Hospitalization for Acute Liver Injury OutcomeBaseline Characteristics

There were 129,520 potentially eligible treatment episodes (dapagliflozin or an eligible comparator GLD) in CPRD, 1,060,582 in the HIRD, and 2,474,817 in Medicare. After all inclusion and exclusion criteria and treatment-episode matching were applied, the final number of treatment episodes was 49,639 (dapagliflozin, 10,466; comparator GLD, 39,173) in CPRD, 212,580 (dapagliflozin, 17,187; comparator GLD, 195,393) in the HIRD, and 212,473 (dapagliflozin, 13,280; comparator GLD, 199,193) in Medicare (Table S1 in Online Resource 1).

Baseline characteristics for the treatment groups in the full hALI cohort (i.e., after matching and before PS trimming) are presented in Table 3. The mean age of patients at the index date was 57 years for the dapagliflozin group and 59 years for comparator GLD group in CPRD, 52 and 70 years for both treatment groups in the HIRD and Medicare, respectively. In CPRD (the only data source with available information on body mass index), more dapagliflozin users were obese or severely obese (74%) than comparator GLD users (61%). In all three data sources, a higher proportion of dapagliflozin users than comparator GLD users had concomitant insulin use on the index date, and dapagliflozin initiators were more likely to have used three or more other classes of GLD medications in the year before the index date. The proportion with one or more dispensing/prescription for a drug with a known association with liver injury (for the list of drugs, see Table S2 in Online Resource 1) as well as the prevalence of most baseline medical conditions were similar across the dapagliflozin and comparator GLD groups within each data source.

Table 3 Selected baseline characteristics of cohorts to assess hospitalization for acute liver injury, full sample before propensity score trimming

Propensity score trimming and stratification were effective in achieving balance between the treatment groups for the variables included in the PS models (Fig. S1 in Online Resource 1). For the included covariates, most absolute standardized differences were below 0.10, corresponding to small differences in the distribution of the variable between the dapagliflozin and comparator GLD groups. The baseline characteristics for the hALI cohort after PS trimming are presented in Table S3 in Online Resource 1.

Incidence and Comparative Analyses

The incidence and comparative analyses were performed by using hALI events identified by the case-finding algorithm, which, in CPRD, included more than 20 but fewer than 25 events combined across both treatment groups (CPRD policy does not allow values of 1 to 4 to be reported, which in this case, applies to the small number of hALI events identified in the dapagliflozin group; a range is given to prevent back calculation of the small number of events in the dapagliflozin group). There were 186 and 202 total hALI events in the HIRD and Medicare, respectively. Table 4 presents the number of hALI events, exposure time, and adjusted IRs by exposure group for each data source. The estimated PS-adjusted IR of hALI per 1000 person-years for dapagliflozin and comparator GLD treatment episodes, respectively, was 0.37 (95% CI 0.10–0.93) and 0.62 (95% CI 0.27–1.11) in CPRD, 1.36 (95% CI 0.74–2.28) and 1.83 (95% CI 1.55–2.15) in the HIRD, and 1.92 (95% CI 1.02–3.29) and 1.70 (95% CI 1.42–2.02) in Medicare.

Table 4 Adjusted incidence rates of hospitalization for acute liver injury

The adjusted IRR estimates were below the null value of 1.0 in CPRD, and the HIRD and was slightly above the null value in Medicare (Fig. 2). The overall adjusted hALI IRR estimate (pooled across all data sources) was 0.85 (95% CI 0.59–1.24). The 95% CIs were wide for all adjusted IRR estimates because of a small number of hALI events.

Fig 2

Adjusted IRRs of hospitalization for acute liver injury. CI confidence interval, CPRD Clinical Practice Research Datalink, HIRD HealthCore Integrated Research Database, IRR incidence rate ratio

Sensitivity and Bias Analyses

The adjusted IRR results from all sensitivity analyses for hALI in the HIRD and Medicare were generally similar to the primary analysis and, in CPRD, were variable because of a small number of hALI events (Fig. S2 in Online Resource 1). The assessment of the potential impact of possible unmeasured confounders indicates that it is unlikely that an unmeasured hypothetical confounder would mask a harmful association of hALI with dapagliflozin (the results from this analysis are described in detail in ‘Methods and Results’, Section 1.4 and Fig. S7, of Online Resource 1).

The electronic algorithms had low to moderate validity in identifying true cases of hALI in each of the three data sources [37,38,39]; however, simulation analyses to assess the impact of potential outcome misclassification indicated that it is unlikely that an increased risk of hALI associated with dapagliflozin, if it exists, is being masked by outcome misclassification that differs between the treatment groups (data on file with the corresponding author).

