Liraglutide in the Treatment of Type 1 Diabetes Mellitus

Hypothesis 1: Treatment with Liraglutide in patients with type 1 diabetes decreases fasting, postprandial and the overall mean glucose concentrations.

Aim 1.1: To compare the mean fasting, the mean weekly glucose and the standard deviation of weekly blood glucose concentrations as recorded by continuous glucose monitoring prior to and following 6 weeks and 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily. In addition, the time spent at glucose concentrations >150 and 200mg/dl and <70 and <40 mg/dl will also be compared.

Aim 1.2: To compare the postprandial glucose concentrations following a test meal before and after 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily. Glucose concentrations will be measured as areas under the curve for the data obtained from the meal challenge.

Aim 1.3: To compare HbA1c levels(glycated hemoglobin) before and after 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily Hypothesis 2: Treatment with Liraglutide in patients with type 1 diabetes decreases postprandial glucagon concentrations and increases postprandial C-peptide concentrations.

Aim 2.1: To compare fasting and postprandial glucagon and C-peptide concentrations following a test meal before and after 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily.

Hypothesis 3: Treatment with Liraglutide in patients with type 1 diabetes delays gastric emptying.

Aim 3.1: To compare the gastric emptying as measured by acetaminophen absorption before and after 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Placebo; Drug: Liraglutide

Detailed Description

RESEARCH DESIGN AND METHODS This investigation will be a prospective, randomized, double blind, placebo controlled study conducted in type 1 diabetics. The study will be conducted at Diabetes - Endocrinology Center of WNY at Millard Fillmore Hospital, affiliated to the State University of New York at Buffalo.

Study Population: Seventy two patients with type 1 diabetes on treatment with either continuous subcutaneous insulin infusion (CSII; also known as insulin pump) or multiple (four or more) injections of insulin per day will be included in the study. They will be randomized into 4 groups of 18 patients each. The patients will be randomized to placebo or 0.6 mg, 1.2 mg or 1.8 mg liraglutide daily. In view of the possibility of hypoglycemia and the side effect of nausea all patients will be started on 0.6 mg of liraglutide per day. The dose will then be titrated up to 1.2 and 1.8 mg on a weekly basis. No increases will be made once the target dose has been achieved in each group. Subjects will be recruited from our own patients, our existing database and from advertisements. The following insulin preparations will be used in the study: insulin detemir, glargine, aspart, glulisine and lispro. Subjects will continue to obtain their insulin supplies from their respective pharmacies.

STUDY DESIGN:

Screening Day (day -14):- Each patient will have completed the following procedures prior to participating in the study.

1. Medical History;
2. Physical Exam;
3. Informed consent.
4. Baseline lab draw to measure Complete blood count, comprehensive metabolic panel, Hba1c and lipid profile. All labs will be drawn in the fasting state in the morning before 10am.

Randomization Visit (day -7)

Randomization Method: After the screening visit, subjects who meet the inclusion and exclusion criteria, will be assigned a number by a computerized random number generation program (Microsoft office - Excel) and randomized to receive subcutaneous injection daily of either Liraglutide 0.6mg (18 subjects), 1.2 mg (18 subjects), 1.8 mg (18 subjects) or placebo (18 subjects) for 12 weeks. The subjects and the study coordinators will be blinded to the treatment. The Liraglutide/placebo will be administered via a pen kit (obtained from Novo Nordisk Pharmaceuticals). The dose will be given in the morning. The sponsor is providing study medication in blinded form.

All subjects will be instructed by the study staff in the dosing and administration of the study medication and will be seen by a Certified Diabetes Educator for instruction on injection technique. All subjects will also be seen by a registered dietitian who will review their carbohydrate counting and diet and make an assessment of their calorie and carbohydrate intake. The subjects will be randomized but will not start the placebo or liraglutide injection till study intervention visit 1.

All subjects will be advised to monitor their capillary blood glucose by fingerstick before and 2 hours after each meal and to wear their CGM constantly for the duration of the study The subjects will be asked to keep a diary of their food intake to measure their calorie intake. For the entire duration of the study, the patients will maintain a diary to record any hypoglycemia and other untoward side effects like nausea, changes in appetite and other experiences. Patients will be instructed to call the Diabetes Center or an endocrinology fellow directly in case of any problem or untoward side effects. They will be specifically asked to call if they have hypoglycemia (blood sugar <70 mg/dl) or hyperglycemia (blood sugar >250 mg/dl) on more than one occasion.

