Risk Profiles for Microvascular and Macrovascular Disease at Baseline in the Glycemia Reduction Approaches in Diabetes—A Comparative Effectiveness (GRADE) Study

Abstract

Microvascular and macrovascular complications drive morbidity, mortality, and health care costs in type 2 diabetes (T2D). The GRADE trial enrolled 5047 participants with T2D <10 years and treated with metformin only, with creatinine <1.4 (women) <1.5 (men) mg/dL, and HbA1c 6.8-8.6% at enrollment. The enrolled population was 36% female, 57±10 years old (mean±SD), had T2D duration 4.2±2.8 years, and HbA1c 8.0±1.0%. Baseline prevalence was 1.0% for retinopathy (self-report), 15.8% for moderately increased albuminuria (albumin/creatinine ratio 31-300 mg/g), 2.4% for decreased eGFR (30-60 ml/minutes/1.73m2), 41.8% for neuropathy (Michigan Neuropathy Screening Instrument clinical score >2), 5.1% for myocardial infarction (self-report); and 2.0% for stroke (self-report). The Table describes age- and sex-adjusted associations between individual risk factors and complications as odds ratios comparing the presence vs. absence of the complication. Notable features include associations of HbA1c, obesity and blood pressure with micro- but not macrovascular disease; association of triglycerides with microvascular disease only; and associations of smoking and HDL with both micro- and macrovascular disease. These data reveal unexpected patterns in the clustering of risk factors with complications in GRADE patients with short T2D duration. ACR≥30eGFR<60RetinopathyMNSI>2MIStrokeORpORpORpORpORpORpHBA1C at screening (%)1.0380.30660.6580.00300.8370.28541.0940.00170.9960.95910.9370.5605BMI (kg/m2)1.040<0.00011.0440.00290.9800.38861.045<0.00010.9960.71930.9960.8481Waist Circumference (cm)1.017<0.00011.0110.07570.9910.34301.022<0.00011.0000.93651.0010.7997Smoking former*1.0360.68770.8740.52510.4260.02931.0650.34731.5460.00431.1010.6799Smoking current*1.5000.00021.1540.64391.2300.57701.2380.01562.492<0.00012.1800.0036Systolic BP (mm Hg)1.021<0.00010.9950.47831.0200.02351.0020.19370.9990.82981.0100.0956Diastolic BP (mm Hg)1.022<0.00010.9940.58971.0160.27460.9980.60630.9940.41311.0110.2546LDLc (mg/dl) **1.0010.29020.9990.68031.0090.04370.9990.26620.9960.15261.0040.2398HDLc (mg/dl)0.9890.00210.9800.02551.0190.07870.9930.01740.9760.00031.0040.5854(log) Triglycerides (mg/dl)1.477<0.00011.5890.00640.7980.37341.1150.03151.1520.21420.8690.4324OR=odds ratio per unit increase in a quantitative covariate or for the stated category versus the complement.*Versus never smoking.** Further adjusted for statin exposure. Disclosure K.J. Mather: Research Support; Self; Merck & Co., Inc., Sanofi-Aventis, Novo Nordisk A/S, Abbott. Advisory Panel; Self; Merck & Co., Inc. R. Pop-Busui: Research Support; Self; AstraZeneca. I. Bebu: None. C. Baker: None. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb Company. J.P. Crandall: None. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Merck & Co., Inc.. Advisory Panel; Self; Medscape. J.B. Green: Consultant; Self; Merck Sharp & Dohme Corp.. Research Support; Self; AstraZeneca. Consultant; Self; Daiichi Sankyo Company, Limited. Research Support; Self; GlaxoSmithKline plc., Intarcia Therapeutics, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. M. Kirkman: Research Support; Self; Bayer AG, Theracos, Inc.. Consultant; Self; National Institutes of Health. Research Support; Self; National Institutes of Health, Centers for Disease Control and Prevention. H. Krause-Steinrauf: None. M.E. Larkin: None. J. Pettus: Advisory Panel; Self; Sanofi, Novo Nordisk Inc.. Consultant; Self; MannKind Corporation. Advisory Panel; Self; Insulet Corporation. Consultant; Self; Senseonics. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc.. E.Z. Soliman: None. E.B. Schroeder: None. D.J. Wexler: None. G. Research Group: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung, and Blood Institute. Other Relationship; Self; Bristol-Myers Squibb Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi-Aventis, Roche Diagnostics Corporation, Becton, Dickinson and Company, Centers for Disease Control and Prevention, National Diabetes Education Program.