Whether biomarkers associated with cardiovascular disease risk also predict incident diabetes mellitus (DM) is unknown. Our objective was to determine if a panel of 18 biomarkers previously associated with risk of cardiovascular disease also predicts incident DM in statin-treated patients with coronary artery disease (CAD). The Treating to New Targets (TNT) study is a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of coronary heart disease events. Fasting plasma levels of standard lipids and of 18 emerging CAD risk biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in a random sample of 1,424 TNT patients. After exclusion of patients with DM at baseline (n = 253), 101 patients developed DM during the median follow-up of 4.9 years. Patients with incident DM had lower levels of total and high-molecular weight adiponectin, lipoprotein-associated phospholipase A2 (Lp-PLA2), soluble receptor of advanced glycation end products, and vitamin D compared with patients without incident DM. In contrast, insulin, soluble CD40 ligand, and soluble intercellular adhesion molecule-1 levels were higher in patients with incident DM compared with those without. Plasma levels of C-reactive protein, cystatin C, lipoprotein(a), monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, neopterin, N-terminal fragment of pro–B-type natriuretic peptide, osteopontin, and soluble vascular cell adhesion molecule-1 were comparable in patients with and without incident DM. After multivariate adjustment, total and high-molecular weight adiponectin as well as Lp-PLA2 were negatively associated with incident DM. Results of this study suggest that plasma lipids and some emerging CAD risk biomarkers, such as adiponectin and Lp-PLA2, may be useful for predicting incident DM in statin-treated patients with stable CAD.
The prevalence of type 2 diabetes mellitus (DM) is increasing in the vast majority of countries around the world. Patients who already cope with chronic diseases such as cardiovascular disease (CVD) are at increased risk of developing type 2 DM. We and others have previously documented that traditional risk factors such as hypertension and obesity, as well as triglyceride and high-density lipoprotein (HDL) cholesterol levels are associated with DM risk in patients with coronary artery disease (CAD). We have also recently shown that plasma levels of some emerging biomarkers of lipoprotein–lipid metabolism, inflammation, and glucose–insulin homeostasis may predict CVD risk in statin-treated patients with CAD. Whether these emerging CVD risk biomarkers are also associated with incident DM and whether they have any clinical value in such patients are unknown. The objective of the present study was to determine whether a panel of 18 biomarkers associated with the risk of CVD also predicted incident DM in statin-treated patients with CAD.
Methods
The study protocol and outcome measures for the Treating to New Targets (TNT) study have been published previously. In brief, patients with clinically manifest CAD commenced 8 weeks of open-label treatment with atorvastatin 10 mg/day. After this run-in period, 10,001 patients with low-density lipoprotein cholesterol levels <130 mg/dl (<3.4 mmol/L) were randomized in a double-blind design to therapy with either 10 mg or 80 mg of atorvastatin per day and followed for a median of 4.9 years. Incident DM was defined prospectively as at least 2 postbaseline fasting blood glucose measurements >7 mmol/L and at least 1 postbaseline fasting blood glucose measurement >2 mmol/L above baseline. We also included patients for whom incident DM was identified through adverse event reporting. Only patients from whom informed consent was obtained for measuring nonlipid biomarkers (in addition to that originally collected for the primary study) were selected for this substudy. Biomarker concentrations were measured in a random sample of 1,424 patients. Biomarkers concentrations were measured in fasting plasma samples collected at the time of randomization (after the 8-week atorvastatin 10 mg run-in period) and again 1 year after randomization. The biomarkers were selected based on previous studies linking them with cardiovascular risk and were selected in such a way that they represent specific biologic pathways associated with CVD. For instance, systemic inflammation is represented by C-reactive protein (CRP), macrophage recruitment/activity is represented by monocyte chemotactic protein-1, neopterin, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1, oxidative stress is represented by myeloperoxidase and lipoprotein-associated phospholipase A2 (Lp-PLA2), tissue remodeling is represented by matrix metalloproteinase-9, and osteopontin, platelet activation/thrombosis is represented by soluble CD40 ligand and lipoprotein(a), insulin resistance is represented by insulin, adiponectin, high-molecular weight (HMW) adiponectin, HMW/total adiponectin (ratio), receptor for advanced glycation endproducts and vitamin D, congestive heart failure is represented by N-terminal fragment of pro–B-type natriuretic peptide and kidney function by cystatin C. The methods used for the measurements of lipid and nonlipid biomarkers as well as the differences in biomarkers levels between baseline and one year have been published previously. The study was approved by the local research ethics committee or institutional review board at each center.
