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ObjectiveSodium glucose cotransporter-2 inhibitors (SGLT2i) exert cardiorenal protection in people with diabetes. By inducing glycosuria, SGLT2i predispose to genital infections. In addition, rare occurrence of Fournier’s gangrene (FG) has been reported. We aimed to investigate such association through the U.S. Food and Drug Administration (FDA) adverse event (AE) reporting system (FAERS).Research design and methodsWe mined the FAERS up to 2018q3 (before FDA warning about SGLT2i-associated FG) to retrieve reports including FG as an AE and SGLT2i as suspect or concomitant drugs, and calculated proportional reporting ratios (PRR).ResultsWe retrieved 47 cases of FG and 17 cases of other severe AEs of the genital area associated with SGLT2i. Patients with FG were ~10 years older than those with other severe genital AEs. Overall, 77% occurred in men. Three patients were concomitantly treated with systemic immunosuppressive drugs. Increased reporting frequency emerged for SGLT2i compared with other drugs, with a PRR ranging from 5 to 10. The disproportional reporting of FG with SGLT2i remained robust and consistently significant when restricting to the period when SGLT2i were available, to reports filed for glucose-lowering medications or for drugs with the diabetes indication, and after refining the definition of FG. FG was disproportionally associated with psoriasis and with the combination of immunosuppressants and SGLT2i.ConclusionsAlthough causality cannot be demonstrated, SGLT2i may predispose to FG and other severe genital AEs. Since the use of SGLT2i is expected to increase significantly, clinicians should be aware of these severe, although rare, AEs and their predisposing factors.

Genitourinary tract infections (GUTIs) are the most common adverse event (AE) occurring during therapy with sodium-glucose co-transporter-2 (SGLT2) inhibitors. We evaluated whether dipeptidyl peptidase-4 inhibitors moderate the risk of GUTI during SGLT2 inhibitor therapy, using two approaches. First, we screened the literature for randomized controlled trials (RCTs) directly comparing the frequency of GUTIs in patients receiving DPP-4 inhibitor/SGLT2 inhibitor combination therapy vs those receiving an SGLT2 inhibitor only. In the five trials we retrieved, the pooled risk ratio for genital tract infections (GTIs) in patients on DPP-4 inhibitor/SGLT2 inhibitor combination therapy vs those on SGLT2 inhibitors alone was 0.51 (95% confidence interval [CI] 0.28-0.92). Second, we found that within the Food and Drug Administration AE Reporting System, the frequency of GUTIs among reports listing both SGLT2 and DPP-4 inhibitors as suspect or concomitant drugs was significantly lower than among reports listing SGLT2 inhibitors without DPP-4 inhibitors, with a proportional reporting ratio of 0.74 (95% CI 0.61-0.90). In conclusion, in RCTs and in a large pharmacovigilance database, combination therapy with a DPP-4 inhibitor appears to reduce the frequency of G(U)TIs associated with SGLT2 inhibitors.

ObjectivesGlucagon-like peptide-1 receptor agonists (GLP-1RA) are widely used for the treatment of type 2 diabetes. In large trials, the GLP-1RAs liraglutide and semaglutide improved cardiovascular outcomes, but semaglutide was associated with an increased risk of retinopathy progression. We herein evaluated the association between GLP-1RA and retinal adverse events (AE) in the Food and Drug Administration Adverse Event Reporting System (FAERS).Research design and methodsWe mined the FAERS between 2004q1 and 2017q1 (for a total of 9 217 555 AE reports) to analyze disproportionality and evaluate the association between GLP-1RAs and AEs involving the retina. We compared the frequency of retinal AEs among reports including GLP-1RAs and in those including other glucose-lowering medications (GLMs) as suspect or concomitant drugs.ResultsWe retrieved 114 814 reports involving GLP-1RA and 694 725 reports involving other GLMs as suspect or concomitant drugs. The cumulative frequency of retinal AEs was 2.53/1000 for reports involving GLP-1RA vs 6.62/1000 for reports involving other GLMs, with a proportional reporting ratio of 0.38 (95% CI 0.34 to 0.43; P<0.0001). Reports involving GLP-1RAs listed significantly more comorbid conditions and concomitant medications. Findings were consistent after filtering the diabetes indication irrespective of concomitant GLM, in reports including and in those not including insulin, and for the various GLP-1RAs.ConclusionsIn the FAERS there is no evidence that GLP-1RAs are associated with AEs suggestive of retinopathy progression. Despite more comorbid conditions and concomitant medications, in reports with GLP-1RA the frequency of retinal AEs was significantly lower than in reports with other GLMs.

IntroductionIn the SAVOR-TIMI trial, the risk of heart failure (HF) was increased by 27% in T2D patients randomized to the dipeptidyl peptidase-4 inhibitor (DPP4i) saxagliptin. Other studies have provided inconsistent results regarding this association. Herein, we performed a pharmacovigilance analysis of the rate of HF associated with DPP4is, focusing on stimulated reporting and moderation by drug–drug interactions.MethodsWe mined the FDA adverse event (AE) reporting system (FAERS) from 2004q1 to 2017q3, including a total of 9906,642 AE reports. Rates (/1000 reports) of HF within the reports for DPP4is and reports for other antidiabetic drugs were calculated for the period up to 2013q3 (date of publication of the SAVOR-TIMI trial results) and from 2013q4 to 2017q3. Analyses were refined by filtering according to therapeutic area, concomitant diseases and drugs, and competing AEs.ResultsThe rate of HF among the AE reports filed for DPP4is significantly increased after 2013q3, especially for saxagliptin. When compared to non-insulin non-glitazone antidiabetic drugs, the proportional reporting ratio (PRR) of HF for DPP4is was 0.62 (95% CI 0.56–0.68) up to 2013q3 and 2.12 (95% CI 1.96–2.28) from 2013q4 to 2017q3. This stimulated reporting was consistent in subanalyses based on the presence/absence of cardiac disorders and after controlling for competing AEs. The rate of HF among AE reports for DPP4is was modestly moderated by the concomitant use of metformin (− 15%) and strongly moderated by the concomitant use of SGLT2 inhibitors (− 63%), even after excluding competing AEs.ConclusionsWithin the FAERS, the association between HF and DPP4is was biased by stimulated reporting, implying that the publication of the SAVOR-TIMI trial and the subsequent regulatory warnings primed clinicians to report HF events in DPP4i users as drug-related AEs. The rate of HF associated with DPP4is was moderated when they were used in combination with SGLT2 inhibitors.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0408-2) contains supplementary material, which is available to authorized users.