Exenatide Compared With Insulin Glargine to Change Liver Fat Content in Type 2 Diabetes

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Exenatide BID Compared With Insulin Glargine to Change Liver Fat Content in Non-alcoholic Fatty-liver Disease Patients With Type 2 Diabetes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02303730
• Other study ID #: ESR-14-10096
• Status: Completed
• Phase: Phase 4
• Start date: March 2015
• Est. completion date: November 2017

Study information

• Verified date: August 2019
• Source: Fudan University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate whether exenatide is superior to insulin glargine (after 24 weeks) in reducing liver fat content (by MRS) in patients with newly diagnosed type 2 diabetes mellitus and concomitant non-alcoholic fatty-liver disease(NAFLD).

Description:

This is a randomized, open-label, parallel-group, active controlled, multi-center clinical trial to investigate whether exenatide is superior to insulin glargine in reducing liver fat content in patients with newly diagnosed type 2 diabetes mellitus and concomitant NAFLD.Patients with type 2 diabetes and concomitant NAFLD from 18-70 years of age, with inadequate glycaemic control defined as 7% ≤ HbA1c ≤ 10% and BMI≥24kg/ m2 at the time of screening. Patients should be on diet and exercise but drug treatment naive, no use of any glucagon-like peptide-1(GLP-1) analogues or insulin within 3 months before enrolment.Patients will have an screening period 2 weeks, and a 24-week open label treatment period.

All demographic data variables collected by descriptive analysis tests are used. Qualitative variables use absolute frequency and percentage, and numeric variables use average, mean, median, standard deviation, maximum, minimum, quartiles, etc. Unless specifically stated, statistical significance will be defined as P＜0.05 in the whole analysis procedure.For the primary endpoint of this study, superiority test will be applied to the quantitative data of these two groups. For secondary and exploratory efficacy variables, difference test will be used to analyse repeated measurement data from two groups. For essential Safety parameters, difference test will be used to analyse the differences between two groups.The analysis of all primary and secondary endpoints of efficacy and safety must be based on the Full Analysis Set (FAS). As supporting evidence, the analysis of primary endpoint variables must also comply with the Pre-protocol (PPS) Analysis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 76
• Est. completion date: November 2017
• Est. primary completion date: November 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Male or female, 18 = age = 70 years old.

• Newly diagnosed type 2 diabetes mellitus (WHO Diagnostic criteria for diabetes mellitus, 1999).

• Patients with NAFLD, MRS measurement of liver fat content> 10%.

• 7% = HbA1c = 10%

• No heavy drinking history within the last 5 years (alcohol intake: male < 20 g/d, female < 10 g/d)

• HBsAg (-), hepatitis C virus antibody (HCV-Ab) (-)

• BMI = 24 kg/m2;

Exclusion Criteria:

• Pregnancy, lactation, intended pregnancy, or failure to take adequate contraceptive measures taken (contraception measures including sterilization, intrauterine device, oral contraceptives, and persistent use of condoms).

• Type 1 diabetes mellitus, gestational diabetes mellitus or other special types of diabetes.

• Liver and renal dysfunction (ALT or aspartate aminotransferase(AST) is 2.5 times higher than the upper limit of normal, or total bilirubin is 1.5 times higher than the upper limit of normal, or Cr = 115 µmol/L).

• increased amylase (blood amylase is 2.5 times higher than the upper limit of normal) or presence of gastrointestinal disease.

• Use of drugs that may affect liver fat content within one month before or during the trial period, such as glucocorticoids, thyroid hormone, etc.

• Use of GLP-1 receptor agonist, dipeptidyl peptidase -4 (DPP-4) inhibitors or insulin within 3 months before enrolment

• Presence of serious dyslipidemia or other endocrine diseases (hypothyroidism, hypothalamic-pituitary dysfunction, etc).

• Fatty liver caused by viral hepatitis, drug, alcohol, Wilson disease or total parenteral nutrition.

• Presence of liver cancer, infection, biliary tract disease or recently increased liver enzyme due to medication.

• Participation in strenuous exercise or administration of any drugs that affect glucose metabolism.

• History of pancreatitis, alcohol abuse, metal disorders or history of allergy to investigational drug.

• Congestive heart failure defined as New York Heart Association (NYHA) class III or IV, unstable angina or myocardial infarction in recent 6 months.

• Any situation that may affect the implementation or results of the study.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Fatty Liver
• Liver Diseases
• Non-alcoholic Fatty Liver Disease

Intervention

Drug:
• Exenatide
The starting dose of exenatide is 5 ug bid, subcutaneously, for 4 weeks, followed by 10 ug bid, subcutaneously, for 20 weeks. If hypoglycaemia (blood glucose<2.9 mmol/l or < 3.9 mmol/l at least 2 times) or serious intolerance occurs, the dose will be adjusted to 5 ug bid, subcutaneously.
• insulin glargine
The starting dose of insulin glargine will depend upon the HbA1c level at screening(HbA1c <8% use 0.1 -0.2 U/kg per day;HbA1c >8% use 0.2 -0.3 U/kg per day). Dose adjustment protocol for insulin glargine (at least 3 determinations of fasting blood glucose per week): fasting blood glucose(FBG) > 180 mg/dL(10 mmol/l): add 4 U; FBG 140-180 mg/dL(7.8-10 mmol/l): add 2 U; FBG 126-139 mg/dL(7.0-7.8 mmol/l): add 1 U. If hypoglycemia, reduce insulin glargine by: blood glucose <70mg/dl(3.9mmol/l): 10%-20%; blood glucose <40mg/dl(2.2mmol/l): 20%-40%.

