Glucose Control

1
Glucose Control Complications New Trials
Modify The Paradigm
2

• Does glucose control reduce complications in
  older patients with
• diabetes? Maybe
• Are our current requirements for rigid glucose
  control appropriate and
• evidence based? No
• Should we treat patients, not numbers?
• Yes

3
Glucose Control ComplicationsNew Trials Modify
the Paradigm

• The World At The Dawn of The 21st Century
• Macrovascular Disease
• Microvascular Disease
• Modifying The Paradigm

4
The World At The Dawn of The 21st Century

• Epidemiologic Data Suggested Deleterious Effects
  Of Glucose On CV Risk In Type 2 DM

5
Fatal and Non-Fatal Myocardial Infarction
UKPDS Group BMJ 321 405-412, 2000
6
Fatal and Non-Fatal Stroke
UKPDS Group BMJ 321 405-412, 2000
7
The World At The Dawn of The 21st Century

• No Clear Prospective Data Showed CV Risk
  Reduction By Excellent Glycemic Control

8
Glucose Control ComplicationsNew Trials Modify
the Paradigm

• The World At The Dawn of The 21st Century
• Macrovascular Disease
• Microvascular Disease
• Modifying The Paradigm

9
VADT Veterans Affairs Diabetes Trial
Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
10
VADT Veterans Affairs Diabetes Trial
VADT
ACCORD
ADVANCE
UKPDS
Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
11
VADT Veterans Affairs Diabetes Trial
9.4
8.4
6.9
Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
12
VADT Veterans Affairs Diabetes Trial

• Primary Outcomes
• Major CV Events
• CV Death
• MI
• Stroke
• CHF
• Amputation
• Interventions for CAD, PVD

Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
13
VADT Veterans Affairs Diabetes Trial

• HR (CI) 0.88 (0.74, 1.05)
• P 0.14

Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
14
VADT Veterans Affairs Diabetes Trial

• HR (CI) 1.07 (0.81, 1.42)
• P 0.62

Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
15
VADT Veterans Affairs Diabetes Trial

• HR (CI) 1.32 (0.81, 2.14)
• P 0.26

Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
16
VADT Veterans Affairs Diabetes Trial

• Non-Glycemic Risk Factor Control

Intensive
Standard
127/68
125/69
BP mmHg
80
80
LDL-C mg/dl
40
41
HDL-C mg/dl
151
159
TG mg/dl
94
91
on ASA
86
83
on Statin
Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
17
Glucose CV Risk

• If other CV risk factor control is good, there is
  no additional CV benefit of lowering HbA1c from
  8.4 to 6.9 in older people with advanced DM
  (VADT).

18
ACCORD Action to Control Cardiovascular Risk in
Diabetes
VADT
ACCORD
ADVANCE
UKPDS
ACCORD Study Group. NEJM 358 2545-2559, 2008.
19
ACCORD Action to Control Cardiovascular Risk in
Diabetes
VADT 9.4
8.1
VADT 8.4
7.5
6.4
6.9
ACCORD Study Group. NEJM 358 2545-2559, 2008.
20
ACCORD Action to Control Cardiovascular Risk in
Diabetes

• First Occurrence of Non-Fatal MI, Non-Fatal
  Stroke, or CV Death

• HR (CI) 0.90 (0.78, 1.04)
• P 0.16

ACCORD Study Group. NEJM 358 2545-2559, 2008.
21
ACCORD Action to Control Cardiovascular Risk in
Diabetes
ACCORD Study Group. NEJM 358 2545-2559, 2008.
22
ACCORD Action to Control Cardiovascular Risk in
Diabetes
ACCORD Study Group. NEJM 358 2545-2559, 2008.
23
ACCORD Action to Control Cardiovascular Risk in
Diabetes
Number Needed To Harm 95
ACCORD Study Group. NEJM 358 2545-2559, 2008.
24
Hypoglycemia and CV Disease
Hypoglycemia
HR For Mortality
ACCORD
VADT
Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009 ACCORD Study Group. NEJM
358 2545-2559, 2008.
25
A Reasonable Hypothesis
Intensive glycemic therapy increased all-cause
and cardiovascular mortality because there was
more overall hypoglycemia with intensive therapy.
Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009 ACCORD Study Group. NEJM
358 2545-2559, 2008.
26

• Problems with severe hypoglycemia
• in older patients.
• Disability
• CV events
• Functional
• Death
• Dementia
• JAMA April 15, 2009 Vol 3011565

27
(No Transcript)
28
Risk for death

• Any severe event 0.02
• Cumulative severe events 0.001

29
Hypoglycemia and CV Disease
Hemodynamic
Hypoglycemia
Thrombotic
Ischemia
Inflammatory
Wright R et al Diabetes/ Metabolism Research and
Reviews , 2008
30
Glucose CV Risk

• If other CV risk factor control is good, there is
  no additional CV benefit of lowering HbA1c from
  8.4 to 6.9 in older people with advanced DM
  (VADT).
• If other CV risk factor control is good, there
  may be CV harm in lowering HbA1c from 7.5 to
  6.4 in older people with advanced DM, perhaps
  due to hypoglycemia (ACCORD).

