SLIDE 1
LDL Particle Number is Highly Heterogeneous Among Patients with Type 2 Diabetes Mellitus at LDL Cholesterol Target Goal <100 mg/dL
W.C. Cromwell and J.D. Otvos American Journal of Cardiology 2006;98:1599-1602
SLIDE 2 Background
1. The dyslipidemia inherent to type 2 diabetes mellitus (T2DM) is often characterized as:
- Elevated triglycerides (TG)
- Low high-density lipoprotein cholesterol (HDL-C)
- Relatively normal low-density lipoprotein cholesterol (LDL-C) levels
2. Patients with T2DM often have low-density lipoprotein (LDL) particles that are smaller in size and contain less cholesterol than normal. 3. As a result, many such patients have elevated numbers of atherogenic LDL particles (LDL-P) despite having low or normal levels of LDL cholesterol (LDL-C).
SLIDE 3 HDL Cholesterol (mg/dL)
1000 1200 1400 1600 1800
20 40 60 80 100
100 120 140 160 180
LDL Cholesterol LDL Particles
100 200 300 400
100 120 140 160 180 1000 1200 1400 1600 1800
Triglycerides (mg/dL) LDL Particles LDL Cholesterol
LDL Particles (nmol/L) LDL Cholesterol (mg/dL)
Framingham Offspring Study
Otvos JD, Jayarajah E, Cromwell, WC. AJC 2002;90(8A):22i-29i
Relations of LDL Particles and LDL Cholesterol to Levels of HDL Cholesterol and Triglycerides
SLIDE 4
Increased Small LDL Particle Number: A Prominent Feature of the Metabolic Syndrome in the Framingham Offspring Study
Sekar Kathiresan, James Otvos, Lisa Sullivan, Michelle Keyes, Ernst Schaefer, Peter Wilson, Ralph D’Agostino, Sander Robins Circulation 2006;113:20-27
SLIDE 5 110 120 130 140 150 160 170 180 1 2 3 4 5 6 1100 1200 1300 1400 1500 1600 1700 1800
LDL-C LDL-P 0 1 2 3 4 5
N=286 N=407 N=355 N=233 N=113 N=30
LDL Subclasses in Framingham Men with Increasing Numbers of Metabolic Syndrome Features
Kathiresan S, et al. Circulation 2006;113:20-27
SLIDE 6 110 120 130 140 150 160 170 180 1 2 3 4 5 6 1100 1200 1300 1400 1500 1600 1700 1800
LDL-C LDL-P
N=562 N=464 N=298 N=134 N=102 N=29
LDL Subclasses in Framingham Women with Increasing Numbers of Metabolic Syndrome Features
0 1 2 3 4 5
Kathiresan S, et al. Circulation 2006;113:20-27
SLIDE 7 5 10 15 20
70 100 130 160 190 220 250 mg/dL
Percent
Subjects
LDL-C Framingham Offspring1
Percentile: 20th 50th 80th
Population Distribution of LDL Levels
1 Freedman et al. Sex and age differences in lipoprotein subclasses measured by NMR spectroscopy: The Framingham Study.
Clin Chem 2004;50:1189-1200.
2 Multi-Ethnic Study of Atherosclerosis (MESA), data on file at LipoScience (n=6,945).
5 10 15 20
700 1000 1300 1600 1900 2200 2500 nmol/L
Percent
Subjects
LDL-P MESA2
Percentile: 20th 50th 80th
SLIDE 8 LDL Particle Number Distribution in MetS “Optimal” LDL-C < 100 mg/dL (<20th Percentile)
10 20 30
1000 1300 1600
LDL Particles (nmol/L)
23% (n=21) 43% (n=39) 28% (n=26) 6% (n=6)
Percent
Subjects
20th 50th 80th percentile
Otvos JD, Cromwell WC, et al. AHA Scientific Sessions 2003
SLIDE 9
Background (continued)
4. Data from several prospective trials show that LDL-P levels may be a better indicator of cardiovascular disease (CVD) risk than LDL-C. 5. Current guidelines recommend an LDL-C goal of <100 mg/dL for T2DM patients, and an optional goal of <70 mg/dL for those judged to be at very high risk. 6. The present study assessed the heterogeneity of LDL-P levels among T2DM patients with low LDL-C seen in clinical practice.
SLIDE 10
1. The study population consisted of patients with type 2 diabetes mellitus (T2DM) managed in clinical practice with documented LDL cholesterol (LDL-C) < 100 mg/dL. 2. Split-sample measurements of lipids and lipoprotein particle numbers were performed on fresh plasma samples. LDL-C was determined by Friedewald calculation. LDL particle number (LDL-P) was measured by NMR spectroscopy. 3. 2,355 patients with LDL-C < 100 mg/dL were categorized according to their LDL-P values, using cut-points corresponding to the 5th, 20th, 50th, and 80th percentile values of a reference population consisting of > 6900 subjects enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). 4. LDL-P heterogeneity was assessed as a function of LDL-C (< 70 mg/dL or 70-99 mg/dL), triglycerides (< 200 mg/dL or > 200 mg/dL) and Non HDL cholesterol (< 100 mg/dL or 100-129 mg/dL).
