Lipid Disorders and Management Lipid Disorders and Management in Diabetesin Diabetes

Om P. Ganda MDJoslin Diabetes Center

Harvard Medical school

Boston, MA

Web-conference, April 8, 2010Web-conference, April 8, 2010

1420

29

46

62

8592

130

0

50

100

150

<180 200-220 240-260

Controls

Type 2 diabetes

Stamler et al. Diabetes Care. 1993;16:434-444.

Ag

e-A

dju

ste

d C

VD

de

ath

s p

er1

0,0

00

per

son

-yea

rs

Plasma cholesterol (mg/dL)280

MRFIT: Cholesterol and CVD Mortality MRFIT: Cholesterol and CVD Mortality in Men With Type 2 Diabetesin Men With Type 2 Diabetes

Pathophysiology of Pathophysiology of Dyslipidemia in Type 2 DiabetesDyslipidemia in Type 2 Diabetes

Krauss RM. Krauss RM. Diabetes CareDiabetes Care. 2004;27:1496-1504.. 2004;27:1496-1504.

TG pool

High

Low

Smaller VLDL

IDL

Larger VLDL

Large LDL

Small LDL

HDL Smaller HDL

Remnants Smaller

LDL

LPLLPL LPLLPL

LPLLPL LPL/HLLPL/HL

CETPCETPTGTG

HLHL

LDLRLDLR

Rate ratio & 95% CISTATIN better PLACEBO better

0.4 0.6 0.8 1.0 1.2 1.4

The Heart Protection Study Collaborative Group. Lancet. 2003;361:2005-2016.

HPS: Major Vascular Events by LDL-HPS: Major Vascular Events by LDL-C and Prior DiabetesC and Prior Diabetes

24% SE 3 reduction (2P<.00001)

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 Diabetes 410 (23.3%) 496 (27.9%)

No diabetes 1,025 (20.0%) 1,333 (26.2%)

ALL PATIENTS 2,033 (19.8%) 2,585 (25.2%)

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

CARDS: Treatment Effect CARDS: Treatment Effect ononthe Primary End Points by the Primary End Points by SubgroupSubgroup

Colhoun HM, et al. Lancet 2004;364:685-696

Major Vascular Events with or without Diabetes: Effect per 1mM/L reduction in LDL-cholesterol Major Vascular Events with or without Diabetes: Effect per 1mM/L reduction in LDL-cholesterol

14 RCTs18686 with DM71370 without DM

CTT Collaborators Lancet 2008, 371: 117-125

No differences by Presence or absence of vascular disease, Other risk-factors, or baseline lipid levels

Total mortality RR 0-88 (0.84-0.91)

Meta-analysis of Intensive Statin Trials:Coronary Death or Myocardial Infarction

Cannon,CP et al JACC 2006; 48: 438-445

DM : Similar outcome

ARR : 0.77 vs 1.36 %/yr

Statins and Primary End PointsStatins and Primary End Points

30 3724 24 31 27

15 9

36

70 6376 76 69 73

85 91

64

0

20

40

60

80

100

Risk reduction (%) Events not avoided (%)

Kastelein et al. Kastelein et al. Eur Heart JEur Heart J. 2005;7(suppl F):F27-F33.. 2005;7(suppl F):F27-F33.

Ris

k o

f P

rim

ary

Eve

nt

(%)

Ris

k o

f P

rim

ary

Eve

nt

(%)

TG <150 mg/dL Associated With Lower Risk of CHD Events Independent of LDL-C Level

PROVE IT-TIMI 22 Trial

Miller M, et al. J ACC. 2008;51:724-730.

CH

D E

vent

a R

ate

Afte

r 30

Day

sc , %

Death, MI, and recurrent ACS ACS patients on atorvastatin 80 mg or pravastatin 40 mgAdjusted for age, gender, low HDL-C, smoking, hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment

N = 4162

TG <150 TG ≥150

LDL-C ≥70

LDL-C <70

HR: 0.72P=.017

HR: 0.85P=.180

HR: 0.84P=.192

Referent

TNT: major CVD Events in Patients with LDL < 70 TNT: major CVD Events in Patients with LDL < 70 mg/dlmg/dl

Barter,P et al NEJM 2007; 357: 1301-1310

Lifestyle changes and secondary causes

Pharmacologic therapy

• Fibrate

• Niacin

• Omega-3 Fatty acids

Combination therapy

Management of Dyslipidemia beyond LDL

The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282

ACCORD- Lipid Results

The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282

ACCORD Lipid: Primary Outcome in Prespecified Subgroups

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 GOALSTREATMENT GOALS LDL-C LDL-C (mg/dL)(mg/dL)

Non–HDL-C Non–HDL-C (mg/dL)(mg/dL)

ApoB ApoB (mg/dL)(mg/dL)

Highest-risk patientsHighest-risk patients

Including those with Including those with 1) Known CVD or 1) Known CVD or 2) Diabetes plus one or more additional 2) Diabetes plus one or more additional CVD risk factor*CVD risk factor*

< 70 < 100 < 80

High-risk patientsHigh-risk patients

Including those with Including those with 1) No diabetes or known clinical CVD but 2 1) No diabetes or known clinical CVD but 2 or more additional major CVD risk factors or more additional major CVD risk factors or or 2) Diabetes but no other CVD risk factors2) Diabetes but no other CVD risk factors

< 100 < 130 < 90

Brunzell JD et al. Diabetes Care. 2008;31:811-822.

*Smoking, HBP, f/h premature CHD*Smoking, HBP, f/h premature CHD

Algorithm for Apo-B Testing in Patients with Dyslipidemia

Order Lipid profile

LDL-C > 100mg/dl TG >500 mg/dl

Lifestyle + Statin RxGoal: LDL-C < 100 mg/dl

Treat TG to < 500 mg/dlFibrates and/or Fish oil if > 1000 mg/dl

CVD-yes CVD-No

Intensify Statin Rx Statin Rx if LDL > 100

LDL< 70, TG > 200* LDL< 100, 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

Ganda, OP Endocrine Practice 2009; 15: 370-376Ganda, OP Endocrine Practice 2009; 15: 370-376 * 150 if fasting* 150 if fasting