Many patients with type 2 diabetes mellitus (T2DM) have relatively normal levels of low-density lipoprotein (LDL) cholesterol yet have increased risk for cardiovascular events. Distribution of lipoprotein subclasses in patients with T2DM who have achieved very low levels of LDL cholesterol (<50 mg/dl) or non–high-density lipoprotein (HDL) cholesterol (<80 mg/dl) have not been extensively examined. The aim of this study was to assess variations in lipoprotein particle concentration in patients with diabetes with “very low” LDL cholesterol and non-HDL cholesterol levels to elucidate the drivers of residual cardiovascular risk. Data were selected from a single large clinical laboratory database. Cases were patients with T2DM diagnosis codes (International Classification of Diseases, Ninth Revision, codes 250 to 250.93). Lipoprotein particle concentrations were analyzed using nuclear magnetic resonance spectroscopy. The Friedewald equation was used to calculate LDL cholesterol. Among the 1,970 patients with T2DM, the mean age was 61 years, and approximately 51% were men. At LDL cholesterol concentrations <50 mg/dl (triglyceride <150 mg/dl and HDL cholesterol >40 mg/dl), 16% had LDL particle concentrations <500 nmol/L, 70% had concentrations of 500 to 1,000 nmol/L, and 14% had concentrations >1,001 nmol/L. At non-HDL cholesterol levels <80 mg/dl, 8% had LDL particle concentrations <500 nmol/L, 67% had concentrations of 500 to 1,000 nmol/L, and 25% had concentrations >1,001 nmol/L. In conclusion, despite attainment of LDL cholesterol <50 mg/dl or non-HDL cholesterol <80 mg/dl, patients with diabetes exhibited significant variation in LDL particle levels, with most having LDL particle concentrations >500 nmol/L, suggesting the persistence of potential residual coronary heart disease risk.
Type 2 diabetes mellitus (T2DM) is a group of metabolic disorders characterized by insulin resistance, hyperglycemia, and dyslipoproteinemia. Cardiovascular disease is the major source of mortality in patients with T2DM. The current guidelines recommend the achievement of a low-density lipoprotein (LDL) cholesterol goal of <100 mg/dl for all patients with this condition and an optional LDL cholesterol goal of <70 mg/dl in patients with diabetes with associated cardiovascular disease. Unfortunately, despite adequate screening and LDL-lowering therapy, it has been recognized that many patients with T2DM with LDL cholesterol <100 mg/dl continue to experience coronary heart disease (CHD) events and have elevated LDL particle numbers. Most epidemiologic and mechanistic studies have shown that of all circulating lipoprotein particles, LDL particles play a major role in atherosclerosis. No study to date has investigated the differences in LDL particle concentrations in patients with T2DM who have achieved “very low” levels of LDL cholesterol (<50 mg/dl) or non–high-density lipoprotein (HDL) cholesterol (<80 mg/dl) in the setting of relatively low triglyceride levels (<150 mg/dl) and normal HDL cholesterol levels (>40 mg/dl). The aim of this study was to assess LDL particle heterogeneity in a diabetic population with “very low” concentrations of LDL cholesterol and non-HDL cholesterol.
Methods
Data were selected from a large single laboratory database (LipoScience, Inc., Raleigh, North Carolina). Cases were patients with T2DM diagnosis codes as reported by the ordering physician (International Classification of Diseases, Ninth Revision, codes 250 to 250.93). No patient-identifying information, degree of glycemic control, co-morbid conditions, or medication use information was available to the investigators. The 1,970 patients selected were those with LDL cholesterol levels <70 mg/dl, non-HDL cholesterol levels <100 mg/dl, triglycerides <150 mg/dl, and HDL cholesterol >40 mg/dl.
Lipoprotein particle concentrations (LDL particles, HDL particles, and very low density lipoprotein particles) were analyzed using nuclear magnetic resonance spectroscopy. The nuclear magnetic resonance lipoprotein profile was determined using a 400-MHz proton nuclear magnetic resonance analyzer, as previously described. Total cholesterol, triglycerides, and HDL cholesterol were measured using standardized automated methods, and LDL cholesterol was calculated using the Friedewald equation. Non-HDL cholesterol was calculated by subtracting HDL cholesterol from total cholesterol concentration.
Patients were assigned to LDL particle categories using cut points corresponding to the 2nd, 5th, 20th, 50th, and 80th percentiles of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, as listed in Table 1 . An LDL cholesterol goal <70 mg/dl corresponds approximately to the <5th percentile.
| Percentile | LDL Cholesterol (mg/dl) | Non-HDL Cholesterol (mg/dl) | LDL Particle Concentration (nmol/L) |
|---|---|---|---|
| 2 | 58 | 78 | 670 |
| 5 | 69 | 90 | 770 |
| 20 | 91 | 113 | 990 |
| 50 | 115 | 140 | 1,260 |
| 80 | 141 | 169 | 1,560 |
| 95 | 170 | 202 | 1,900 |
Results
Among the 1,970 patients with T2DM in the LipoScience database, the mean age was 61 years, and 51% were men ( Table 2 ). Mean total cholesterol was 126 mg/dl, mean triglycerides were 83 mg/dl, mean HDL cholesterol was 51 mg/dl, mean LDL cholesterol was 58 mg/dl, and mean LDL particle concentration was 907 nmol/L.
| Variable | Value |
|---|---|
| Men | 51% |
| Age (years) | 61 ± 16 |
| Total cholesterol (mg/dl) | 126 ± 13 |
| Triglycerides (mg/dl) | 83 ± 31 |
| HDL cholesterol (mg/dl) | 51 ± 8 |
| Non-HDL cholesterol (mg/dl) | 75 ± 11 |
| LDL cholesterol (mg/dl) | 58 ± 9 |
| LDL particle concentration (nmol/L) | 907 ± 255 |
Figures 1, 2, and 3 present the distribution of LDL particle values in patients with T2DM with low and very low LDL cholesterol and non-HDL cholesterol levels. At LDL cholesterol concentrations <70 mg/dl (n = 1,970), triglycerides <150 mg/dl, and HDL cholesterol >40 mg/dl, 22% had LDL particle concentrations <700 nmol/L, 44% had concentrations of 700 to 1,000 nmol/L, and 34% had concentrations >1,001 nmol/L. At LDL cholesterol concentrations <50 mg/dl (n = 360), 16% had LDL particle concentrations <500 nmol/L, 70% had concentrations of 500 to 1,000 nmol/L, and 14% had concentrations >1,001 nmol/L. At non-HDL cholesterol concentrations of <80 mg/dl (n = 1,242), 8% had LDL particle concentrations <500 nmol/L, 67% had concentrations of 500 and 1,000 nmol/L, and 25% had concentrations >1,001 nmol/L ( Figure 3 ).
