Type 2 DiabetesPhase 4FLAT-SUGARNCT01524705
FLuctuATion Reduction With inSULin and Glp-1 Added togetheR (FLAT-SUGAR)
A Phase 4 study testing Insulin Glargine, Metformin and Prandial insulin in people with Type 2 Diabetes, run by University of Washington at 12 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 40 to 75 years
- Conditions the study is for
- Type 2 Diabetes
- What is being tested?
- Insulin Glargine, Metformin and Prandial insulin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 102 participants
- Where
- 12 sitesUnited States
- Study dates
- Aug 2012to Jul 2014
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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')
- 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
Who cannot join
- 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
Show all 15Show fewer
- 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
Trial locations and contacts
12 sites in 1 country.
12 sites in 1 country
United States12 sites
Atlanta Diabetes Associates
Atlanta, Georgia, 30309
Joslin Diabetes Center
Boston, Massachusetts, 02215
Kaledia Health of Western New York
Buffalo, New York, 14209
University of Vermont
Colchester, Vermont, 05446
Diabetes Care Center
Durham, North Carolina, 27713
University of Miami
Miami, Florida, 33136
International Diabetes Center
Minneapolis, Minnesota, 55416
Oregon Health and Science University
Portland, Oregon, 97239
So Calif. Permanente Medical Group
San Diego, California, 92109
University of Washington
Seattle, Washington, 98105
Washington State University Spokane, College of Pharmacy Spokane WA 99202 USA
Spokane, Washington, 99202
Washington University
St Louis, Missouri, 63110
About this study
Official title: FLAT-SUGAR: FLuctuATion Reduction With inSULin and Glp-1 Added togetheR
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.
Read the 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.
- Conditions
- Type 2 Diabetes
- Being tested
- Insulin Glargine, Metformin, Prandial insulin, Exenatide
- Keywords
- Pilot Study, Prospective Randomized Trial, Comparative Effectiveness, Glycemic Variability, insulin glargine, exenatide, basal insulin, bolus insulin
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Insulin GlargineDrug
Also called Basal insulin
Glargine-injectable, variable, once daily (QD), 6 months
MetforminDrug
Also called Generic metformin
Metformin-oral, up to 1000mg, twice daily (BID), 6 months
Prandial insulinDrug
Also called Aspart or glulisine or lispro
Aspart or glulisine or lispro
ExenatideDrug
Also called Glucagon-like polypeptide-1-agonist (GLP-1-agonist), Byetta
Injectable, 5mcg, twice daily (BID), 6 months
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: Drug: Insulin Glargine; Drug: Metformin; Drug: Prandial insulin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: At baseline, 6 months of intervention
Secondary outcomes (2)
Number of Participants With Hypoglycemia
Severe hypoglycemia-documented glucose <50mg/dl (participant journal), and hypoglycemic attacks requiring hospitalization, or treatment by emergency personnel.
Measured: 26 weeks
Weight Change During Trial
Weight in kg at 26 weeks minus weight at baseline.
Measured: Baseline vs 26 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Feb 2012 (estimated)
- Study startAug 2012
- Primary completionJul 2014
- Study completionJul 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (46)Papers the sponsor has linked to this study.
- Other trials for Type 2 DiabetesStudies of the same condition, open and under way.
- More trials run by University of WashingtonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 102 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Washington
- Sponsor type
- University, hospital or other
- Collaborators
- Eli Lilly and Company, Sanofi, Astra Zeneca, Bristol-Myers Squibb, DexCom, Inc., Bayer, Becton, Dickinson and Company, Medicomp, University of Texas, US Department of Veterans Affairs, Biomedical Research Institute of New Mexico
- Responsible party
- Principal investigator, Jeff Probstfield, University of Washington
- Investigators
- Jeffrey L Probstfield, MD, Principal investigator, Professor of Medicine, University of Washington
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01524705
- Sponsor's protocol ID
- 42178
- Acronym
- FLAT-SUGAR
- Status last verified
- Dec 2023
- First submitted
- 17 Jan 2012
- Last updated
- 29 Dec 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data available from the authors
Publications
Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59. doi: 10.1056/NEJMoa0802743. Epub 2008 Jun 6.
PubMed 18539917ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72. doi: 10.1056/NEJMoa0802987. Epub 2008 Jun 6.
PubMed 18539916Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129-39. doi: 10.1056/NEJMoa0808431. Epub 2008 Dec 17.
PubMed 19092145Davi G, Ciabattoni G, Consoli A, Mezzetti A, Falco A, Santarone S, Pennese E, Vitacolonna E, Bucciarelli T, Costantini F, Capani F, Patrono C. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation. 1999 Jan 19;99(2):224-9. doi: 10.1161/01.cir.99.2.224.
