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

NCT01524705 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: 42178
• Study Type: interventional
• Target: 102
• Locations: 1 country
• Sites: 12

Brief 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.

Conditions

Type 2 Diabetes

Keywords

Pilot Study; Prospective Randomized Trial; Comparative Effectiveness; Glycemic Variability; insulin glargine; exenatide; basal insulin; bolus insulin

Outcome Measures

Primary Outcomes (1)

• Coefficient of Variation at 26 Weeks Minus Coefficient of Variation at Baseline

  The change in the coefficient of variation (CV) of continuous glucose readings, as assessed by Continuous Glucose Monitoring (CGM)

  At baseline, 6 months of intervention

Secondary Outcomes (2)

• Number of Participants With Hypoglycemia

  26 weeks

• Weight Change During Trial

  Baseline vs 26 weeks

Other Outcomes (1)

• HbA1C Levels

  Baseline vs 26 weeks

Study Arms (2)

Insulin Glargine, metformin, exenatide

EXPERIMENTAL

Approximately 60 Type 2 diabetes mellitus (DM) participants will be instructed on an American Heart Association/American Diabetes Association (AHA/ADA) meal plan. Insulin Glargine, metformin and exenatide will used as a combination strategy to control individual glycosylated hemoglobin level (HbA1Cs) between 6.7 and 7.3% throughout the trial. The use of exenatide makes this the intervention arm

Drug: Insulin Glargine; Drug: Metformin; Drug: Exenatide

glargine, metformin, prandial insulin

ACTIVE COMPARATOR

Approximately 60 type 2 DM participants will be instructed in AHA/ADA meal plan. Insulin Glargine, metformin and one of 3 prandial insulins will be used as combination strategy to control individual HbA1Cs between 6.7 and 7.3%. Prandial Insulins (aspart, glulisine or lispro). The use of the short acting insulins make this the control arm

Drug: Insulin Glargine; Drug: Metformin; Drug: Prandial insulin

Interventions

Insulin Glargine DRUG

Glargine-injectable, variable, once daily (QD), 6 months

Also known as: Basal insulin

Insulin Glargine, metformin, exenatide; glargine, metformin, prandial insulin

Metformin DRUG

Metformin-oral, up to 1000mg, twice daily (BID), 6 months

Also known as: Generic metformin

Insulin Glargine, metformin, exenatide; glargine, metformin, prandial insulin

Prandial insulin DRUG

Aspart or glulisine or lispro

Also known as: Aspart or glulisine or lispro

glargine, metformin, prandial insulin

Exenatide DRUG

Injectable, 5mcg, twice daily (BID), 6 months

Also known as: Glucagon-like polypeptide-1-agonist (GLP-1-agonist), Byetta

Insulin Glargine, metformin, exenatide

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• T2DM for \>12 months defined according to current ADA criteria
• C-peptide \>0.5 ng/mL-after informed consent has been signed, samples will be drawn fasting and sent to a central lab
• 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)
• HbA1c 7.5-8.5% for enrollment
• 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
• 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
• Ability to speak \& read English

You may not qualify if:

• 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
• Cannot have had any cardiovascular event or interventional procedure, (MI, Stroke or revascularization) or been hospitalized for unstable angina within the last 3 months
• Inability or unwillingness to discontinue use of acetaminophen products during CGM use
• 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)
• Intolerance of metformin dose \<500 mg/day
• Inability or unwillingness to perform blood glucose testing a minimum of 3 times/per day
• Creatinine level ≥1.5 for males or 1.4 for females
• ALT level ≥ 3 times upper limit of normal
• Current symptomatic heart failure, history of NYHA Class III or IV congestive heart failure at any time, or ejection fraction (by any method) \< 25%
• Inpatient psychiatric treatment in the past 6 months
• Currently participating in an intervention trial
• Chronic inflammatory diseases, such as collagen vascular diseases or inflammatory bowel disease
• History of pancreatitis
• BMI \>45kg/m2
• For females, pregnant or intending to become pregnant during the next 7 months

Sponsors & Collaborators

• University of Washington: lead
• Eli Lilly and Company: collaborator
• Sanofi: collaborator
• Astra Zeneca, Bristol-Myers Squibb: collaborator
• DexCom, Inc.: collaborator
• Bayer: collaborator
• Becton, Dickinson and Company: collaborator
• Medicomp: collaborator
• University of Texas: collaborator
• US Department of Veterans Affairs: collaborator
• Biomedical Research Institute of New Mexico: collaborator

Study Sites (12)

So Calif. Permanente Medical Group

San Diego, California, 92109, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Atlanta Diabetes Associates

Atlanta, Georgia, 30309, United States

Location

Joslin Diabetes Center

Boston, Massachusetts, 02215, United States

Location

International Diabetes Center

Minneapolis, Minnesota, 55416, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Kaledia Health of Western New York

Buffalo, New York, 14209, United States

Location

Diabetes Care Center

Durham, North Carolina, 27713, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

University of Vermont

Colchester, Vermont, 05446, United States

Location

University of Washington

Seattle, Washington, 98105, United States

Location

Washington State University Spokane, College of Pharmacy Spokane WA 99202 USA

Spokane, Washington, 99202, United States

Location

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• FLAT-SUGAR Trial Investigators. Glucose Variability in a 26-Week Randomized Comparison of Mealtime Treatment With Rapid-Acting Insulin Versus GLP-1 Agonist in Participants With Type 2 Diabetes at High Cardiovascular Risk. Diabetes Care. 2016 Jun;39(6):973-81. doi: 10.2337/dc15-2782. Epub 2016 Apr 19.

  PMID: 27208320 RESULT

• FLAT-SUGAR Trial Investigators; Probstfield JL, Hirsch I, O'Brien K, Davis B, Bergenstal R, Kingry C, Khakpour D, Pressel S, Branch KR, Riddle M. Design of FLAT-SUGAR: Randomized Trial of Prandial Insulin Versus Prandial GLP-1 Receptor Agonist Together With Basal Insulin and Metformin for High-Risk Type 2 Diabetes. Diabetes Care. 2015 Aug;38(8):1558-66. doi: 10.2337/dc14-2689. Epub 2015 Jun 11.

  PMID: 26068865 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Insulin Glargine; Metformin; Insulin Aspart; Insulin Lispro; Exenatide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Insulin, Long-Acting; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Biguanides; Guanidines; Amidines; Organic Chemicals; Insulin, Short-Acting; Venoms; Complex Mixtures; Toxins, Biological; Biological Factors

Results Point of Contact

• Title: Jeffrey L Probstfield, MD
• Organization: University of Washington

jeffprob@uw.edu

206-616-0292

Study Officials

• Jeffrey L Probstfield, MD

  Professor of Medicine, University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 17, 2012
• First Posted: February 2, 2012
• Study Start: August 1, 2012
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2014
• Last Updated: December 29, 2023
• Results First Posted: December 29, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Starting 6 months after publication
• Access Criteria: Written request to the investigators

Locations

US (12)