Study Intervention Visit 1 day 0:- Subjects will come fasting for this visit. Records of blood glucose concentrations monitored by fingerstick and CGM for the previous 7 days will be obtained to assess their glycemic control prior to liraglutide treatment. They will undergo a meal challenge test (described below), Liraglutide or placebo injections at a dose of 0.6 mg per day will then be started. No reduction will be made in the dose of pre-prandial insulin boluses and basal insulin if A1C is greater than or equal to 7.5%. Subjects will decrease the dose of pre-prandial insulin boluses by 25% and the basal by 25% if their A1C is less than or equal to 7%. Subjects will decrease the dose of pre-prandial insulin boluses and basal insulin by 10% if the A1C is between 7 and & 7.5%. This reduction is based on our experience (see preliminary data). Careful adjustments will be made to insulin doses at the discretion of the investigators on the basis of the glucose data obtained from the patients. The target blood glucose will be preprandial 90-120mg/dl and 2hour PP < 140mg/dl, without increasing the incidence of blood glucose < 70mg/dl. Patients will return to the center after 7 days

Study Intervention Visit 2 day 7:- Blood glucose concentrations will be reviewed. Insulin dose will be adjusted at the discretion of the study investigator to optimize blood sugar control as per the targets mentioned above on day 0 visit. Patients will be advised to increase the Liraglutide dose to 1.2 mg a day in those whose target dose is 1.2 or 1.8 mg. They will return in 7 days.

Study Intervention Visit 3 day 14:- Blood glucose concentrations will be reviewed. Insulin dose will be adjusted at the discretion of the study investigator to optimize blood sugar control as per the targets mentioned above on day 0 visit. Patients with a target dose of 1.8 mg will be advised to increase the dose while others will continue on their previous dose. They will return in 7 days.

Study Intervention Visit 4 day 21, Visit 5 day 28:

Records of blood glucose concentrations of the last 7 days will be collected. Insulin dose will be adjusted at the discretion of the study investigator to optimize blood sugar control as per the targets mentioned above on day 0 visit.

Study Intervention Visit 6 day 42, Visit 7 day 56, Visit 8 day 70:

Records of blood glucose concentrations of the last 15 days will be collected. Insulin dose will be adjusted at the discretion of the study investigator to optimize blood sugar control as per the targets mentioned above on day 0 visit.

Study Intervention Visit 9 day 84 Subjects will come fasting for this visit. Records of blood glucose concentrations monitored by fingerstick or CGM for the previous 7 days will be obtained to assess their glycemic control. They will undergo meal challenge test (described below). After this visit, subjects will be discharged from the study.

Meal challenge test:- In order to assess the changes induced by liraglutide, a meal challenge will be carried out prior to and following liraglutide (day 0 and day 84). (910 Calorie High fat High carbohydrate meal as in several of our previous papers). Acetaminophen (1000 mg for body weight <70 kg or 1500 mg for body weight >70 kg) will be ingested at the beginning of the meal, and the blood levels of acetaminophen will be determined at intervals for assessment of the rate of gastric emptying. Bolus Insulin will be injected immediately before the meal based on the insulin carbohydrate ratio and correction factor for each individual subject. Liraglutide will be injected only on day 84 (45 min prior to the meal). Sequential blood samples will be obtained at 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 and 300 min. Samples at 15, 30, 45, 90, 150 and 210 min will be 5 ml while those at 0, 60, 120, 180, 240 and 300 min will be 30 ml (total volume=210 ml). Blood will be collected from an indwelling intravenous canula in a superficial forearm vein.

Data safety and monitoring:

Timely, accurate, and complete reporting and analysis of safety information obtained from clinical trials are crucial for the protection of subjects and investigators.

All subjects will be referred to liraglutide's labeling safety information, and will be provided a copy of the package insert of the medication. Discussion of the potential side effects and the different warning and precautions will take place at the time of signing the informed consent.

The following Information from the boxed warning in the package insert regarding the risk of thyroid c-cell tumors will be discussed in details with all participating subjects "Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Liraglutide is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors."

In addition, the following FDA text regarding the risk of developing fibrosarcomas will be discussed with all participating subjects "In a 2-year repeat subcutaneous dose carcinogenicity study of liraglutide injected once a day in CD-1 mice, a treatment-related increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used for drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 mg/mL) is 10 times higher than the concentration in the formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study (0.6 mg/mL)".

All Adverse events(AEs) will be reported at the time of the visit or by telephone when it occurs. Those meeting the definition of Serious Adverse Events(SAE's) must be reported using the SAE Form. Medical events that occur between the signing of the Informed Consent and the first intake of study drug will be documented in the medical history. Subjects should voluntarily report any AEs or in response to general, non-directed questioning. For each AE volunteered by the subject, the investigator will obtain all the information required to complete the AE page of the Case Report Form(CRF), in accordance with the guidelines that accompany it.