Patient characteristics at baseline were compared across 3 patients groups: those without DM at baseline who did not have incident DM, those without DM at baseline who did have incident DM, and those who had DM at baseline. A chi-square test was used for categorical variables, and a Wilcoxon rank-sum test for continuous variables. The association between on-treatment lipids and biomarker levels (at time of randomization), and incident DM was assessed in Cox proportional hazard analyses after adjustment for age, gender, treatment arm, smoking, hypertension, body mass index (BMI), and HDL cholesterol and triglyceride levels, using time to primary end point as the dependent variable.
Results
The clinical characteristics of the 3 study groups are presented in Table 1 . Patients with incident DM during follow-up and those with DM at baseline had a higher mean BMI, mean systolic blood pressure, and higher prevalence of metabolic syndrome than those without DM at baseline and without incident DM during follow-up. These differences in clinical characteristics of study patients who did versus those who did not develop incident DM were comparable to what we have previously reported in the entire TNT study population.
| Baseline Follow-up | Diabetes Mellitus | ||
|---|---|---|---|
| No | Yes (N=253) | ||
| Without incident DM (N=1070) | With incident DM (N=101) | ||
| Atorvastatin 80 mg | 528 (49.4%) | 56 (55.5%) | 123 (48.6) |
| Men | 872 (81.5%) | 80 (79.2%) | 186 (73.5%) ∗ |
| White | 1013 (94.7%) | 92 (91.1%) | 228 (90.1%) ∗ |
| Age (years) | 60.9±9.0 | 61.1±8.0 | 64.0±7.8 ∗ † |
| Body mass index (kg/m 2 ) | 27.9±4.0 | 31.0±4.9 ∗ | 31.0±5.6 ∗ |
| Systolic blood pressure (mmHg) | 129.4±16.1 | 133.9±15.9 ∗ | 135.3±18.0 ∗ |
| Diastolic blood pressure (mmHg) | 77.6±9.0 | 78.5±8.0 | 76.2±10.3 ∗ † |
| Hypertension | 566 (52.9%) | 53 (52.5%) | 193 (76.3%) ∗ † |
| Smoker | |||
| Current | 11 (10.9%) | 155 (14.5%) | 15 (5.9) ∗ |
| Past | 72 (71.3%) | 652 (60.9) ∗ | 176 (69.6) ∗ |
| Never | 18 (17.8%) | 263 (24.6) | 62 (24.5) |
| Metabolic syndrome | 506 (47.3%) | 78 (77.2) ∗ | 210 (83.0) ∗ |
| Estimated glomerular filtration rate (mL/min/1.72 m 2 ) | 64.9 ± 10.8 | 64.7 ± 11.3 | 63.6 ± 12.9 |
| Angiotensin-converting-enzyme inhibitors | 561 (53.8%) | 49 (49.5%) | 145 (58.7%) |
| Angiotensin II receptor blockers | 170 (16.3%) | 16 (16.2%) | 35 (14.2%) |
| Beta blockers | 727 (69.8%) | 64 (64.6%) | 172 (69.6%) |
| Calcium channel blockers | 412 (39.5%) | 34 (34.3%) | 103 (41.7%) |
| Antiplatelets | 146 (14.0%) | 9 (9.1%) | 43 (17.4%) |
| Vitamin K antagonists | 162 (15.5%) | 20 (20.2%) | 39 (15.8%) |
| Other anticoagulants | 6 (0.6%) | 0 (0%) | 0 (0%) |
| Aspirin | 957 (91.8%) | 84 (84.8%) | 226 (91.5%) |
∗ Significantly different than patients without incident diabetes.
† Significantly different than patients with incident diabetes; p <0.05.
Plasma levels of lipid and nonlipid biomarkers in these patients are presented in Table 2 . Patients with incident DM had higher levels of triglycerides and total cholesterol levels and lower levels of HDL cholesterol compared with patients without incident DM. They were also characterized by a higher total cholesterol/HDL cholesterol ratio. With regards to nonlipid biomarkers, patients with incident DM had lower levels of total and HMW adiponectin, Lp-PLA2, soluble receptor of advanced glycation end products, and vitamin D compared with patients without incident DM. However, insulin, soluble CD40 ligand, and soluble intercellular adhesion molecule-1 levels were higher in patients with incident DM compared with patients without incident DM. Plasma levels of low-density lipoprotein cholesterol, high sensitivity CRP, cystatin C, lipoprotein(a), monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, neopterin, N-terminal fragment of pro–B-type natriuretic peptide, osteopontin, and soluble vascular cell adhesion molecule-1 were comparable in patients with versus without incident DM.
