Transcript Targeting Insulin Resistance for Vascular Protection

Clinical Imperatives When
Treating Patients with Diabetes
Diabetes, IFG, IGT: Diagnostic criteria
Plasma glucose (mg/dL)
Casual
Fasting
2-hr postload*
≥200
≥126
≥200
Impaired fasting
glucose (IFG)
–
100 to 125 (ADA)
–
Impaired glucose
tolerance (IGT)
–
Diabetes
>110 to <126 (AACE)
–
140 to 199 (ADA)
>140 to <200 (AACE)
*Following equivalent of 75 g
anhydrous glucose in water
ADA. Diabetes Care. 2006;29(suppl 1):S43-8.
AACE. Endocr Pract. 2003;9:240-52.
AHA/ACC/ADA: Multiple risk reduction
in diabetes
Target
A1C
BP (mm Hg)
Lipids (mg/dL)
LDL-C
HDL-C
TG
<7%
<130/<80
Recommendations
<6% if possible without inducing
hypoglycemia
ACEI or ARB in BP-lowering
regimen
Statin for CV history or age >40 yr
<100 (<70 optional)
(regardless of baseline LDL) to
>40 men, >50 women
lower LDL 30%–40%
<150
• ASA: Age >40 yr or with other risk factors, all with CV disease history
• ACE inhibitor: Age >55 yr with another CV risk factor
Pearson T et al. Circulation 2002.
Grundy SM et al. Circulation 2004.
ADA. Diabetes Care 2006.
AACE: Managing diabetes
American Association of Clinical Endocrinologists
Intensive
glycemic control
• A1C ≤6.5%
• Glucose (mg/dL)
– Preprandial ≤110
– Postprandial ≤140
Lifestyle
intervention
•
•
•
•
Optimal nutrition
Physical activity
Smoking cessation
Weight control
*Dyslipidemia, hypertension, early renal disease
Intensive
management of
comorbid
conditions*
• Lipid modifying
• BP lowering
• ASA for prevention of
vascular events
AACE. Endocr Pract. 2002;8(suppl 1):40-65.
AHA/ACC secondary prevention guidelines:
Diabetes management
A1C goal <7%
• Initiate lifestyle and pharmacotherapy to achieve nearnormal A1C (IB)
• Begin vigorous modification of other risk factors (eg,
physical activity, weight management, BP control,
cholesterol management) (IB)
• Coordinate diabetic care with patient’s primary care
physician or endocrinologist (IC)
Smith SC et al. Circulation. 2006;113:2363-72.
DPP: Benefit of diet/exercise or metformin on
diabetes prevention in at-risk patients
N = 3234 with IFG/IGT without diabetes
40
Placebo
P
30
Cumulative
incidence
of diabetes 20
(%)
Metformin
31%
< 0.001
Lifestyle
58%
< 0.001
10
0
0
1.0
2.0
3.0
4.0
Years
DPP Research Group. N Engl J Med. 2002;346:393-403.
DPP: Benefit of diet/exercise or metformin on
diabetes by race/ethnicity
N = 3234 with IFG/IGT and without diabetes
White
n = 1768
African
American
n = 645
Hispanic
n = 508
American
Indian
n = 171
Asian
n = 142
0
-20
Reduction in
new-onset
-40
diabetes
(%)
-60
-80
Lifestyle vs placebo
Metformin vs placebo
Lifestyle vs metformin
DPP Research Group. N Engl J Med. 2002;346:393-403.
3-Week diet + exercise yield favorable
metabolic changes
N = 31 overweight/obese men; weight 8.4 lbs
250
35
30
200
150
*
25
*
mg/dL
*
100
μU/mL 20
15
*
10
†
50
*
5
0
0
Total-C
LDL-C
Baseline
*P < 0.01
†P < 0.05
HDL-C
TG
Serum
glucose
Insulin
Follow-up
Roberts CK. et al. J Appl Physiol. 2006;100:1657-65.
3-Week diet + exercise reduce
proatherogenic factors
N = 31 overweight/obese men; weight 8.4 lbs
