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.

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