UMIN-CTR Clinical Trial

Public title

Effects of liraglutide and empagliflozin add-on to insulin therapy in patients with type 2 diabetes: a randomized controlled study

Acronym

ELLENA-IT study

Scientific Title

Effects of liraglutide and empagliflozin add-on to insulin therapy in patients with type 2 diabetes: a randomized controlled study

Scientific Title:Acronym

ELLENA-IT study

Region

Japan

Condition

Type 2 diabetes

Classification by specialty

Endocrinology and Metabolism

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

The aim of this study is to compare the effect of GLP-1 receptor agonist liraglutide and SGLT-2 inhibitor empagliflozin on glucose metabolism in patients with type 2 diabetes.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

Comparing the two groups of change in HbA1c over the 24-week treatment period.

Key secondary outcomes

Comparing the two groups of change over the 24-week treatment period.

1.HOMA2-%beta (%)
2.HOMA2-IR
3.CPR-index
4.Glycated albumin
5.Fasting plasma glucose (mg/dL)
6.Self-measured postprandial glucose (mg/dL)
7.Systolic blood pressure(mmHg)
8. Diastolic blood pressure(mmHg)
9.Pulse rate
10.Lipid profile
11.Serum creatinine(mg/dL),eGFR (ml/min/1.73m2),cystatinC(mg/L)
12.UA(mg/dL)
13.AST,ALT,gamma-GTP
14.Urine albumin/creatinine ratio (mg/g･Cr)
15.Urine natrium/creatinine ratio
16.Insulin dose(units/day)
17.Body weight (kg)
18.Waist circumference (cm)
19.Fat mass (kg)
20.Body fat percentage(%)
21.Lean tissue mass (kg)
22.Hypoglicemic events
23.Medication compliance(%)
24.Other adverse events

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -no one is blinded

Control

Active

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Liraglutide 0.9mg/day,24 weeks

Starting at 0.3mg once daily with weekly increments of 0.3mg,reaching a final daily dose of 0.9mg.

Interventions/Control_2

Empagliflozin 10mg/day,24 weeks

Provided that from 12 weeks onward,if FPG is>=180mg/dL or HbA1c>=8.5%,the dose of empagliflozin is increased up to 25mg/day.

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

80

years-old

>=

Gender

Male and Female

Key inclusion criteria

(1)Outpatients with type 2 diabetes ; age between 20 and 80 years
(2)Both gender
(3)Patients without GLP-1RA,SGLT2i,DPP4i more than 8 weeks before intervention
(4)Patients under insulin therapy
glycemic control: HbA1c >=7.0%,=<9.5%
(5)Fasting plasma C-peptide >=0.5ng/mL or casual plasma C-peptide >=1.0ng/mL
(6)Having provided voluntary written consent for participation in this study.

Key exclusion criteria

(1)Type 1 diabetes or secondary forms of diabetes
(2)Fasting plasma glucose <70mg/dL
(3)Renal dysfunction (eGFR <30ml/min/1.73m2)
(4)Steroid medication
(5)Hepatic dysfunction(AST and/or ALT >3X upper limit of normal)
(6)Active Malignant neoplasm
(7)Severe infection or injury
(8)Hypersensitivity to liraglutide or empagliflozin
(9)Pregnant or willing to be pregnant during this study
(10)Unable to obtain informed consent to this study
(11)Inadequacy of using this therapy

Target sample size

110

Name of lead principal investigator

1st name	Yasuo
Middle name
Last name	Terauchi

Organization

Graduate School of Medicine,Yokohama City University

Division name

Department of Endocrinology and Metabolism

Zip code

236-0004

Address

3-9 Fuku-ura Kanazawa-ku, Yokohama, Kanagawa, Japan

TEL

045-787-2639

Email

terauchi@yokohama-cu.ac.jp

Name of contact person

1st name	Hirotatsu
Middle name
Last name	Nakaguchi

Organization

Graduate School of Medicine,Yokohama City University

Division name

Department of Endocrinology and Metabolism

Zip code

236-0004

Address

3-9 Fuku-ura Kanazawa-ku, Yokohama, Kanagawa, Japan

TEL

045-787-2639

Homepage URL

Email

t156054d@yokohama-cu.ac.jp

Institute

Yokohama City University

Institute

Department

Personal name

Organization

None

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Japan Community Health Care Organization,Yokohama Chuo Hospital

Name of secondary funder(s)

Organization

Medical Ethics Committee for Humans, Yokohama City University

Address

3-9 Fuku-ura Kanazawa-ku, Yokohama, Kanagawa, Japan

Tel

045-370-7627

Email

rinri@yokohama-cu.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

横浜市立大学附属病院（神奈川県）　Yokohama City University Hospital(kanagawa)
地域医療機能推進機構　横浜中央病院（神奈川県）
Japan Community Health Care Organization,Yokohama Chuo Hospital(kanagawa)

Date of disclosure of the study information

2017

Year

06

Month

03

Day

URL releasing protocol

https://onlinelibrary.wiley.com/doi/10.1111/jdi.13270

Publication of results

Published

URL related to results and publications

https://onlinelibrary.wiley.com/doi/10.1111/jdi.13270

Number of participants that the trial has enrolled

64

Results

Liraglutide induced greater changes in glycated hemoglobin and glycated albumin than empagliflozin (glycated hemoglobin -1.24 +- 0.15% vs -0.35 +- 0.11%, P < 0.0001; glycated albumin -4.4 +- 0.6% vs -2.4 +- 0.5%, P < 0.01).