31
ADVANCE Action in Diabetes and Vascular Disease
VADT
ACCORD
ADVANCE
UKPDS
ADVANCE Collaborative Group. NEJM 358 2560-2572,
2008.
32
ADVANCE Action in Diabetes and Vascular Disease
7.5
7.3
6.5
ADVANCE Collaborative Group. NEJM 358 2560-2572,
2008.
33
ADVANCE Action in Diabetes and Vascular Disease

• HR (CI) 0.90 (0.82, 0.98)
• P 0.01

ADVANCE Collaborative Group. NEJM 358 2560-2572,
2008.
34
ADVANCE Action in Diabetes and Vascular Disease

• HR (CI) 0.94 (0.84, 1.06)
• P 0.32

ADVANCE Collaborative Group. NEJM 358 2560-2572,
2008.
35
ADVANCE Action in Diabetes and Vascular Disease

• Non-Glycemic Risk Factor Control

Intensive
Standard
136/74
138/74
BP mmHg
102
102
LDL-C mg/dl
48
48
HDL-C mg/dl
141
128
TG mg/dl
55
57
on ASA
47
46
on Statin
ADVANCE Collaborative Group. NEJM 358 2560-2572,
2008.
36
ADVANCE Action in Diabetes and Vascular Disease

• HR (CI) 0.93 (0.83, 1.06)
• P 0.28

ADVANCE Collaborative Group. NEJM 358 2560-2572,
2008.
37
VADT, ACCORD, ADVANCE
HbA1c ()
Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009 ACCORD Study Group. NEJM
358 2545-2559, 2008. ADVANCE Collaborative
Group. NEJM 358 2560-2572, 2008.
38
VADT, ACCORD, ADVANCE
Hypoglycemia ()
Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009 ACCORD Study Group. NEJM
358 2545-2559, 2008. ADVANCE Collaborative
Group. NEJM 358 2560-2572, 2008.
39
UKPDS United Kingdom Prospective Diabetes Study
VADT
ACCORD
ADVANCE
UKPDS
UKPDS Group Lancet 352 837-853 and 854-865,
1998
40
UKPDS United Kingdom Prospective Diabetes Study

• Intensive Glycemic Control
• Reduced Photocoagulation
• From 11 To 8 Photocoagulations/1000 Patient
  Years
• Reduced Cataract Extraction
• From 7.4 To 5.6 Extractions/1000 Patient Years
• Increased Total Insulin Reactions (P.0001)

UKPDS Group Lancet 352 837-853 and 854-865,
1998
41
UKPDS United Kingdom Prospective Diabetes Study

• Intensive Glycemic Control
• No Difference In Visual Acuity Or Vision Loss
• No Difference In ESRD
• No Difference In Mortality
• No Difference In CV Events
• No Difference In Severe Insulin Reactions

UKPDS Group Lancet 352 837-853 and 854-865,
1998
42
Effect of Tight BP and Glycemic Control on
Outcomes UKPDS
Microvascular
Stroke
Any DM Endpoint
DM Death
Complications
0
-10

-20

-30



-40

-50
Tight Glucose Control
Tight BP Control
plt 0.05 UKPDS 38. BMJ.
1998317703-713. UKPDS 33.Lancet.1998352837-853
.
43
UKPDS United Kingdom Prospective Diabetes Study
Follow-Up
3,277 Entered Post Trial Monitoring Median
Follow-Up 17 Years
Holman R et al NEJM 359 1565-1576, 2008.
44
UKPDS United Kingdom Prospective Diabetes Study
Follow-Up
HbA1c
Holman R et al NEJM 359 1565-1576, 2008.
45
UKPDS United Kingdom Prospective Diabetes Study
Follow-Up
Any Diabetes Related End Point
Holman R et al NEJM 359 1565-1576, 2008.
46
UKPDS United Kingdom Prospective Diabetes Study
Follow-Up
Myocardial Infarction
Holman R et al NEJM 359 1565-1576, 2008.
47
UKPDS United Kingdom Prospective Diabetes Study
Follow-Up
All Cause Mortality
Holman R et al NEJM 359 1565-1576, 2008.
48
Glucose CV Risk

• If other CV risk factor control is good, there is
  no additional CV benefit of lowering HbA1c from
  8.4 to 6.9 in older people with advanced DM
  (VADT).
• If other CV risk factor control is good, there
  may be CV harm in lowering HbA1c from 7.5 to
  6.4 in older people with advanced DM, perhaps
  due to hypoglycemia (ACCORD).
• Reducing blood glucose early in the course of the
  disease may not be harmful (ADVANCE) and may
  even confer CV benefit (UKPDS Follow-Up).

