Trial Outcomes & Findings for Safety and Efficacy of the Combination of Empagliflozin and Linagliptin Compared to Linagliptin Alone Over 24 Weeks in Patients With Type 2 Diabetes (NCT NCT01734785)

Last Updated: 2024-09-19

Results Overview

Change from baseline in Glycated haemoglobin (HbA1c) \[%\] after 24 weeks of treatment with double-blind trial medication. Baseline was defined as the last observation before the first intake of any double-blind randomised trial medication. The term 'baseline' was not used to refer to measurements before the administration of open-label medication.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

607 participants

Primary outcome timeframe

Baseline and 24 weeks

Results posted on

2024-09-19

Participant Flow

16-week open-label (OL) lina 5 period followed by a 1-week OL period with additional placebo administration preceded randomisation to double-blind treatment. Patients were randomised to double blind treatment only when they had not met glycaemic control criteria after the 16-week OL period. All treatments were administered in addition to metformin.

Participant milestones

Participant milestones
Measure	Empagliflozin 25 mg Patients received 1 fixed dose combination (FDC) Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Empagliflozin 10 mg Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Placebo Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Linagliptin 5 mg Patients received 5mg dose of Linagliptin (lina 5), administered orally, once daily for 16 weeks during the OL treatment period, thereafter patients received 1 matching placebo tablet to FDC empa 25/lina 5, and 1 matching placebo tablet to FDC empa 10/lina 5 per day in addition to lina 5 OL, for 1 week during the open-label placebo add-on treatment period.
Open-Label Period STARTED	0	0	0	606
Open-Label Period COMPLETED	0	0	0	333
Open-Label Period NOT COMPLETED	0	0	0	273
Double-Blind Period STARTED	111	112	110	0
Double-Blind Period COMPLETED	106	103	105	0
Double-Blind Period NOT COMPLETED	5	9	5	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Empagliflozin 25 mg Patients received 1 fixed dose combination (FDC) Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Empagliflozin 10 mg Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Placebo Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Linagliptin 5 mg Patients received 5mg dose of Linagliptin (lina 5), administered orally, once daily for 16 weeks during the OL treatment period, thereafter patients received 1 matching placebo tablet to FDC empa 25/lina 5, and 1 matching placebo tablet to FDC empa 10/lina 5 per day in addition to lina 5 OL, for 1 week during the open-label placebo add-on treatment period.
Open-Label Period Adverse Event	0	0	0	9
Open-Label Period Lack of Efficacy	0	0	0	1
Open-Label Period Protocol Violation	0	0	0	13
Open-Label Period Lost to Follow-up	0	0	0	14
Open-Label Period Withdrawal by Subject	0	0	0	12
Open-Label Period Other Reasons	0	0	0	224
Double-Blind Period Adverse Event	0	3	2	0
Double-Blind Period Lack of Efficacy	0	1	0	0
Double-Blind Period Protocol Violation	0	1	1	0
Double-Blind Period Lost to Follow-up	2	4	2	0
Double-Blind Period Withdrawal by Subject	2	0	0	0
Double-Blind Period Not treated	1	0	0	0

Baseline Characteristics

Safety and Efficacy of the Combination of Empagliflozin and Linagliptin Compared to Linagliptin Alone Over 24 Weeks in Patients With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Empagliflozin 25 mg n=110 Participants Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Empagliflozin 10 mg n=112 Participants Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Placebo n=110 Participants Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Total n=332 Participants Total of all reporting groups
Age, Continuous	55.4 Years STANDARD_DEVIATION 9.9 • n=5 Participants	54.3 Years STANDARD_DEVIATION 9.5 • n=7 Participants	55.9 Years STANDARD_DEVIATION 9.6 • n=5 Participants	55.2 Years STANDARD_DEVIATION 9.7 • n=4 Participants
Sex: Female, Male Female	39 Participants n=5 Participants	46 Participants n=7 Participants	49 Participants n=5 Participants	134 Participants n=4 Participants
Sex: Female, Male Male	71 Participants n=5 Participants	66 Participants n=7 Participants	61 Participants n=5 Participants	198 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and 24 weeks

Population: The full analysis set (FAS) consisted of all patients in the treated set (TS) who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the double-blind part of the trial. Observed Case (OC): In the OC analysis, values after the use of rescue medication were set to missing.

Outcome measures

Outcome measures
Measure	Empagliflozin 25 mg n=110 Participants Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Empagliflozin 10 mg n=109 Participants Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Placebo n=106 Participants Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.
HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment	-0.56 Percentage of HbA1c Standard Error 0.08	-0.65 Percentage of HbA1c Standard Error 0.08	0.14 Percentage of HbA1c Standard Error 0.09

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: FAS (OC)

Change from baseline FPG (mmol/L) after 24 weeks of treatment with double-blind trial medication.

Outcome measures

Outcome measures
Measure	Empagliflozin 25 mg n=109 Participants Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Empagliflozin 10 mg n=109 Participants Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Placebo n=106 Participants Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.
Fasting Plasma Glucose (FPG) Change From Baseline After 24 Weeks of Double-blind Treatment.	-1.75 mmol/L Standard Error 0.18	-1.46 mmol/L Standard Error 0.18	0.34 mmol/L Standard Error 0.19

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: FAS (OC)

Change from baseline Body weight after 24 weeks of treatment with double-blind trial medication.

Outcome measures

Outcome measures
Measure	Empagliflozin 25 mg n=110 Participants Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Empagliflozin 10 mg n=109 Participants Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Placebo n=106 Participants Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.
Body Weight Change From Baseline After 24 Weeks of Double-blind Treatment	-2.52 kg Standard Error 0.25	-3.06 kg Standard Error 0.25	-0.30 kg Standard Error 0.26

Adverse Events

Empagliflozin 25 mg

Serious events: 4 serious events

Other events: 11 other events

Deaths: 0 deaths

Empagliflozin 10 mg

Serious events: 5 serious events

Other events: 19 other events

Deaths: 0 deaths

Placebo

Serious events: 10 serious events

Other events: 34 other events

Deaths: 0 deaths

Linagliptin 5 mg

Serious events: 18 serious events

Other events: 78 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Empagliflozin 25 mg n=110 participants at risk Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Empagliflozin 10 mg n=112 participants at risk Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Placebo n=110 participants at risk Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.	Linagliptin 5 mg n=606 participants at risk Patients received 5mg dose of Linagliptin (lina 5), administered orally, once daily for 16 weeks during the OL treatment period, thereafter patients received 1 matching placebo tablet to FDC empa 25/lina 5, and 1 matching placebo tablet to FDC empa 10/lina 5 per day in addition to lina 5 OL, for 1 week during the open-label placebo add-on treatment period.
Infections and infestations Nasopharyngitis	3.6% 4/110 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	4.5% 5/112 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	7.3% 8/110 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	4.1% 25/606 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).
Infections and infestations Urinary tract infection	2.7% 3/110 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	7.1% 8/112 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	6.4% 7/110 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	4.6% 28/606 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).
Investigations Lipase increased	2.7% 3/110 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	3.6% 4/112 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	5.5% 6/110 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	1.7% 10/606 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).
Metabolism and nutrition disorders Hyperglycaemia	0.91% 1/110 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	0.89% 1/112 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	6.4% 7/110 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	0.99% 6/606 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).
Nervous system disorders Headache	1.8% 2/110 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	2.7% 3/112 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	7.3% 8/110 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).	2.3% 14/606 • From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

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Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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