Results date posted

2023

Year

04

Month

16

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

(i) outpatients with type 2 diabetes, aged 20 to 80 years; (ii) patients of either sex; (iii) patients without GLP-1RA, SGLT2i or dipeptidyl peptidase-4 inhibitor (DPP4i) treatment for >8 weeks before intervention (if DPP4i was taken orally, it was washed out for 8 weeks before the start of the study); (iv) patients under insulin therapy glycemic control: 7.0% <= HbA1c <= 9.5%; (v) fasting plasma C-peptide >=0.5 ng/mL or casual plasma C- peptide >=1.0 ng/mL; and (vi) patients that provided voluntary written consent for participation in this study.

The exclusion criteria were as follows: (i) type 1 diabetes or secondary forms of diabetes; (ii) fasting plasma glucose (FPG) <70 mg/dL; (iii) renal dysfunction (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2); (iv) steroid medication; (v) hepatic dysfunction (aspartate transaminase and/or alanine aminotransferase >3 times the upper limit of normal); (vi) active malignant neoplasm; (vii) severe infection or injury; (viii) hypersensitivity to liraglutide or empagliflozin; (ix) pregnant or intending to become pregnant during this study; (x) unable to obtain informed consent for this study; and (xi) inadequate use of this therapy.

Participant flow

Of 66 patients for which consent was obtained, 64 were divided into two groups. Eventually, 61 patients started medication and 59 (96.7%) completed the 24-week trial; two of the 64 patients withdrew consent before the start of medication, and one withdrew from the study owing to a steep deterioration in blood glucose control at the start. Treatment was self-interrupted in two of the 61 patients after 12 weeks, and their data up to 12 weeks were analyzed by last observation carried forward. Baseline parameters were well balanced between the groups.

Adverse events

37.7% of individuals experienced one adverse effect, and 3.3% of individuals experienced two adverse effects. There were no serious, life-threatening side-effects. There were no cases of test drug discontinuation owing to side-effects.
Hypoglycemia (blood glucose <70 mg/dL) occurred in 21 patients (34.4%), but all cases were non-severe hypoglycemia. There was no difference in hypoglycemia frequency between the two groups (P = 0.74). In addition, three cases of abdominal symptoms (severe constipation, diarrhea or anorexia) occurred in the liraglutide group. Two of these patients continued with a reduced dose of liraglutide (0.6 mg/day). In the empagliflozin group, one patient showed vulvar pruritus, but this improved with symptomatic treatment.

Outcome measures

No differences in pancreatic beta cell function were observed between the two groups. The fasting plasma C-peptide 0 value did not significantly change, and HOMA2-%beta showed improvement in both groups after 24 weeks; however, there was no difference between the groups. HOMA-IR also did not significantly change.

Insulin dose was maintained for 24 weeks with little change in either group. In the empagliflozin group, two patients met the drug increase criteria and the empagliflozin dose was increased to 25 mg/day. No other differences were observed between the groups regarding changes in serum creatinine, eGFR, liver function and lipids.

Body composition was evaluated by using dual-energy X-ray absorptiometry. Comparisons were made at the start of intervention and 24 weeks later (n = 45). Although the total BW decreased in both groups, there was no difference between the two groups in terms of changes in body fat mass and lean tissue mass; both groups showed nearly the same amount of change.

The urine albumin/creatinine ratio was not normally distributed; the baseline urine albumin/creatinine ratio was: liraglutide, median 52.9 mg/g-creatinine (interquartile range [IQR] 15.7-505.5 mg/g-creatinine) versus empagliflozin, median 66.6 mg/g-creatinine (IQR 20.7-134.2 mg/g-creatinine), P = 0.71. There was no difference between the groups in terms of change in urinary albumin excretion (change in urine albumin/creatinine ratio: liraglutide, median -5.3 mg/g-creatinine [IQR -60.6, 9.9 mg/g-creatinine] vs empagliflozin, median -12.9 mg/g-creatinine [IQR -70.8, -2.0], P = 0.23).
Urinary natrium excretion remained nearly unchanged pre- and post-administration, and there was no difference between the two groups.

There was no significant difference in blood pressure in the examination room, but neither group had worse values: change in systolic blood pressure: liraglutide, -4.9 +- 2.7 mmHg versus empagliflozin, -1.4 +- 2.7 mmHg, P = 0.37; change in diastolic blood pressure: liraglutide, -2.0 +- 1.4 mmHg versus empagliflozin, -2.3 +- 1.9 mmHg, P = 0.88. In terms of pulse rate, the mean value was slightly elevated in the liraglutide group; however, there was no difference between the two groups: change in pulse rate: liraglutide, 0.8 +- 1.5 bpm. versus empagliflozin, -1.8 +- 1.6 bpm, P = 0.24.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2017

Year

02

Month

17

Day

Date of IRB

2017

Year

05

Month

25

Day

Anticipated trial start date

2017

Year

06

Month

02

Day

Last follow-up date

2019

Year

05

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

2019

Year

10

Month

31

Day

Other related information

Registered date

2017

Year

06

Month

02

Day

Last modified on

2023

Year

04

Month

16

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000031631