Methods
SLIDE 11
Characteristics of T2DM Subjects with LDL-C < 100 mg/dL (n=2,355)
Male Female p Value Number 1295 1060 Mean Age 65 66 Total-C (SD) mg/dL 144 (23.5) 153 (24.0) <0.0001 Trig (SD) mg/dL 153 (81.2) 157 (78.4) 0.182 HDL-C (SD) mg/dL 40.2 (10.8) 46.9 (12.7) <0.0001 LDL-C (SD) mg/dL 72.9 (18.4) 74.9 (17.8) 0.0086 LDL-P (SD) nmol/L 1120 (315) 1110 (319) 0.7824
SLIDE 12 LDL-C 71-99 mg/dL (n=1,484) LDL-C < 70 mg/dL (n=871)
5 10 15 20
24% (n=364)
Percent
Subjects
1% (n=19) 5th 20th 50th 80th percentile
700 1000 1300 1600 (nmol/L)
43% (n=631) 21% (n=307) 11% (n=163)
5 10 15 20 700 1000 1300 1600 (nmol/L)
43% (n=377) 30% (n=260) 9% (n=76) 2% (n=15)
Percent
Subjects
16% (n=147)
40%
LDL Cholesterol and LDL Particle Number Distribution in T2DM Subjects with LDL-C < 100 mg/dL
SLIDE 13 LDL Particle Number Distribution in T2DM Subjects with Triglycerides > 200 mg/dL
LDL-C 71-99 mg/dL Non HDL-C 101-129 mg/dL
10 20 30 700 1000 1300 1600 (nmol/L)
14% (n=68) 32% (n=157) 29% (n=144) 23% (n=114)
Percent
Subjects
2% (n=12)
84%
10 20 30
8% (n=25)
Percent
Subjects
1% (n=5) 5th 20th 50th 80th percentile
700 1000 1300 1600 (nmol/L)
28% (n=90) 31% (n=100) 32% (n=104)
91%
SLIDE 14 LDL Particle Number Distribution in T2DM Subjects with Triglycerides > 200 mg/dL
10 20 30 700 1000 1300 1600 (nmol/L)
49% (n=40) 22% (n=18) 5% (n=4) 0% (n=0)
Percent
Subjects
24% (n=19)
27%
5 10 15 20
33% (n=83)
Percent
Subjects
10% (n=26) 5th 20th 50th 80th percentile
700 1000 1300 1600 (nmol/L)
34% (n=85) 19% (n=48) 4% (n=10)
57%
LDL-C < 70 mg/dL Non HDL-C < 100 mg/dL
SLIDE 15 LDL Particle Number Distribution in T2DM Subjects with Triglycerides < 200 mg/dL
LDL-C 71-99 mg/dL Non HDL-C 101-129 mg/dL
5 10 15 20 25
29% (n=339)
Percent
Subjects
1% (n=14) 5th 20th 50th 80th percentile
700 1000 1300 1600 (nmol/L)
47% (n=541) 18% (n=207) 5% (n=59)
70%
5 10 15 20 25 700 1000 1300 1600 (nmol/L)
23% (n=210) 49% (n=442) 21% (n=184) 6% (n=57)
Percent
Subjects
<1% (n=4)
76%
SLIDE 16 LDL Particle Number Distribution in T2DM Subjects with Triglycerides < 200 mg/dL
5 10 15 20 25 700 1000 1300 1600 (nmol/L)
48% (n=423) 31% (n=274) 6% (n=51) 1% (n=7)
Percent
Subjects
14% (n=127)
38%
5 10 15 20 25
47% (n=294)
Percent
Subjects
19% (n=117) 5th 20th 50th 80th percentile
700 1000 1300 1600 (nmol/L)
28% (n=175) 5% (n=28) 1% (n=5)
34%
LDL-C < 70 mg/dL Non HDL-C < 100 mg/dL
SLIDE 17 Summary
1. Patients with T2DM at NCEP goal LDL-C < 100 mg/dL are extremely heterogeneous with regard to LDL particle number (LDL-P) and, by inference, LDL-related cardiovascular disease risk. 2. Overall, 62% of 2,355 T2DM patients with LDL-C <100 mg/dL (< 20th percentile) manifested LDL-P > 1000 nmol/L (> 20th percentile).
- 75% of patients with LDL-C 71-99 mg/dL (5th - 20th percentile)
- 40% of 871 patients with LDL-C < 70 mg/dL (< 5th percentile)
- Similar values were noted in men and women
3. Patients with TG > 200 mg/dL showed the highest prevalence of LDL-P > 1000 nmol/L (> 20th Percentile).
- 91% with LDL-C 71-99 mg/dL (5th - 20th percentile)
- 57% with LDL-C < 70 mg/dL (< 5th percentile)
4. Among patients with TG < 200 mg/dL, LDL-P > 1000 nmol/L (> 20th Percentile) occurred:
- 70% with LDL-C 71-99 (5th - 20th percentile)
- 34% with LDL-C < 70 mg/dL (< 5th percentile)
SLIDE 18 Summary
5. Among patients with TG > 200 mg/dL, substantial differences appeared in the prevalence of LDL-P > 1000 nmol/L (> 20th percentile) at corresponding LDL-C versus non HDL-C values:
- 91% with LDL-C 71-99 mg/dL versus 72% with non HDL-C 101-
129 mg/dL
- 57% with LDL-C < 70 mg/dL versus 27% with non HLD-C < 100
mg/dL 6. Among patients with TG < 200 mg/dL, similar percentages of patients showed LDL-P > 1000 nmol/L (> 20th percentile) at corresponding LDL-C versus non HDL-C values:
- 70% with LDL-C 71-99 versus 77% with non HDL-C 101-129
mg/dL vs.
- 34% with LDL-C < 70 mg/dL versus 38% with non HDL-C 101-129
mg/dL
SLIDE 19
Conclusions
1. Patients with T2DM at NCEP goal LDL-C < 100 mg/dL are extremely heterogeneous with regard to LDL particle number (LDL-P) and, by inference, CVD risk. 2. Individualized assessment of LDL-P may enable the CVD risk of patients with low LDL-C or even extremely low LDL-C to be managed more effectively.
