Post-authorization Safety Study in Type 2 Diabetic Patients in Saudi Arabia Treated With Empagliflozin to Assess the Incidence of Ketoacidosis, Severe Complications of Urinary Tract Infection, Volume Depletion, and Dehydration: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Post-authorization Safety Study in Type 2 Diabetic Patients in Saudi Arabia Treated With Empagliflozin to Assess the Incidence of Ketoacidosis, Severe Complications of Urinary Tract Infection, Volume Depletion, and Dehydration (NCT03764631), a registered phase not stated study. The primary outcome is Number of Participants With Ketoacidosis.

2. Clinical Question

The study’s broader safety question also concerns severe complications of urinary tract infection, volume depletion, and dehydration. Its stated objective was to assess these outcomes among patients initiating the two medication groups over a 12-month follow-up period, including Ramadan. The registry lists corresponding secondary outcomes during Ramadan periods.

This is a safety question about events observed in patient groups, not a randomized efficacy comparison. The study is identified as a post-authorization safety study, and the record does not state that treatment was assigned randomly. It therefore does not establish that any difference between the groups would be caused by the medication rather than by differences in the patients, their care, or other factors. The main question can be described, but the registry record does not report the primary outcome results or an analysis comparing the groups.

3. Trial Design

The study is titled as a post-authorization safety study of patients with type 2 diabetes in Saudi Arabia. It compares patients treated with empagliflozin with patients treated with DPP-4 inhibitors. The registry lists an enrollment of 1502 and a status of completed. The listed study start is 2018-09-26, and the primary completion date is 2021-01-11.

The registry describes new users as patients receiving an index prescription for one of the two medication groups. The primary outcome timeframe is up to 12 months after that individual index date. The stated study objective includes follow-up over a 12-month period and explicitly includes Ramadan. Four listed secondary outcomes concern the number of participants experiencing ketoacidosis, severe urinary tract infections, volume depletion, and dehydration during Ramadan periods.

The registry record does not state how treatment allocation occurred. It does not describe randomization, masking, or a protocol for making the groups comparable. The record specifically indicates that this is not a randomized comparison and that the arms are not a like-for-like control comparison. Consequently, the comparison should be read as a comparison between treatment groups in a safety study, with the possibility of differences between groups that could affect observed event counts.

The record lists eight outcome measures but no analyses. It does not report the primary endpoint results, group-specific primary outcome counts, a comparative effect estimate, or an uncertainty interval. The 1502 enrollment figure describes the study enrollment; it does not, by itself, explain how many participants contributed information to each endpoint analysis. The registry record does not report the analysis populations, participant flow, or reasons that follow-up information might be unavailable.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Only patients who met all of the inclusion and none of the exclusion criteria were enrolled into the study after signing the informed consent form.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Enrolled Set: All patients with type 2 diabetes mellitus included in the study who signed the informed consent.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Enrolled Set: All patients with type 2 diabetes mellitus included in this study who signed the informed consent.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Ketoacidosis, measured over Up to 12 months after the index date (defined as the date on which each identified new user received the index prescription for Empagliflozin or DPP-4 inhibitor)..

The primary endpoint is the number of participants with ketoacidosis. It is defined as a participant count, rather than a continuous measurement or a time-to-event estimate. The stated timeframe is up to 12 months after each participant’s index prescription date. The registry defines ketoacidosis as a serious complication of diabetes characterized by high levels of ketones in the body due to lack of insulin and low food intake.

Counting participants who experience an event is a direct way to describe how many people had the specified safety outcome during the defined observation period. In general, such an endpoint can make the outcome clinically interpretable, but a count alone does not describe how precisely the groups differ. Interpretation also depends on how many participants were observed, the duration and completeness of their follow-up, and how the outcome was identified and classified.

The registry record does not report primary endpoint counts by treatment group or a comparative analysis. The serious adverse event figures listed elsewhere in the record should not be treated as the primary endpoint results: they are not presented as a group-specific analysis of ketoacidosis over the primary endpoint timeframe. The record also does not report the criteria or process used to confirm primary endpoint events beyond the endpoint definition itself. As a result, the endpoint and its intended observation period are described, but the primary comparison cannot be quantified from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help distinguish the event counts observed in groups from estimates of how groups compare and how uncertain those estimates are. The registry record identifies a participant-count endpoint and describes a planning approach, but it does not report a primary endpoint analysis or the detailed methods used for the study’s results. The explanations below are general unless explicitly described as a registry detail.

