronary Events– Recommendations
The following individuals with diabetes should be considered at
high risk for CV events (cont’d):
• Men <45 years and women <50 years with ≥1
of the following [Grade D, Consensus]:





Macrovascular disease (e.g. silent MI or ischemia, evidence of PAD,
carotid arterial disease or cerebrovascular disease)
Microvascular disease (especially nephropathy and retinopathy)
Multiple additional risk factors, especially with a family history of
premature coronary or cerebrovascular disease in a first-degree
relative
Extreme level of a single risk factor (e.g. LDL-C >5.0 mmol/L,
systolic BP >180 mm Hg)
Duration of diabetes >15 years with age >30 years.
Canadian Diabetes Association 2009
Fasting Glucose (mmol/L)
Diagnostic Criteria for Diabetes, IFG & IGT
(mg/dL)
8.5
126
Diabetes
7.5
100 6.5
5.5
4.5
3.5
2.5
IFG
IFG + IGT
Normal
glucose
IGT
4.5
6.5
IFG = Impaired fasting glucose
IGT = Impaired glucose tolerance
8.5
10.5
7.0
11.1
140
200
12.5
14.5
(mg/dL)
2-h Postload Glucose (mmol/L)
American Diabetes Association. Diabetes Care 2003;26(suppl 1):S5-S20.
‘Glucose triad’ of diabetes management
HbA1c ≥ 6,5%
Average long-term
glucose level
Fasting glucose
HbA1c = glycated haemoglobin
Post-meal
glucose
What is HbA 1c?
• Glycated Hb derived from non enzymatic addition
glucose to amino gps of Hb
• Concentration depends on both blood glucose & RBC
life span
• Because RBC’s in circulation ~ 120 days it represents
integrated glucose conc’n over preceding 8-12 weeks
• Free from large fluctuations in daily blood glucose
Diabetes and CV Disease
Outcomes
♦ Influences both Choice & Intensity CV Rx
♦ Some Diabetes Rx may Worsen Outcomes
♦ Diabetes Rx Targets may be Misleading
ANTI DIABETICS
Evidence Based Medicine?
Anti-Diabetic Drugs
• Sensitizers
•
Biguanides
Metformin# , buformin, phenformin
TZDs (PPAR)
Pioglitazone · Rivoglitazone† · Rosiglitazone · Troglitazone
Dual PPAR agonists Aleglitazar† · Muraglitazar, Tesaglitazar
Secretagogues K+ ATP



Sulfonylureas
1st generation: Acetohexamide · Carbutamide · Chlorpropamide · Gliclazide ·
Tolbutamide · Tolazamide
2nd generation: Glibenclamide (Glyburide)# · Glipizide · Gliquidoe ·
Glyclopyramie
3rd generation: Glimepirie
Meglitinides/"glinides“ Nateglinide · Repaglinie· Mitiglinide
GLP-1 analog
DPP-4 inhibitors
•
Analogs/other insulins
•
Other
•
•
•
•
Alpha-glucosidase inhibitors
Amylin analog
SGLT2 inhibitor
Other
Exenatide · Liraglutide† · Albiglutide†
Alogliptin† · Linagliptin† · Saxagliptin · Sitagliptin · Vildagliptn
fast acting (lispro · aspart · glulisine) · long acting (glargine · detemir) · NPH insulin
Acarbose · Miglitol · Vogliboe
Pramlintide
Dapagliflozin† · Remogliflozin† · Sergliflozin†
Benfluorex · Tolrestat
Metformin: WHO EM; Rivoglitazone: In clinical trials; phenformin: Withdrawn from market
Recommendations
The following antihyperglycemic agents (listed in alphabetical
order), should be considered to lower postprandial BG levels:
• Alpha-glucosidase inhibitors [Grade B, Level 2 (10)]
• DPP-4 inhibitors [Grade A, Level 1 (13,14,74)].
