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

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, [34,35,36], 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.

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