| Baseline Follow-up | Diabetes Mellitus | ||
|---|---|---|---|
| No | Yes (N=253) | ||
| Without incident DM (N=1070) | With incident DM (N=101) | ||
| Total cholesterol | 174±24 mg/dL (4.51±0.61 mmol/L) | 180±27 mg/dL (4.67±0.70 mmol/L) ∗ | 176±25 mg/dL (4.54±0.64 mmol/L) |
| LDL cholesterol | 97±17 mg/dL (2.52±0.45 mmol/L) | 99±20 mg/dL (2.56±0.51 mmol/L) | 96±18 mg/dL (2.47±0.47 mmol/L) |
| HDL cholesterol | 48±11 mg/dL (1.24±0.29 mmol/L) | 46±11 mg/dL ∗ (1.18±0.29 mmol/L) ∗ | 44±10 mg/dL ∗ (1.15±0.27 mmol/L) ∗ |
| Total/HDL cholesterol | 3.80 ± 0.85 | 4.09 ± 0.87 ∗ | 4.12 ± 0.97 ∗ |
| Triglycerides | 133 (101-174) mg/dL (1.50 [1.14–1.96] mmol/L) | 154 (120-218) mg/dL ∗ (1.74 [1.35–2.46] mmol/L) ∗ | 162 (120-221) mg/dL ∗ (1.83 [1.35–2.50] mmol/L) ∗ |
| Total adiponectin (μg/mL) | 6.75 (4.92–9.54) | 5.19 (4.26–7.30) ∗ | 6.12 (4.43–9.85) ∗ † |
| HMW adiponectin (μg/mL) | 2.02 (1.21–3.26) | 1.45 (1.01–2.01) ∗ | 1.80 (1.14–2.87) † |
| C-reactive protein (mg/L) | 1.57 (0.72–3.56) | 1.77 (0.76–4.16) | 2.10 (0.95–4.58) ∗ |
| Cystatin C, (μg/mL) | 0.77 (0.67–0.90) | 0.80 (0.69–0.91) | 0.81 (0.67–0.97) ∗ |
| Insulin (μU/mL) | 11 (8–15) | 15 (11–20) ∗ | 16 (12–27) ∗ † |
| Lipoprotein(a) (mg/dL) | 15 (5–40) | 14 (5–34) | 13 (4–41) |
| Lipoprotein-associated phospholipase A2 (ng/mL) | 335 (275–395) | 310 (237–356) ∗ | 305 (241–355) ∗ |
| Monocyte chemoattractant protein-1 (pg/mL) | 98 (74–129) | 99 (76–134) | 107 (81–147) ∗ |
| Matrix metalloproteinase-9 (ng/mL) | 43.6 (29.8–66.1) | 46.0 (30.8–83.4) | 43.5 (29.8–68.2) |
| Myeloperoxidase (ng/mL) | 21.3 (10.1–56.3) | 19.6 (10.1–50.8) | 23.8 (11.0–60.5) |
| Neopterin (ng/mL) | 2.85 (2.30–3.50) | 2.80 (2.10–3.62) | 3.10 (2.54–3.83) ∗ † |
| N-terminal pro-B-type natriuretic peptide (fmol/mL) | 510.4 (405.0–649.2) | 506.7 (392.1–621.8) | 512.9 (404.8–668.5) |
| Osteopontin (ng/mL) | 46.2 (32.3–58.8) | 45.4 (30.1–59.6) | 48.2 (35.1–63.2) |
| Soluble receptor for advanced glycation end products (ng/mL) | 1.34 (1.02–1.80) | 1.22 (0.94–1.60) ∗ | 1.33 (1.02–1.79) † |
| soluble CD40 ligand (ng/mL) | 3.87 (1.86–9.21) | 5.69 (2.51–11.4) ∗ | 4.13 (2.16–10.8) |
| soluble intracellular adhesion molecule-1 (ng/mL) | 140 (104–182) | 160 (114–202) ∗ | 149 (114–195) ∗ |
| soluble vascular cell adhesion molecule-1 (μg/mL) | 1.04 (0.86–1.26) | 1.11 (0.92–1.26) | 1.09 (0.90–1.32) ∗ |
| Vitamin D, ng/mL | 77.0 (76.0–79.0) | 71.5 (67.0–80.0) ∗ | 69.0 (65.0–75.0) ∗ |
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