• Meglitinides (repaglinide, nateglinide) instead of
sulfonylureas [Grade B, Level 2 (75,76)]
• Premixed insulin analogues (i.e. biphasic insulin aspart
and insulin lispro/protamine) instead of regular/
NPH pre-mixtures [Grade B, Level 2 (72,73)]
• Rapid-acting insulin analogues (aspart, glulisine, lispro)
instead of short-acting insulin (i.e. regular insulin)
[Grade B, Level 2 (21,77,78)].
Nateglinide vs placebo: NAVIGATOR co-primary endpoint outcomes
Co-primary end
points
Nateglinide,
n=4645 (%)
Placebo, n=4661
(%)
HR (95% CI)
pa
Progression to
diabetes
36.0
33.9
1.07 (1.00–1.15)
0.05
Composite CV
events, extendedb
14.2
15.2
0.93 (0.83–1.03)
0.16
Composite CV
events, corec
7.9
8.3
0.94 (0.82–1.09)
0.43
a. two-sided test
b. cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization from unstable angina, heart failure, or arterial revascularization
c. cardiovascular death, nonfatal MI, nonfatal stroke, or heart-failure hospitalization
Holman RR et al. N Engl J Med 2010; available at:
http://www.nejm.org.
Oral Agent Classification
• α-Glucosidase inhibitors delay intestinal CHO abs’n
• Biguanides target hepatic insulin resistance
• Insulin secretagogues e.g. sulfonylureas that increase
pancreatic insulin secretion
• Insulin sensitizers= TZDs target adipocyte & muscle
insulin resistance
• Intestinal lipase inhibitors of fat abs’n that promote
weight loss in obesity
Target organs & actions:Oral
antihyperglycemics in DM
(metformin)
sulfonylureas
Cheng, A. Y.Y. et al. CMAJ 2005;172:213-226
AGI= α-glycosidase( acarbose)
Algorithm for the metabolic
management of type 2 diabetes
Diagnosis
Lifestyle intervention + metformin
No
Add basal insulin
most effective
No
HbA1c≥7%
Intensify insulin
No
Yesa
HbA1c≥7%
Add sulfonylurea
least expensive
Yesa
No
Add glitazoneb,c
HbA1c≥7%
Yesa
HbA1c≥7%
Add glitazone b
no hypoglycemia
Yesa
No
HbA1c≥7%
Yesa
Add basal insulin
Add sulfonylureac
No
Yesa
HbA1c≥7%
Add basal or intensify insulin
Intensive insulin + metformin +/- glitazoneb
Nathan et al. Diabetes Care. 2008;31:173-175.
AHA / ACCF Science Advisory: TZD
Drugs and Cardiovascular Risks
Summary recommendations regarding
TZD’s in cardiovascular disease:
– Should not be used with expectation of
benefit on CAD events
– Potential risk of increased heart failure
– Potential excess of events with
rosiglitazone (Avandia) versus
pioglitazone (Actos)
– Should not be initiated in Class III/IV CHF
TZD’s and Cardiovascular Risk. AHA/ACCF Science Advisory. Circulation 2010
New Hypoglycemic Agents
• Incretin effect = augmentation glucose/stimulated
insulin secretion by intestinally derived peptides
– Incretins released in presence of glucose and
nutrients in the gut
– Oral glucose load more effective than same
glucose given IV in releasing insulin
– Incretins rapidly inactivated by dipeptidyl
peptidase-4 (DPP4) = very short half-life
– Incretin pathway attenuated in type 2 diabetes
GLP-1 & GIP Degraded by the DPP-4 Enzyme
Meal
Intestinal
GLP-1 and
GIP
release
GLP-1 and GIP
Intact
X
DPP-4 inhibitor:
Sitagliptin
DPP-4
Enzyme
Rapid Inactivation
GLP-1, GIP
Metabolites
Half-life*
incretins ~ 2 minutes
GLP-1 and GIP
Actions
Deacon CF et al. Diabetes. 1995;44:1126–1131.
