1. Lipid Disorders and Management in Diabetes
Om P. Ganda MD
Joslin Diabetes Center
Harvard Medical school
Boston, MA
Web-conference, April 8, 2010

2. MRFIT: Cholesterol and CVD Mortality in Men With Type 2 Diabetes
Age-Adjusted CVD deaths per 10,000 person-years
Age adjusted CVD mortality in > 350, 000 subjects participating in the MRFIT study.
More than 5000 had diabetes.
280
Plasma cholesterol (mg/dL)
Stamler et al. Diabetes Care. 1993;16:

3. Pathophysiology of Dyslipidemia in Type 2 Diabetes
TG pool
High
Low
Smaller VLDL
IDL
Larger VLDL
Large LDL
Small LDL
HDL
Smaller HDL
Remnants
Smaller LDL
LPL
LPL/HL
CETP TG HL
LDLR
Krauss RM. Diabetes Care. 2004;27:

4. HPS: Major Vascular Events by LDL-C and Prior Diabetes
Rate ratio & 95% CI
STATIN better
PLACEBO better
0.4
0.6
0.8
1.0
1.2
1.4
HPS: Major Vascular Events by LDL-C and Prior Diabetes
LDL-C & DIABETES
SIMVASTATIN
(10,269)
PLACEBO
(10,267)
< 116 mg/dL
Diabetes
191 (15.7%)
252 (20.9%)
No diabetes
407 (18.8%)
504 (22.9%)
116 mg/dL
410 (23.3%)
496 (27.9%)
1,025 (20.0%)
1,333 (26.2%)
ALL PATIENTS
2,033 (19.8%)
2,585 (25.2%)
24% SE 3 reduction (2P<.00001)
There were similar proportional reductions in risk of major vascular events irrespective of various lipid values at baseline, both in those with and those without diabetes.
The Heart Protection Study Collaborative Group. Lancet. 2003;361:

5. Hazard Ratio Risk Reduction (CI)
CARDS: Treatment Effect on the Primary End Points by Subgroup
Subgroup*
Placebo**
Atorva**
Hazard Ratio Risk Reduction (CI)
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)
40 (5.5)
44% (18-62)
Trig. <1.7 (150)
60 (8.4)
43 (6.1)
29% (-5-52) P=.40
* units in mmol/L (mg/dL)
** N (% of randomised) .2 .4 .6 .8 1
1.2
Favors Atorvastatin Favors Placebo
Colhoun HM, et al. Lancet 2004;364:

6. 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
Meta –analysis of participants in 14 megatrials of statin therapy.
CTT Collaborators
Lancet 2008,
371:
Total mortality RR 0-88 ( ) 6

7. Meta-analysis of Intensive Statin Trials: Coronary Death or Myocardial Infarction
DM : Similar outcome
Cannon,CP et al JACC 2006; 48:

9. ARR : 0.77 vs 1.36 %/yr

10. Statins and Primary End Points
Risk of Primary Event (%)
In all of these major statin trials, significant residual cardiovascular risk remains even after reducing LDL-C
Kastelein et al. Eur Heart J. 2005;7(suppl F):F27-F33. 10

11. TG <150 mg/dL Associated With Lower Risk of CHD Events Independent of LDL-C Level
PROVE IT-TIMI 22 Trial
N = 4162
Referent
HR: 0.85
P=.180
CHD Eventa Rate
After 30 Daysc, %
HR: 0.84
P=.192
A subgroup analyses of the PROVE- IT trial based on baseline triglyceride concentrations and achieved LDL.
HR: 0.72
P=.017
LDL-C ≥70
LDL-C <70
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
Miller M, et al. J ACC. 2008;51: 11

12. TNT: major CVD Events in Patients with LDL < 70 mg/dl
A re- analysis of TNT trial according to HDL quintiles in those achieving intensive LDL – C reduction.
Barter,P et al NEJM 2007; 357: 12 12 12

13. Management of Dyslipidemia beyond LDL
Lifestyle changes and secondary causes
Pharmacologic therapy
Fibrate
Niacin
Omega-3 Fatty acids
Combination therapy 13 13 13

14. ACCORD- Lipid Results
Shown are mean plasma levels of total cholesterol (Panel A), low-density lipoprotein (LDL) cholesterol (Panel B), and high-density lipoprotein (HDL) cholesterol (Panel C) and median levels of triglycerides (Panel D) at baseline, 4 months, 8 months, 1 year, and annually thereafter. Nominal P values for differences between the study groups at 4 months and at the end of the study were, respectively: total cholesterol, P<0.001 and P=0.02; LDL cholesterol, P=0.11 and P=0.16; HDL cholesterol, P<0.001 and P=0.01; and triglycerides, P<0.001 for both comparisons with the use of nonparametric tests. End-of-study visits were those that occurred in early 2009 and included follow-up at years 4, 5, 6, and 7. The I bars represent 95% confidence intervals. To convert the values for cholesterol to millimoles per liter, multiply by To convert the values for triglycerides to millimoles per liter, multiply by
The ACCORD Study Group. N Engl J Med 2010; /NEJMoa 14

15. ACCORD Lipid: Primary Outcome in Prespecified Subgroups
Hazard Ratios for the Primary Outcome in Prespecified Subgroups. The horizontal bars represent 95% confidence intervals, and the vertical dashed line indicates the overall hazard ratio. The size of each square is proportional to the number of patients. P values are for tests for interaction. To convert the values for cholesterol to millimoles per liter, multiply by To convert the values for triglycerides to millimoles per liter, multiply by
The ACCORD Study Group. N Engl J Med 2010; /NEJMoa 15

16. 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 16 16

17. ADA and ACC Consensus Statement on Lipoprotein Management
TREATMENT GOALS
LDL-C (mg/dL)
Non–HDL-C (mg/dL)
ApoB (mg/dL)
Highest-risk patients
Including those with 1) Known CVD or 2) Diabetes plus one or more additional CVD risk factor*
< 70
< 100
< 80
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
< 130
< 90
*Smoking, HBP, f/h premature CHD
Brunzell JD et al. Diabetes Care. 2008;31:

18. 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< 100, TG > 200*
LDL< 70, TG > 200*
Measure Apo-B
Apo-B >80mg/dl
ApoB< 90mg/dl
Intensify LDL Rx or add Fibrate/Niacin
Continue current Rx; may need Fibrate/ Niacin
* 150 if fasting
Ganda, OP Endocrine Practice 2009; 15: 18 18 18