Novel glucose-lowering drugs and the risk of acute kidney injury in routine care; the Stockholm CREAtinine Measurements (SCREAM) project

Diabetes mellitus type 2 (T2DM) is a global health problem with a high risk of complications and death [1]. Sodium glucose cotransporter-2 inhibitors (SGLT2i) are novel oral diabetes medications that, in addition to glucose lowering effects, have been shown in clinical trials to reduce the risk of hospitalization for heart failure, kidney disease progression, kidney failure, death from renal or cardiovascular causes, and all-cause mortality [2‐7]. On the basis of these trials, clinical guidelines recommend administering SGLT2i in addition to metformin to patients with or at high risk for atherosclerotic cardiovascular disease, those with clinical heart failure, and those with chronic kidney disease (CKD) [8, 9].

There is often an acute drop in estimated glomerular filtration rate (eGFR) during the first weeks of SGLT2i therapy, [4] which may lead to acute kidney injury (AKI) [10]. A review of more than 100 spontaneous reports of confirmable cases of AKI related to SGLT2i led the US Federal Drug Administration (FDA) to issue a warning in December 2015 stating that SGLT2 inhibitors might cause AKI [11]. The FDA recommended following and quantifying this risk in post-marketing surveillance studies [10, 11].

Case reports contrast with trial data: a recent network meta-analysis of RCTs indicates that SGLT2 inhibitors may have a lower AKI risk compared with dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) [12]. However, in these trials, AKI was documented as an adverse event rather than a prespecified outcome, and the strict inclusion/exclusion criteria alongside stringent monitoring protocols may have led to an underestimation of adverse event rates. In the heterogeneous setting of routine clinical practice, various North American studies have reported similar AKI event rates among new users of SGLT2i compared to other oral diabetes medications [13‐15]. However, the family of oral diabetes medications is heterogeneous, and risks may be better ascertained through comparative safety analyses. Three studies have compared AKI risks of SGLT2i versus DPP-4 inhibitors and GLP-1RAs, observing either no difference between therapies, [16] or a lower AKI risk for SGLT2i [17, 18]. Identified limitations for these studies include the use of administrative codes to identify AKI, which are insensitive, lack information on baseline eGFR, which may modulate subsequent AKI risks, and restrictions by certain health insurance companies, or to persons older than 65 years. Replication of consistent adverse drug event relationships across geographically distinct health systems and variations in prescribing practices may provide greater confidence in results. Against this background, we conducted an observational study comparing risks of AKI among routine care users of novel glucose-lowering drugs in Stockholm (Fig. 1).

We included 17,407 participants who met the inclusion and exclusion criteria (Figure S1). Of these, 10,605 initiated DPP-4i treatment (61%), 4448 initiated GLP1-RA (26%) and 2354 initiated SGLT2i (13%). Overall, mean age was 62.8 years, 61% were male and median (IQR) eGFR was 89 (73–100) ml/min/1.73m². Unweighted characteristics by treatment group are shown in Supplemental Table S3. In brief, DPP-4i users were generally older and with a slightly lower median eGFR level than participants who started on GLP1-RA or SGLT2i. Users of SGLT2i (of whom 59% started on empagliflozin, 40.5% on dapagliflozin, and < 1% on canagliflozin) included a higher proportion of men and with cardiovascular comorbidities, mainly history of ischemic events. There were no major differences in baseline HbA1c between groups, but patients on GLP1-RA tended to have a higher proportion of concomitant insulin treatment. After weighting, most covariates achieved balance (shown in Table 1 with additional covariates listed in Tables S3 and S4), except for calendar year and CKD stage.

During a median follow-up of 2.5 (IQR 0.96, 4.84) years, 1411 (8.1%) participants experienced AKI (Table 2). Users of SGLT2i exhibited the lowest crude incidence rate of AKI (18.3 [CI 95% 14.1–23.4] per 1000 person-years), followed by GLP1-RA users (22.5 [CI 95% 19.9–25.3] per 1000 person-years) and DPP-4i users (26.6 [CI 95% 25–28.2] per 1000 person-years). The weighted absolute risk of AKI at 3 years was 5.79% [95% CI 3.63–8.52] for the SGLT2i group, 7.03% [95% CI 5.69–8.69] for the GLP1-RA group and 7.00% [95% CI 6.43–7.58] for the DPP-4i group. In weighted Cox regression, and compared to DPP-4i, risks of AKI were similar for GLP1-RA (0.98 [CI 95% 0.82–1.18]) or SGLT2i (0.73 [CI 95% 0.45–1.16]). Although broad confidence intervals rendered associations statistically non-significant, risk magnitudes were lowest for patients on SGLT2i. Compared to GLP1-RA, the risk of AKI for patients started on SGLT2i did not differ, with a weighted HR of 0.74 [CI 95% 0.46–1.19].