*Meier JJ et al. Diabetes. 2004;53:654–662.
GIP=glucose-dependent insulinotropic polypeptide
GLP= glucagon-like peptide
Attaining normal A1C reduce CV risk
in patients with type 2 DM?
• ACCORD: Action to Control Cardiovascular
Risk in Diabetes
• ADVANCE: Action in Diabetes and Vascular
Disease: PRETRAX AND DIAMICRON MR
CONTROLLED EVALUATION
• VADT: Veterans Affairs Diabetes Trial
ACCORD Glucose Arm
A1C < 6.0%
Any strategy
5.6 years duration
N ≈ 5000/group
A1C 7.0 -7.9 %
•Type 2 diabetes for > 3 months
•A1c of 7.5 to 11.0 %
•Eligible for lipid or BP component
•High risk of CVD events - clinical or
subclinical disease or 2 RF
•Age  55 with risk factors
 40 with established CV
Any strategy
RESEARCH QUESTION:
In middle-aged/older type 2 diabetics
at high risk for CVD events because
of existing CVD or risk factors, does a
Rx strategy targeting A1c < 6.0% reduce
CVD events more than A1c 7.0-7.9% target?
Baseline Characteristics:
Age 62yo; Duration diabetes 10 years
Existing CVD 35%; BMI 32; On insulin 35%
A1C mean 8.3% median 8.1%
1. ACCORD Study Group. N Engl J Med 2008;358:2545-59.
ACCORD: Treatment Effects on Glucose Control:
Median A1C at Each Study Visit
1. Adapted from ACCORD Study Group. N Engl J Med 2008;358:2545-59.
ACCORD: Hypoglycemia
Hypoglycemia
N (%)
Intensive
Therapy
n=5128
Standard
Therapy
n=5123
P value
Requiring medical
assistance
538
(10.5%)
179
(3.5%)
< 0.001
Requiring
any
assistance
830
(16.2%)
261
(5.1%)
< 0.001
1. Adapted from ACCORD Study Group. N Engl J Med 2008;358:2545-59.
ACCORD: Deaths in Intensive vs.
Standard Glycemic Control Gps
Standard
(N=5123)
Intensive
(N=5128)
N
203
257
%
4.0
5.0
% per yr
1.14
1.41
Deaths in ACCORD:
• HR = 1.22 (1.01-1.46); p=0.04
• Low absolute rates in both groups and low absolute risk
increase (0.27% per yr)
• Single medications, medication combinations, or increased
hypoglycemic events did not explain the increased mortality in
the intensive group
1. Adapted from ACCORD Study Group. N Engl J Med 2008;358:2545-59.
ACCORD: Conclusions
• In type 2 diabetics at high risk for CVD & an A1C of ≥7.5% a
Rx strategy targeting an A1C <6% vs. 7.0-7.9% increases
mortality over 3.5 years
• No significant effect of the glycemic intervention
demonstrated on the primary outcome
• Follow-up & analyses (epidemiologic & within baseline
subgroups) may add further insight
1. ACCORD Study Group. N Engl J Med 2008;358:2545-59.
Would attaining normal A1C reduce CV
risk in patients with type 2 DM?
• ACCORD: Action to Control Cardiovascular
Risk in Diabetes
• ADVANCE: Action in Diabetes and Vascular
Disease: PRETRAX AND DIAMICRON MR
CONTROLLED EVALUATION
• VADT: Veterans Affairs Diabetes Trial
Acute Complications and Effects
of Severe Hypoglycemia
Plasma glucose level
6
5
4
3
2
1
mmol/L
Increased Risk of
Cardiac Arrhythmia1
Progressive
Neuroglycopenia2
• Abnormal prolonged
cardiac repolarization
↑ QTc and QTd
• Sudden death
• Cognitive
impairment
• Unusual behaviour
• Seizure
• Coma, Brain death
1. Landstedt-Hallin L et al. J Intern Med. 1999; 246:299307
2. Cryer PE. J Clin Invest. 2007; 117(4):868-70
More Hypoglycemic Events Have Been Reported by
Patients Treated With a Sulfonylurea (Glyburide) vs.