Locations

Country	Name	City	State
China	Department of Endocrinology and Metabolism, Shanghai Minhang Central Hospital	Shanghai	Shanghai
China	Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University	Shanghai	Shanghai
China	Department of Endocrinology and Metabolism,Huadong Hospital	Shanghai	Shanghai
China	Department of Endocrinology and Metabolism,Shanghai 6th People's Hospital	Shanghai	Shanghai
China	Department of Endocrinology and Metabolism,Shanghai Changzheng Hospital	Shanghai	Shanghai

Sponsors (5)

Lead Sponsor	Collaborator
Fudan University	Huadong Hospital, Shanghai 6th People's Hospital, Shanghai Changzheng Hospital, Shanghai Minhang Central Hospital

Country where clinical trial is conducted

China, 

References & Publications (10)

Cuthbertson DJ, Irwin A, Gardner CJ, Daousi C, Purewal T, Furlong N, Goenka N, Thomas EL, Adams VL, Pushpakom SP, Pirmohamed M, Kemp GJ. Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists. PLoS One. 2012;7(12):e50117. doi: 10.1371/journal.pone.0050117. Epub 2012 Dec 6. — View Citation

Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, Anania FA. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology. 2010 May;51(5):1584-92. doi: 10.1002/hep.23569. — View Citation

Juurinen L, Tiikkainen M, Häkkinen AM, Hakkarainen A, Yki-Järvinen H. Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2007 Mar;292(3):E829-35. Epub 2006 Nov 7. — View Citation

Kenny PR, Brady DE, Torres DM, Ragozzino L, Chalasani N, Harrison SA. Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol. 2010 Dec;105(12):2707-9. doi: 10.1038/ajg.2010.363. — View Citation

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. — View Citation

ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-28. doi: 10.1056/NEJMoa1203858. Epub 2012 Jun 11. — View Citation

Sathyanarayana P, Jogi M, Muthupillai R, Krishnamurthy R, Samson SL, Bajaj M. Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes. Obesity (Silver Spring). 2011 Dec;19(12):2310-5. doi: 10.1038/oby.2011.152. Epub 2011 Jun 9. — View Citation

Shao N, Kuang HY, Hao M, Gao XY, Lin WJ, Zou W. Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes. Diabetes Metab Res Rev. 2014 Sep;30(6):521-9. doi: 10.1002/dmrr.2561. — View Citation

Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS One. 2011;6(9):e25269. doi: 10.1371/journal.pone.0025269. Epub 2011 Sep 21. — View Citation

Xu W, Bi Y, Sun Z, Li J, Guo L, Yang T, Wu G, Shi L, Feng Z, Qiu L, Li Q, Guo X, Luo Z, Lu J, Shan Z, Yang W, Ji Q, Yan L, Li H, Yu X, Li S, Zhou Z, Lv X, Liang Z, Lin S, Zeng L, Yan J, Ji L, Weng J. Comparison of the effects on glycaemic control and ß-cell function in newly diagnosed type 2 diabetes patients of treatment with exenatide, insulin or pioglitazone: a multicentre randomized parallel-group trial (the CONFIDENCE study). J Intern Med. 2015 Jan;277(1):137-50. doi: 10.1111/joim.12293. Epub 2014 Aug 5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in cardiac function measured by echocardiography	Change in cardiac function measured by echocardiography	baseline and 24 weeks
Other	Change in ß-cell function (fasting C-peptide, 2-hour postprandial C-peptide)	Change in ß-cell function (fasting C-peptide, 2-hour postprandial C-peptide)	baseline and 24 weeks
Other	Change in liver enzymes and laboratory parameters (hematology, biochemical tests)	Change in liver enzymes and laboratory parameters (hematology, biochemical tests)	baseline and 24 weeks
Other	Incidence of hypoglycaemia events	Incidence of hypoglycaemia events	up to 24 weeks
Other	Incidence of adverse events(AEs)and Severe adverse events(SAEs)	Incidence of adverse events(AEs)and Severe adverse events(SAEs)	up to 24 weeks
Primary	Change in liver fat content(%) measured by MRS	Change in liver fat content(%) measured by MRS	baseline and 24 weeks
Secondary	Change in intra-abdominal visceral fat content (cm2), abdominal subcutaneous fat content (cm2), and ratio between intra-abdominal visceral fat and subcutaneous fat area by MRI	Change in intra-abdominal visceral fat content (cm2), abdominal subcutaneous fat content (cm2), and ratio between intra-abdominal visceral fat and subcutaneous fat area by MRI	baseline and 24 weeks
Secondary	Change in glucose metabolism (fasting blood glucose, postprandial plasma glucose, HbA1c)	Change in glucose metabolism (fasting blood glucose, postprandial plasma glucose, HbA1c)	baseline and 24 weeks
Secondary	Change in blood lipid profile (total cholesterol, triglyceride, HDL, LDL)	Change in blood lipid profile (total cholesterol, triglyceride, HDL, LDL)	baseline and 24 weeks
Secondary	Change in body weight,waist circumference and hip circumference	Change in body weight,waist circumference and hip circumference	baseline and 24 weeks