Severe Complication of Urinary Tract Infection OutcomeBaseline Characteristics

After all inclusion and exclusion criteria and treatment-episode matching were applied, the final number of treatment episodes in the sUTI female cohort was 26,315 (dapagliflozin, 5508; comparator GLD, 20,807) in CPRD, 135,299 (dapagliflozin, 10,544; comparator GLD, 124,755) in the HIRD, and 200,976 (dapagliflozin, 12,561; comparator GLD, 188,415) in Medicare; the final number of treatment episodes selected into the male cohort was 36,805 (dapagliflozin, 7610; comparator GLD, 29,195) in CPRD, 160,828 (dapagliflozin, 13,091; comparator GLD, 147,737) in the HIRD, and 204,519 (dapagliflozin, 12,783; comparator GLD, 191,736) in Medicare (Table S4 in Online Resource 1).

Baseline characteristics for the full sample of patients in the sUTI cohorts (i.e., after matching and before PS trimming) are presented in Table 5. The mean age at the index date was similar among males and females within each data source. Among both females and males, the mean age in CPRD was approximately 57 years in the dapagliflozin group and approximately 59 years in the comparator GLD group; the mean age in the HIRD was approximately 52 years for both treatment groups, and in Medicare it was approximately 72 years for both treatment groups. In CPRD, the proportion of users who were obese or severely obese was higher in dapagliflozin users (79% of females, 72% of males) than in comparator GLD users (67% of females, 58% of males). In all data sources for females and males, the prevalence of insulin use at the index date was higher for the dapagliflozin group than the comparator GLD group, and dapagliflozin initiators were more likely to have used 3 or more other classes of GLD medications in the year before the index date. For females and males, a history of kidney disease of all types (acute and chronic) was more common in the comparator GLD group than the dapagliflozin group, but the prevalence of chronic or recurring urinary tract infections was similar between the two treatment groups. Other medical conditions were similarly distributed between the dapagliflozin and comparator GLD groups.

Table 5 Selected baseline characteristics of cohorts to assess severe complications of urinary tract infection, full sample before propensity score trimming, by sex

Similar to the hALI cohorts, PS trimming and stratification were very effective in achieving balance between the treatment groups for the variables in the PS models in both the female and male sUTI cohorts in all the data sources; most PS-stratified values of the absolute standardized difference were below 0.10 (Fig. S3 in Online Resource 1). The baseline characteristics for the sUTI sample after PS trimming are presented in Table S5 in Online Resource 1.

Incidence and Comparative Analyses

The total number of algorithm-identified sUTI events for the incidence and comparative analyses in females was 27 in CPRD, 450 in the HIRD, and 904 in Medicare, and in males it was 25 in CPRD, 230 in the HIRD, and 584 in Medicare. Across the data sources in both females and males, the PS-adjusted IR estimates per 1000 person-years was consistently lower in the dapagliflozin group than in the comparator GLD group (Table 6).

Table 6 Adjusted incidence rates of severe complications of urinary tract infection, by sex

For both females and males, when the IRs of sUTI were compared between the dapagliflozin group and the comparator GLD group, the adjusted IRR estimates were below the null value of 1.0 for all data sources, although the CIs were wide in CPRD due to the small number of sUTI events (Fig. 3). The overall adjusted sUTI IRR estimate pooled across all data sources was similar for females (0.76 [95% CI 0.60–0.96]) and males (0.74 [95% CI 0.56–1.00]).

Fig 3

Adjusted IRRs for severe complications of urinary tract infection, by sex. CPRD Clinical Practice Research Datalink, HIRD HealthCore Integrated Research Database, IRR incidence rate ratio

Sensitivity and Bias Analyses

The adjusted IRR results of most sensitivity analyses were consistent with those of the primary analyses of sUTI for both males and females (Fig. S4 in Online Resource 1). The assessment of potential unmeasured confounders for the sUTI analysis had similar results to those for the hALI analysis (the results from this analysis are described in detail in ‘Methods and Results’, Section 1.4 and Fig. S8, in Online Resource 1).

The case-finding algorithms had moderate validity in identifying true cases of sUTI in each of the three data sources [37,38,39], and, similar to hALI, simulation analyses indicate that it is unlikely that a potential increased risk of sUTI associated with dapagliflozin, if it exists, is being masked by misclassification of sUTI that differs between the treatment groups (data on file with the corresponding author).