clinical imperatives when treating patients with diabetes
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Clinical Imperatives When Treating Patients with Diabetes. ≥200 – 140 to 199 (ADA) >140 to 110 toTRANSCRIPT
Clinical Imperatives When Treating Patients with Diabetes
Diabetes, IFG, IGT: Diagnostic criteria
≥200
–
140 to 199 (ADA)
>140 to <200 (AACE)
Casual Fasting 2-hr postload*
Plasma glucose (mg/dL)
*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.
Diabetes
Impaired fasting glucose (IFG)
Impaired glucose tolerance (IGT)
≥200
–
–
≥126
100 to 125 (ADA)
>110 to <126 (AACE)
–
Target Recommendations
A1C <7%<6% if possible without inducing hypoglycemia
BP (mm Hg) <130/<80ACEI or ARB in BP-lowering regimen
Lipids (mg/dL)LDL-C
HDL-C TG
<100 (<70 optional)>40 men, >50 women <150
Statin for CV history or age >40 yr (regardless of baseline LDL) to lower LDL 30%–40%
AHA/ACC/ADA: Multiple risk reduction in diabetes
Pearson T et al. Circulation 2002.Grundy SM et al. Circulation 2004.
ADA. Diabetes Care 2006.
• ASA: Age >40 yr or with other risk factors, all with CV disease history
• ACE inhibitor: Age >55 yr with another CV risk factor
Intensive glycemic control
Intensive management of
comorbid conditions*
• A1C ≤6.5%• Glucose (mg/dL)
– Preprandial ≤110– Postprandial ≤140
• Lipid modifying• BP lowering• ASA for prevention of
vascular events
AACE: Managing diabetes
Lifestyle intervention
• Optimal nutrition• Physical activity• Smoking cessation• Weight control
AACE. Endocr Pract. 2002;8(suppl 1):40-65.
American Association of Clinical Endocrinologists
*Dyslipidemia, hypertension, early renal disease
AHA/ACC secondary prevention guidelines:Diabetes management
• Initiate lifestyle and pharmacotherapy to achieve near-normal 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.
A1C goal <7%
DPP: Benefit of diet/exercise or metformin on diabetes prevention in at-risk patients
DPP Research Group. N Engl J Med. 2002;346:393-403.
Years
N = 3234 with IFG/IGT without diabetes
0
0
10
20
30
40
1.0 2.0 3.0 4.0
Placebo
Metformin
Lifestyle
Cumulativeincidence
of diabetes(%)
31%
58%
P
< 0.001
< 0.001
DPP: Benefit of diet/exercise or metformin on diabetes by race/ethnicity
DPP Research Group. N Engl J Med. 2002;346:393-403.
Reduction in new-onset diabetes
(%)
Whiten = 1768
AfricanAmerican
n = 645Hispanicn = 508
American
Indiann = 171
Asiann = 142
N = 3234 with IFG/IGT and without diabetes
Lifestyle vs placebo Metformin vs placebo Lifestyle vs metformin
0
-20
-40
-60
-80
3-Week diet + exercise yield favorable metabolic changes
*
*
†
*
*
0
50
100
150
200
250
Total-C LDL-C HDL-C TG Serumglucose
mg/dL
*P < 0.01†P < 0.05 Roberts CK. et al. J Appl Physiol. 2006;100:1657-65.
*
0
5
10
15
20
25
30
35
Insulin
μU/mL
N = 31 overweight/obese men; weight 8.4 lbs
Baseline Follow-up
3-Week diet + exercise reduce proatherogenic factors
0
0.5
1
1.5
2
2.5
CRP
0
100
200
300
400
MPO sICAM-1 sP-selectin
ng/mL
0
50
100
150
200
250
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.
pg/mL mg/L
*
N = 31 overweight/obese men; weight 8.4 lbs
†
†
† *
Baseline Follow-up
8-iso-PGF2α
Beyond lifestyle: Aggressive medical therapy in diabetes
Adapted from Beckman JA et al. JAMA. 2002;287:2570-81.
Atherosclerosis
Platelet activationand aggregation
Dyslipidemia
HyperglycemiaInsulin resistance
Hypertension
MetforminTZDs
SulfonylureasNonsulfonylureas
SecretagoguesInsulin
StatinsFibric acid derivatives
ACE inhibitorsARBs
β-blockersCCBs
Diuretics
ASAClopidogrelTiclopidine
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 outcomesN = 160 with type 2 diabetes and microalbuminuria
Gæde P et al.N Engl J Med. 2003;348:383-93.
*CV death, MI, stroke, CABG/PCI, amputation, PAD surgery†Adjusted for duration of diabetes, age, sex, smoking, CV disease
Primary composite outcome*
(%)
60
50
40
30
20
10
0
53% RRR†
P = 0.01
Follow-up (months)
Conventional
Intensive
0 12 24 36 48 60 72 84 96
8
Steno-2: Better risk factor control with intensive therapy
Gæde P et al. N Engl J Med. 2003;348:383-93.