What does a participant count describe?

For a binary safety outcome, each participant is classified according to whether the event occurred during the defined observation period. The endpoint is then the number of participants with the event. A count is easy to interpret, but it does not on its own describe the chance of an event in a group. That interpretation needs the relevant group denominator and a clear account of who was observed and for how long. In follow-up studies, time at risk and completeness of observation can also matter, particularly if participants have different follow-up durations.

The primary endpoint is defined as a count of participants with ketoacidosis, with follow-up up to 12 months after the individual index date. The record does not post the group-specific primary counts, an analysis denominator for that endpoint, or an estimate comparing the groups. The serious adverse event counts elsewhere in the record do not fill that gap because they are not identified as the primary endpoint analysis.

How should a group comparison be interpreted?

In general, a comparative analysis may report an absolute difference, a relative measure, or another summary of the relationship between treatment group and outcome. Each has a different interpretation. A confidence interval describes a range of values compatible with the data and the analysis assumptions; a wider interval indicates less precision, while a narrower interval indicates greater precision. Statistical significance, when reported, does not establish that an observed relationship is causal or clinically important.

No comparative estimate, confidence interval, or hypothesis test for the primary endpoint is reported in the registry record. No new comparison can be reconstructed from the posted safety summaries without assuming that those figures are the primary outcome data, which the record does not say. In particular, the serious adverse event totals should not be substituted for the primary endpoint counts.

Why does the nonrandomized design matter?

General statistical principle: random assignment can help balance known and unknown characteristics between groups, on average. In a nonrandomized comparison, patients receiving different treatments may differ before follow-up begins. Differences in health status, treatment history, clinical decisions, or other factors could affect the likelihood of receiving a particular medication and the likelihood of an outcome. This is one reason an unadjusted contrast between groups does not necessarily estimate a causal treatment effect.

The registry identifies the study as not randomized and states that the arms are not a like-for-like control comparison. It does not state how treatment allocation occurred or report adjusted analyses. The record therefore does not establish whether or how potential group differences were addressed. An adjusted analysis can sometimes account for measured characteristics, but it cannot guarantee removal of bias from unmeasured or poorly measured factors.

What is the role of planning calculations?

The registry describes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect. Such a calculation is a planning exercise: it describes a sample-size requirement under specified assumptions. It is not the number of participants actually observed with an event, nor is it evidence that the study had a particular probability of detecting an effect after completion.

The record’s planning description does not give a sample-size justification for the study’s own design, and the primary effect estimate needed to interpret the illustration is not reported in the registry record. A planning calculation based on an observed effect is also sensitive to uncertainty in that effect. It should not be treated as an independent confirmation of the result or as observed power. The record does not report the trial’s own sample-size rationale.

What can be said about precision and rare events?

General statistical principle: when an outcome is uncommon, estimates can be imprecise because relatively few participants experience it. Confidence intervals are useful because they show the range of uncertainty around an estimate; counts alone do not. Methods for binary outcomes may also need care when event counts are sparse, since some common approximations may perform poorly under sparse data. The registry does not report a primary outcome estimate or interval, so the precision of the primary comparison cannot be assessed.

The listed serious adverse event counts are small in absolute terms, but the registry does not provide an uncertainty interval or an analysis for them. No calculation of comparative rates or differences is made. The record also does not report a time-to-event method, a model for repeated or recurrent events, or whether participants with incomplete follow-up were included in any outcome analysis.

What does the registry say about analysis methods?

The record lists eight outcome measures and zero analyses. It does not describe a statistical analysis plan, covariate adjustment, handling of competing events, or the method for dealing with missing outcome information. It also does not report whether outcomes were reviewed or adjudicated using a common process across groups. These absences limit the ability to judge how any eventual estimates were generated, because no primary endpoint analysis is posted in the registry record.