400
†
300
250
2.5
200
2
150
ng/mL 200
1.5
†
pg/mL
†
*
100
0
MPO
sICAM-1
Baseline
sPselectin
*
mg/L
100
1
50
0.5
0
0
8-iso-PGF2α
CRP
Follow-up
MPO = myeloperoxidase; 8-iso-PGF2α = 8-isoprostaglandin F2α
sICAM-1 = soluble intracellular adhesion molecule 1
*P < 0.05; †P < 0.01
Roberts CK. et al.
J Appl Physiol. 2006;100:1657-65.
Beyond lifestyle: Aggressive medical therapy
in diabetes
Statins
Fibric acid derivatives
ACE inhibitors
ARBs
β-blockers
CCBs
Diuretics
Metformin
TZDs
Sulfonylureas
Nonsulfonylureas
Secretagogues
Insulin
ASA
Clopidogrel
Ticlopidine
Dyslipidemia
Atherosclerosis
Hypertension
Hyperglycemia
Insulin resistance
Platelet activation
and aggregation
Adapted from Beckman JA et al. JAMA. 2002;287:2570-81.
Steno-2 supports aggressive multifactorial
intervention in type 2 diabetes
• Objective: Target-driven, long-term, intensified
intervention aimed at multiple risk factors compared
with conventional therapy
• N = 160 patients with type 2 diabetes and
microalbuminuria
• Intensive treatment targets
–
–
–
–
BP <130/80 mm Hg
A1C <6.5%
Total-C <175 mg/dL
Triglycerides <150 mg/dL
Gæde P et al. N Engl J Med. 2003;348:383-93.
Steno-2: Multifactorial intervention on
CV outcomes
N = 160 with type 2 diabetes and microalbuminuria
60
50
Primary
composite
outcome*
(%)
Conventional
53% RRR†
P = 0.01
40
30
20
Intensive
10
0
0
12
24
36
48
60
72
84
96
Follow-up (months)
*CV death, MI, stroke, CABG/PCI, amputation, PAD surgery
†Adjusted for duration of diabetes, age, sex, smoking, CV disease
Gæde P et al.
N Engl J Med. 2003;348:383-93.
Steno-2: Better risk factor control with
intensive therapy
170
160
150
SBP
140
(mm Hg)
130
120
110
0
P < 0.001
0
350
300
250
TG
200
(mg/dL)
150
100
50
0
1
2
3
4
5
6
7
8
350
300
250
Total-C 200
(mg/dL)
150
100
50
0
0
P = 0.015
AlC
(%)
0
1
2 3 4 5 6 7
Follow-up (years)
8
Conventional therapy (n = 80)
P < 0.001
1
2
3
4
11
10
9
8
7
6
5
0
5
6
7
8
7
8
P < 0.001
0
1
2 3 4 5 6
Follow-up (years)
Intensive therapy (n = 80)
Gæde P et al. N Engl J Med. 2003;348:383-93.
Steno-2: Effects of multifactorial intervention on
microvascular and neuropathic outcomes
Variable
RR
P
Intensive
better
Nephropathy
0.39
0.003
Retinopathy
0.42
0.02
Autonomic
neuropathy
0.37
0.002
Peripheral
neuropathy
1.09
0.66
Conventional
better
Reductions in the
risk of microvascular
complications were
maintained at 8 years
0.0
0.5
1.0
1.5
2.0
2.5
Relative risk
Gæde P et al. N Engl J Med. 2003;348:383-93.
Benefits of aggressive LDL-C lowering in
diabetes
Primary event rate (%)
Treatment
TNT
Diabetes, CHD
ASCOT-LLA
Diabetes, HTN
CARDS
Diabetes, no CVD
HPS
All diabetes
Control
Aggressive
lipid-lowering
better
Aggressive
lipid-lowering
worse
P
Difference in
LDL-C
(mg/dL)
0.026
22*
0.036
35†
0.001
46†
<0.0001
39†
0.0003
39†
0.75
13.8
17.9
0.77
9.2
11.9
0.63
5.8
9.0
0.73
9.4
12.6
9.3
13.5
0.67
Diabetes, no CVD
0.5
*Atorvastatin 10 vs 80 mg/day
†Statin vs placebo
0.7
0.9 1
Relative risk
1.7
Shepherd J et al. Diabetes Care 2006. Sever PS et al. Diabetes Care 2005.
HPS Collaborative Group. Lancet 2003. Colhoun HM et al. Lancet 2004.
