Lipid Disorders and Management
in Diabetes
Om P. Ganda MD
Joslin Diabetes Center
Harvard Medical school
Boston, MA
Web-conference, April 8, 2010
Age-Adjusted CVD deaths per
10,000 person-years
MRFIT: Cholesterol and CVD Mortality in
Men With Type 2 Diabetes
150
Controls
Type 2 diabetes
100
130
92
85
62
46
50
20
14
29
0
<180
200-220
240-260
Plasma cholesterol (mg/dL)
Stamler et al. Diabetes Care. 1993;16:434-444.
280
Pathophysiology of
Dyslipidemia in Type 2 Diabetes
TG
pool
Smaller
VLDL
Low
LPL
LPL
Large
LDL
IDL
LDLR
High
Larger
VLDL
LPL
LPL/HL
Small
LDL
Remnants
Smaller
LDL
HL
TG
CETP
Krauss RM. Diabetes Care. 2004;27:1496-1504.
HDL
Smaller
HDL
HPS: Major Vascular Events by LDL-C
and Prior Diabetes
LDL-C & DIABETES
< 116 mg/dL
Diabetes
No diabetes
SIMVASTATIN
(10,269)
PLACEBO
(10,267)
191 (15.7%)
252 (20.9%)
407 (18.8%)
504 (22.9%)
410 (23.3%)
496 (27.9%)
1,025 (20.0%)
1,333 (26.2%)
2,033 (19.8%)
2,585 (25.2%)
Rate ratio & 95% CI
STATIN better
PLACEBO better
116 mg/dL
Diabetes
No diabetes
ALL PATIENTS
0.4
24% SE 3
reduction
(2P<.00001)
0.6
The Heart Protection Study Collaborative Group. Lancet. 2003;361:2005-2016.
0.8
1.0
1.2
1.4
CARDS: Treatment Effect on
the Primary End Points by Subgroup
Subgroup*
Hazard Ratio Risk Reduction (CI)
Placebo**
Atorva**
LDL-C ≥3.06 (120)
66 (9.5)
44 (6.1)
38% (9-58)
LDL-C <3.06 (120)
61 (8.5)
39 (5.6)
37% (6-58)
p=0.96
HDL-C ≥1.35 (54)
62 (8.4)
36 (5.2)
41% (11-61)
HDL-C <1.35 (54)
65 (9.6)
47 (6.4)
35% (5-55)
P=.71
Trig. ≥1.7 (150)
67 (9.6)
* units
in mmol/L
Trig.
<1.7
(150) (mg/dL) 60 (8.4)
** N (% of randomised)
Colhoun HM, et al. Lancet 2004;364:685-696
40 (5.5)
44% (18-62)
43 (6.1).2 .4 .6 .8 1 1.2
29% (-5-52)
Favors Atorvastatin
Favors Placebo
P=.40
Major Vascular Events with or without Diabetes:
Effect per 1mM/L reduction in LDL-cholesterol
14 RCTs
18686 with DM
71370 without DM
No differences by
Presence or absence of
vascular disease,
Other risk-factors,
or baseline lipid levels
CTT Collaborators
Lancet 2008,
371: 117-125
Total mortality RR 0-88 (0.84-0.91)
Meta-analysis of Intensive Statin Trials:
Coronary Death or Myocardial Infarction
DM : Similar outcome
Cannon,CP et al JACC 2006; 48: 438-445
ARR : 0.77 vs 1.36 %/yr
Statins and Primary End Points
Events not avoided (%)
100
80
63
70
60
76
76
69
24
24
31
64
73
85
91
40
20
37
30
36
27
15
Kastelein et al. Eur Heart J. 2005;7(suppl F):F27-F33.
9
ER
AL
LH
AT
-L
LT
AS
C
O
TLL
A
SP
H
PS
PR
O
W
O
SC
O
PS
ID
LI
P
E
C
AP
Te
x
S/
C
AP
AF
C
AR
S
0
4S
Risk of Primary Event (%)
Risk reduction (%)
TG <150 mg/dL Associated With Lower Risk of CHD
Events Independent of LDL-C Level
PROVE IT-TIMI 22 Trial
N = 4162
CHD Eventa Rate
After 30 Daysc, %
20
17.9%
15.0%
15
10
5
Referent
HR: 0.85
P=.180
11.7%
16.5%
HR: 0.84
P=.192
HR: 0.72
P=.017
LDL-C ≥70
0
TG <150
TG ≥150
Death, MI, and recurrent ACS
ACS patients on atorvastatin 80 mg or pravastatin 40 mg
Adjusted for age, gender, low HDL-C, smoking, hypertension, obesity,
diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment
LDL-C <70
Miller M, et al. J ACC. 2008;51:724-730.
TNT: major CVD Events in Patients with LDL < 70
mg/dl
Barter,P et al NEJM 2007; 357: 1301-1310
Management of Dyslipidemia beyond LDL
 Lifestyle changes and secondary causes
 Pharmacologic therapy
• Fibrate
• Niacin
• Omega-3 Fatty acids
 Combination therapy
ACCORD- Lipid Results
The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282
ACCORD Lipid: Primary Outcome in Prespecified
Subgroups
The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282
ADA Lipid Goals and Recommendations 2009
 Lifestyle modifications
 Primary LDL –C goal < 100 mg/dl ; If CVD:LDL-C < 70 mg/dl is an option
 Statin therapy added to lifestyle changes, regardless of baseline LDL , if
• Overt CVD;
• Without CVD but age > 40 yr + one or more other CVD risk factors
 Without overt CVD and age < 40 yr
-Consider statin if LDL-C > 100 mg/dl or multiple risk factors , despite
lifestyle therapy.
 In drug treated patients, a reduction in LDL-C of ~30-40% from baseline , if
LDL targets not achieved with maximum tolerated statin therapy.
 Triglycerides < 150 mg/dl; HDL-C > 40 mg/dl (men),> 50 mg/dl (women):
Desirable
• Combination therapy to achieve lipid goals may be needed but outcome
studies pending.
Diabetes Care 2009; 32(suppl1): S13-S61
ADA and ACC Consensus Statement on
Lipoprotein Management
TREATMENT GOALS
LDL-C
(mg/dL)
Non–HDL-C
(mg/dL)
ApoB
(mg/dL)
< 70
< 100
< 80
< 100
< 130
< 90
Highest-risk patients
Including those with
1) Known CVD or
2) Diabetes plus one or more additional
CVD risk factor*
High-risk patients
Including those with
1) No diabetes or known clinical CVD but 2
or more additional major CVD risk factors
or
2) Diabetes but no other CVD risk factors
*Smoking, HBP, f/h premature CHD
Brunzell JD et al. Diabetes Care. 2008;31:811-822.
Algorithm for Apo-B Testing in Patients with Dyslipidemia
Order Lipid profile
LDL-C > 100mg/dl
TG >500 mg/dl
Lifestyle + Statin Rx
Goal: LDL-C < 100 mg/dl
Treat TG to < 500 mg/dl
Fibrates and/or Fish oil if > 1000 mg/dl
CVD-No
CVD-yes
Statin Rx if LDL > 100
Intensify Statin Rx
LDL< 70, TG > 200*
LDL< 100, TG > 200*
Measure Apo-B
Apo-B >80mg/dl
Intensify LDL Rx or add Fibrate/Niacin
Ganda, OP Endocrine Practice 2009; 15: 370-376
ApoB< 90mg/dl
Continue current Rx; may need Fibrate/ Niacin
* 150 if fasting