PubMed 9892587Tannock LR, O'Brien KD, Knopp RH, Retzlaff B, Fish B, Wener MH, Kahn SE, Chait A. Cholesterol feeding increases C-reactive protein and serum amyloid A levels in lean insulin-sensitive subjects. Circulation. 2005 Jun 14;111(23):3058-62. doi: 10.1161/CIRCULATIONAHA.104.506188. Epub 2005 Jun 6.
PubMed 15939816Festa A, D'Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000 Jul 4;102(1):42-7. doi: 10.1161/01.cir.102.1.42.
PubMed 10880413Dandona P, Chaudhuri A, Ghanim H, Mohanty P. Insulin as an anti-inflammatory and antiatherogenic modulator. J Am Coll Cardiol. 2009 Feb 3;53(5 Suppl):S14-20. doi: 10.1016/j.jacc.2008.10.038.
PubMed 19179212Dogne JM, Hanson J, Pratico D. Thromboxane, prostacyclin and isoprostanes: therapeutic targets in atherogenesis. Trends Pharmacol Sci. 2005 Dec;26(12):639-44. doi: 10.1016/j.tips.2005.10.001. Epub 2005 Oct 21.
PubMed 16243403Buscemi S, Verga S, Cottone S, Azzolina V, Buscemi B, Gioia D, Cerasola G. Glycaemic variability and inflammation in subjects with metabolic syndrome. Acta Diabetol. 2009 Mar;46(1):55-61. doi: 10.1007/s00592-008-0061-8. Epub 2008 Sep 26.
PubMed 18818862Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006 Apr 12;295(14):1681-7. doi: 10.1001/jama.295.14.1681.
PubMed 16609090Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, Boemi M, Giugliano D. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008 May;57(5):1349-54. doi: 10.2337/db08-0063. Epub 2008 Feb 25.
PubMed 18299315Esposito K, Ciotola M, Carleo D, Schisano B, Sardelli L, Di Tommaso D, Misso L, Saccomanno F, Ceriello A, Giugliano D. Post-meal glucose peaks at home associate with carotid intima-media thickness in type 2 diabetes. J Clin Endocrinol Metab. 2008 Apr;93(4):1345-50. doi: 10.1210/jc.2007-2000. Epub 2008 Jan 15.
PubMed 18198229Esposito K, Giugliano D, Nappo F, Marfella R; Campanian Postprandial Hyperglycemia Study Group. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation. 2004 Jul 13;110(2):214-9. doi: 10.1161/01.CIR.0000134501.57864.66. Epub 2004 Jun 14.
PubMed 15197140Stehouwer CD, Gall MA, Twisk JW, Knudsen E, Emeis JJ, Parving HH. Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death. Diabetes. 2002 Apr;51(4):1157-65. doi: 10.2337/diabetes.51.4.1157.
PubMed 11916939Shikano M, Sobajima H, Yoshikawa H, Toba T, Kushimoto H, Katsumata H, Tomita M, Kawashima S. Usefulness of a highly sensitive urinary and serum IL-6 assay in patients with diabetic nephropathy. Nephron. 2000 May;85(1):81-5. doi: 10.1159/000045634.
PubMed 10773760
Study at a glance
From the registry record, last updated by the sponsor on 29 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- FLAT-SUGAR: FLuctuATion Reduction With inSULin and Glp-1 Added togetheR
- ClinicalTrials.gov ID
- NCT01524705
- Acronym / sponsor ID
- FLAT-SUGAR / 42178
- Conditions
- Type 2 Diabetes
- Keywords
- Pilot Study, Prospective Randomized Trial, Comparative Effectiveness, Glycemic Variability, insulin glargine, exenatide, basal insulin, bolus insulin
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 102 participants (actual)
- Lead sponsor
- University of WashingtonUniversity, hospital or other
- Collaborators
- Eli Lilly and Company, Sanofi, Astra Zeneca, Bristol-Myers Squibb, DexCom, Inc., Bayer, Becton, Dickinson and Company, Medicomp, University of Texas, US Department of Veterans Affairs, Biomedical Research Institute of New Mexico
- Study start
- Aug 2012
- Primary completion
- Jul 2014 (actual)
- Study completion
- Jul 2014 (actual)
- First posted
- 2 Feb 2012 (estimated)
- Results
- Posted 29 Dec 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Insulin Glargine, metformin, exenatide | Experimental | Drug: Insulin Glargine, Drug: Metformin, Drug: ExenatideApproximately 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 |
| glargine, metformin, prandial insulin | Active comparator | Drug: Insulin Glargine, Drug: Metformin, Drug: Prandial insulinApproximately 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 |
Who may qualify
- Ages
- 40 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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')
Key exclusion criteria (15 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Insulin GlargineAlso: Basal insulinGlargine-injectable, variable, once daily (QD), 6 months | Drug | Insulin Glargine, metformin, exenatide, glargine, metformin, prandial insulin |
| MetforminAlso: Generic metforminMetformin-oral, up to 1000mg, twice daily (BID), 6 months | Drug | Insulin Glargine, metformin, exenatide, glargine, metformin, prandial insulin |
| Prandial insulinAlso: Aspart or glulisine or lisproAspart or glulisine or lispro | Drug | glargine, metformin, prandial insulin |
| ExenatideAlso: Glucagon-like polypeptide-1-agonist (GLP-1-agonist), ByettaInjectable, 5mcg, twice daily (BID), 6 months | Drug | Insulin Glargine, metformin, exenatide |
Primary outcome
Coefficient of Variation at 26 Weeks Minus Coefficient of Variation at Baseline
Time frame: At baseline, 6 months of intervention
The change in the coefficient of variation (CV) of continuous glucose readings, as assessed by Continuous Glucose Monitoring (CGM)
2 secondary outcomes
Number of Participants With Hypoglycemia
Time frame: 26 weeks
Weight Change During Trial
Time frame: Baseline vs 26 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Dec 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 18539917Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59. doi: 10.1056/NEJMoa0802743. Epub 2008 Jun 6.