Conventional therapy (n = 80) Intensive therapy (n = 80)
0056789
1110
AlC(%)
Follow-up (years)
0
110120130
140
150160170
0
SBP(mm Hg)
Follow-up (years)
0
50100150200250300350
0
TG (mg/dL)
00
50100150200250300350
Total-C(mg/dL)
1 2 3 4 5 6 7 8
P < 0.001
1 2 3 4 5 6 7 8
P < 0.001
1 2 3 4 5 6 7
P = 0.015
1 2 3 4 5 6 7 8
P < 0.001
Steno-2: Effects of multifactorial intervention on microvascular and neuropathic outcomes
Gæde P et al. N Engl J Med. 2003;348:383-93.
Nephropathy
Retinopathy
Autonomicneuropathy
Peripheralneuropathy
Variable RR P
0.39
0.42
0.37
1.09
0.003
0.02
0.002
0.66
Reductions in the risk of microvascular complications were maintained at 8 years
0.0 0.5 1.0 1.5 2.0 2.5
Intensive better
Conventionalbetter
Relative risk
Benefits of aggressive LDL-C lowering in diabetes
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.
Difference in LDL-C
(mg/dL)
Aggressive lipid-lowering
better
Aggressive lipid-loweringworse
0.026
0.036
0.001
<0.0001
0.0003
Primary event rate (%)
17.9
11.9
9.0
12.6
13.5
Control
13.8
9.2
5.8
9.4
9.3
Treatment
0.63
0.67
0.73
P
TNT Diabetes, CHD
ASCOT-LLA Diabetes, HTN
CARDS Diabetes, no CVD
HPS All diabetes
Diabetes, no CVD
*Atorvastatin 10 vs 80 mg/day†Statin vs placebo
Relative risk
0.7 0.9 10.5 1.7
0.77
22*
35†
46†
39†
39†
0.75
Event rate (%)
HPS: Statin beneficial irrespective of baseline lipid level and diabetes status
Placebon = 10,267
0.4 1.0 1.40.6 0.8 1.2
Simvastatinn = 10,269
Event rate ratio
Statin better Placebo betterLDL-C <116 mg/dL
With diabetes
No diabetes
15.7
18.8
20.9
22.9
LDL-C ≥116 mg/dL
With diabetes
No diabetes
23.3
20.0
27.9
26.2
24% reductionP < 0.000125.219.8All patients
HPS Collaborative Group. Lancet. 2003;361:2005-16.
Heart Protection Study
ASCOT-LLA: Atorvastatin reduces CV events in patients with diabetes and hypertension N = 2532, baseline LDL-C 128 mg/dL
Nonfatal MI, CV mortality, UA, stable angina, arrhythmias, stroke, TIA, PAD, retinal vascular thrombosis, revascularization
Sever PS et al. Diabetes Care. 2005;28:1151-7.
%
Number at riskPlacebo 1258
Atorvastatin 1274
14.0
12.0
10.0
8.0
6.0
4.0
2.0
00
1231 1209 1191 1171 1065 699 3701237 1219 1200 1175 1058 714 375
0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years
Atorvastatin 10 mg
Placebo
HR = 0.77 (0.61–0.98)
23% Risk reductionP = 0.036
HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005;26:1369-78.
PERSUADE(n = 1502)
CV death/MI/cardiac arrest
MICRO-HOPE(n = 3577)
CV death/MI/stroke
MICRO-HOPE, PERSUADE: ACEI reduces CV events in diabetes
Placebo
25
Ramipril10 mg
20
15
10
5
0
Primary outcome
(%)
Follow-up (years)0 1 2 3 4 5
25% RRRP = 0.0004
20
15
10
5
0
0 1 2 3 4 5Follow-up (years)
Placebo
Perindopril8 mg
19% RRRP = 0.13
25
-50
-40
-30
-20
-10
0
CRP MMP- 9 sCD40L
0
50
100
150
200
250
300
350
TZD + statin: Favorable effects on inflammatory markers and adiponectin
*P < 0.05 vs baseline; †P < 0.05 vs ROSI monotherapy Chu C-S et al. Am J Cardiol. 2006;97:646-50.
N = 30 with DM2 and hyperlipidemia treated with rosiglitazone; add-on atorvastatin after 3 months; follow-up 6 months
Adiponectin†
Change from
baseline (%)
†
†
*
*
*
* **
ROSI 4 mg ROSI 4 mg + ATORVA 10 mg
Principal mechanisms of action for oral diabetic agents
Adapted from Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411.
α-Glucosidase inhibitors
Intestine: ↓glucose absorption
Biguanides
Liver: ↓hepatic glucose output
↑glucose uptake
Blood glucose
Sulfonylureas and repaglinide
Pancreas: ↑insulin
secretion
Muscle and adipose tissue: ↓insulin resistance
↑glucose uptake
Thiazolidinediones
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 MetforminInsulin
secretagogues* AGI
Insulin resistance
Hypertension or or
Altered hemostasisPAI-1tPA
or or
NANA
DyslipidemiaTGHDL-CLDL particle size
or or
or or
NA
or or
NA
C-reactive protein NA
*Sulfonylureas and meglitinides AGI = alpha glucosidase inhibitor = no change
Adapted from Granberry MC, Fonseca VA.Am J Cardiovasc Drugs. 2005;5:201-9.
