Premeal insulin lispro plus bedtime NPH or twice-daily NPH in patients with type 2 diabetes: acute postprandial and chronic effects on glycemic control and cardiovascular risk factors Antonio Ceriello a , Stefano Del Prato b , Juliana Bue-Valleskey c , Scott Beattie c , Jeffrey Gates c , Amparo de la Pen ˜a c , James Malone c, 4 a Department of Pathology and Medicine, Experimental and Clinical, University of Udine, Udine, Italy b Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy c Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA Received 1 July 2005; received in revised form 18 November 2005; accepted 30 November 2005 Abstract Objective: Two insulin regimens were used to explore acute and chronic postprandial changes in glycemia, lipemia, and metabolic markers associated with increased risk of cardiovascular disease. Methods: An open-label, randomized, two-period crossover study (12 weeks/period) compared a prandial regimen [premeal insulin lispro + bedtime neutral protamine Hagedorn (NPH)] with a basal regimen (twice-daily NPH). There were 30 patients (12 women and 18 men; mean age=61 years) with type 2 diabetes mellitus (mean duration=16 years) who were randomized after a 2-month lead-in with twice-daily NPH treatment. A standard lunch test meal developed according to each patient’s caloric needs was administered at the end of each treatment period. Results: Insulin lispro was associated with significantly lower postprandial glucose (area under the curve 0–5 h =43.54 vs. 57.65 mM/h; Pb.001), elevated insulin concentrations, and acutely altered lipid fractions that included an early decrease followed by an increase in free fatty acids, lower triglycerides, elevated total cholesterol, elevated low- density lipoprotein cholesterol (LDL), and elevated high-density lipoprotein cholesterol. After 12 weeks of treatment, insulin lispro + bedtime NPH reduced hemoglobin A 1c (HbA 1c ; meanFSE=7.6F0.2 vs. 8.2F0.2%; Pb.001) without increasing hypoglycemia or insulin dose as compared with twice-daily NPH. Furthermore, treatment with the prandial insulin regimen resulted in lower total cholesterol, lower LDL cholesterol, and lower oxidized LDL. Conclusion: Improved postprandial glycemic control, as observed in a regimen containing both prandial insulin lispro and NPH as the basal insulin, is associated with significantly lower HbA 1c and acute modulation of lipid fractions after a test meal. These biochemical modifications may potentially have a favorable impact on cardiovascular risk in patients with type 2 diabetes mellitus. D 2007 Elsevier Inc. All rights reserved. Keywords: Diabetes; Lispro; NPH; Postprandial; Test meal 1. Introduction Patients with type 2 diabetes are notably more suscep- tible to morbidity and mortality than the general population, with nearly 80% of patients dying of a cardiovascular event (Colwell, 1993). Recently, the contribution of postprandial hyperglycemia and hyperlipidemia to the progression of atherosclerosis has received more interest (Ceriello, 2000; Lebovitz, 2001). In particular, it has been suggested that an abnormally high flux and excess concentration of plasma glucose and lipids, characteristic of the postprandial state in patients with diabetes, creates a glucotoxic and lipotoxic environment of oxidative stress, resulting in progressive endothelial dysfunction and atherogenesis (Ceriello, 2000; Ceriello et al., 2002; Jagla & Schrezenmeir, 2001). 1056-8727/07/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2005.11.005 4 Corresponding author. Tel.: +1 317 277 6472; fax: +1 317 655 2834. E-mail address: jkmalone@lilly.com (J. Malone). Journal of Diabetes and Its Complications 21 (2007) 20 – 27