Metformin or a Thiazolidinedione
Patients self-reporting
hypoglycemic events (%)
ADOPT (patients with new-onset diabetes)
50
P≤0.01 vs. Thiazolidinedione
38.7
40
30
20
10
9.8
11.6
Thiazolidinedione
Metformin
0
Sulfonylurea
Other studies have also shown an increased frequency of hypoglycemic
events in patients with type 2 diabetes treated with a sulfonylurea compared
with patients treated with metformin or Thiazolidinedione
Kahn SE et al. N Engl J Med. 2006; 355(23):2427-43
Bolen S et al. Ann Intern Med. 2007; 147(6):386-99
Survival: HbA1C and Diabetes
All Cause Mortality(3.9 yrs)
Oral Combo n=27,965
Oral / Insulin n=20,005
Lancet 2010
New Markers of CHD Risk: What to Look for, What
to Target?
Atherogenic Dyslipidemia
Triglycerides
 HDL cholesterol
Cholesterol/HDL cholesterol ratio
"Normal" LDL cholesterol but  apo B
Small, dense LDL and HDL
Postprandial hyperlipidemia
Inflammation
Insulin Resistance
Insulin resistance
Hyperinsulinemia
Hyperglycemia
Type 2 diabetes
Thrombotic State
 PAI-1
Fibrinogen
Thin
fibrous cap
Lipid
Core
Coronary
Atherosclerosis
Unstable Plaque
Inflammatory State
CRP
 Cytokines
Abdominal
Obesity
Metabolic Risk Factors
 Risk of Acute Coronary
Syndrome
Does It Make a Difference?? We Should Not Treat a Black Box!
Adapted from Després JP, et al. Progress in Obesity Research: 9; 2003:29-35.
Managing the High-Risk Patient with Type 2 Diabetes
and/or “Hypertriglyceridemic Waist”
Type 2
Diabetic Patient:
Hypertriglyceridemic Waist
Risk Factors
Hypertension
Coronary
Heart Disease
Dyslipidemia
Type 2
Diabetes
Treating the Cause
Treating
the Complications
Després JP et al. BMJ 2001;322:716-720.
Management of
Coronary Heart
Disease Risk
Primary Composite Endpoint* (%)
Intensive Multiple Risk Factor Management in
Patients with Type 2 Diabetes: STENO-2
60
N=160; follow-up = 7.8 years
50
Conventional Therapy
40
20% Absolute
Risk Reduction
30
20
Aggressive treatment of†:
Intensive Therapy†
10
0
0
12
24
36
48
60
72
Months of Follow-up
84
96
– Microalbuminuria with
ACEIs, ARBs, or
combination
– Hypertension
– Hyperglycemia
– Dyslipidemia
– Secondary prevention
of CVD
Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%).
from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for peripheral
atherosclerotic artery disease. †Behavior modification and pharmacologic therapy.
*Death
Adapted from Gaede P et al. N Eng J Med 2003;348:383–393.
Intensive LDL-C Goals for High Risk
Patients
Recommended LDL-C treatment goals
ATP III
Update 20041
<100 mg/dL:
Patients with CHD or
CHD risk equivalents
(10 year risk >20%)1
AHA/ACC guidelines
for patients with
CHD*,2
<100 mg/dL
<70 mg/dL:
Therapeutic option for
very high risk patients1
2006
Update
<100 mg/dL:
Goal for all patients
with CHD†,2
<70 mg/dL:
A reasonable goal for
all patients with CHD2
<70 mg/dL
• If it is not possible to attain LDL-C <70 mg/dL
because of a high baseline LDL-C,
it generally is possible to achieve LDL-C
reductions of >50% with more intensive LDLC–lowering therapy, including drug
combinations.