HPS: Statin beneficial irrespective of baseline
lipid level and diabetes status
Heart Protection Study
Event rate (%)
Simvastatin
n = 10,269
Placebo
n = 10,267
With diabetes
15.7
20.9
No diabetes
18.8
22.9
With diabetes
23.3
27.9
No diabetes
20.0
26.2
19.8
25.2
Statin better Placebo better
LDL-C <116 mg/dL
LDL-C ≥116 mg/dL
All patients
24% reduction
P < 0.0001
0.4
0.6
0.8 1.0 1.2
Event rate ratio
1.4
HPS Collaborative Group. Lancet. 2003;361:2005-16.
ASCOT-LLA: Atorvastatin reduces CV events in
patients with diabetes and hypertension
N = 2532, baseline LDL-C 128 mg/dL
14.0
10.0
%
Placebo
23% Risk reduction
P = 0.036
12.0
8.0
6.0
Atorvastatin 10 mg
4.0
2.0
HR = 0.77 (0.61–0.98)
0
0
Number at risk
Placebo 1258
Atorvastatin 1274
0.5
1.0
1.5
2.0
2.5
3.0
3.5
1231
1237
1209
1219
1191
1200
1171
1175
1065
1058
699
714
370
375
Nonfatal MI, CV mortality, UA, stable angina, arrhythmias, stroke,
TIA, PAD, retinal vascular thrombosis, revascularization
Years
Sever PS et al. Diabetes Care.
2005;28:1151-7.
MICRO-HOPE, PERSUADE: ACEI reduces
CV events in diabetes
MICRO-HOPE
PERSUADE
(n = 3577)
CV death/MI/stroke
(n = 1502)
CV death/MI/cardiac arrest
25
25
Placebo
20
20
25% RRR
P = 0.0004
Primary 15
outcome
(%)
10
19% RRR
P = 0.13
Placebo
15
Ramipri
l
10 mg
5
Perindopril
8 mg
10
5
0
0
0
1
2
3
4
Follow-up (years)
5
0
1
2
3
4
Follow-up (years)
5
HOPE Study Investigators. Lancet. 2000;355:253-9.
Daly CA et al. Eur Heart J. 2005;26:1369-78.
TZD + statin: Favorable effects on inflammatory
markers and adiponectin
N = 30 with DM2 and hyperlipidemia treated with rosiglitazone;
add-on atorvastatin after 3 months; follow-up 6 months
CRP
MMP- 9
sCD40L
0
350
300
-10
Change
from
baseline
(%)
-20
*
*†
250
200
*
*†
-30
150
*
100
-40
-50
50
0
*†
ROSI 4 mg
Adiponectin
ROSI 4 mg + ATORVA 10 mg
*P < 0.05 vs baseline; †P < 0.05 vs ROSI monotherapy
Chu C-S et al. Am J Cardiol. 2006;97:646-50.
Principal mechanisms of action for oral
diabetic agents
α-Glucosidase inhibitors
Thiazolidinediones
Muscle and adipose tissue:
↓insulin resistance
↑glucose uptake
Intestine: ↓glucose absorption
Biguanides
Blood glucose
Liver: ↓hepatic
glucose output
↑glucose uptake
Sulfonylureas
and repaglinide
Pancreas:
↑insulin
secretion
Adapted from Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411.
Oral antihyperglycemic agents
Drug class
Agents
Mechanism of action
Alpha-glucosidase
inhibitors
Acarbose, miglitol
Delay intestinal carbohydrate
absorption
Biguanides
Metformin
↓ Hepatic glucose production
↑ Liver and muscle insulin
sensitivity
Insulin secretagogues—
Sulfonylureas
Glimepiride, glipizide,
glyburide
↑ Insulin secretion from
pancreatic β-cells
Insulin secretagogues—
Meglitinides
Nateglinide, repaglinide
↑ Insulin secretion from
pancreatic β-cells
Thiazolidinediones
Pioglitazone, rosiglitazone ↑ Adipose and muscle insulin
sensitivity
Trujillo J. Formulary. 2006;41:130-41.
Luna B, Feinglos MN. Am Fam Physician. 2001;63:1747-56.
Beyond glucose lowering: Effects of
antidiabetic agents
TZD
Metformin
Insulin
secretagogues*
Insulin resistance




