FLuctuATion Reduction With inSULin and Glp-1 Added togetheR (FLAT-SUGAR)
Condition: Type 2 Diabetes
Intervention: Insulin Glargine; Metformin; Prandial insulin; Exenatide
Intervention description: 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
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Metformin; Insulin Glargine; Exenatide; Glucagon
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Enrollment: 102.0
Sex: All
Minimum age: 40 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Pilot Study; Prospective Randomized Trial; Comparative Effectiveness; Glycemic Variability; insulin glargine; exenatide; basal insulin; bolus insulin

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. T2DM for >12 months defined according to current ADA criteria

          2. C-peptide >0.5 ng/mL-after informed consent has been signed, samples will be drawn
             fasting and sent to a central lab

          3. Participants must be on insulin therapy. Diabetes, Blood Pressure & Lipid therapy must
             be stable (in both dose and agent) for ≥3 months (dose of any 1 drug has not changed
             by more than 2-fold, & new agents not been added within the previous 3 months)

          4. HbA1c 7.5-8.5% for enrollment

          5. Age at enrollment (screening): 40-75 years (inclusive) when there is a history of
             cardiovascular disease (defined in 'a'), or 55 to 75 years (inclusive) when there is
             not a history of cardiovascular disease but 2 or more risk factors (with or without
             treatment) are present (defined in 'b')

             a) Established cardiovascular disease defined as presence of one of the following: i.
             Previous myocardial infarction (MI). (most recent must be > 3 months prior enrollment)
             ii. Previous stroke. (most recent must be >3 months prior enrollment) iii. History of
             coronary revascularization (e.g., coronary artery bypass graft surgery, stent
             placement, percutaneous transluminal coronary angioplasty, or laser atherectomy)(most
             recent must be > 3 months prior enrollment) iv. History of carotid or peripheral
             revascularization (e.g., carotid endarterectomy, lower extremity atherosclerotic
             disease atherectomy, repair of abdominal aortic aneurysm, femoral or popliteal
             bypass). (most recent must be >3 months prior enrollment) v. Angina with either
             ischemic changes on a resting ECG, or ECG changes on a graded exercise test (GXT), or
             positive cardiac imaging study vi. Ankle/brachial index <0.9 vii. LVH with strain by
             ECG or ECHO viii. >50% stenosis of a coronary, carotid, renal or lower extremity
             artery. ix. Urine albumin to urine creatinine ratio of >30 mg albumin/g creatinine in
             2 samples, separated by at least 7 days, within past 12 months) [Target of 50% of
             study cohort] or b) Increased CVD risk defined as presence of 2 or more of the
             following: i. Untreated LDL-C >130 mg/dL or on lipid treatment ii. Low HDL-C (<40
             mg/dL for men and <50 mg/dL for women) iii. Untreated systolic BP >140 mm Hg, or on
             antihypertensive treatment iv. Current cigarette smoking v. Body mass index 25-45
             (Asian populations 23-45) kg/m2

          6. No expectation that participant will move out of clinical center area during the next
             8 months, unless move will be to an area served by another trial center

          7. Ability to speak & read English

        Exclusion Criteria:

          1. The presence of a physical disability, significant medical or psychiatric disorder;
             substance abuse or use of a medication that in the judgment of the investigator will
             affect the use of CGM, wearing of the sensors, Holter or Telemetry monitor, complex
             medication regimen, or completion of any aspect of the protocol

          2. Cannot have had any cardiovascular event or interventional procedure, (MI, Stroke or
             revascularization) or been hospitalized for unstable angina within the last 3 months

          3. Inability or unwillingness to discontinue use of acetaminophen products during CGM use

          4. Inability or unwillingness to discontinue use of all other diabetes agents other than
             insulin & metformin during trial (including insulin pump participants who will need to
             convert to BBI)

          5. Intolerance of metformin dose <500 mg/day

          6. Inability or unwillingness to perform blood glucose testing a minimum of 3 times/per
             day

          7. Creatinine level ≥1.5 for males or 1.4 for females

          8. ALT level ≥ 3 times upper limit of normal

          9. Current symptomatic heart failure, history of NYHA Class III or IV congestive heart
             failure at any time, or ejection fraction (by any method) < 25%

         10. Inpatient psychiatric treatment in the past 6 months

         11. Currently participating in an intervention trial

         12. Chronic inflammatory diseases, such as collagen vascular diseases or inflammatory
             bowel disease

         13. History of pancreatitis

         14. BMI >45kg/m2

         15. For females, pregnant or intending to become pregnant during the next 7 months