Signal Detection of Acute Renal Failure Following the Use of SGLT-2 Inhibitors: Stratified Analysis and Time Trend Analysis in Japan and the United States.

The results of previous studies that have used databases to investigate the associations between sodium-glucose-cotransporter-2 (SGLT-2) inhibitors and acute renal failure (ARF) have differed, and the impact of biases such as the Weber effect and stimulated reporting has not been fully examined. This study aimed to determine the associations between SGLT-2 inhibitors and ARF using signal detection, the effects on signals of regulatory agency alerts for ARF, and the publication of prominent studies by measuring changes in signals over time. Data registered in the Food and Drug Administration's Adverse Event Reporting System from January 2013 to March 2020 were downloaded, signals were detected, and reporting odds ratios (RORs) were calculated for each country of occurrence (Japan/the United States). Quarterly changes in the number of reports and RORs were examined. Although an association between SGLT-2 inhibitor use and ARF was suggested in the United States, this study did not suggest such an association in Japan. The number of reports and RORs fluctuated when regulatory alerts and prominent studies were published, and events affecting the number of reports and RORs varied by country. This study revealed the difference in the associations between SGLT-2i and ARF in Japan and the United States. Additionally, the signal was identified to be influenced by alerts and the publication of studies. Therefore, these results should be interpreted cautiously as there could be a possibility of overestimation due to alert biases and publication of studies.

A pitfall in hemoglobin A1c measurement with high performance liquid chromatography method in the diagnosis of onset of fulminant type 1 diabetes mellitus.

We showed a case with the onset of fulminant type 1 diabetes mellitus (FT1DM) whose HbA1c could not be measured with HPLC method. We think that the reason why his HbA1c was not be detected was associated with the presence of labile hemoglobin A1c (LHbA1c). These result mean that it is possible that LHbA1c can bring about a pitfall on HPLC method in diagnosis of onset of FT1DM.

Correlations Between SGLT-2 Inhibitors and Acute Renal Failure by Signal Detection Using FAERS: Stratified Analysis for Reporting Country and Concomitant Drugs.

BACKGROUND: Previous studies have shown conflicting observations regarding the correlation between sodium-glucose-cotransporter-2 inhibitors (SGLT2i) and acute renal failure. Although wide use has contributed to the accumulation of safety information on SGLT2i, the examination of the countries reporting cases of SGLT2i use and influence of concomitant drugs has been insufficient in studies using spontaneous adverse event reporting databases. OBJECTIVE: We aimed to re-examine the correlation between SGLT2i and acute renal failure using the latest United States Food and Drug Administration's Adverse Event Reporting System (FAERS) records and to conduct a stratified analysis for the reporting countries (Japan or other countries), as well as the concomitant use of drugs such as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) with SGLT2i. PATIENTS AND METHODS: The reporting odds ratio (ROR) and 95% confidence interval (CI) for cases recorded on FAERS from January 2013 to March 2020 were calculated. We then limited the cases to patients using SGLT2i and receiving treatment for diabetes mellitus and then calculated the ROR. A stratified analysis was performed for reporting countries (Japan or other countries), and the presence or absence of concomitant use of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) to examine their influence on the correlation between SGLT2i and acute renal failure. RESULTS: Of the 5,337,069 cases of adverse events recorded on FAERS, 410,569 were cases in which patients had received treatment for diabetes. The ROR for SGLT2i calculated from the total analysis subjects was 4.16 (95% CI 4.01-4.31), suggesting its correlation with acute renal failure. Similar results were obtained for the cases in which patients had received treatment for diabetes. However, the stratified analysis of these diabetes-treatment cases for reporting countries showed no correlation between SGLT2i and acute renal failure in cases reported in Japan with ROR 0.58 (95% CI 0.49-0.69). In contrast, a correlation was suggested in cases reported in countries other than Japan with ROR 1.91 (95% CI 1.83-1.98). Moreover, the stratified analysis for the concomitant use of an ACEi or ARB showed that the ROR tended to be low in the cases with one of these drugs. CONCLUSION: Examination with the signal detection method using FAERS suggested the correlation between SGLT2i and the onset of acute renal failure. However, when focusing on the cases reported in Japan, such a correlation was not suggested. In addition, this study indicated that the signal of acute renal failure tends to be reduced in cases with the concomitant use of either an ACEi or ARB. Through this study we suggest that patients should be closely monitored when they take SGLT2i without an ACEi or ARB.

Acute Renal Failure, Ketoacidosis, and Urogenital Tract Infections with SGLT2 Inhibitors: Signal Detection Using a Japanese Spontaneous Reporting Database.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of oral anti-hyperglycemic agents that have been available on the market in Japan since 2014. Although safety information has accumulated alongside the clinical use, the warnings issued by each country based on adverse events associated with the drug are different and examination of the safety of the drug is insufficient. OBJECTIVE: This study examined the safety of SGLT2 inhibitors by using a Japanese spontaneous reporting database and focusing on the cautions issued in each country and the disparities within existing research into the occurrence of the adverse events of acute renal failure (ARF), ketoacidosis, and urogenital tract infections (UTIs). PATIENTS AND METHODS: We analyzed data recorded on the Japanese Adverse Drug Event Report database (JADER) between April 2014 and February 2019. We calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) with sex and age as adjustment factors. RESULTS: JADER contained 366,501 cases with the adverse events of interest; 4322 involved SGLT2 inhibitors. The ROR for SGLT2 inhibitors was calculated as 1.0 (95% CI 0.9-1.2) for ARF, 72.2 (95% CI 59.3-87.8) for ketoacidosis, and 14.0 (95% CI 11.0-17.8) for UTIs. Analysis of only subjects receiving treatment for diabetes showed a similar trend. CONCLUSION: The results suggested a correlation between SGLT2 inhibitors and the onset of ketoacidosis and UTIs, but not between SGLT2 inhibitors and ARF. Further verification of the safety of SGLT2 inhibitors, through continued risk assessments and large-scale clinical studies, are necessary.