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Comprehensive
Cardiometabolic
Risk-Reduction
Program
Phase 2
2009
Sponsored by National Lipid Association
Case Study
Insulin Resistance and
Type 2 Diabetes
Case Study
Initial MD Appointment
• 59-year-old man was referred for
evaluation of cardiovascular disease
(CVD) risk
• Previous history of hypertension, but no
knowledge of diabetes; nonsmoker
• No family history of premature CVD, but
he has a sister with obesity and type 2
diabetes
Case Study
Initial MD Appointment
• Physical examination
– Weight: 212 lbs, height: 69 inches, body mass index
(BMI): 31.3 kg/m2, waist: 42 inches, blood pressure:
140/88 mm Hg (sitting, relaxed, lowest of several repeats)
• Medications
– Metoprolol 100-mg BID
• Diet
– Includes 3 servings of fruit/vegetables daily, 2 servings of
whole grains, and no fish
• Physical activity
– Sedentary vocation with no planned recreational activity
Case Study
Laboratory Results
•
•
•
•
•
•
•
•
TC
HDL-C
LDL-C (direct)
TG
Non–HDL-C
SCr
eGFR
Glucose
197 mg/dL
25 mg/dL
94 mg/dL
340 mg/dL
172 mg/dL
1.2 mg/dL
>60 mL/min
182 mg/dL
– After fasting hyperglycemia was confirmed, type 2 diabetes
was diagnosed and an HbA1c test was ordered: HbA1c 8.2%
TC=total cholesterol, HDL-C=high-density lipoprotein cholesterol, LDL-C=low-density lipoprotein cholesterol,
TG=triglycerides, SCr=serum creatinine, eGFR=estimated glomerular filtration rate, HbA1c=hemoglobin A1c
ARS Question
According to the American Diabetes
Association, the diagnosis of diabetes is
made by
A.
B.
C.
D.
E.
HbA1c >6.0%
FPG >110 mg/dL on 2 consecutive visits
FPG >125 mg/dL on 2 consecutive visits
OGTT >200 mg/dL
Answers C or D
FPG= fasting plasma glucose, OGTT=oral glucose tolerance test
Pathogenesis of Type 2 Diabetes
pancreatic
insulin
secretion
incretin
effect
pancreatic
glucagon
secretion
gut
carbohydrate
delivery and
absorption
-
hepatic
glucose
production
peripheral
glucose
uptake
Obesity → Insulin Resistance →
β-cell Dysfunction → Type 2 Diabetes
Normal
IFG/IGT
Type 2 diabetes
Insulin
resistance
Increased insulin
resistance
Insulin
secretion
Hyperinsulinemia,
then β-cell failure
Postprandial
glucose
Abnormal
glucose tolerance
Fasting
glucose
Hyperglycemia
IGT=impaired glucose tolerance
Adapted from International Diabetes Center. Type 2 Diabetes BASICS. 1st ed. Minneapolis, Minn.:
International Diabetes Center Publishing; 2000.
Clinical Pearl
20% of type 2 diabetes
occurs in the
absence of obesity
ARS Question
Which of the following non-type 2 diabetes
(T2D) agent(s) is (are) recommended to add
initially to the treatment of this patient (T2D
treatment later)?
A. Aspirin
B. Statin
C. Calcium channel blocker
D. A and B
E. B and C
ADA: Standards of Medical Care
• In patients 40 years of age with another
cardiovascular risk factor, aspirin and
statin therapy (if not contraindicated)
should be used to reduce the risk of
cardiovascular events
• Medication should be initiated for glycemic
control
ADA=American Diabetes Association
American Diabetes Association. Diabetes Care. 2009;32:S13-S61.
Type 2 Diabetes:
2009 Treatment Options
•
Diet and exercise
•
Sulfonylureas (SU) (glyburide, glipizide, glimepiride)
•
Non-SU secretagogues (repaglinide, nateglinide)
•
Insulin
•
Biguanides (metformin)
 Insulin resistance
 Insulin
production
or supply
 Glucagon
 Hepatic glucose prod ( insulin resistance)
• α-Glucosidase inhibitors (acarbose, miglitol)
 Carb absorption
Type 2 Diabetes:
2009 Treatment Options (cont.)
•
Thiazolidinediones (rosi-, pioglitazone)
•
DPP-4 inhibitors* (sitagliptin)
•
GLP-1 agonists* (exenatide)
•
Amylin analogue* (pramlintide)
 Insulin resistance
 Insulin
 Satiety
 Gastric
emptying
 Glucagon
*DPP-4 inhibitors, GLP-1 mimetics, and amylin analogues constitute the Incretin Superclass
DPP-4=dipeptidyl peptidase-4, GLP-1=glucogon-like peptide-1
ARS Question
Which initial choice for the pharmacological
treatment of diabetes in this patient would
be optimal?