Hypertension

 or 
 or 

Altered hemostasis
PAI-1
tPA


 or 
 or 


NA
NA
Dyslipidemia
TG
HDL-C
LDL particle size
 or 
 or 

 or 
 or 



NA
 or 
 or 
NA

NA
C-reactive protein
*Sulfonylureas and meglitinides
AGI = alpha glucosidase inhibitor
 = no change


NA = data not available
AGI
Adapted from Granberry MC, Fonseca VA.
Am J Cardiovasc Drugs. 2005;5:201-9.
TZD vs sulfonylurea: Glycemic control over time
N = 203 patients with type 2 diabetes
A1C
Fasting plasma glucose
250
10.0
9.5
%
9.0
mg/dL
200
8.5
8.0
7.5
0
0
-8 -4 0 4 8 12 16
28
40
52
ROSI
GLYB
Treatment week
ROSI 8 mg/d
GLYB = glyburide
GLYB
Baseline
Week 8
Week 52
St. John Sutton M et al. Diabetes Care. 2002;25:2058-64.
TZD + sulfonylurea efficacy in type 2 diabetes
N = 102; changes after 16 weeks
HOMA-IR
40
Intact
proinsulin
Adiponectin‡
CRP
160
†
20
0
%
Change
*
80
-20
-40
†
*
*
-60
0
†
-80
-20
GLIM
GLIM + ROSI 4 mg
*P < 0.05 vs baseline
†P < 0.005 vs baseline
‡Adjusted for BMI changes
GLIM = glimepiride 3 mg; ROSI = rosiglitazone
*
GLIM + ROSI 8 mg
Pfützner A et al. Metabol Clin Exp. 2006;55:20-5.
PROactive: Reduced requirement for insulin use
25
Placebo
n = 362 (21%)
20
Patients
(%)
53% RRR
HR 0.47 (0.39–0.56)*
P < 0.0001
15
10
Pioglitazone
n = 183 (11%)
5
0
0
6
12
18
24
30
36
Follow-up (months)
*Unadjusted
Dormandy JA et al. Lancet. 2005;366:1279-89.
Sulfonylurea + TZD or metformin: Comparison of
lipid and renal effects
N = 639 with poorly controlled DM2; change after 52 weeks
TG
HDL-C
TC:HDL-C
LDL-C
Alb:Cr
†
15
10
5
Change
(%)
†
0
-5
-10
‡
-15
-20
*
Pioglitazone 15–45 mg + sulfonylurea
*P = 0.008, †P < 0.001, ‡P = NS
†
Metformin 850–2550 mg + sulfonylurea
Hanefeld M et al. Diabetes Care. 2004;27:141-7.
TZDs and metformin reduce risk of MI
Case-control study of first MI in patients with type 2 diabetes
n
Controls
38
87
0.01
7
19
0.03
7
18
0.04
40
62
0.19
Monotherapy
Metformin
TZD
Combination therapy
TZD + sulfonylurea
Metformin +
sulfonylurea
Insulin- Sulfonylurea
sensitizing drugs monotherapy
Patients
0
*Adjusted for age, sex, BMI, ACE inhibitor use,
history of hypertension or hypercholesterolemia
P
0.2 0.4 0.6 0.8 1.0 1.2
Odds ratio for MI (95% CI)*
Sauer WH et al. Am J Cardiol. 2006; 97:651-4.
Improving blood glucose control: Potential role
of combination therapy
58.1
60
48.4
50
Patients
reaching
A1C goal
(%)
40
30
AACE
Goal
6.5%
20
10
ADA
Goal
<7%
0
Metformin 1 g/day
Uptitrated to 2 g/day
Rosiglitazone 8 mg/day +
Metformin 1 g/day
