FLuctuATion Reduction With inSULin and Glp-1 Added togetheR (FLAT-SUGAR)

Recent medical endpoint studies employing conventional basal bolus insulin therapy (BBI) in type 2 diabetes mellitus (T2DM) have been disappointing, showing either inconsistent or no effect of treatments on risks for micro- or macro-vascular events, or a long interval between treatment initiation and evidence of clinical benefit. In fact, one trial has suggested that treating glycosylated hemoglobin (HbA1C) to lower targets may even lead to harm. This has raised the possibility that more aggressive glucose lowering approaches lead to harm that overwhelms benefit in those with T2DM. Potential explanations for these results include three closely related physiologic processes: glycemic variability, weight gain and hypoglycemia. Too much variability of glucose, especially post-prandial hyperglycemia, poses the dilemma of how to achieve near-normal mean glucose and HbA1C levels without causing insulin-induced hypoglycemia and/or weight gain. All three of these processes have been linked to worsening systemic inflammation and oxidative stress, and to increased renal and cardiovascular risks. Fortunately, new tools are available that allow us to assess the severity of glycemic variability (continuous glucose monitoring, or CGM), and to investigate the mechanisms through which it may lead to cardiovascular risk (e.g., systemic inflammation and oxidative stress, sensitive measures of diabetic renal disease, and Holter or Telemetry monitoring for hypoglycemia-induced arrhythmias). In addition, preliminary studies have suggested that replacement of rapid-acting analogue (RAA) in traditional BBI with the glucagon-like polypeptide-1 (GLP-1) agonist, exenatide, may substantially reduce glycemic variability without a strong tendency to increase body weight or hypoglycemia. This research trial, "FLuctuATion reduction with inSUlin and Glp-1 Added togetheR (FLAT-SUGAR)", by using these new methods to optimize glycemic control while limiting unwanted adverse effects, will be a definitive comparative effectiveness trial. This trial is designed to address the following primary hypothesis: In middle aged and older individuals with T2DM and additional risk factors for cardiovascular disease, and on a background therapy of basal insulin (insulin glargine) and metformin, the addition of the GLP-1 analogue, exenatide, reduces glycemic variability more than the addition of a rapid-acting-analogue (RAA) (insulin aspart, insulin glulisine or insulin lispro) during an active treatment period of 26 weeks. The primary outcome measure will be the change in the coefficient of variation of continuous glucose readings, as assessed by CGM. Importantly, FLAT-SUGAR will plan, a priori, to assess glycemic variability using CGM. Secondary trial goals will be to explore potential between-group differences in complications that may result from glycemic variability, including hypoglycemia, systemic inflammation and oxidant stress, diabetic renal disease, weight gain and cardiac arrhythmias. If, as we expect, FLAT-SUGAR demonstrates that CGM provides objective verification of reduced glycemic variability in T2DM with the new GLP-1 agonist-based regimen, the main goal of the trial will be accomplished. If reduced variability is associated with lower risks of adverse events of inflammation, albuminuria progression, weight gain, hypoglycemia, and/or cardiac arrhythmia, a long term clinical comparative effectiveness trial powered to evaluate medical outcomes will be justified. In order to conduct FLAT-SUGAR, a randomized, controlled, multicenter, open-label investigator-initiated trial, the primary funding is supported by Sanofi-Aventis US with donations of other medications and devices by several other companies. The Sponsor-Investigator is the University of Washington, which will also be the Operation Center (OC).The Data Center (DC) is the University of Texas at Houston School of Public Health. There will be 12 clinical sites with diabetes and CGM expertise to screen and enroll qualified participants for approximately 8-10 weeks of a run-in period, then ultimately randomize, and follow 120 total participants for an active treatment period of 26 weeks.