Hypoglycemia Associated with Antibiotics Alone and in Combination with Sulfonylureas and Meglitinides: An Epidemiologic Surveillance Study of the FDA Adverse Event Reporting System (FAERS)

Abstract

Background:

Fluoroquinolones, clarithromycin, linezolid, tigecycline, cefditoren, doxycycline, and trimethoprim-sulfamethoxazole are known to be associated with hypoglycemia, but few studies have considered concomitant glucose-lowering medications.

Objective:

The objective of this study was to evaluate the association between hypoglycemia and antibiotics using the FDA Adverse Event Reporting System (FAERS), while accounting for concomitant glucose-lowering medications including sulfonylureas and meglitinides.

Methods:

FAERS reports from January 1, 2004 to December 31, 2017 were included in the study. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (95% CI) for the association between antibiotics and hypoglycemia were calculated. An association was considered to be statistically significant when the lower limit of the 95% CI was greater than 1.0.

Results:

A total of 2,334,959 reports (including 18,466 hypoglycemia reports) were considered, after inclusion criteria were applied. Statistically significant hypoglycemia RORs (95% CI) for antibiotics were: cefditoren 14.03 (8.93–22.03), tigecycline 3.32 (1.95–5.65), clarithromycin 2.41 (1.89–3.08), ertapenem 2.07 (1.14–3.75), moxifloxacin 2.06 (1.59–2.65), levofloxacin 1.66 (1.37–2.01), and linezolid 1.54 (1.07–2.20). After adjusting for concomitant sulfonylureas and meglitinides, the following antibiotics were still significantly associated with hypoglycemia: cefditoren 14.25 (9.08–22.39), tigecycline 3.34 (1.96–5.68), ertapenem 1.93 (1.03–3.60), and clarithromycin 1.56 (1.15–2.11).

Conclusion:

Many patients on antibiotics, including fluoroquinolones, are associated with hypoglycemia when they are also taking sulfonylureas or meglitinides. Patients on cefditoren, tigecycline, ertapenem, and clarithromycin are associated with hypoglycemia even if they are not taking sulfonylureas or meglitinides. The association between ertapenem and hypoglycemia has not been previously reported.

1. Introduction

In July of 2018, the United States Food and Drug Administration (FDA) published a drug safety warning for the potential risk of developing hypoglycemia from fluoroquinolones [1]. Even though hypoglycemia is a common adverse drug reaction (ADR) of insulin and sulfonylureas, it can become serious and lead to coma, seizure, life-threatening arrhythmias, myocardial infarction, and death [2]. It is important to know if an antibiotic could increase the risk of developing hypoglycemia, especially in patients at risk of developing hypoglycemia, such as patients with diabetes, and especially those taking glucose-lowering medications.

Other antibiotics have been reported to be associated with hypoglycemia in the literature. A study of FDA Adverse Event Reporting System (FAERS) demonstrated a relationship between linezolid and hypoglycemia [3]. Another FAERS study demonstrated that tigecycline was associated with hypoglycemia. As a result, the FDA added a warning with this information to the tigecycline package insert [4]. In a cohort study of insurance claims, diabetic patients on three oral fluoroquinolones, levofloxacin, ciprofloxacin, or moxifloxacin, had higher odds of experiencing hypoglycemia than those on two macrolides (clarithromycin or azithromycin). This study also demonstrated that patients taking moxifloxacin had a higher risk of hypoglycemia than those taking ciprofloxacin [5]. In a retrospective chart review study, dysglycemia occurred more frequently in patients receiving levofloxacin or ciprofloxacin than those receiving ceftriaxone [6]. A few case reports have also been published that report hypoglycemia from doxycycline and trimethoprim-sulfamethoxazole use [7–12]. Lastly, two case reports demonstrated that cefditoren is associated with hypoglycemia [13,14]. However, very few of these studies accounted for the concomitant use of glucose-lowering medications when assessing risk of hypoglycemia with these antibiotics.

Drug-drug interactions involving antibiotics can put patients at an even greater risk of hypoglycemia. Several antibiotics interact with sulfonylureas to increase the risk of hypoglycemia. A cohort study of insurance claims demonstrated that when glipizide or glyburide were prescribed, clarithromycin, levofloxacin, trimethoprim-sulfamethoxazole, metronidazole, and ciprofloxacin were all associated with higher risks of hypoglycemia than non-interacting antibiotics [15]. A case report also demonstrated severe hypoglycemia associated with a clarithromycin-repaglinide drug interaction [16]. The clarithromycin drug label warns that the concomitant use of oral hypoglycemic agents and/or insulin with clarithromycin may cause hypoglycemia [17].

