Concomitant use of statins and sodium‐glucose co‐transporter 2 inhibitors and the risk of myotoxicity reporting: A disproportionality analysis

Abstract

Aims Recent case reports have suggested that sodium‐glucose co‐transporter 2 (SGLT2) inhibitors may interact with statins to increase their risk of myotoxicity. We assessed the risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins. Methods We queried the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2013 to 2021 for reports including SGLT2 inhibitors, statins or both. We estimated several measures of disproportionate reporting of myopathy and rhabdomyolysis associated with concomitant use of SGLT2 inhibitors and statins: reporting odds ratio (ROR) with 95% confidence interval (CI), Ω shrinkage measure (safety signal if >0) and an extension of the proportional reporting ratio (PRR) (two‐criteria set, safety signal if both criteria are met), using the full FAERS dataset as the reference set. In sensitivity analyses, we focussed on specific SGLT2 inhibitor‐statin pairs with higher interaction potential (canagliflozin‐rosuvastatin, empagliflozin‐rosuvastatin) and accounted for stimulated reporting. Results There were 456 myopathy and 77 rhabdomyolysis reports involving both an SGLT2 inhibitor and a statin. Concomitant use of SGLT2 inhibitors and statins was not associated with an increased risk of myopathy (ROR 0.79, 95% CI 0.70 to 0.89) or rhabdomyolysis (ROR 0.58, 95% CI 0.41 to 0.83) reporting. For both outcomes, the Ω shrinkage measure was negative and only one criterion of the PRR extension was met. SGLT2 inhibitor‐statin pairs with higher interaction potential yielded potential signals for rhabdomyolysis; these signals disappeared after accounting for stimulated reporting. Conclusion There was no increased risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins or for specific drug pairs.

Spotlight commentary: The value of spontaneous reporting systems to detect (the lack of) clinically relevant drug–drug interactions in clinical practice

“…In this regard, multiple DDIs represent the next challenge for a personalized clinically oriented pharmacovigilance, especially in complex scenarios such as cardiovascular and oncological areas, where network analyses might offer a real-world perspective on iatrogenic syndromes. 25 Taken together, the studies by Gravel et al 13 and Alkabbani et al 16 have confirmed, once more, the value of well-conceived, carefully designed, properly reported and correctly interpreted disproportionality analyses for timely evaluation of DDIs with high clinical relevance and large public health impact. The lack of a signal, though reassuring, deserves proper validation and should not be viewed as a safety endorsement by clinicians, who should remain vigilant for the occurrence of myopathy in polymedicated people with diabetes.…”

“…Our personal opinion is that replication studies are welcome, provided that they are carefully planned to offer an additional complementary perspective. This is the case with the work by Gravel et al, 13 who tackled major biases, including stimulated reporting, to increase the robustness of findings. A side‐by‐side comparison is provided in Table 1, including methodological aspects when planning, conducting, reporting and interpreting a disproportionality analysis 18 .…”

“…Gravel et al 13 Alkabbani et al powered and well-designed analytical observational research. 22,23 We strongly believe that Gravel et al 13 have already started to pursue this further.…”

“…Gravel et al 13 explored the potential association between reporting of myotoxicity and concomitant exposure to statins and sodium‐glucose co‐transporter 2 inhibitors (SGLT2‐is) using the Food and Drug Administration Adverse Event Reporting System (FAERS), one of the largest publicly accessible databases of spontaneous reports. The study stems from a well‐conceived rationale, namely plausible (albeit weak) pharmacokinetic/pharmacodynamic basis, as well as preliminary clinical evidence (i.e., case report) 14,15 .…”

Considerations on the use of different comparators in pharmacovigilance: A methodological review

“…30 Indeed, imposing calendar time restrictions through left or right truncation might include a period of heightened reporting unrelated to drug utilization. For example, the publication of a drug safety warning by a regulatory authority could be followed by stimulated reporting, [31][32][33] thereby decreasing signal detection estimates for other drugs with similar indications. Hence, masking could temporally alter the bias influencing disproportionality analysis estimators, and the active-comparator reference set may exacerbate this in comparison to the full data reference set, given that the biasing influence impacts the entire comparator group and not a small subset which may reduce the magnitude of its influence.…”