All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, will be recorded using medical terminology in the source document and on the CRF. Whenever possible, diagnoses will be given when signs and symptoms are due to a common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory infection). Investigators will record on the CRF their opinion concerning the relationship of the AE to study therapy. All measures required for AE management will be recorded in the source document and reported according to sponsor instructions.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New York
    • Williamsville, New York, United States, 14221
      • Diabetes-Endocrinology Center of Western NY

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Patients with type 1 diabetes mellitus: Fasting c-peptide < 0.1nmol/l on insulin therapy for more than 12 months with or without history of diabetic ketoacidosis.
2. Using a continuous glucose monitoring device (CGM) and regularly measuring their blood sugars four times daily
3. HbA1c of less than 8.5%.
4. Well versed with carbohydrate counting
5. Age 18-75 years

Exclusion Criteria:

1. Type 1 diabetes for less than 12 months;
2. Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) in the previous four weeks;
3. Hepatic disease (transaminase > 3 times normal) or cirrhosis;
4. Renal impairment (serum creatinine > 1.5);
5. HIV or Hepatitis C positive status;
6. Participation in any other concurrent clinical trial;
7. Any other life-threatening, non-cardiac disease;
8. Use of an investigational agent or therapeutic regimen within 30 days of study.
9. history of pancreatitis
10. pregnancy
11. inability to give informed consent
12. history of gastroparesis
13. history of medullary thyroid carcinoma or MEN 2 syndrome.
14. Family history of MEN 2, Family history of medullary thyroid cancer, or familial medullary thyroid cancer
15. Women of childbearing potential who are not using adequate contraception 16) Women who are pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Daily Injection	Drug: Placebo; Patients randomized to 1.2 mg of placebo: They will start placebo 0.6 mg sc once daily for one week and then increase to 1.2 mg once daily thereafter. Patients randomized to 1.8 mg of placebo: They will start placebo 0.6 mg sc once daily for one week; increase to 1.2 mg sc once daily for second week and then to 1.8 mg sc once daily from third week onwards.
Active Comparator: Liraglutide 1.8mg; Daily Injection	Drug: Liraglutide; Patients randomized to 1.2 mg of liraglutide : They will start liraglutide 0.6 mg sc once daily for one week and will increase the dose to 1.2 mg sc once daily thereafter. Patients randomized to 1.8 mg of liraglutide: They will start liraglutide 0.6 mg sc once daily for one week; will increase to 1.2 mg sc once daily for second week and will stay on 1.8 mg of liraglutide from third week onwards.; Other Names: Victoza
Active Comparator: Liraglutide 1.2mg; Daily injections	Drug: Liraglutide; Patients randomized to 1.2 mg of liraglutide : They will start liraglutide 0.6 mg sc once daily for one week and will increase the dose to 1.2 mg sc once daily thereafter. Patients randomized to 1.8 mg of liraglutide: They will start liraglutide 0.6 mg sc once daily for one week; will increase to 1.2 mg sc once daily for second week and will stay on 1.8 mg of liraglutide from third week onwards.; Other Names: Victoza
Active Comparator: Liraglutide 0.6 mg; Daily injection	Drug: Liraglutide; Patients randomized to 1.2 mg of liraglutide : They will start liraglutide 0.6 mg sc once daily for one week and will increase the dose to 1.2 mg sc once daily thereafter. Patients randomized to 1.8 mg of liraglutide: They will start liraglutide 0.6 mg sc once daily for one week; will increase to 1.2 mg sc once daily for second week and will stay on 1.8 mg of liraglutide from third week onwards.; Other Names: Victoza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mean Weekly Glucose Concentrations	The primary endpoint of the study is to detect a difference from baseline in mean weekly blood glucose concentrations before and after 12 weeks of treatment in each of the Liraglutide groups.	12 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c	Change from baseline (week 0) in HbA1c at 12 weeks after treatment	12 Weeks
Change in Body Weight From Baseline	Change in Body weight in Kg from baseline after 12 weeks of treatment	12 weeks
Change in Total Insulin Dose From Baseline	Total daily insulin dose = Basal insulin dose plus bolus insulin dose. Change from baseline in Total daily insulin dose at 12 weeks from treatment.	12 weeks
Change in the Area Under Curve (AUC) of Glucose Following the Meal	Change in the Area Under Curve (AUC0h-5h) of glucose concentration measured following meal challenge of up to 5hrs performed at baseline (week 0) at 12 weeks following treatment.	12 weeks
Change in Carbohydrate Intake	Change from baseline (0 week) in Daily Carbohydrate intake (in grams) at 12 weeks after treatment.	12 weeks
Change in Glucagon Concentrations	change from baseline (week 0) in glucagon concentrations following 12 weeks of treatment	12 weeks