There is no current literature that has systematically compared antibiotics and the risk of developing hypoglycemia. The objective of this study was to evaluate both the association between antibiotics and hypoglycemia, and the influence of concomitant glucose-lowering medications, using the FDA Adverse Event Reporting System (FAERS) [18].

2. Methods

2.1. Data Source

FAERS is a publicly available database composed of adverse event reports that were submitted to United States Food and Drug Administration (FDA) [18]. FAERS data contain drug information, including drug name, active ingredient, route of administration, the drug’s reported role in the event, and reaction information. Each report has a primary suspected drug with one or more ADRs and may include other drugs taken by the patient.

2.2. Study Design

FAERS data from January 1, 2004 to December 31, 2017, which were organized into Quarterly Data Files, were included in the study. If a report was submitted to the FDA multiple times with updated information, only the most recently submitted version was included in this study. Duplicate reports were also removed by matching age, sex, event date, and reporter country.

2.3. Drug Exposure Definition

Each antibiotic was identified in FAERS by generic and brand names listed in the Drugs@FDA Database [19–24]. Drugs with a reported role coded as “PS” (Primary Suspect Drug) or “SS” (Secondary Suspect Drug) were evaluated for inclusion [25]. Antibiotics with less than three ADR reports were excluded from this data analysis [26].

2.4. Adverse Drug Reaction Definition

FAERS defines ADRs using Preferred Terms (PT) from the Medical Dictionary for Regulatory Activities (MedDRA) [27]. The following Preferred Terms: “Blood glucose decreased”, “Hypoglycaemia”, “Hypoglycaemic coma”, “Hypoglycaemic encephalopathy”, “Hypoglycaemic seizure”, “Hypoglycaemic unconsciousness”, and “Shock hypoglycaemic” were used to identify hypoglycemia cases for this study.

2.5. Statistical Analysis

A disproportionality analysis was conducted by computing Reporting Odds Ratios (ROR) and corresponding 95% confidence intervals (95%CI) for the association between hypoglycemia and each antibiotic class or individual antibiotic [28]. ROR was calculated as the ratio of the odds of reporting hypoglycemia versus all other ADRs for a given drug, compared with this reporting odds for all other drugs present in FAERS [28]. An association was considered to be statistically significant if the lower limit of 95% CI was above 1.0 [28]. An adjusted ROR was calculated after removing reports of potentially confounding sulfonylureas (chlorpropamide, gliclazide, glimepiride, glipizide, glyburide, tolazamide, and tolbutamide) and meglitinides (repaglinide and nateglinide) from the database. Data analysis was performed using Microsoft Access 2016, Microsoft Excel 2016 (Microsoft Corporation, Redmond, WA), SAS 9.4, and JMP Pro 13.2.1 (SAS Institute, Cary, NC).

3. Results

A total of 2,334,959 reports (including 18,466 hypoglycemia reports) were considered, after inclusion criteria were applied. Cefditoren had the greatest proportion of hypoglycemia reports, representing 10% of all cefditoren reports. Statistically significant hypoglycemia RORs (95% CI) for antibiotics were: cefditoren 14.03 (8.93–22.03), tigecycline 3.32 (1.95–5.65), clarithromycin 2.41 (1.89–3.08), ertapenem 2.07 (1.14–3.75), moxifloxacin 2.06 (1.59–2.65), levofloxacin 1.66 (1.37–2.01), and linezolid 1.54 (1.07–2.20) (Figure 1).

Figure 1.

Reporting Odds Ratios (ROR) for hypoglycemia with antibiotics.

An adjusted ROR was calculated after removing reports of concomitant sulfonylureas or meglitinides. The adjusted RORs for agents significantly associated with hypoglycemia were: cefditoren 14.25 (9.08–22.39), tigecycline 3.34 (1.96–5.68), ertapenem 1.93 (1.03–3.60), and clarithromycin 1.56 (1.15–2.11) (Figure 2).

Figure 2.

Adjusted Reporting Odds Ratios (aROR) for hypoglycemia with antibiotics in patients not on a sulfonylurea or a meglitinide.

Another adjusted ROR was calculated to quantify the impact of a drug-drug interaction between clarithromycin and repaglinide. The hypoglycemia ROR (95% CI) for clarithromycin taken with repaglinide was 20.91 (2.52–173.69), while the hypoglycemia ROR (95% CI) for clarithromycin taken without repaglinide was 2.38 (1.86–3.04) (Figure 3).

