Efficacy of Exenatide-LAR and Dapagliflozin in Overweight/Obese, Insulin Treated Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to see what the effects of using one or two additional diabetes drugs (dapagliflozin and exenatide-LAR) are on blood sugar levels in patients who are taking insulin. This research study is being done to investigate which of these commonly-used medications, medication combinations or increasing insulin dose is better.

Detailed Description
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This is a single center prospective, randomized, placebo-controlled trial in overweight/obese patients with insulin treated uncontrolled type 2 diabetes Eligible subjects willing to participate in the study will be randomized to one of 3 treatment groups: Group 1: Insulin titration + behavioral therapy Basal insulin titration upto 12 weeks with 2 U increment every 3 days (Fasting glucose goal <110) based on self-monitored blood glucose. After 12 weeks, patients with HbA1c >8% will switch to a basal bolus regimen. Group 2: Exenatide-LAR 2mg q week x 24 weeks + Dapagliflozin placebo x 52 weeks + titrated basal insulin +behavioral therapy. Group 3: Exenatide-LAR 2mg q week x 24 weeks plus Dapagliflozin 5mg QD x 2 weeks followed by 10mg QD x22 weeks +titrated basal insulin + behavioral therapy. Behavioral therapy will be delivered by registered dietitians and will include the BMIQ program -a web based medical weight loss program.

Official Title
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Efficacy of Exenatide-LAR Alone and in Combination With Dapagliflozin in Overweight/Obese, Insulin Treated Patients With Uncontrolled Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Exenatide-LAR plus Dapagliflozin placebo
* Drug: Exenatide-LAR plus Dapagliflozin
* Drug: Insulin Titration
* Behavioral: Behavioral Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Diagnosis of Type 2 diabetes BMI ≥27kg/m^2 Hemoglobin A1C 8-12% English speaking provided written consent on a stable dose of metformin and/or glitazone and/or alpha-glucosidase inhibitors for ≥ to 8 weeks Exclusion Criteria: History of type 1 diabetes fasting c-peptide <.8 ng/ml eGFR <60 ml/min/1.73 m^2 urine albumin-to-creatinine ratio greater or equal to 300 mg/g AST/ALT greater or equal to 2.5 upper limits of normal history of infectious liver disease (HBV, HCV) creatine kinase greater or equal to 3 times the upper limits of normal unstable or serious cardiovascular, renal, or hepatic disease symptoms of severely uncontrolled diabetes history of more than 1 episode of severe/major hypoglycemia within 6 months, active/history of bladder cancer female patients who are pregnant or intending to become pregnant women who are breastfeeding personal/family history of medullary thyroid cancer or MEN2 fasting triglyceride levels > 500 mg/dl history of confirmed pancreatitis known hypersensitivity or allergy to exenatide or dapagliflozin are currently enrolled in or discontinued within last 30 days from another study have any other condition that precludes the patient from following and completing the protocol history of diabetic ketoacidosis anti-diabetes medication other than those listed in the inclusion criteria within 8 weeks of screening history of previous bariatric surgery or planned bariatric surgery during the course of the study clinically significant abnormal free T4/TSH requiring initiation or adjustment of thyroid treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group 1<br>Insulin titration and behavioral therapy. | Drug: Insulin Titration<br>* Basal insulin titration up to 12 weeks followed by basal-bolus regimen in those with HbA1c>8%<br>* Other names: Lantus, Levemir, Novolog, Lispro;Behavioral: Behavioral Therapy<br>* Subjects will be seen by a registered dietitian and receive nutritional and lifestyle counseling according to a web-based weight management program.<br>|
| Placebo Comparator: Group 2<br>Exenatide-LAR plus Dapagliflozin placebo, basal insulin titration, and behavioral therapy. | Drug: Exenatide-LAR plus Dapagliflozin placebo<br>* Exenatide-LAR 2 mg every week x 24 weeks plus Dapagliflozin placebo x 52 weeks and behavioral therapy.<br>* Other names: Farxiga;Drug: Insulin Titration<br>* Basal insulin titration up to 12 weeks followed by basal-bolus regimen in those with HbA1c>8%<br>* Other names: Lantus, Levemir, Novolog, Lispro;Behavioral: Behavioral Therapy<br>* Subjects will be seen by a registered dietitian and receive nutritional and lifestyle counseling according to a web-based weight management program.<br>|
| Experimental: Group 3<br>Exenatide-LAR plus Dapagliflozin, basal insulin titration, and behavioral therapy. | Drug: Exenatide-LAR plus Dapagliflozin<br>* Exenatide-LAR 2 mg every week x 24 weeks plus Dapagliflozin 5 mg x 2 weeks, then 10 mg for 22 weeks and behavioral therapy.<br>* Other names: Farxiga;Drug: Insulin Titration<br>* Basal insulin titration up to 12 weeks followed by basal-bolus regimen in those with HbA1c>8%<br>* Other names: Lantus, Levemir, Novolog, Lispro;Behavioral: Behavioral Therapy<br>* Subjects will be seen by a registered dietitian and receive nutritional and lifestyle counseling according to a web-based weight management program.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | To determine the efficacy of Exenatide-LAR and Exenatide-LAR plus dapagliflozin in lowering HbA1c compared with insulin titration in obese, insulin treated subjects with uncontrolled Type 2 Diabetes Mellitus at 24 weeks | baseline, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight | To determine the effect of Exenatide-LAR and Exenatide-LAR plus dapagliflozin vs insulin titration on body weight in obese, insulin treated subjects with uncontrolled T2DM | baseline, 24 weeks | 
| Change in waist circumference | To determine the effect of Exenatide-LAR and Exenatide-LAR plus dapagliflozin vs insulin titration on waist circumference in obese, insulin treated subjects with uncontrolled T2DM | baseline, 24 weeks | 
| Change in fasting glucose | To determine the effect of Exenatide-LAR and Exenatide-LAR plus dapagliflozin vs insulin titration on fasting glucose (FG) in obese, insulin treated subjects with uncontrolled T2DM | baseline, 24 weeks | 
| Change in fasting lipids | To determine the effect of Exenatide-LAR and Exenatide-LAR plus dapagliflozin vs insulin titration on fasting lipids in obese, insulin treated subjects with uncontrolled T2DM | baseline, 24 weeks | 
| Change in blood pressure | To determine the effect of Exenatide-LAR and Exenatide-LAR plus dapagliflozin vs insulin titration on blood pressure in obese, insulin treated subjects with uncontrolled T2DM | baseline, 24 weeks | 
| Change in total dose insulin | To determine the effect of Exenatide-LAR and Exenatide-LAR plus dapagliflozin vs insulin titration on total dose insulin in obese, insulin treated subjects with uncontrolled T2DM | baseline, 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity