Trial Outcomes & Findings for Empa PASS on Urinary Tract Malignancies (NCT NCT03464045)

Results Overview

Occurrence of urinary tract cancer, which include malignant neoplasm and carcinoma in situ of the urinary tract, is reported as incidence rates per 1000 patient years. Incidence rates were estimated using Poisson regression and computed as the number of outcome events divided by the total person-time-at-risk (in years), multiplied by 1,000 for easier comparison. The country-level datasets were analyzed separately. Thereafter, pooled incidence rates were estimated using the aggregated number of outcome events and time-at-risk of all study countries using the Poisson regression.

Recruitment status

COMPLETED

Target enrollment

344995 participants

Primary outcome timeframe

From 181 days after index date until the occurrence of a censoring event or cancer outcome event. Up to 6 (Sweden/Finland) or 7 years (UK).

Results posted on

2025-04-20

Participant Flow

This was a non-interventional, comparative, cohort-based Post-authorisation-safety study (PASS) to assess the risk of urinary tract malignancies in patients affected by type 2 diabetes mellitus initiating empagliflozin or dipeptidyl peptidase-4 inhibitor (DPP-4i) between 1-Aug-2014 and 31-Dec-2021 in the United Kingdom (UK), Sweden, and Finland.

Throughout the study, different data extraction timepoints were used, starting from 2016 to 2023, and retrospective data was analyzed. Only subjects that met all inclusion and none of the exclusion criteria were included.

Participant milestones

Participant milestones
Measure	Empagliflozin Initiators - UK Participants with Type 2 diabetes mellitus (T2D) initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2021 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from Clinical Practice Research Datalink (CPRD) (General practitioner Online Data \[GOLD\], and Aurum) in the United Kingdom (UK).	DPP4-i Initiators - UK Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2021 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from CPRD (General practitioner Online Data \[GOLD\], and Aurum) in the UK.	Empagliflozin Initiators - Sweden Participants with T2D initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Sweden.	DPP4-i Initiators - Sweden Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Sweden.	Empagliflozin Initiators - Finland Participants with T2D initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Finland.	DPP4-i Initiators - Finland Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Finland.
Overall Study STARTED	27410	123334	35954	73623	21942	62732
Overall Study COMPLETED	27410	123334	35954	73623	21942	62732
Overall Study NOT COMPLETED	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Empagliflozin Initiators - UK n=27410 Participants Participants with Type 2 diabetes mellitus (T2D) initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2021 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from Clinical Practice Research Datalink (CPRD) (General practitioner Online Data \[GOLD\], and Aurum) in the United Kingdom (UK).	DPP4-i Initiators - UK n=123334 Participants Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2021 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from CPRD (General practitioner Online Data \[GOLD\], and Aurum) in the UK.	Empagliflozin Initiators - Sweden n=35954 Participants Participants with T2D initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Sweden.	DPP4-i Initiators - Sweden n=73623 Participants Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Sweden.	Empagliflozin Initiators - Finland n=21942 Participants Participants with T2D initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Finland.	DPP4-i Initiators - Finland n=62732 Participants Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Finland.	Total n=344995 Participants Total of all reporting groups
Age, Continuous	56.51 Years STANDARD_DEVIATION 10.96 • n=27410 Participants	63.50 Years STANDARD_DEVIATION 13.24 • n=123334 Participants	62.75 Years STANDARD_DEVIATION 11.18 • n=35954 Participants	66.65 Years STANDARD_DEVIATION 12.66 • n=73623 Participants	60.11 Years STANDARD_DEVIATION 11.84 • n=21942 Participants	66.04 Years STANDARD_DEVIATION 13.42 • n=62732 Participants	63.78 Years STANDARD_DEVIATION 12.93 • n=344995 Participants
Sex: Female, Male Female	16922 Participants n=27410 Participants	72124 Participants n=123334 Participants	24825 Participants n=35954 Participants	44352 Participants n=73623 Participants	13048 Participants n=21942 Participants	34233 Participants n=62732 Participants	205504 Participants n=344995 Participants
Sex: Female, Male Male	10488 Participants n=27410 Participants	51210 Participants n=123334 Participants	11129 Participants n=35954 Participants	29271 Participants n=73623 Participants	8894 Participants n=21942 Participants	28499 Participants n=62732 Participants	139491 Participants n=344995 Participants
Race and Ethnicity Not Collected	—	—	—	—	—	—	0 Participants Race and Ethnicity were not collected from any participant.

PRIMARY outcome

Timeframe: From 181 days after index date until the occurrence of a censoring event or cancer outcome event. Up to 6 (Sweden/Finland) or 7 years (UK).

