Targeting the Underlying Pathophysiology of Type 2 Diabetes

1
Targeting the Underlying Pathophysiology of Type
2 Diabetes
This slideset was developed with support from
GlaxoSmithKline
2
Aim

• Provide practical guidance on improving diabetes
• care through highlighting the need to
• understand that insulin resistance and b-cell
  dysfunction are core defects of type 2 diabetes
• address the underlying pathophysiology

3
Type 2 diabetes

• Characterized by chronic hyperglycemia
• Associated with microvascular and macrovascular
  complications
• Generally arises from a combination of insulin
  resistance and ?-cell dysfunction

Definition, Diagnosis and Classification of
Diabetes Mellitus and its Complications.
Department of Noncommunicable Disease
Surveillance,World Health Organization, Geneva
1999. Available at http//www.diabetes.org.uk/inf
ocentre/carerec/diagnosi.doc
4
What is insulin resistance?

• Major defect in individuals with type 2 diabetes1
• Reduced biological response to insulin13
• Strong predictor of type 2 diabetes4
• Closely associated with obesity5

1American Diabetes Association. Diabetes Care
1998 21310314. 2Beck-Nielsen H Groop LC. J
Clin Invest 1994 9417141721. 3Bloomgarden ZT.
Clin Ther 1998 20216231. 4Haffner SM, et al.
Circulation 2000 101975980. 5Boden G. Diabetes
1997 46310.
5
What is ?-cell dysfunction?

• Major defect in individuals with type 2 diabetes
• Reduced ability of ?-cells to secrete insulin in
  response to hyperglycemia

DeFronzo RA, et al. Diabetes Care 1992
15318354.
6
Insulin resistance and ?-cell dysfunction are
core defects of type 2 diabetes
Rhodes CJ White MF. Eur J Clin Invest 2002
32 (Suppl. 3)313.
7
How do insulin resistance and ?-cell dysfunction
combine to cause type 2 diabetes?
8
How is insulin resistance measured?

• Several methods exist, including
• continuous sampling of insulin/glucose1
• gold standard, but impractical for large-scale
  use
• single measure of insulin/glucose2
• simple estimate from fasting insulin and glucose
• useful for assessment on a larger scale

1Bergman RN, et al. Eur J Clin Invest 2002 32
(Suppl. 3)3545. 2Matthews DR, et al.
Diabetologia 1985 28412419.
9
More than 80 of patients progressing to type 2
diabetes are insulin resistant
Insulin sensitivelow insulin secretion (16)
Insulin sensitivegood insulin secretion (1)
Insulin resistantlow insulin secretion (54)
83
Insulin resistant good insulin secretion (29)
Haffner SM, et al. Circulation 2000
101975980.
10
Insulin resistance reduced response to
circulating insulin
Insulin resistance
Adiposetissue
Liver
Muscle
? Glucose output
? Glucose uptake
? Glucose uptake
Hyperglycemia
11
Overall, 75 of patients with type 2 diabetes
die from cardiovascular disease
Gray RP Yudkin JS. Cardiovascular disease in
diabetes mellitus. In Textbook of Diabetes 2nd
Edition, 1997. Blackwell Sciences.
12
Insulin resistance is as strong a risk factor for
cardiovascular disease as smoking
1.8
1.6
1.4
Odds ratio for incident CVD
1.2
1.0
0.8
0.6
Age
Smoking
Insulinresistance
Total cholesterolHDL cholesterol
Bonora E, et al. Diabetes Care 2002
2511351141.
13
Insulin resistance is closely linked to
cardiovascular disease
Present in gt 80 of people with type 2
diabetes1 Approximately doubles the risk of a
cardiac event2 Implicated in almost half of CHD
events in individuals with type 2 diabetes2
Insulin resistance
1Haffner SM, et al. Circulation 2000
101975980. 2Strutton D, et al. Am J Man Care
2001 7765773.
14
Insulin resistance is linked to a range of
cardiovascular risk factors
Zimmet P. Trends Cardiovasc Med 2002
12354362.
15
90 of people with type 2 diabetes are
overweight or obese
World Health Organization, 2005.
http//www.who.int/dietphysicalactivity/publicatio
ns/facts/obesity
16
How is ?-cell function measured?