* And other forms of atherosclerotic disease.2
† Factors that place a patient at very high risk: established cardiovascular disease plus: multiple major risk
factors (especially diabetes); severe and poorly controlled risk factors (e.g., cigarette smoking);
metabolic syndrome (triglycerides ≥200 mg/dL + non–HDL-C ≥130 mg/dL with HDL-C <40 mg/dL); and
acute coronary syndromes.1
1. Grundy SM et al. Circulation 2004;110:227–239.
2. Smith SC Jr et al. Circulation 2006; 113:2363–2372.
Risk Assessment and Treatment Targets
Risk
Assessment
HIGH
FRS ≥ 20%
RRS≥ 20%
Initiate/consider treatment
if any of the following:
•
•
•
•
CAD
PVD
Atherosclerosis
Most Diabetic Patients
Primary Target
LDL-C
Primary Alternate
ApoB
< 2 mmol/L or
↓ LDL-C 50%
ApoB < 0.80
(consider treatment in all patients)
Moderate
FRS 10-19%
•
•
•
•
LDL-C > 3.5 mmol/L
TC/HDL-C > 5.0
hsCRP > 2 mg/L *
Family history
A
A
(strive towards )
LOW
FRS < 10%
• LDL-C > 5.0mmol/L
↓ LDL-C 50%
A
* Only screen for hsCRP in men ≥ 50 and women ≥ 60 if they do NOT already have CVD, diabetes, multiple risk factors, family history or hyperlipidemia
Genest J et al. Can J Cardiol 2009 Oct;[in press].
ASA & Diabetes
• Pts with DM have numerous abnormalities of
platelet function: in aggregate yielding a prothrombotic milieu
• DM platelets exist in a relatively active state
and have accelerated turnover
• Likely that higher doses of anti-platelet
therapies required to achieve comparable PD
effects compared with pts without DM.
ASA & Diabetes
• Efficacy of low-dose ASA for T2DM pts has been difficult to
prove & effect magnitude smaller than anticipated, with
data derived primarily from primary prevention studies.
• In aggregate, the epidemiologic, mechanistic,&
primary/secondary prevention data support the hypothesis
that T2DM pts may require more aggressive anti-platelet Rx
to yield commensurate anti-platelet effects to affect CVD
risk reduction,
• More aggressive anti-platelet dosing in this setting would
not be expected to increment bleeding risk.
ASA & Diabetes
• “While no comparative data exist with regard to
ASA dosing in the setting of T2DM and prevalent
CVD, the hypothesis that DM patients may benefit
from more aggressive anti-platelet therapy is
supported by observations of…
 1)exaggerated clinical efficacy in the absence of
increased bleeding risk that derive from DM subanalyses in the setting of parenteral GPIIb/IIIa
antagoinists for the treatment of NSTEMI
 2) the head-to-head comparison of prasugrel vs.
clopidogrel in the setting of ACS planned to
undergo PCI.”
Vascular Protection in Diabetes
CDA Guidelines 2008
• All people with diabetes
–
–
–
–
Life-style intervention
Smoking cessation
Optimize glycemic control
Optimize BP control
• People with diabetes considered at
high risk of a CV event:
–
–
–
–
All above+
ACEI or ARB therapy
Antiplatelet therapy
Lipid lowering medication
Diabetes Take Home Messages
• Huge/growing health care problem
• Key multifactorial aggressive approach
to primary secondary prevention
• Real potential for harm
• Complex pharmacologic Rx choices
• Revascularization choices
Diabetes and CV Disease
♦
♦
♦
♦
Raging Global Epidemic
The Major Risk Factor for CV Disease
Worsens CV Outcomes
Influences both Choice & Intensity CV
Rx
♦ Some Diabetes Rx may Worsen
Outcomes
♦ Diabetes Rx Targets may be Misleading