Population: Main analysis population: participants that were matched using propensity scores (PS) conditional on variables such as index date, disease progression, comorbidities, treatment history, age, and sex; and who did not have observations of any censoring events or outcome cancer events within the latency period (spanning 180 days after the index date).

Occurrence of urinary tract cancer, which include malignant neoplasm and carcinoma in situ of the urinary tract, is reported as incidence rates per 1000 patient years. Incidence rates were estimated using Poisson regression and computed as the number of outcome events divided by the total person-time-at-risk (in years), multiplied by 1,000 for easier comparison. The country-level datasets were analyzed separately. Thereafter, pooled incidence rates were estimated using the aggregated number of outcome events and time-at-risk of all study countries using the Poisson regression.

Outcome measures

Outcome measures
Measure	DPP4-i Initiators - All Countries, PS-matched n=95677 Participants This arm includes all the DPP4-i initiators in the propensity scored-matched cohorts. Participants with T2D initiating (first purchase/prescription) a DPP-4i (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the CPRD (General practitioner Online Data \[GOLD\], and Aurum) in the UK, and from the from the nationwide registers in Sweden and Finland. As no patients initiated empagliflozin treatment in 2014 in Sweden and Finland, DPP-4i initiators in 2014 were excluded from PS matching.	Empagliflozin Initiators - UK, PS-matched n=18838 Participants Participants with Type 2 diabetes mellitus (T2D) initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2021 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from Clinical Practice Research Datalink (CPRD) (General practitioner Online Data \[GOLD\], and Aurum) in the United Kingdom (UK). The cohort was propensity scored-matched.	DPP4-i Initiators - UK, PS-matched n=44838 Participants Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2021 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from CPRD (General practitioner Online Data \[GOLD\], and Aurum) in the UK. The cohort was propensity scored-matched.	Empagliflozin Initiators - Sweden, PS-matched n=20844 Participants Participants with T2D initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Sweden. The cohort was propensity scored-matched. As no patients initiated empagliflozin treatment in 2014 in Sweden, DPP-4i initiators in 2014 were excluded from PS matching.	DPP4-i Initiators - Sweden, PS-matched n=25682 Participants Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Sweden. The cohort was propensity scored-matched. As no patients initiated empagliflozin treatment in 2014 in Sweden, DPP-4i initiators in 2014 were excluded from PS matching.	Empagliflozin Initiators - Finland, PS-matched n=15696 Participants Participants with T2D initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Finland. The cohort was propensity scored-matched. As no patients initiated empagliflozin treatment in 2014 in Finland, DPP-4i initiators in 2014 were excluded from PS matching.	DPP4-i Initiators - Finland, PS-matched n=25157 Participants Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Finland. The cohort was propensity scored-matched. As no patients initiated empagliflozin treatment in 2014 in Finland, DPP-4i initiators in 2014 were excluded from PS matching.	Empagliflozin Initiators - All Countries, PS-matched n=55378 Participants This arm includes all the empagliflozin initiators in the propensity scored-matched cohorts. Participants with T2D initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2021 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the CPRD (General practitioner Online Data \[GOLD\], and Aurum) in the UK, and from the from the nationwide registers in Sweden and Finland. As no patients initiated empagliflozin treatment in 2014 in Sweden and Finland, DPP-4i initiators in 2014 were excluded from PS matching.
Occurrence of Urinary Tract Cancer	1.29 Events per 1000 patient years Interval 1.11 to 1.51	0.73 Events per 1000 patient years Interval 0.46 to 1.16	1.07 Events per 1000 patient years Interval 0.84 to 1.37	1.34 Events per 1000 patient years Interval 0.95 to 1.89	1.52 Events per 1000 patient years Interval 1.13 to 2.05	1.27 Events per 1000 patient years Interval 0.86 to 1.87	1.49 Events per 1000 patient years Interval 1.13 to 1.96	1.10 Events per 1000 patient years Interval 0.88 to 1.38

PRIMARY outcome

Timeframe: From 181 days after index date until the occurrence of a censoring event or cancer outcome event. Up to 6 (Sweden/Finland) or 7 years (UK).

Population: Main analysis population: participants that were matched using propensity scores (PS) conditional on variables such as index date, disease progression, comorbidities, treatment history, age, and sex; and who did not have observations of any censoring events or outcome cancer events within the latency period (spanning 180 days after the index date).

Occurrence of bladder cancer, malignant and carcinoma in situ, is reported as incidence rates per 1000 patient years. Incidence rates were estimated using Poisson regression and computed as the number of outcome events divided by the total person-time-at-risk (in years), multiplied by 1,000 for easier comparison. The country-level datasets were analyzed separately. Thereafter, pooled incidence rates were estimated using the aggregated number of outcome events and time-at-risk of all study countries using the Poisson regression.

