To study the effect of dapagliflozin vs sitagliptin on liver fat accumulation in patients
with diabetes and liver transplantation.
Material and Methods Ethical considerations The trial protocol is approved by the Medanta
ethics committees. The trial will be conducted in accordance with the principles of the
Declaration of Helsinki and Good Clinical Practice guidelines. All the patients will be
provided with written informed consent before participation.
Patients and study area A total of 100 patients will be enrolled for the study.
Consecutive patients undergoing liver transplantation and attending outpatient Department
of Endocrinology and Diabetes for management of diabetes mellitus will be enrolled.
Diabetes mellitus will include both pre-transplantation type 2 diabetes as well as
new-onset diabetes after transplantation (NODAT).
Statistical Analysis Plan:
The analysis will include profiling of patients on different demographic, clinical and
laboratory parameters etc. Quantitative data will be presented in terms of means and
standard deviation and qualitative/categorical data will be presented as absolute numbers
and proportions. Cross tabulation will be generated and chi square test will be used for
testing of association. Student t test will be used for comparison of quantitative
outcome parameters and standard normal deviate test for proportions. P-value < 0.05 is
considered statistically significant. SPSS software will be used for analysis.
Eligibility criteria Inclusion criteria
Diagnosis of diabetes (pre-transplantation type 2 diabetes or new onset diabetes
after transplantation)
Subjects taking insulin and/or metformin and/or sulfonylurea for at least 3 months
since liver transplantation
Body mass index (BMI) more than or equal to 18.5 kg/m2
Exclusion criteria
Type 1 diabetes
Estimated glomerular filtration rate (eGFR) <45 ml/min/1.73 m2, calculated by the
Chronic Kidney Disease - Epidemiology (CKD-EPI) equation
Liver aminotransferases >3 times the upper limit of the reference range (upper
normal limit AST or ALT >=40 units/L)
History of recurrent urinary tract infection
History or current acute or chronic pancreatitis
Pregnancy
Presence of major contraindications to magnetic resonance imaging (cardiac
pacemakers, claustrophobia, foreign bodies and implanted medical devices with
ferromagnetic properties).
All patients will be randomized to one of the following intervention groups: Sita group
(n = 50): patients with diabetes mellitus receiving multiple doses of insulin plus
metformin 500 mg twice daily plus sitagliptin 100 mg once daily and Dapa group (n = 50):
patients with diabetes mellitus receiving multiple doses of insulin plus metformin 500 mg
daily plus dapagliflozin 10 mg once daily. Glycemic equipoise will be maintained between
the two groups by adjusting insulin doses and maintaining target fasting glucose,
post-prandial glucose and glycated hemoglobin (HbA1c) in accordance with the ADA 2021.
Imaging Liver fat content and pancreatic fat content will be assessed by magnetic
resonance imaging (MRI) proton density fat Fraction (PDFF) at the beginning of study and
again after 12 months of intervention. MRI-PDFF is a robust technique for noninvasive
quantification of liver fat. Multiple human studies have shown that this method
accurately estimates PDFF in the liver. This method has been shown to be both accurate,
and reproducible. Investigators have validated this technique for Indian population and
is already used in the E-LIFT and D-LIFT trials.
Body composition by Dual energy X-ray absorptiometry (DEXA) Body composition will be
assessed by DEXA using the Hologic Horizon DXA System (USA) with Discovery software,
version 12.3 (Bellingham, WA, USA). DEXA provides a rapid and non-invasive fat mass, fat
free mass and bone mineral density. DEXA is considered to be the reference method for
body composition assessment in clinical research. The DEXA-measured body composition
variables that will be included for analysis are weight (kg), body mass index (BMI),
total fat mass (kg), android fat mass (g), gynoid fat mass (g), visceral adipose tissue
(VAT) mass (g), VAT area (cm2), and abdominal subcutaneous adipose tissue (SAT) mass (g).
Obesity will be defined as BMI >25 kg/m2 in accordance with World Health Organization
(WHO) Asia pacific guidelines. The skeletal muscle mass index (SMI) will be the
appendicular skeletal muscle divided by the height in meters squared. Low appendicular
skeletal mass index will be defined as <7.0 kg/m2 for men and <5.4 kg/m2 for women, as
per Consensus Report of the Asian Working Group for Sarcopenia (AWGS).
Bioelectrical impedance (BIA) analysis Multi-frequency bioelectrical impedance analysis
was completed using InBody 570 body composition analyzer (Biospace, Inc. Seoul, Korea).
The InBody 570 is a multi-frequency analyzer and divides the body into five components:
two arms, two legs, and a trunk. The electrodes are situated beneath the subject's feet
on the platform and on the palms and thumbs attached to handles on the device. Age,
height and gender are manually entered after weight is determined by a scale positioned
within device.
Laboratory workup Biochemical parameters will include fasting plasma glucose,
glycosylated hemoglobin (HbA1C), lipid profile, hemogram, kidney function test (urea,
creatinine) and liver function test (total and fractionated bilirubin, alanine
transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase
(GGT), total protein, albumin) before and after the intervention period.
End points and safety assessments The primary endpoint will be changes from baseline in
MRI-PDFF assessed liver and pancreatic fat content at month 12. The secondary outcome
measures will be changes from baseline in liver aminotransferases (AST, ALT and GGT) at
month 12. Changes from baseline in body composition variables (weight, BMI, body fat
percentage, visceral adipose tissue, skeletal muscle mass and bone mineral content) at
month 12. Efficacy variables will include proportion of individuals requiring insulin
therapy at months 6 and 12, changes from baseline in HbA1c at months 6 and 12, and the
percentage change from baseline in the total daily insulin dose (by collecting the daily
record of the last week at months 6 and 12). Safety assessment will include adverse
events (AEs), serious AEs (SAEs), physical examination findings, vital signs and
laboratory values. AEs of special interest will be genital infections, urinary tract
infections, volume depletion, fractures, worsening renal function, hepatobiliary AEs,
hypersensitivity, and cardiovascular AEs.
Study outcomes The primary outcome measures are
Changes from baseline to month 12 in liver and pancreatic fat content. The secondary
outcome measures are
Change from baseline in body composition variables (body weight, BMI, body fat
percentage, visceral adipose tissue, skeletal muscle mass and bone mineral content)
at month 12
Changes from baseline in liver aminotransferases (AST, ALT and GGT)
Changes in efficacy variables (proportion of individuals requiring insulin therapy
at months 6 and 12, changes from baseline in HbA1c at months 6 and 12, and the
percentage change from baseline in the total daily insulin dose at months 6 and 12).
Safety assessment at months 3, 6, 9 and 12 (as described above).
Table 2. Safety summary Characteristic
>=1 AEs >=1 AEs related to the study drug AE leading to study discontinuation AEs of
special interest Genital infection Urinary tract infection Renal impairment Fractures
Hypotension/dehydration/hypovolemia Hypersensitivity Cardiovascular events SAEs >=1 SAEs
>=1 SAEs related to the study drug SAEs leading to study discontinuation Death