A. Sulfonylurea
B. Metformin
C. Pioglitazone
D. Exenatide
E. Sitagliptin
F. Insulin
Type 2 Diabetes:
2009 Pharmacologic Treatment Options
• Sulfonylureas (glyburide, glipizide, glimepiride)
• Non-SU secretagogues (repaglinide,
nateglinide)
• Insulin
• Biguanides (metformin)
• α-glucosidase inhibitors (acarbose, miglitol)
• Thiazolidinediones (rosi-, pioglitazone)
• GLP-1 agonists (exenatide)
• DPP-4 inhibitors (sitagliptin)
• Amylin analogue (pramlintide)
Orange=weight gain; Yellow=weight neutral; Green=weight favorable
EASD/ADA
Type 2 Diabetes: Consensus Algorithm on
Pharmacological Therapy for Hyperglycemia*
Metformin +
basal insulin
Metformin +
intensive insulin
Metformin
Metformin +
sulfonylureaa
At diagnosis
STEP 3
STEP 2
Tier 2: Less well-validated therapies
Metformin +
pioglitazone
Metformin +
GLP-1 agonistb
*In combination with lifestyle
Nathan DM, et al. Diabetes Care. 2008;31:1–11.
Metformin +
pioglitazone +
sulfonylurea
Metformin +
basal insulin
aSulfonylurea
other than glyburide or chlorpropamide
clinical use to be confident regarding safety
EASD=European Association for the Study of Diabetes
bInsufficient
Case Study
Month 1: MD Follow-Up Visit 1
• Physical examination
– Weight: 215 lbs, height: 69 inches, body mass
index (BMI): 31.7 kg/m2, waist: 42 inches, blood
pressure: 140/88 mm Hg
• Action plan
– Initiate metformin 850-mg BID, atorvastatin 10mg QD, aspirin 162 mg/day
– Discontinue metoprolol 100-mg BID, initiate
ramipril 5-mg BID
– Refer to certified diabetes educator
– Schedule follow-up appointment for 3 months
Clinical Pearl
Pharmacologic therapy for patients with
diabetes and hypertension should be
with a regimen that includes either
an ACE inhibitor or
an angiotensin receptor blocker
ACE=angiotensin-converting enzyme
American Diabetes Association. Diabetes Care. 2009;32:S13-S61.
ARS Question
What benefits might be derived from early
glycemic control in a patient with new-onset
diabetes?
A. Significant improvement in microvascular
complications, but not macrovascular
B. Significant improvement in microvascular and
macrovascular complications, but not mortality
C. Significant improvement in microvascular and
macrovascular complications and mortality
UKPDS:
Effect of Earlier Glucose Control
Aggregate Endpoint
Any diabetes related endpoint
RRR:
P:
1997
12%
0.029
2007
9%
0.04
Microvascular disease
RRR:
P:
25%
24%
0.0099 0.001
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
UKPDS=United Kingdom Prospective Diabetes Study, RRR=relative risk reduction, P=log rank
Holman RR, et al. N Engl J Med. 2008;359:1577-1589.
UKPDS. Lancet. 1998;352:837-853.