7.9
277
8.0
296
Baseline A1C (%) =
n=
Adapted from Weissman P et al. Curr Med Res Opin. 2005;21:2029-2035.
DPP-IV inhibitors
• Potentially important in early DM2 to prevent
deterioration of glucose metabolism
• Decrease rate of GLP-1 degradation
• Partially restore impaired insulin secretion
• Protect -cells
• Oral DPP-IV inhibitors in phase 3 development
– Sitagliptin
– Vildagliptin
DPP-IV = dipeptidyl peptidase-IV
GLP-1 = glucagon-like peptide-1
Smyth S, Heron A. Nat Med. 2005;12:75-80.
DPP-IV inhibitors, GLP-1 analogs:
New classes of antidiabetic agents
GLP-1: An incretin hormone
GLP-1 is released after meals
Glucose-dependent insulin secretion from -cells
Levels in type 2 diabetes (“incretin defect”)
Rapidly inactivated by DPP-IV
New antidiabetic agents: Dual actions
GLP-1 analogs
DPP-IV inhibitors
Glucose-dependent insulin secretion
Resistant to DPP-IV degradation
GLP-1 degradation
Glucose-dependent insulin secretion
Mest H-J, Mentlein R. Diabetologia. 2005;48:616-20.
Smyth S, Heron A. Nat Med. 2005;12:75-80.
AMIGO trials: GLP-1 analog in type 2 diabetes
AC 2993: Diabetes Management for Improving Glucose Outcomes; 30-week,
placebo-controlled trials of exenatide sc added to oral hypoglycemic therapy
Active treatment
Change from
baseline
Exenatide
5 µg bid
Exenatide
10 µg bid
Placebo
Sulfonylurea1
A1C (%)
–0.46
–0.86
+0.12
(N = 377)
Weight (lb)
–2.0
–3.6
–1.3
Metformin2
A1C (%)
–0.40
–0.78
+0.08
(N = 336)
Weight (lb)
–3.6
–6.2
–0.7
Metformin + sulfonylurea3
A1C (%)
–0.55
–0.77
+0.23
(N = 733)
Weight (lb)
–3.6
–3.6
–2.0
1Buse
JB et al. Diabetes Care. 2004;27:2628-35.
RA et al. Diabetes Care. 2005;28:1092-100.
3Kendall DM et al. Diabetes Care. 2005;28:1083-91.
2DeFronzo
Managing diabetes as a CHD equivalent:
ABCs of coronary prevention
A
Aspirin
ACE inhibition
A1C control
B
-blockade
Blood pressure control
C
Cholesterol management
D
Diet
Don’t smoke
Decrease diabetes risk
E
Exercise
Adapted from Cohen JD. Lancet. 2001;357:972-3.
Proatherogenic effects of insulin resistance
Insulin resistance
Hypertension Obesity
Inflammation Hyperinsulinemia
Diabetes
Atherosclerosis
Dyslipidemia
Thrombosis
Summary: Expanding risk factor control to
enhance CV outcomes
• Insulin resistance is an independent risk factor for
atherosclerosis
• Aggressive lifestyle modification and pharmacotherapy
can decrease CV risk and prevent new-onset diabetes
• TZDs target insulin resistance and appear to improve
CV risk factors