- Background: PubMed 18539916ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72. doi: 10.1056/NEJMoa0802987. Epub 2008 Jun 6.
- Background: PubMed 19092145Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129-39. doi: 10.1056/NEJMoa0808431. Epub 2008 Dec 17.
- Background: PubMed 9892587Davi G, Ciabattoni G, Consoli A, Mezzetti A, Falco A, Santarone S, Pennese E, Vitacolonna E, Bucciarelli T, Costantini F, Capani F, Patrono C. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation. 1999 Jan 19;99(2):224-9. doi: 10.1161/01.cir.99.2.224.
- Background: PubMed 15939816Tannock LR, O'Brien KD, Knopp RH, Retzlaff B, Fish B, Wener MH, Kahn SE, Chait A. Cholesterol feeding increases C-reactive protein and serum amyloid A levels in lean insulin-sensitive subjects. Circulation. 2005 Jun 14;111(23):3058-62. doi: 10.1161/CIRCULATIONAHA.104.506188. Epub 2005 Jun 6.
- Background: PubMed 10880413Festa A, D'Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000 Jul 4;102(1):42-7. doi: 10.1161/01.cir.102.1.42.
- Background: PubMed 19179212Dandona P, Chaudhuri A, Ghanim H, Mohanty P. Insulin as an anti-inflammatory and antiatherogenic modulator. J Am Coll Cardiol. 2009 Feb 3;53(5 Suppl):S14-20. doi: 10.1016/j.jacc.2008.10.038.
- Background: PubMed 16243403Dogne JM, Hanson J, Pratico D. Thromboxane, prostacyclin and isoprostanes: therapeutic targets in atherogenesis. Trends Pharmacol Sci. 2005 Dec;26(12):639-44. doi: 10.1016/j.tips.2005.10.001. Epub 2005 Oct 21.
- Background: PubMed 18818862Buscemi S, Verga S, Cottone S, Azzolina V, Buscemi B, Gioia D, Cerasola G. Glycaemic variability and inflammation in subjects with metabolic syndrome. Acta Diabetol. 2009 Mar;46(1):55-61. doi: 10.1007/s00592-008-0061-8. Epub 2008 Sep 26.
- Background: PubMed 16609090Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006 Apr 12;295(14):1681-7. doi: 10.1001/jama.295.14.1681.
- Background: PubMed 18299315Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, Boemi M, Giugliano D. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008 May;57(5):1349-54. doi: 10.2337/db08-0063. Epub 2008 Feb 25.
- Background: PubMed 18198229Esposito K, Ciotola M, Carleo D, Schisano B, Sardelli L, Di Tommaso D, Misso L, Saccomanno F, Ceriello A, Giugliano D. Post-meal glucose peaks at home associate with carotid intima-media thickness in type 2 diabetes. J Clin Endocrinol Metab. 2008 Apr;93(4):1345-50. doi: 10.1210/jc.2007-2000. Epub 2008 Jan 15.
- Individual participant dataSharing planned: Yes. Data available from the authors
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jeffrey L Probstfield, MD principal investigator
Professor of Medicine, University of Washington
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Insulin Glargine, Metformin and Prandial insulin in people with Type 2 Diabetes, run by University of Washington at 12 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Dec 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Coefficient of Variation at 26 Weeks Minus Coefficient of Variation at Baseline (time frame: At baseline, 6 months of intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01524705, which also lists 46 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Dec 2023.