• ?-cell function is difficult to measure and most
  methods are impractical for large-scale use1
• Homeostasis model assessment (HOMA) provides a
  simple estimate of ?-cell function2
• Proinsulininsulin ratio is sometimes used as a
  marker of ?-cell dysfunction1

1Matthews DR, et al. Diabetologia 1985
28412419. 2Bergman RN, et al. Eur J Clin Invest
2002 32 (Suppl. 3)3545.
17
Why does the ?-cell fail?
Oversecretion of insulin to compensate for
insulin resistance1,2
Glucotoxicity2
Lipotoxicity3
Chronic hyperglycemia
High circulating free fatty acids
Pancreas
?-cell dysfunction
1Boden G Shulman GI. Eur J Clin Invest 2002
321423. 2Kaiser N, et al. J Pediatr Endocrinol
Metab 2003 16522. 3Finegood DT Topp B.
Diabetes Obes Metab 2001 3 (Suppl. 1)S20S27.
18
Glycemic control declines over time
9 8 7 6 0
UK Prospective Diabetes Study (UKPDS) Group.
Lancet 1998 352837853.
19
Loss of ?-cell function occurs before diagnosis
100
Up to 50 loss
Diagnosis
80
60
?-cell function ()
40
20
0
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
1
2
3
4
5
6
Time from diagnosis (years)
Holman RR. Diabetes Res Clin Prac 1998 40
(Suppl.)S21S25.
20
Oral antidiabetic agents do they target insulin
resistance and ?-cell dysfunction?
21
Barriers to achieving good glycemic control
Inadequate targeting of underlying
pathophysiology
22
Primary sites of action of oral antidiabetic
agents
Biguanides
Thiazolidinediones
? Insulin resistance
? Glucose output ? Insulin resistance
Kobayashi M. Diabetes Obes Metab 1999 1 (Suppl.
1)S32S40. Nattrass M Bailey CJ. Baillieres
Best Pract Res Clin Endocrinol Metab 1999
13309329.
23
The dual action of thiazolidinediones reduces
HbA1c

Insulin resistance
?-cell function
HbA1c
Lebovitz HE, et al. J Clin Endocrinol Metab
2001 86280288.
24
Potential to prevent progression to type 2
diabetes in at-risk women
Troglitazone reduced progression to type 2
diabetes by gt 50
Troglitazone 400 mg/day
0.6
Placebo
0.5
0.4
Proportion with diabetes
0.3
0.2
0.1
0.0
10
0
20
30
40
50
60
Time on trial (months)
Troglitazone is no longer available
Buchanan TA, et al. Diabetes 2002 5127962803.
25
Can thiazolidinediones delay progression from IGT
to T2DM?
Placebo
Rosiglitazone 8 mg/day
100
T2DM
11
80
IGT
56
60
Subjects ()
IGT
IGT
IGT
100
100
89
40
NGT
20
44
0
Screening
Week 12
Screening
Week 12
Bennett SM, et al. Diabet Med 2004 21415422.
26
Does decreasing insulin resistance decrease
macrovascular complications?
UK Prospective Diabetes Study (UKPDS) Group.
Lancet 1998 352854865.
27
Insulin sensitizers reduce cardiovascular events
in type 2 diabetes
60
50
40
12-month combined event rate ()
30
20
10
0
Non-sensitizers
Sensitizers
Kao JA, et al. J Am Coll Cardiol 2004 4337A.
28
How can diabetes care and outcomes be improved?
The Global Partnership recommends
Address the underlying pathophysiology, including
treatment of insulin resistance
Del Prato S, et al. Int J Clin Pract 2005
5913451355.