Collaborators and Investigators

• Sponsor: University at Buffalo
• Collaborators: Novo Nordisk A/S
• Investigators: Principal Investigator: Paresh Dandona, MBBS, PhD, Kaleida Health

Publications and helpful links

General Publications

• Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Maggs DG, Wintle ME. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther. 2007 Jan;29(1):139-53. doi: 10.1016/j.clinthera.2007.01.015.
• Kuhadiya ND, Malik R, Bellini NJ, Patterson JL, Traina A, Makdissi A, Dandona P. Liraglutide as additional treatment to insulin in obese patients with type 1 diabetes mellitus. Endocr Pract. 2013 Nov-Dec;19(6):963-7. doi: 10.4158/EP13065.OR.
• Varanasi A, Bellini N, Rawal D, Vora M, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P. Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol. 2011 Jul;165(1):77-84. doi: 10.1530/EJE-11-0330. Epub 2011 Jun 6.
• Kielgast U, Asmar M, Madsbad S, Holst JJ. Effect of glucagon-like peptide-1 on alpha- and beta-cell function in C-peptide-negative type 1 diabetic patients. J Clin Endocrinol Metab. 2010 May;95(5):2492-6. doi: 10.1210/jc.2009-2440. Epub 2010 Mar 5.
• Rother KI, Spain LM, Wesley RA, Digon BJ 3rd, Baron A, Chen K, Nelson P, Dosch HM, Palmer JP, Brooks-Worrell B, Ring M, Harlan DM. Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes. Diabetes Care. 2009 Dec;32(12):2251-7. doi: 10.2337/dc09-0773. Epub 2009 Oct 6.
• Ghanim H, Aljada A, Daoud N, Deopurkar R, Chaudhuri A, Dandona P. Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects. Diabetologia. 2007 Feb;50(2):278-85. doi: 10.1007/s00125-006-0508-9. Epub 2006 Dec 16.
• Wajchenberg BL, Feitosa AC, Rassi N, Lerario AC, Betti RT. Glycemia and cardiovascular disease in type 1 diabetes mellitus. Endocr Pract. 2008 Oct;14(7):912-23. doi: 10.4158/EP.14.7.912.
• Montanya E, Sesti G. A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. Clin Ther. 2009 Nov;31(11):2472-88. doi: 10.1016/j.clinthera.2009.11.034.
• Varanasi A, Patel P, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P. Clinical use of liraglutide in type 2 diabetes and its effects on cardiovascular risk factors. Endocr Pract. 2012 Mar-Apr;18(2):140-5. doi: 10.4158/EP11169.OR.
• Varanasi A, Chaudhuri A, Dhindsa S, Arora A, Lohano T, Vora MR, Dandona P. Durability of effects of exenatide treatment on glycemic control, body weight, systolic blood pressure, C-reactive protein, and triglyceride concentrations. Endocr Pract. 2011 Mar-Apr;17(2):192-200. doi: 10.4158/EP10199.OR.
• Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hypertens. 2010 Mar;23(3):334-9. doi: 10.1038/ajh.2009.245. Epub 2009 Dec 17.
• Lebovitz HE. Adjunct therapy for type 1 diabetes mellitus. Nat Rev Endocrinol. 2010 Jun;6(6):326-34. doi: 10.1038/nrendo.2010.49. Epub 2010 Apr 20.
• Kuhadiya ND, Dhindsa S, Ghanim H, Mehta A, Makdissi A, Batra M, Sandhu S, Hejna J, Green K, Bellini N, Yang M, Chaudhuri A, Dandona P. Addition of Liraglutide to Insulin in Patients With Type 1 Diabetes: A Randomized Placebo-Controlled Clinical Trial of 12 Weeks. Diabetes Care. 2016 Jun;39(6):1027-35. doi: 10.2337/dc15-1136. Epub 2016 Apr 5.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2012
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: November 2, 2012
• First Submitted That Met QC Criteria: November 5, 2012
• First Posted (Estimated): November 6, 2012

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 1, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: HbA1c; Liraglutide; Systolic blood pressure; Weight; Insulin dose; Glucagon; Carbohydrate intake; Post-prandial glucagon
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: NN1962

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No