Clinical Trials and Guidelines for Lipid Management in the Diabetic Patient Steven Haffner, MD
UKPDS Design
Aim
To determine whether intensified blood glucose control, with either sulphonylurea or insulin, reduces the risk of macrovascular or microvascular complications in type 2 diabetes
Patients
3867 newly diagnosed type 2 diabetic patients who were asymptomatic after 3 months of diet; fasting glucose 6.1-15 mmol/L (110-270 mg/dl); treat for 10 years
Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; Turner R et al. Ann Intern Med 1996;124:136-145.
UKPDS Group. Lancet 1998;352:837-853.
UKPDS 10-Year Follow-up Results: Glycemic Control, Weight, and Plasma Insulin
Years from Randomization
Years from Randomization
Conventional
Conventional
Intensive
Intensive
Conventional
Intensive
Intensive
Conventional
Fasting plasma glucose
Median (mmol/L)
Hemoglobin A1c
Weight
Plasma insulin
11
10
9
8
7
6
0
Median (%)
9
8
7
6
0
7.5
5
2.5
0
-2.5
Baseline = 75 kg
Mean Change (kg)
40
30
20
10
0
-10
-20
Median Change (pmol/L)
Baseline = 89 pmol/L
UKPDS: Proportion of Patients Taking Different Therapies in the Conventional-Therapy Group
Courtesy of Dr. Amanda Adler
% of patients
100
80
60
40
20
Diet alone
1
3
5
7
9
11
Years from randomization
Additional pharmacologic therapy
UKPDS: Causes of Death by Glucose Treatment Group
Rate/1000 patient-years
MI Stroke Sudden death PVD
All macrovascular
Renal disease
Cancer Other specified Unknown
Total
UKPDS Group. Lancet 1998;352:837-853.
%
Rate/1000 patient-years
%
7.6 1.6 0.9 0.1
10.2
0.3
4.4 2.4 0.5
17.8
Cause
43 9 5 1
58
2
25 13 3
100
8.0 1.3 1.6 0.3
11.2
0.2
4.4 2.7 0.2
18.7
43 7 8 2
60
1
24 14 1
100
Conventional
Intensive
UKPDS: Endpoints by Glucose Treatment Group
Rate/1000 Patient-Years
Any diabetes-related*
MI
Stroke
PVD**
Microvascular
UKPDS Group. Lancet 1998;352:837-853.
Rate/1000 Patient-Years
P
Cause
40.9
14.7
5.6
1.1
8.6
*Combined microvascular and macrovascular events **Amputation or death from PVD
% Risk Reduction
46.0
17.4
5.0
1.6
11.4
0.029
0.052
0.52
0.15
0.0099
12
16
–
–
25
Conventional
Intensive
UKPDS: Impact of Glucose-Lowering Agents on MI and Stroke
Sulphonylurea or exogenous insulin (n=2729)
MI 16% reduction (P = 0.052)
Stroke 11% increase (P = 0.52)
Metformin in overweight subjects (n = 342)
MI 39% reduction (P = 0.01)
Stroke 41% reduction (P = 0.13)
Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-865.
UKPDS Results: Intensive Blood Pressure Control
Any diabetes-related endpoint
Deaths related to diabetes
Myocardial infarction
Stroke
Microvascular disease
Intensive Blood Pressure Control
24
32
21
44
37
0.0046
0.019
NS
0.013
0.092
Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:703-713.
Reduction (%)
P Value
Comparison of Captopril vs. Atenolol in UKPDS
Primary
Any diabetes-related endpoint
Death related to diabetes
All-cause mortality
Secondary
Myocardial infarction
Stroke
Peripheral vascular disease
Microvascular disease
Clinical Endpoint
Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:713-720.
RR for Captopril
P Value
1.10 (0.86–1.41)
1.27 (0.82–1.97)
1.14 (0.81–1.61)
1.20 (0.82–1.76)
1.12 (0.59–2.12)
1.48 (0.35–6.19)
1.29 (0.80–2.10)
0.43
0.28
0.44
0.35
0.74
0.59
0.30
Comparison of Glucose Lowering and Blood Pressure Lowering in UKPDS
Any diabetes-related endpoint
Myocardial infarction
Stroke
Microvascular disease
12
16
11?
25
Reduction %
? = Increase in risk
Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; UK Prospective Diabetes Study Group. BMJ 1998;317:703-713.
P Value
Reduction %
P Value
Intensive Blood Glucose Control (n=2729)
Intensive Blood Pressure Control (n=758)
0.029
0.052
NS
0.0099
24
21
44
37
0.0046
NS
0.013
0.092
Treatment Strategies for Diabetic Dyslipidemia
Primary Strategy
- Lower LDL cholesterol
Secondary Strategy
- Raise HDL cholesterol
- Lower triglycerides
Other Approaches
- Non-HDL cholesterol
- ApoB
- Remnants
Adapted from American Diabetes Association. Diabetes Care. 2000;23(suppl 1):S57-S60; Chait A, Brunzell JD. Diabetes Mellitus. A Fundamental and Clinical Text. Philadelphia: Lippincott Raven, 1996;772-779; European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730.
CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses
Primary Prevention
AFCAPS/TexCAPS
Secondary Prevention
CARE
4S
LIPID
Baseline LDL-C, mg/dl (mmol/L)
*Values for overall group
Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Py?r?l? K et al. Diabetes Care 1997;20:614-620; Haffner SM et al. Arch Intern Med 1999;159:2661-2667; The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357.
Drug
No.
LDL-C Lowering
Lovastatin
Pravastatin
Simvastatin
Pravastatin
25%
28%
36%
25%*
150 (3.9)
136 (3.6)
186 (4.8)
150* (3.9)
239
586
202
782
Study
CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses (cont’d)
Primary Prevention
AFCAPS/TexCAPS
Secondary Prevention
CARE
4S
LIPID
4S-Extended
CHD Risk Reduction (overall)
Drug
No.
Lovastatin
Pravastatin
Simvastatin
Pravastatin
Simvastatin
43%
25% (p=0.05)
55% (p=0.002)
19%
42% (p=0.001)
37%
23%
32%
25%
32%
239
586
202
782
483
CHD Risk Reduction (diabetes)
Study
Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Py?r?l? K et al. Diabetes Care 1997;20:614-620; The Long-Term Intervention with Pravastatin in