Overall, statistical interpretation requires both an estimate and information about its uncertainty, together with a clear account of the analysis population and design. The registry describes the endpoint and some general planning assumptions, but does not provide those elements for the primary comparison. The posted safety figures can be described as counts; they cannot be used to infer an unreported treatment effect.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Empagliflozin", "DPP-4 Inhibitors")
n      <- c(751, 751)
events <- c(1, 1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Empagliflozin  751  1  0.1  0.0  0.7  0.0  0.8  0.0  0.7
ARM  DPP-4 Inhibitors  751  1  0.1  0.0  0.7  0.0  0.8  0.0  0.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists eight outcome measures, including the primary ketoacidosis endpoint and secondary Ramadan-period outcomes for ketoacidosis, severe urinary tract infections, volume depletion, and dehydration. It does not report how the outcomes were organized into a statistical testing strategy, whether any outcomes were prioritized beyond the stated primary endpoint, or whether adjustments for multiple comparisons were planned. Multiplicity methods are used in general to address the increased chance of false-positive findings when many hypotheses are tested. Without a reported testing strategy or analyses, the effect of multiplicity on interpretation cannot be assessed.

Missing-data methods are also not described. The record does not report whether all enrolled participants had complete follow-up, how participants who stopped treatment or changed treatment were handled, how missing outcome information was treated, or whether any sensitivity analyses were conducted. These details matter because incomplete observation can affect the number of events captured and the denominator used for an analysis.

The primary endpoint population is described as the enrolled set of patients with type 2 diabetes mellitus who signed informed consent. The record does not provide a participant flow or explain whether the analysis population differed from this definition. It also does not report the number of participants with complete outcome data for each measure. The registry lists zero analyses, so there are no posted analysis populations or missing-data results to evaluate.

These omissions do not establish that missing data or multiplicity affected the findings; rather, they mean the registry record does not report the information needed to assess those issues. Interpretation should remain confined to the study details and safety counts that are actually posted.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: myocardial ischaemia (0.1%), anal fissure (0.1%), hernia (0.1%), pneumonia (0.1%), diabetic ketoacidosis (0.1%).

The registry lists 751 participants at risk in each medication group for serious adverse events. It reports 6 participants affected in the empagliflozin group and 2 in the DPP-4 inhibitor group. For other adverse events, it reports zero participants affected in each group. The listed number of deaths is zero in each group. These are descriptive safety figures in the registry record, not a reported analysis of the primary ketoacidosis endpoint.

The record also lists serious adverse event terms with a frequency of 0.1% for each named term: myocardial ischaemia, anal fissure, hernia, pneumonia, diabetic ketoacidosis, and obesity. The available information does not provide a group-specific count for each term or explain whether these terms represent unique participants. They should therefore be read as term-level listings, not as a basis for reconstructing group-specific outcome rates.

General statistical principle: safety counts are most informative when the event definitions, observation time, denominators, and method of collection are clear. The registry describes the primary endpoint timeframe, but it does not report an adverse-event analysis method or uncertainty intervals for these safety figures. The counts alone do not show whether groups were comparable before treatment, whether every participant had equal observation, or whether a difference was caused by treatment. They should be interpreted as descriptive posted results, distinct from a causal comparison.

13. What the Result Does, and Does Not, Mean

The record identifies a clinically important safety question: whether ketoacidosis and other specified events occur among patients with type 2 diabetes receiving empagliflozin or DPP-4 inhibitors during follow-up that includes Ramadan. It defines the primary endpoint and its observation period, names the comparison groups, and reports that the study is completed with enrollment of 1502. These elements explain what the investigation set out to examine.

However, the registry record does not report the primary endpoint counts by group or a statistical comparison. It therefore does not establish the magnitude, direction, or precision of a difference in ketoacidosis between the groups. The posted serious adverse event counts are descriptive and are not identified as the primary endpoint analysis. The listed term-level frequency for diabetic ketoacidosis does not supply the missing group-specific primary results.

The registry also does not report Ramadan-period outcome analyses, despite listing those outcomes and including Ramadan in the study objective. No conclusion about the comparative occurrence of the secondary outcomes can be drawn from the listed outcome names alone. The absence of a posted analysis should not be interpreted as evidence that an outcome did or did not occur.

Even if a group difference were available, the nonrandomized design would require caution. The record does not state how treatment allocation occurred and explicitly says the arms are not a like-for-like control comparison. General statistical reasoning indicates that patient characteristics and clinical choices may differ between treatment groups and could influence observed outcomes. Without reported adjustment methods and results, causal interpretation would not be warranted.

