Effects of Co‐administration of Sulfonylureas and Antimicrobial Drugs on Hypoglycemia in Patients with Type 2 Diabetes Using a Case‐Crossover Design

Abstract

Objectives The purpose of this study was to investigate the effect of sulfonylureas (SUs) and antimicrobial co‐administration on hypoglycemia in patients with type 2 diabetes mellitus (T2DM). Methods We conducted a case‐crossover study using the Korean Health Insurance Review and Assessment Service‐National Inpatient Sample database, using data from 2014 to 2016. Hospitalized adult patients with T2DM who were diagnosed with hypoglycemia and prescribed SUs for at least 120 days were included. Different risk ratings of severity of drug–drug interactions were considered, including “level X, D, or C” in Lexi‐Interact online and “contraindicated, major, or moderate” in Micromedex. Exposure to antimicrobials in the 30‐day period before the first hypoglycemia diagnosis was assessed. Two control periods (61–90 and 91–120 days) were matched before the diagnosis date. Conditional logistic regression analysis was conducted to compare the odds of antimicrobial exposure. Results A total of 9339 patients were included. The mean age of the patients was 71.3 ± 10.6 years, and 4818 (51.6%) were women. An increased risk of hypoglycemia was associated with co‐administration of SUs and certain antimicrobials (adjusted odds ratio [aOR] 2.56, 95% confidence interval [CI] 2.34–2.80). The antimicrobial agents that were associated with an increased risk of hypoglycemia, when co‐administered with SUs, were sulfonamides (aOR 2.99, 95% CI 1.99–4.52), fluoroquinolones (aOR 2.62, 95% CI 2.38–2.89), macrolides (aOR 2.48, 95% CI 1.88–3.27), and tetracyclines (aOR 1.56, 95% CI 1.05–2.33). Conclusions Co‐administration with SUs and certain antimicrobials increased the risk of hypoglycemia. Thus, clinically relevant interactions in patients concurrently using SUs and antimicrobials should be monitored, especially within 30 days after co‐administration.

Evaluating the use of methods to mitigate bias from non‐transient medications in the case‐crossover design: A systematic review

“…Of the 114 included articles, the case‐crossover design was the most common (100, 88%), 18–117 followed by the case‐time‐control (19, 17%), 38,63,67,71,86,118–131 and case‐case‐time‐control (4, 3%) 33,47,48,86 . (Table 1) The most common outcomes measured in these studies were hospitalization (43, 38%), cardiovascular events (22, 19%) and fall‐related injury/fracture (15, 13%).…”

“…Researchers sometime use multiple control windows in case‐crossover studies to increase study power and use washout periods to eliminate carryover effects of drugs or to account for non‐adherence to medications, especially when non‐transient medications are evalauted 10 . Of 48 articles that used multiple control windows, half of the articles reported no washout period between each control period 19,24,25,27,28,37,39,41,44,46,53,55,59,66,72,73,77,79,81,84,90,103,104,106,113,114 . It is unclear whether these multiple control windows were analyzed as a single large control window or time‐dependent control windows.…”

6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes—2024

“…Clinicians should be aware of medication interactions that may precipitate hypoglycemia. Notably, sulfonylureas interact with a number of commonly used antimicrobials (fluoroquinolones, clarithromycin, sulfamethoxazole-trimethoprim, metronidazole, and fluconazole) that can dramatically increase their effective dose, leading to hypoglycemia (143)(144)(145). Clinicians should consider temporarily decreasing or stopping sulfonylureas when these antimicrobials are prescribed.…”

Safety and Tolerability of Antimicrobial Agents in the Older Patient

“…Coadministration of these antimicrobials and other selected CYP3A4 substrates, including dihydropyridine calcium channel blockers, simvastatin, atorvastatin, lovastatin, cyclosporine, midazolam, and tacrolimus, may be harmful because of drug–drug interactions and increased risk of adverse effects. Careful evaluation of drug regimens is thus needed in order to limit the risk of confusion, sedation and falls from benzodiazepines [ 59 , 60 ], hypoglycemia from sulfonylureas [ 61 ], rhabdomyolysis from statins [ 62 ], severe hypotension from calcium channel blockers [ 63 ], nephrotoxicity from immunosuppressive medications [ 25 ], and toxicity of phenytoin and theophylline [ 25 , 57 , 58 , 64 ]. Furthermore, erythromycin, and to a smaller extent clarithromycin, and telithromycin may increase the risk of bleeding in older patients taking warfarin [ 25 , 57 , 58 ].…”