FLuctuATion Reduction With inSULin and Glp-1 Added togetheR (FLAT-SUGAR)
Condition: Type 2 Diabetes
Study type: Interventional
Phase: Phase 4

Summary: 
      Results of recent studies using standard long and short acting insulin therapy (Basal - Bolus
      or BBI) in type 2 diabetes mellitus (T2DM) have not shown benefits to lower risks for heart
      attacks, strokes, or eye, nerve and kidney problems. Some studies also show a long time
      between the start of treatment and signs of benefit. This has led to a review of current ways
      to normalize blood glucose control with basal bolus insulin and how to make blood glucose
      better. Improving blood sugar with insulin therapy usually causes weight gain, more high
      sugar levels after meals, and more low blood sugars. Early studies suggest that when people
      take long-acting insulin and metformin, they have fewer blood sugar extremes when they also
      take a new type of medicine called glucagon-like polypeptide-1 (GLP-1) agonist named
      exenatide (Byetta), instead of meal-time insulin. This means there might be a better way to
      treat Type 2 diabetes.

      Participants are asked to take part in an eight month study to find out if middle-aged and
      older people with Type 2 diabetes who have added risk factors for heart disease can even out
      their blood sugar levels. They will start on long-acting insulin, mealtime insulin, and
      metformin, if they are not already on these medications. Their kidney function tests must be
      normal and they must not be allergic to metformin. Then, after a 2 month run-in phase, they
      must be willing to be assigned by chance into one of two groups. This means that they will
      have a 50/50 chance (like flipping a coin) of being in either group. Half of them will be
      started on the new medicine known as Byetta rather than the meal-time insulin and the other
      half will remain on the meal-time insulin during the next 6 months (26 weeks) to see which
      group has more steady blood sugars. They will be asked to use a continuous blood sugar
      monitoring system called DexCom. A sensor is inserted under the skin in the same areas the
      insulin is injected. The DexCom can check their blood sugars 24 hours of the day and night
      and will be worn until 7 days of recordings are collected. In the same 7 day period, they
      will also be asked to wear a Holter or Telemetry monitor that will record their heart beats
      and rhythm which will be compared to the blood sugar readings. They will also use home
      glucose meters to check their glucose levels about 3 to 4 times a day. The study will take
      place at 12 centers in the United States and enroll about 120-130 people.
    

Detailed description: 
      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.
    

Intervention name(s): Insulin Glargine; Metformin; Prandial insulin; Exenatide
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Glargine-injectable, variable, once daily (QD), 6 months; Metformin-oral, up to 1000mg, twice daily (BID), 6 months; Aspart or glulisine or lispro; Injectable, 5mcg, twice daily (BID), 6 months
Other intervention name(s): Basal insulin; Generic metformin; Aspart or glulisine or lispro; Glucagon-like polypeptide-1-agonist (GLP-1-agonist); Byetta
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Metformin; Insulin Glargine; Exenatide; Glucagon
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Pilot Study; Prospective Randomized Trial; Comparative Effectiveness; Glycemic Variability; insulin glargine; exenatide; basal insulin; bolus insulin