Among Patients with Type 2 Diabetes Mellitus at LDL Cholesterol - PowerPoint PPT Presentation

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

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).

Relations of LDL Particles and LDL Cholesterol to Levels of HDL Cholesterol and Triglycerides Framingham Offspring Study 180 1800 180 1800 LDL Cholesterol (mg/dL) LDL Particles LDL Particles (nmol/L) LDL Particles 160 1600 160 1600 140 1400 140 1400 LDL Cholesterol 120 1200 120 1200 LDL Cholesterol 100 1000 100 1000 20 40 60 80 100 0 100 200 300 400 HDL Cholesterol (mg/dL) Triglycerides (mg/dL) Otvos JD, Jayarajah E, Cromwell, WC. AJC 2002;90(8A):22i-29i

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

LDL Subclasses in Framingham Men with Increasing Numbers of Metabolic Syndrome Features 180 1800 170 1700 160 1600 150 1500 LDL-C LDL-P 140 1400 130 1300 120 1200 110 1100 0 1 2 3 4 5 1 2 3 4 5 6 N=286 N=407 N=355 N=233 N=113 N=30 Kathiresan S, et al. Circulation 2006;113:20-27

LDL Subclasses in Framingham Women with Increasing Numbers of Metabolic Syndrome Features 180 1800 170 1700 160 1600 150 1500 LDL-C LDL-P 140 1400 130 1300 120 1200 110 1100 0 1 2 3 4 5 1 2 3 4 5 6 N=562 N=464 N=298 N=134 N=102 N=29 Kathiresan S, et al. Circulation 2006;113:20-27

Population Distribution of LDL Levels Percentile: 20 th 50 th 80 th 20 15 Percent Framingham LDL-C of 10 Offspring 1 Subjects 5 0 70 100 130 160 190 220 250 mg/dL Percentile: 20 th 50 th 80 th 20 15 Percent MESA 2 LDL-P 10 of Subjects 5 0 700 1000 1300 1600 1900 2200 2500 nmol/L 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).

LDL Particle Number Distribution in MetS “Optimal” LDL -C < 100 mg/dL (<20 th Percentile) 20 th 50 th 80 th percentile 30 23% 43% 28% 6% (n=21) (n=39) (n=26) (n=6) 20 Percent of Subjects 10 0 1000 1300 1600 LDL Particles (nmol/L) Otvos JD, Cromwell WC, et al. AHA Scientific Sessions 2003

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.

Methods 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 5 th , 20 th , 50 th , and 80 th 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).

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

LDL Cholesterol and LDL Particle Number Distribution in T2DM Subjects with LDL-C < 100 mg/dL 5 th 20 th 50 th 80 th percentile 20 1% 24% 43% 21% 11% (n=19) (n=364) (n=631) (n=307) (n=163) 15 LDL-C Percent 10 of 71-99 mg/dL Subjects (n=1,484) 5 0 700 1000 1300 1600 (nmol/L) 20 16% 43% 30% 9% 2% (n=147) (n=377) (n=260) (n=76) (n=15) 15 40% LDL-C Percent 10 of < 70 mg/dL Subjects (n=871) 5 0 700 1000 1300 1600 (nmol/L)

LDL Particle Number Distribution in T2DM Subjects with Triglycerides > 200 mg/dL 5 th 20 th 50 th 80 th percentile 30 1% 8% 28% 31% 32% (n=5) (n=25) (n=90) (n=100) (n=104) 20 LDL-C 91% Percent of 71-99 mg/dL Subjects 10 0 700 1000 1300 1600 (nmol/L) 30 2% 14% 32% 29% 23% (n=12) (n=68) (n=157) (n=144) (n=114) 20 Non HDL-C 84% Percent of 101-129 mg/dL Subjects 10 0 700 1000 1300 1600 (nmol/L)

LDL Particle Number Distribution in T2DM Subjects with Triglycerides > 200 mg/dL 5 th 20 th 50 th 80 th percentile 20 10% 33% 34% 19% 4% (n=26) (n=83) (n=85) (n=48) (n=10) 15 57% LDL-C Percent 10 of < 70 mg/dL Subjects 5 0 700 1000 1300 1600 (nmol/L) 30 24% 49% 22% 5% 0% (n=19) (n=40) (n=18) (n=4) (n=0) 20 Non HDL-C Percent 27% of < 100 mg/dL Subjects 10 0 700 1000 1300 1600 (nmol/L)

LDL Particle Number Distribution in T2DM Subjects with Triglycerides < 200 mg/dL 5 th 20 th 50 th 80 th percentile 25 1% 29% 47% 18% 5% (n=14) (n=339) (n=541) (n=207) (n=59) 20 15 LDL-C 70% Percent of 71-99 mg/dL 10 Subjects 5 0 700 1000 1300 1600 (nmol/L) 25 <1% 23% 49% 21% 6% (n=4) (n=210) (n=442) (n=184) (n=57) 20 Non HDL-C 15 76% Percent of 101-129 mg/dL 10 Subjects 5 0 700 1000 1300 1600 (nmol/L)

LDL Particle Number Distribution in T2DM Subjects with Triglycerides < 200 mg/dL 5 th 20 th 50 th 80 th percentile 25 19% 47% 28% 5% 1% (n=117) (n=294) (n=175) (n=28) (n=5) 20 15 LDL-C 34% Percent of < 70 mg/dL 10 Subjects 5 0 700 1000 1300 1600 (nmol/L) 25 14% 48% 31% 6% 1% (n=127) (n=423) (n=274) (n=51) (n=7) 20 Non HDL-C 15 Percent 38% of < 100 mg/dL 10 Subjects 5 0 700 1000 1300 1600 (nmol/L)

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. Overall, 62% of 2,355 T2DM patients with LDL-C <100 mg/dL (< 20 th 2. percentile) manifested LDL-P > 1000 nmol/L (> 20 th percentile). - 75% of patients with LDL-C 71-99 mg/dL (5 th - 20 th percentile) - 40% of 871 patients with LDL-C < 70 mg/dL (< 5 th 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 (> 20 th Percentile). - 91% with LDL-C 71-99 mg/dL (5 th - 20 th percentile) - 57% with LDL-C < 70 mg/dL (< 5 th percentile) Among patients with TG < 200 mg/dL, LDL-P > 1000 nmol/L (> 20 th 4. Percentile) occurred: - 70% with LDL-C 71-99 (5 th - 20 th percentile) - 34% with LDL-C < 70 mg/dL (< 5 th percentile)

Summary 5. Among patients with TG > 200 mg/dL, substantial differences appeared in the prevalence of LDL-P > 1000 nmol/L (> 20 th 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 (> 20 th 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