Figure 3.

Adjusted Reporting Odds Ratios (aROR) of hypoglycemia for clarithromycin taken with or without repaglinide.

4. Discussion

Seven antibiotics were found to be significantly associated with hypoglycemia. These antibiotics included: cefditoren, tigecycline, clarithromycin, ertapenem, moxifloxacin, levofloxacin, and linezolid. Four antibiotics were found to be significantly associated with hypoglycemia in patients not concomitantly taking a sulfonylurea or a meglitinide. These antibiotics included: cefditoren, tigecycline, ertapenem, and clarithromycin. While several of the antibiotics have prior studies or case reports indicating an association with hypoglycemia, ertapenem has no previous literature regarding hypoglycemia. Trimethoprim-sulfamethoxazole was not significantly associated with hypoglycemia, even though case reports have reported hypoglycemia as an ADR of trimethoprim-sulfamethoxazole [7–9]. Finally, doxycycline was not associated with developing hypoglycemia, despite some prior case reports to the contrary [10–12]. Potential mechanisms and implications for clinical practice are discussed below.

Concerning the fluoroquinolones, a retrospective cohort study that evaluated the risk of developing hypoglycemia with gatifloxacin, levofloxacin, and ciprofloxacin found only gatifloxacin and levofloxacin had a significantly greater risk of developing hypoglycemia [29]. Before that study was published, gatifloxacin was removed from the market due to an increased risk of dysglycemia [30]. The July 2018 FDA drug safety warning required all drugs in the fluoroquinolone class to have additional labeling that warned patients and providers of the risk of developing hypoglycemia [1]. However, the FDA drug safety warning was based on only 56 reports in FAERS. Levofloxacin accounted for 79% of the total reports. Forty-seven of these patients were found to be diabetic patients. Thirty-five of the 47 diabetic patients were also taking a sulfonylurea medication. However, in our study, only levofloxacin and moxifloxacin were significantly associated with hypoglycemia, and ciprofloxacin was not. Furthermore, when patients on sulfonylureas or meglitinides were removed from the sample, there was no significant association for any of the fluoroquinolones and hypoglycemia.

The mechanisms of how antibiotics could cause hypoglycemia are not fully understood. However, there are some proposed mechanisms. Fluoroquinolones may activate the L-type voltage-dependent Ca²⁺ channel [31]. Fluoroquinolones may also increase insulin secretion by inhibiting the K⁺ATP channels in pancreatic beta cells [32]. Sulfonylureas stimulate insulin secretion by inhibiting the K+ATP channels in pancreatic beta cells [33]. This compounded mechanism could explain why hypoglycemia was commonly seen in patients taking fluoroquinolones with a concomitant sulfonylurea.

Cefditoren had the highest ROR of 14.03, with a confidence interval of 8.93–22.03. Cefditoren is a cephalosporin that contains pivalic acid, and antibiotics containing a pivalic acid moiety have been shown to decrease serum carnitine concentration. Severe carnitine deficiency can lead to the inability to produce glucose, which could lead to hypoglycemia [13].

Finally, clarithromycin interacts with several medications, including repaglinide, an oral glucose-lowering medication. Clarithromycin is a CYP3A4 inhibitor, and repaglinide is metabolized by CYP3A4. Even low doses of clarithromycin can increase the plasma concentration of repaglinide. This increased plasma concentration can lead to severe hypoglycemia [34]. This finding prompted us to calculate the ROR of hypoglycemia in patients taking clarithromycin and repaglinide concomitantly. The hypoglycemia ROR for clarithromycin taken with repaglinide was 20.91, with a confidence interval of 2.52–173.69, while hypoglycemia ROR for clarithromycin taken without repaglinide was 2.38, with a confidence interval of 1.86–3.04. The wide confidence interval of hypoglycemia ROR for clarithromycin taken with repaglinide was due to the small number of reports of clarithromycin taken with repaglinide. Data with wide confidence intervals should be interpreted with caution. Clarithromycin also interacts with sulfonylureas and may increase the sulfonylurea concentration by inhibiting P-glycoprotein in the intestinal wall [35].

There are important study limitations to acknowledge, many of which are well known with regard to the FAERs database. Drug names are sometimes misspelled in FAERS. A causal relationship between a drug and an ADR cannot be determined by FAERS. