Identifying and Treating Patients with Insulin Resistance

1
Identifying and Treating Patients with Insulin
Resistance
2
Diagnosis of diabetes, IFG, and IGT
Plasma glucose (mg/dL)
Fasting
2-hr postload
Casual
126 100 to 125 (ADA) gt110 to 126 (AACE)

• 200
• 140 to 199 (ADA)
• gt140 to lt200 (AACE)

Diabetes Impaired fasting glucose
(IFG) Impaired glucose tolerance (IGT)
200
Following equivalent of 75 g anhydrous glucose
in water
ADA. Diabetes Care. 200528(suppl 1)S4-36.AACE.
Endocr Pract. 20039240-52.
3
Metabolic syndrome diagnosis ATP III emphasizes
clinical practice

• Risk factor Defining level
• Abdominal obesity (in) Waist Men gt40 Women gt35
  
• Triglycerides (mg/dL) 150
• HDL-C (mg/dL) Men lt40 Women lt50
• BP (mm Hg) 130/85
• Fasting glucose (mg/dL) 110 (ADA 100)

NCEP ATP III. JAMA. 20012852486-97.
4
Metabolic syndrome diagnosis IDF emphasizes
central obesity
International Diabetes Federation

• Central obesity
• Plus any 2 of the following

• Defined according to waist circumference
  (ethnic- and gender-specific)

• Plasma triglycerides gt150 mg/dL
• HDL-C lt40 mg/dL
• BP ?140/90 mm Hg
• Fasting glucose ?100 mg/dL or previously
  diagnosed type 2 diabetes

Or receiving specific treatment for this
abnormality
www.idf.org. Accessed August 2005.
5
IDF ethnic- and gender-specific criteria for
central obesity
Waist circumference (inches)
Men
Women

• European ?37 ?32
• Sub-Saharan African
• Middle Eastern
• South Asian ?35 ?32
• South/Central American
• Chinese ?35 ?32
• Japanese ?34 ?35

www.idf.org. Accessed August 2005.
6
Metabolic syndrome diagnosis WHO emphasizes
central role of insulin resistance

• Insulin resistance
• Type 2 diabetes, or
• Impaired fasting glucose, or
• If fasting glucose lt110 mg/dL, glucose uptake
  below lowest quartile

• Plus any 2 of the following
• Antihypertensive medication and/or BP 140/90 mm
  Hg
• Plasma triglycerides 150 mg/dL
• HDL-C lt35 mg/dL (men) or lt39 mg/dL (women)
• BMI gt30 kg/m2 and/or waist-hip ratio gt0.9 (men)
  gt0.85 (women)
• Urinary albumin excretion rate 20 µg/min or
  albumin-creatinine ratio 30 mg/g

Grundy SM et al. Circulation. 2004109433-8.Adap
ted from Alberti KG, Zimmet PZ. Diabet
Med.199815539-53.
7
Other markers of insulin resistance

• Family history of type 2 diabetes or CAD
• Overactive sympathetic nervous system
• ?Uric acid

Cohn GS et al. Am J Hypertens. 2005181099-103.
8
ABCs of coronary prevention
A AspirinACE inhibitionA1C control
B Beta-blockadeBlood pressure control
C Cholesterol management
D Diet Dont smoke
E Exercise
Adapted from Cohen JD. Lancet. 2001357972-3.
9
Multidisciplinary consensus on managingmetabolic
syndrome
AHA / NHLBI / ADA

• Modify lifestyle (weight loss, physical activity)
• Assess risk
• Framingham Risk Score
• CRP (optional)
• Reduce risk factors (ATP III, JNC 7, ADA)
• Lipids, BP, thrombosis, glucose

There is growing interest in the possibility
that drugs that reduceinsulin resistance will
delay onset of type 2 diabetes and will
reduceCVD risk when the metabolic syndrome is
present.
Grundy SM et al. Circulation. 2004109551-6.
10
DPP Impact of lifestyle intervention or
metformin on diabetes
40
Placebo
N 3234, no diabetes Age 50 207 lbs Glucose 107
P
30
Metformin
lt 0.001
?31
Cumulative incidence of diabetes ()
20
Lifestyle
?58
lt 0.001
10

• Lose 510 lbs
• Exercise 2.5 hrs/wk

0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Year
DPP Diabetes Prevention Program
DPP Research Group. N Engl J Med.
2002346393-403.
11
UKPDS Comparison of tight control of BP vs
glycemia on risk of diabetes complications
Any diabetes-related outcome
Diabetes-related death
Coronaryheart failure
Micro-vascular
Retinopathy
Stroke
0
10
20
Patients
30
40
50
60
Tight BP (144/82 vs 154/87 mm Hg)
Tight glucose (A1C 7 vs 7.9)
UKPDS Group. BMJ. 1998317703-13.
UKPDS UK Prospective Diabetes Study
12
HPS and CARDS Benefits of lowering LDL-C in
diabetes
Event rate ()
? LDL-C(mg/dL)
Statin better
Placebo better
Placebo
Statin
P
HPS
0.73
34.8
lt0.0001 0.0003 0.001
12.6 13.5 9.0
9.4 9.3 5.8
All diabetes
0.67
34.8
Diabetes, no CVD
0.63
46.4
CARDS
0.5
0.7
0.9
1
1.7
Relative risk
Statin vs placebo HPS Heart Protection
Study CARDS Collaborative Atorvastatin Diabetes
Study
HPS Collaborative Group. Lancet.
20033612005-16.Colhoun HM et al. Lancet.
2004364685-96.
13
ASCOT-LLA Atorvastatin reduces CV events in
patients with diabetes and hypertension
N 2532, baseline LDL-C 128 mg/dL
14.0
Placebo
12.0
23 Risk reduction P 0.036
10.0
8.0

6.0
Atorvastatin 10 mg
4.0
2.0
HR 0.77 (0.610.98)
0.0
Years
0.5
0.0
1.0
1.5
2.0
2.5
3.0
3.5
Number at risk
1231
1258
1209
1191
1171
1065
699
370
Placebo
1237
1274
1219
1200
1175
1058
714
375
Atorvastatin
Nonfatal MI, CV mortality, UA, stable angina,
arrhythmias, stroke, TIA, PAD, retinal vascular
thrombosis, revascularization ASCOT-LLA
Anglo-Scandinavian Cardiac Outcomes TrialLipid
Lowering Arm
Sever PS et al. Diabetes Care. 2005281151-7.
14
MICRO-HOPE, PERSUADE Reduction in primary
outcome with ACEI
PERSUADE (N 1502) CV death/MI/cardiac arrest
MICRO-HOPE (N 3577) CV death/MI/stroke
25
Placebo
20
19 Risk reduction P 0.131
15
Perindopril 8 mg
10
5
0
0
1
2
3
4
5
Follow-up (years)
HOPE Study Investigators. Lancet.
2000355253-9. Daly CA et al. Eur Heart J.
2005261369-78.
15
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
• Design N 160 patients with type 2 diabetes
  and microalbuminuria
• Intensive treatment targets BP lt130/80 mm Hg
• A1C lt6.5
• Total-C lt175 mg/dL
• Triglycerides lt150 mg/dL

Gæde P et al. N Engl J Med. 2003348383-93.
16
Steno-2 Effects of multifactorial intervention
on CV outcomes
N 160 with type 2 diabetes and microalbuminuria
60
50
Conventional
Primary composite outcome ()
40
30
20
Intensive
10
0
0
12
24
36
48
60
72
84
96
Follow-up (months)
Gæde P et al. N Engl J Med. 2003348383-93.
CV death, MI, stroke, revascularization,
amputation
17
Summary

• The majority of patients seen in cardiology
  practices have insulin resistance
• Synergistic interaction of risk factors
  associated with insulin resistance places
  patients at high risk for CV disease
• Current guidelines recommend aggressive
  multi-factorial treatment in patients with
  diabetes or prediabetes
• PPAR? modulation is a potentially important
  strategy for improving insulin sensitivity and
  blunting atherosclerosis progression