Sensitivity analyses applying overlapping weights yielded similar results to our main analysis (Supplemental Table S6), with a HR for AKI of 0.89 [95% CI 0.66–1.20] among SGLT2i users compared to DPP-4i, and 0.79 [95% CI 0.57–1.09] compared to GLP1-RA.

Concerns about the safety of SGLT2i have been raised by the US FDA [11] after reviewing voluntary reporting of cases in the “Adverse Event Reporting System (FAERS)”. Such possible risks were not noted by pivotal clinical trials [3, 4, 6, 7]. However, AKI is a rare outcome, and these clinical trials were underpowered to assess it robustly. Post-marketing surveillance studies in the heterogeneous routine clinical care are thus a necessary complement to assess the safety of SGLT2i. In this study, we compared the risk of detected AKI among users of novel glucose-lowering drugs in Stockholm´s routine healthcare. We observed that after balancing for an extensive range of confounders, AKI occurrence did not statistically differ between therapies. Instead, we observed numerically lower AKI risk magnitudes among users of SGLT2i compared to DPP4i and GLP1-RA. Results were robust to alternative methods of weighting for confounders and, collectively, add to growing evidence on the safety of initiating SGLT2i in adults with T2DM.

We studied and compared the health trajectories of 17,407 individuals with T2DM initiating these novel oral diabetes medications in our region and can now provide results that agree with and expand previous observations. Two administrative studies from Sweden and Denmark found that SGLT2i were associated with a lower risk of AKI compared with DPP-4 inhibitors (HR, 0.41 [95% CI, 0.32–0.52]) and GLP-1RA (HR, 0.69 [95% CI, 0.45–1.05]) [16, 18]. More recently, Zhuo et al. [17] reported a lower risk for SGLT2i vs DPP4i (HR 0.71, [95% CI 0.65–0.76]) and SGLT2i vs GLP1-RA groups (HR 0.81, [95% CI 0.75–0.87]) among Medicare users in the US. Important limitations of these studies were that they lacked information on the patient’s eGFR and that they identified AKI events through ICD diagnostic codes, which have low sensitivity. However, together with our findings, they provide reassurance on the safety of SGLT2i with respect to the risk of AKI and suggest that SGLT2i may prevent AKI events compared with alternative diabetes treatments. The mechanisms by which SGLT2i may protect against AKI compared with other glucose-lowering agents are still under investigation [26], and may include attenuation of glomerular hyperfiltration [27, 28], possibly due to tubular-glomerular feedback mechanisms through increased sodium delivery to macula densa [28]. Other postulated mechanisms involve altered renal oxygen homeostasis [29], reduced renal inflammation and decreased ischemic proximal tubular cell injury [30].

Our study has several strengths. Regarding the exposure, we ascertained it through pharmacy dispensations, which are better indicators of therapy initiation than prescription claims, in a country that provides universal healthcare access with almost all medication costs financed by the Government. This reduces healthcare access bias and increases face validity. However, we cannot guarantee that the medications dispensed at the pharmacy were taken by the patient. Regarding the outcome, we ascertained AKI events through both inpatient diagnostic codes and transient creatinine elevations according to KDIGO classification. This is important because AKI diagnoses are specific, but have low sensitivity [31]. By applying an active comparator new user design, we were able to minimize both confounding by indication and time-related bias, and we could identify and account for a large battery of confounders through propensity score weighting.

Our study also had limitations. Although our data source covers the healthcare of Stockholm region during 2008–2018, our study was limited in both size and length of follow-up and was also underpowered to compare single SGLT2i subclasses. This data represents AKI risks associated to these therapies in Stockholm between 2008 and 2018. Since then, new indications for SGLT2i have been approved, including a lower eGFR [3, 4, 32] and use in patients with CVD [33]. Future studies should confirm our observations in the broader use of this medication. Some of the currently most popular SGLT2i, such as dapagliflozin, empagliflozin and canagliflozin were approved by the European Medicines Agency (EMA) in 2012–2014, [34‐36], and patients who started SGLT2i during the introduction of these therapies may differ in severity or characteristics from those who start today. Our study had a median follow-up of 2.5 years and it could be argued that, with longer duration of treatment, AKI signals may be more prominent. However, more than half of the AKI cases reported to the Adverse Event Reporting System (58 cases) occurred within 1 month of SGLT2i initiation. As in any observational study, residual and unknown confounding may still exist, and our results only report associations, not causal effects.

To conclude, in this region-representative study of routine care patients with T2DM initiating novel glucose-lowering drugs, we observed similar occurrence of AKI between therapies. Although not-statistically significant, we also observed a lower AKI risk associated to SGLT2i compared with DPP-4 inhibitor and GLP-1RA initiation. Our data thus offer support to mounting evidence on the safety of initiating SGLT2i.