NMR-Based Diabetes Risk Index is Capable of Identifying Normal Weight Subjects with High Likelihood of Progressing to Type 2 Diabetes Margery A. Connelly, Irina Shalaurova and James D. Otvos LipoScience Inc., Raleigh, NC ADA 2014 Poster # 1417P Objective A body mass index (BMI) >30 is often an indicator of high risk for developing Type 2 diabetes (T2DM). However, it is well known that individuals with widely varying BMIs become diabetic. To identify highest-risk patients who would benefit most from intervention, we developed a Diabetes Risk Index (DRI) score (1-10) that uses information derived from a nuclear magnetic resonance (NMR) spectrum of plasma/serum. Methods Baseline samples from participants in the Multi-Ethnic Study of Atherosclerosis (MESA) were used to develop the DRI assay and participants in the Insulin Resistance Atherosclerosis Study (IRAS) to verify it’s predictive performance. Results To determine whether the DRI score was capable of identifying normal weight individuals with a high likelihood of becoming diabetic, we compared the percentage of subjects progressing to T2DM across quartiles of the DRI score in 3 BMI categories in MESA and IRAS participants. Table 4: DRI Adds Significantly and Independently of BMI to Diabetes Prediction in MESA and IRAS Table 1: DRI Prediction Model (5 years) Model Model 2 c-statistic NMR Parameter Proposed Link to Pathophysiology Wald 2 P value Base 300.4 0.796 + DRI 371.2 0.831 LP-IR insulin resistance 28.1 <0.0001 Valine insulin resistance & secretion 4.7 0.03 VLDL-Pmed 6.7 0.009 HDL-Pmed impaired β-cell function6 10.6 0.001 GlycA inflammation 2.7 0.10 HDL-Pmed * GlycA impaired β-cell function 7.4 0.006 MESA (n=234/4031) IRAS (n=88/844) Model Parameter AUC OR (95% CI) P Base age, sex, race, glucose 0.796 _ 0.715 Base + DRI DRI 0.829 2.09 (1.74-2.51) <0.0001 0.775 2.26 (1.68-3.04) Base + DRI + BMI 0.835 1.85 (1.53-2.25) 0.780 2.13 (1.57-2.90) BMI 1.37 (1.18-1.58) 1.21 (0.96-1.53) 0.11 Table 2: Adjusted Diabetes Conversion Rates (%) MESA Body Mass Index (BMI) kg/m2 Normal weight overweight obese DRI Score (1-10) <25 25-30 >30 Q1 1.6 (575) 2.4 (323) 7.4 (113) Q2 0.3 (337) 3.1 (438) 10.7 (226) Q3 4.1 (244) 6.2 (435) 8.9 (336) Q4 9.6 (128) 8.1 (394) 14.7 (483) Figure 1: Diabetes Risk Index (DRI) was developed using metabolic disease markers captured in the NMR LipoProfile® spectrum Logistic regression analyses with base model adjusted for age, gender, race, and glucose. Beta-coefficients for the NMR variables in this model applied to the glucose <110 mg/dL subgroup (n=234 conversions out of 4031 subjects) during 5 year follow-up were used to generate the DRI risk prediction equation. Conclusions The DRI score combines information captured in the LipoScience NMR spectrum related to insulin resistance, inflammation and metabolic derangement, factors which impact pancreatic β-cell function and lead to T2DM. The DRI score gives visibility to a patient’s relative risk for T2DM at any given glucose level. The DRI score can be used in conjunction with clinical evaluation to stratify patients with glucose between 90-110 mg/dL and identify those at highest risk for developing T2DM within 5 years. Regardless of the BMI category, as the DRI score increased there was an increased likelihood of becoming diabetic, even for subjects whose BMI was within the normal range. DRI added predictive value independently of BMI to the assessment of diabetes risk in both the MESA and IRAS populations. LS means for diabetes conversion rates adjusted for age, gender, race and glucose (# subjects) in 4031 MESA subjects with fasting plasma glucose ≤110 mg/dL of which 234 converted to T2DM by the 4th visit (~5 year follow-up); Figure 2: DRI stratifies risk in the intermediate glucose range Table 3: Adjusted Diabetes Conversion Rates (%) IRAS Body Mass Index (BMI) kg/m2 Normal weight overweight obese DRI Score (1-10) <25 25-30 >30 Q1 6.2 (72) 1.3 (62) 6.0 (21) Q2 4.9 (65) 3.2 (86) 5.3 (33) Q3 7.0 (53) 11.5 (107) 17.5 (65) Q4 13.0 (48) 14.5 (132) 23.0 (100) Valine: Branched chain amino acid whose increased plasma levels are associated with insulin resistance and predict progression to T2DM GlycA: NMR signal that arises from the N-acetyl methyl groups on the carbohydrate side-chains of circulating glycoproteins, many of which are acute phase inflammatory proteins. GlycA is a marker of systemic inflammation. Lipoprotein class and subclass information: 6 lipoprotein parameters associated with insulin resistance (LP-IR) plus medium VLDL and medium HDL HDL Particle Number (HDL-P) HDL Size VLDL Particle Number (VLDL-P) VLDL Size LDL Particle Number (LDL-P) LDL Size Large VLDL Medium Small LDL IDL HDL Med Positive Association Negative Association References 1Laakso et al. Arteriosclerosis 1990;10:223-31. 2Garvey et al. Diabetes 2003;52:453-62. 3Festa et al. Circulation 2005;111:3465-72. 4Frazier-Wood et al. Metab Syndr & Rel Disorders 2012;10:1-8. 5Shalaurova et al. Metab Syndr & Rel Disorders 2014; in press. 6Drew et al. Nat Rev Endocrinol 2012;8:237-45. LS means for diabetes conversion rates adjusted for age, gender, race and glucose (# subjects) in 844 IRAS subjects with fasting plasma glucose ≤110 mg/dL of which 88 converted to T2DM (~5 year follow-up); Predicted probabilities of T2DM conversion in 5 years in MESA and IRAS participants.