49
Glucose Control ComplicationsNew Trials Modify
the Paradigm

• The World At The Dawn of The 21st Century
• Macrovascular Disease
• Microvascular Disease
• Modifying The Paradigm

50
VADT Veterans Affairs Diabetes Trial

• Secondary Outcomes
• Angina
• Transient Ischemic Attack, Critical Limb Ischemia
  
• Total Mortality
• Retinopathy, Nephropathy, Neuropathy
• Quality Of Life, Cognitive Function,
  Cost-Effectiveness

Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
51
VADT Veterans Affairs Diabetes Trial
Eye Disease

• No Benefit of Good Glycemic Control On
• Cataract Surgery
• Photocoagulation
• Vitrectomy
• Onset of New Retinopathy
• Retinopathy Progression (p 0.07)
• Progression to Macular Edema

Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
52
VADT Veterans Affairs Diabetes Trial
Kidney Disease

• No Benefit of Good Glycemic Control On
• Doubling Of Serum Creatinine
• Creatinine gt 3 mg/dl
• GFR lt 15 ml/min

Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
53
VADT Veterans Affairs Diabetes Trial
Kidney Disease

• Good Glycemic Control Modestly Retarded Any
  Progression of Albuminuria
• (p 0.05)

Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
54
VADT Veterans Affairs Diabetes Trial
Neurologic Disease

• No Benefit of Good Glycemic Control On
• Any New Neuropathy
• New Mononeuropathy
• New Peripheral Neuropathy
• New Autonomic Neuropathy

Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009
55
ADVANCE Action in Diabetes and Vascular Disease
Kidney Disease

• No Benefit of Good Glycemic Control On
• Doubling Of Serum Creatinine
• Need for Renal Replacement Therapy
• Death Due to Renal Disease

ADVANCE Collaborative Group. NEJM 358 2560-2572,
2008.
56
ADVANCE Action in Diabetes and Vascular Disease
Kidney Disease

• Good Glycemic Control Retarded Development of
• Microalbuminuria (p 0.02)
• Macroalbuminuria (p lt 0.001)

ADVANCE Collaborative Group. NEJM 358 2560-2572,
2008.
57
ADVANCE Action in Diabetes and Vascular Disease

• No Benefit of Good Glycemic Control On New or
  Worsening Neuropathy

Neurologic Disease
ADVANCE Collaborative Group. NEJM 358 2560-2572,
2008.
58
UKPDS United Kingdom Prospective Diabetes Trial
Follow-Up
Holman R et al NEJM 359 1565-1576, 2008.
59
Glucose Microvascular Risk

• Good glucose control seems to confer some
  microvascular benefit in patients with both early
  and more advanced diabetes.

60
Glucose CV Risk

• If other CV risk factor control is good, there is
  no additional CV benefit of lowering HbA1c from
  8.4 to 6.9 in older people with advanced DM
  (VADT).
• If other CV risk factor control is good, there
  may be CV harm in lowering HbA1c from 7.5 to
  6.4 in older people with advanced DM, perhaps
  due to hypoglycemia (ACCORD).
• Reducing blood glucose early in the course of the
  disease may not be harmful (ADVANCE) and may
  even confer CV benefit (UKPDS Follow-Up).

61
Glucose Lowering Complications
Macrovascular
Microvascular
Benefit
Benefit
Early DM
Benefit 
No Benefit Possible Harm
Advanced DM
62
Glucose Control ComplicationsNew Trials Modify
the Paradigm

• The World At The Dawn of The 21st Century
• Macrovascular Disease
• Microvascular Disease
• Modifying The Paradigm

63
Modifying The Paradigm
64
Modifying The Paradigm

• In theory, things that work well in theory work
  well in practice, but in practice they dont
• -- Yogi Berra

65
Modifying The Paradigm

• Its hard to make predictions, especially about
  the future
• -- Yogi Berra

66
Modifying The Paradigm
ACCORD
ADVANCE
VADT
0.88
0.94
0.9
HR 10 Endpoint
(0.74-1.05)
(0.84-1.06)
(0.78-1.04)
 
Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009 ACCORD Study Group. NEJM
358 2545-2559, 2008. ADVANCE Collaborative
Group. NEJM 358 2560-2572, 2008.
67
Modifying The Paradigm
ACCORD
ADVANCE
VADT
Duckworth W, Abraira C, Moritz T, Reda D et al
NEJM 360 129-139, 2009 ACCORD Study Group. NEJM
358 2545-2559, 2008. ADVANCE Collaborative
Group. NEJM 358 2560-2572, 2008.