Case Study
Initial Certified Diabetes-Educator Visit
• Weight: 214 lbs, height: 69 inches, body mass index
(BMI): 31.7 kg/m2, waist: 42 inches
• Patient has hypertension and is newly diagnosed with
type 2 diabetes
– Was prescribed metformin 850-mg BID
• Diet
– 3 servings/day of fruit/vegetables, 2 servings/day whole grains,
no fish
– Has a “sweet tooth” and a preference for red meat
– Breakfast: coffee cake; lunch: cheeseburger, salad; dinner:
barbequed ribs, potato, green beans; snack: banana
• Patient does not exercise
• Patient’s readiness for lifestyle changes
– Says he is “scared” and appears ready to adapt behavior
Case Study
Initial Certified Diabetes-Educator Visit
• Plan
– Discuss patient’s role in disease management
– Begin education
• Blood sugar monitoring
• Medications
• General dietary and physical activity changes that
will improve glucose management
– Develop basic plan for lifestyle changes
– Follow-up in 1 week
Clinical Pearl
Avoid Information Overload
• There is a lot of information for the patient newly
diagnosed with diabetes
– Blood sugar monitoring
– Medications
– Diet and physical activity changes
• Initially choose 1 to 2 main topics to focus on
and give an overview of lifestyle changes
• Provide handouts
• Have patient complete food records
• Follow-up within 1 week for in-depth lifestyle
education and goal-setting
Case Study
Follow-Up Certified Diabetes-Educator Visit—
1 Week
• See if patient has questions
– Questions will initiate education and lifestyle-plan
development
• Work with the patient, determine realistic goals
• Write a prescription for lifestyle changes
– Weight-loss goal: 1 pound/week for first 2 months
– Diet: patient wants to follow a low–glycemic-index diet;
food records
– Exercise: 20 minutes walking every other day at local track
• Discuss obstacles and potential solutions
• Schedule follow-up appointment in 8 weeks
Glycemic Effects of Diet:
High Cereal vs Low-Glycemic Index
• 210 patients with type 2
diabetes
138
mg/dL
• 6-month, randomized,
parallel study
Fasting Glucose
146
130
122
P=0.04
114
0
• Low–glycemic-index diet*:
 fasting glucose,  A1c,
↑ HDL-C vs high-cereal fiber
(P<0.05 for each)
4
8
12
16
20
24
16
20
24
Time, wk
A1c
7.30
%
7.10
6.90
6.70
*Completer population
6.50
P<0.001
6.30
0
HDL-C=high-density lipoprotein cholesterol
4
8
12
Time, wk
High cereal
Jenkins DJ, et al. JAMA. 2008;300:2742-2753.
Copyright restrictions may apply.
Low glycemic
Low–Glycemic-Index/Load Diet
Food Groups
Servings/Specifications (2000 kcal)
Fruits
3 servings/day, temperate fruits, no juice
Vegetables
5 servings/day, nonstarchy
Protein
6 – 8 oz
Grains
7 servings/day, whole grains only
Dairy
3 servings/day, nonfat
Nuts/seeds/legumes
1–2 servings/day
Fats/oils
Olive oil, canola oil preferable
Sweets
None, 1 Tbsp jam/day
Approximate overall composition:
40%–55% carbohydrates, 25%–40% fat, 15%–25% protein
Clinical Pearl
Start a Walking Program
•
•
•
•
Easy on the joints
Universally available
No cost, equipment, or special clothing
Can be done in interesting and safe
environments
• Burns 5–7 kcal/minute
• Try a moderate start (eg, 20–30 minutes/day,
days/week)
• ↑ 30–40 minutes/day, 5–7 days/week
– Burns 250 kcal/day (equals  1 lb/2 weeks)
–  glucose and free fatty acid for 24 hours
3
Case Study
Month 3: Certified Diabetes-Educator Follow-Up
Visit 2
• Weight: 207 lbs, height: 69 inches, body mass
index (BMI): 30.6 kg/m2, waist: 42 inches
• Patient has “turned over a new leaf”
– Walking 30 minutes, 5 days each week
– Food records indicate good adherence to diet
• While doing well on his current regimen, the
patient expresses interest in doing more to
control his diabetes
• Plan
– Refer to local hospital-based program focusing on
intensive lifestyle intervention (ILI)
ARS Question
If, with this intervention, the patient can match
the 1-year success in the Look AHEAD trial,
which of the following would improve
significantly vs standard diabetes treatment?
A. Triglycerides
B. LDL-c
C. FPG
D. All of the above
E. A and C
LDL-C=low-density lipoprotein cholesterol, FPG=fasting plasma glucose
Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383.
Look AHEAD Trial: Improvement in
Metabolic Syndrome Components at 1 Year
Mean Change From Baseline
Intensive
Lifestyle
Intervention
Weight loss (%)
Diabetes Support/
Education
(Control Group)
P value
8.6
0.7
<0.001
-2.4
-0.2
<0.001
-30.3
-14.6
<0.001
3.4
1.4
<0.001
-6.8
-2.8
<0.001
Fasting plasma glucose
(mg/dL)
-21.5
-7.2
<0.001
Metabolic syndrome (%)
-14.7
-7.1
<0.001
Waist circumference (inches)
TG (mg/dL)
HDL-C (mg/dL)
Systolic BP (mm Hg)
LDL changed by -5.2 mg/dL in the ILI group, compared with -5.7 mg/dL in the control group (P=0.49)
TG=triglycerides, HDL-C=high-density lipoprotein cholesterol, BP=blood pressure
Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383.