Outcome measures

Outcome measures
Measure	DPP4-i Initiators - All Countries, PS-matched n=95677 Participants This arm includes all the DPP4-i initiators in the propensity scored-matched cohorts. Participants with T2D initiating (first purchase/prescription) a DPP-4i (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the CPRD (General practitioner Online Data \[GOLD\], and Aurum) in the UK, and from the from the nationwide registers in Sweden and Finland. As no patients initiated empagliflozin treatment in 2014 in Sweden and Finland, DPP-4i initiators in 2014 were excluded from PS matching.	Empagliflozin Initiators - UK, PS-matched n=18838 Participants Participants with Type 2 diabetes mellitus (T2D) initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2021 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from Clinical Practice Research Datalink (CPRD) (General practitioner Online Data \[GOLD\], and Aurum) in the United Kingdom (UK). The cohort was propensity scored-matched.	DPP4-i Initiators - UK, PS-matched n=44838 Participants Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2021 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from CPRD (General practitioner Online Data \[GOLD\], and Aurum) in the UK. The cohort was propensity scored-matched.	Empagliflozin Initiators - Sweden, PS-matched n=20844 Participants Participants with T2D initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Sweden. The cohort was propensity scored-matched. As no patients initiated empagliflozin treatment in 2014 in Sweden, DPP-4i initiators in 2014 were excluded from PS matching.	DPP4-i Initiators - Sweden, PS-matched n=25682 Participants Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Sweden. The cohort was propensity scored-matched. As no patients initiated empagliflozin treatment in 2014 in Sweden, DPP-4i initiators in 2014 were excluded from PS matching.	Empagliflozin Initiators - Finland, PS-matched n=15696 Participants Participants with T2D initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Finland. The cohort was propensity scored-matched. As no patients initiated empagliflozin treatment in 2014 in Finland, DPP-4i initiators in 2014 were excluded from PS matching.	DPP4-i Initiators - Finland, PS-matched n=25157 Participants Participants with T2D initiating (first purchase/prescription) a dipeptidyl peptidase-4 inhibitor (DPP-4i) (comparator), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2020 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the nationwide registers in Finland. The cohort was propensity scored-matched. As no patients initiated empagliflozin treatment in 2014 in Finland, DPP-4i initiators in 2014 were excluded from PS matching.	Empagliflozin Initiators - All Countries, PS-matched n=55378 Participants This arm includes all the empagliflozin initiators in the propensity scored-matched cohorts. Participants with T2D initiating (first purchase/prescription) empagliflozin (study drug), in free form or in fixed-dose combination with metformin, between 1-Aug-2014 and 31-Dec-2021 (index date), and with more than 6 months of possible follow-up (index date less than 6 months prior to end of study date). The study population was identified from the CPRD (General practitioner Online Data \[GOLD\], and Aurum) in the UK, and from the from the nationwide registers in Sweden and Finland. As no patients initiated empagliflozin treatment in 2014 in Sweden and Finland, DPP-4i initiators in 2014 were excluded from PS matching.
Occurrence of Bladder Cancer	0.74 Events per 1000 patient years Interval 0.6 to 0.91	0.45 Events per 1000 patient years Interval 0.25 to 0.81	0.67 Events per 1000 patient years Interval 0.49 to 0.9	0.92 Events per 1000 patient years Interval 0.61 to 1.4	1.03 Events per 1000 patient years Interval 0.71 to 1.48	0.51 Events per 1000 patient years Interval 0.27 to 0.94	0.64 Events per 1000 patient years Interval 0.42 to 0.98	0.63 Events per 1000 patient years Interval 0.47 to 0.85

PRIMARY outcome

Timeframe: From 181 days after index date until the occurrence of a censoring event or cancer outcome event. Up to 6 (Sweden/Finland) or 7 years (UK).

Population: Main analysis population: participants that were matched using propensity scores (PS) conditional on variables such as index date, disease progression, comorbidities, treatment history, age, and sex; and who did not have observations of any censoring events or outcome cancer events within the latency period (spanning 180 days after the index date).

Occurrence of malignant renal cancer is reported as incidence rates per 1000 patient years. Incidence rates were estimated using Poisson regression and computed as the number of outcome events divided by the total person-time-at-risk (in years), multiplied by 1,000 for easier comparison. The country-level datasets were analyzed separately. Thereafter, pooled incidence rates were estimated using the aggregated number of outcome events and time-at-risk of all study countries using the Poisson regression.