NA = data not available
TZD vs sulfonylurea: Glycemic control over time
ROSI GLYB
St. John Sutton M et al. Diabetes Care. 2002;25:2058-64.
N = 203 patients with type 2 diabetes
A1C Fasting plasma glucose
mg/dL
0
8.5
10.0
Treatment week
%
9.5
9.0
8.0
7.5
-8 -4 0 4 8 12 16 28 40 52
GLYBROSI 8 mg/d
GLYB = glyburide
Baseline Week 8 Week 52
0
200
250
TZD + sulfonylurea efficacy in type 2 diabetes
Pfützner A et al. Metabol Clin Exp. 2006;55:20-5.
N = 102; changes after 16 weeks
-80
-60
-40
-20
0
20
40Adiponectin‡
%Change
*P < 0.05 vs baseline†P < 0.005 vs baseline‡Adjusted for BMI changesGLIM = glimepiride 3 mg; ROSI = rosiglitazone
GLIM GLIM + ROSI 4 mg GLIM + ROSI 8 mg
HOMA-IR Intact proinsulin
CRP
*
†
*†
*
†
-20
0
80
160
*
PROactive: Reduced requirement for insulin use
Dormandy JA et al. Lancet. 2005;366:1279-89.
5
10
15
25
06
20
0 12 18 24 30 36
Pioglitazonen = 183 (11%)
Placebon = 362 (21%)
Follow-up (months)
Patients(%)
53% RRRHR 0.47 (0.39–0.56)*
P < 0.0001
*Unadjusted
Sulfonylurea + TZD or metformin: Comparison of lipid and renal effects
Hanefeld M et al. Diabetes Care. 2004;27:141-7.
N = 639 with poorly controlled DM2; change after 52 weeks
-20
-15
-10
-5
0
5
10
15
TG HDL-C TC:HDL-C LDL-C Alb:Cr
*
†
‡
†
†
*P = 0.008, †P < 0.001, ‡P = NS
Pioglitazone 15–45 mg + sulfonylurea Metformin 850–2550 mg + sulfonylurea
Change(%)
TZDs and metformin reduce risk of MICase-control study of first MI in patients with type 2 diabetes
*Adjusted for age, sex, BMI, ACE inhibitor use, history of hypertension or hypercholesterolemia Sauer WH et al. Am J Cardiol. 2006; 97:651-4.
Monotherapy
Metformin
TZD
TZD + sulfonylurea
Metformin + sulfonylurea
Insulin-sensitizing drugs
Sulfonylureamonotherapy
P
0.01
0.03
0.04
0.19
Odds ratio for MI (95% CI)*
Combination therapy
Patients Controls
38 87
7 19
7 18
40 62
0 0.2 0.4 0.6 0.8 1.0 1.2
n
Improving blood glucose control: Potential role of combination therapy
48.4
58.1
0
10
20
30
40
50
60
AACEGoal6.5
%
ADAGoal <7%
Baseline A1C (%) =n =
7.9277
8.0296
Adapted from Weissman P et al. Curr Med Res Opin. 2005;21:2029-2035.
Metformin 1 g/dayUptitrated to 2 g/day
Rosiglitazone 8 mg/day +Metformin 1 g/day
Patients reaching A1C goal
(%)
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
Smyth S, Heron A. Nat Med. 2005;12:75-80.
DPP-IV = dipeptidyl peptidase-IVGLP-1 = glucagon-like peptide-1
DPP-IV inhibitors, GLP-1 analogs: New classes of antidiabetic agents
GLP-1 is released after mealsGlucose-dependent insulin secretion from -cells Levels in type 2 diabetes (“incretin defect”)Rapidly inactivated by DPP-IV
GLP-1: An incretin hormone
GLP-1 degradationGlucose-dependent insulin secretion
DPP-IV inhibitors
Mest H-J, Mentlein R. Diabetologia. 2005;48:616-20. Smyth S, Heron A. Nat Med. 2005;12:75-80.
GLP-1 analogs
Glucose-dependent insulin secretionResistant to DPP-IV degradation
New antidiabetic agents: Dual actions
AMIGO trials: GLP-1 analog in type 2 diabetes
Active treatmentChange 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
AC 2993: Diabetes Management for Improving Glucose Outcomes; 30-week, placebo-controlled trials of exenatide sc added to oral hypoglycemic therapy
1Buse JB et al. Diabetes Care. 2004;27:2628-35.2DeFronzo RA et al. Diabetes Care. 2005;28:1092-100.
3Kendall DM et al. Diabetes Care. 2005;28:1083-91.
Adapted from Cohen JD. Lancet. 2001;357:972-3.
B -blockadeBlood pressure control
A AspirinACE inhibitionA1C control
C Cholesterol management
Managing diabetes as a CHD equivalent: ABCs of coronary prevention
DietDon’t smokeDecrease diabetes risk
D
ExerciseE
Insulin resistance
Proatherogenic effects of insulin resistance
Hypertension Obesity Inflammation Hyperinsulinemia Diabetes Dyslipidemia Thrombosis
Atherosclerosis
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