Case Study
Month 4: MD Follow-Up Visit 2
• Physical examination
– Weight: 205 lbs, height: 69 inches; BMI: 30.3 kg/m2, waist: 41
inches, blood pressure: 128/78 mm Hg
• Current medications
– Metformin 850-mg BID, atorvastatin 10-mg QD, aspirin 162mg/day, ramipril 5-mg BID
• Laboratory test results (fasting)
–
–
–
–
–
–
–
–
TC
HDL-C
LDL-C (direct)
TG
Non-HDL-C
Glucose
HbA1c
SCr
146 mg/dL
28 mg/dL
70 mg/dL
240 mg/dL
118 mg/dL
122 mg/dL
6.9%
1.2 mg/dL
TC=total cholesterol, HDL-C=high-density lipoprotein cholesterol, LDL-C=low-density lipoprotein cholesterol,
TG=triglycerides, HbA1c=hemoglobin A1c, SCr=serum creatinine
ARS Question
What is an appropriate HbA1c target for
this patient?
A. <6.0%
B. <6.5%
C. <7.0%
D. <7.5%
Glucose Targets
Organization
Target
AACE
HbA1c <6.5%
ADA/ ACCF/ AHA
HbA1c <7%
IDF
HbA1c <6.5%
AACE=American Association of Clinical Endocrinologists, ADA=American Diabetes Association,
ACCF=American College of Cardiology Foundation, IDF=International Diabetes Federation
Improved Glycemia Reduces
Microangiopathy
Study
n
Design
DCCT
1441
Insulin vs Insulin
1:  76%
2:  54%
1:  34%*
2:  43%*
 60%
3867
Insulin
Chlorpropamide
Glinbenclamide
Glipizide
Metformin
 23%
30%
 20%
11,140
Gliclazide +
added therapy
 5%
 21%
 4%
1791
Rosiglitazone +
metformin
or glimepiride†
 14%‡
 38%§
 1%
UKPDS
ADVANCE
VADT
Retinopathy Nephropathy Neuropathy
*Risk of developing microalbuminuria, †Insulin was used in each group before change in oral
medications, per protocol-defined A1c cutpoints, ‡New onset retinopathy, §Progression from normal to
micro- or macroalbuminuria
Percentages are approximate.
DCCT=The Diabetes Control and Complications Trial Research Group, UKPDS=UK Prospective
Diabetes Study, ADVANCE=ADVANCE Collaborative Group, VADT=Veterans Affairs Diabetes Trial
DCCT Research Group. New Engl J Med. 1993;329:977-986. UKPDS Group. Lancet. 1998;352:837-853.
ADVANCE Collaborative Group. New Engl J Med. 2008;358:2560-2572. Duckworth W, et al. N Engl J Med. 2009;360:129-139.
ACCORD: Relation Between Coronary Heart
Disease (CHD) Mortality and Glycemic Control
Assigned to either:
Intensive treatment (goal HbA1c <6%)
Standard treatment (goal HbA1c 7.0%–7.9%)
Primary outcome: composite nonfatal MI,
stroke, or cardiovascular death
No effect on primary outcome (P=0.16)
Increased all-cause mortality (P=0.04)
ACCORD=Action to Control Cardiovascular Risk in
Diabetes, MI=myocardial infarction, HR=hazard ratio
Intensive
Standard
0.20
2.29%/yr
0.15
HR=0.90 (0.78–1.04)
P=0.16
0.10
2.11%/yr
0.05
0.0
0
1
2
0.25
Proportion With Events
1-year median HbA1c: 6.4% and 7.5%
Primary Outcome
0.25
Proportion With Events
N=10,251
35% with previous cardiovascular event
Median baseline HbA1c: 8.1%
3
4
Years
5
6
Death From Any Cause
Intensive
0.20
Standard
0.15
HR=1.22 (1.01–1.46)
P=0.04
0.10
0.05
0.0
The ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.
0
1
2
3
4
Years
5
6
ADVANCE: Relation Between Cardiovascular
Events and Glycemic Control
11,140 patients assigned to intensive or
standard treatment
Median baseline HbA1c 7.2%
At median 5-years, HBA1c 6.5% and
7.3%
Intensive treatment reduced combined
major microvascular and macrovascular
events (P=0.01) and major microvascular
events (P=0.01)
No effect on major macrovascular
events (P=0.32) or all-cause mortality
(P=0.28)
Cumulative Incidence (%)
Primary endpoints: composites of
cardiovascular events
Macrovascular Events
25
20
15
10
Intensive
Standard
Relative Risk Reduction
6% (95% Cl: -6%, 16%)
P=0.32
5
0
0
CI=confidence interval
The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572.
6 12 18 24 30 36 42 48 54 60 66
Follow-Up (Months)
Key Learnings: Medical
• HbA1c goal of <7% is well supported by the
literature and significantly reduces
microangiopathy
• The benefit of glucose lowering on
cardiovascular disease (CVD) events is
suggested, but not proven
• Aspirin, blood pressure control, and lipidlowering therapy significantly reduce CVD
events in patients with type 2 diabetes mellitus
• Look AHEAD will address the importance of
weight reduction by lifestyle modification on
CVD risk
Key Learnings: Behavioral
• Working with the patient, set realistic
lifestyle goals
– Patient expectations may need to be managed
• Simple exercise prescriptions (eg, a
walking program) can help patients break
the inertia of physical inactivity
• Intensive lifestyle intervention significantly
benefits all cardiometabolic risk-factors
If this patient had presented following a mild
heart attack, what would be the
implications regarding antiplatelet therapy?
Secondary Prevention Guidelines:
Antiplatelet Medications
• American Diabetes Association
– Aspirin (75–162 mg/d) in patients with diabetes and a history of
cardiovascular disease (CVD)
– Combination therapy (aspirin with other antiplatelet agents) for
diabetes patients with severe and progressive CVD
• American Heart Association/American College of
Cardiology
– Aspirin 75–162 mg/d unless contraindicated
– Clopidogrel 75-mg/d (with aspirin*) for ≤12 months after ACS or
PCI with stent placement
• BM: ≥1 month; SE: ≥3 months; PE: ≥6 months
*After PCI with stent placement, aspirin dosage should temporarily (BM – 1 month, SE – 3 months, PE – 6
months) be increased to 325 mg/d.
ACS=acute coronary syndrome, PCI=percutaneous coronary intervention, BM=bare metal, SE=sirolimuseluting, PE=paclitaxel-eluting
Smith SC, et al. Circulation. 2006;113:2363-2372.
King SB III, et al. Circulation. 2008;117:261-295.
American Diabetes Association. Diabetes Care. 2009;32:S13-S61.
Insulin Resistance, Diabetes, and Obesity Are
Associated With Impaired Platelet Function and
Thrombogenesis
 Sensitivity to antiaggregating
effect of insulin
↑ Oxidative
stress and
isoprostane
production
 Sensitivity to antiaggregating
effect of prostacyclin
and adenosine
↑ Ca2+ fluxes and
platelet hyperactivation
 Sensitivity to antiaggregating
effect of nitric oxide and
organic nitrates
 Sensitivity to
antiaggregating effect of
cyclic nucleotides
(cGMP, cAMP)
cGMP=cyclic guanosine monophosphate, cAMP=cyclic adenosine monophosphate
Adapted from Anfossi G, et al. Curr Diabetes Rev. 2006;2:409-430.
Udvardy M, et al. Experientia. 1985;41:422-423.
Resistance
to aspirin
CAPRIE Trial – Diabetes Subpopulation
Clopidogrel vs Aspirin In Patients with Recent Stroke/MI
or PAD – Primary Composite Endpoint
• 19,185 total study
population
Aspirin
Clopidogrel
– 3,866 patients with
diabetes
– Consistent benefit
favoring clopidogrel vs
aspirin among all of the
individual and composite
end points examined
*P=0.042
Bhatt DL, et al. Am J Cardiol. 2002;90:625-628
Primary Composite Endpoint
Annual Event Rate (%)
• Primary composite
endpoint: vascular death,
stroke, MI, or
rehospitalization for
ischemia or bleeding
18
16
14
12
10
8
6
4
2
0
*
Key Learnings: Antiplatelet
• Diabetes mellitus, insulin resistance, and
obesity are associated with altered platelet
function that increases aggregation
• Altered function may result in resistance to
antiplatelet therapies
• Additional antiplatelet therapies are
recommended in patients with diabetes,
who are post acute coronary syndrome, or
who have severe and progressive
cardiovascular disease