In short, the record describes the safety study’s purpose, endpoints, follow-up frame, enrollment, and some adverse-event summaries. It does not provide the primary analysis needed to determine how the treatment groups compared on the stated primary endpoint or how precise that comparison was. The study’s completion status does not change this distinction between a study being marked complete and its outcome analyses being posted.

14. Why This Trial Matters Statistically

This study raises statistical issues common to post-authorization safety research. Safety questions often concern outcomes that are specific and potentially uncommon, so event definitions, follow-up windows, denominators, and the completeness of observation matter. The registry defines ketoacidosis as the primary participant-count endpoint and sets follow-up at up to 12 months after the index prescription. Those details establish a framework for interpreting an analysis if results are reported.

The comparison also illustrates why design context matters. The record identifies two medication groups but states that the comparison is not randomized and the arms are not a like-for-like control comparison. In general, treatment decisions can be associated with patient characteristics that also relate to outcomes. Statistical adjustment can address measured differences under assumptions, but it cannot by itself guarantee that groups are exchangeable or eliminate unmeasured confounding. The registry record does not report an adjusted primary analysis.

The study objective includes Ramadan, and the listed secondary outcomes specify Ramadan periods. This makes the observation window part of the statistical question: results for a full follow-up period and results for a defined period are not interchangeable. The record does not post the Ramadan-specific counts or analyses, so the stated seasonal focus cannot be evaluated from the available results.

Finally, a completed record with enrollment and safety summaries is not equivalent to a complete statistical report. Without primary outcome estimates, uncertainty intervals, analysis populations, and methods for missing information and multiplicity, readers cannot assess the precision or robustness of the main comparison. This distinction is important when interpreting registry records: the study question and selected descriptive figures can be informative, while conclusions about comparative effects remain limited by what analyses are reported.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The principal limitation for interpreting this specific study is that the registry record does not report the primary outcome results. It names ketoacidosis as the primary endpoint and gives its timeframe and definition, but does not provide group-specific participant counts, an effect estimate, or an uncertainty interval. The listed serious adverse event counts cannot be assumed to represent the primary endpoint analysis.

The record states that the comparison is not randomized and that the arms are not a like-for-like control comparison. It does not state how treatment allocation occurred or describe measured baseline characteristics that would show whether the groups were comparable. It also does not report adjusted estimates or methods for addressing confounding. As a result, any causal interpretation of a group contrast would be unsupported by the registry information.

Although the stated objectives include Ramadan and the secondary outcomes include Ramadan-period events, no corresponding outcome results or analyses are reported. The record also does not report the statistical analysis plan, missing-data handling, participant flow, analysis populations, outcome ascertainment procedures, or any multiplicity strategy. These are specific gaps in the available registry information; they do not prove that the methods were absent from the study itself.

The serious adverse event summary has limited detail for comparative interpretation. It gives overall affected counts by group and a list of serious-event terms with frequencies, but does not provide group-specific term counts or uncertainty estimates. The registry’s completed status and enrollment figure do not resolve these limitations. Consequently, the record supports description of the study’s aims and posted safety summaries, but not a complete evaluation of its primary comparison.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Post-authorization Safety Study in Type 2 Diabetic Patients in Saudi Arabia Treated With Empagliflozin to Assess the Incidence of Ketoacidosis, Severe Complications of Urinary Tract Infection, Volume Depletion, and Dehydration — NCT03764631.
• Registry record last updated 2022-02-10; status last verified 2022-02.
• Results first posted 2022-02-10.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

This completed post-authorization safety study concerns patients with type 2 diabetes in Saudi Arabia treated with empagliflozin or DPP-4 inhibitors. Enrollment is listed as 1502. The primary endpoint is the number of participants with ketoacidosis, assessed up to 12 months after the index prescription date. The stated objectives also include severe urinary tract infections, volume depletion, and dehydration, including outcomes during Ramadan periods.

The record states that the comparison is not randomized and that the arms are not a like-for-like control comparison. It lists 751 participants at risk in each group for serious adverse events, with 6 affected in the empagliflozin group and 2 in the DPP-4 inhibitor group; deaths are listed as zero in both groups. These figures are descriptive and are not identified as the primary endpoint analysis.

The registry lists eight outcome measures and zero analyses. It does not report group-specific primary endpoint results, comparative estimates, uncertainty intervals, or the statistical methods needed to evaluate the primary comparison. The study purpose and some safety summaries are available, but the primary outcome comparison cannot be assessed from the registry record.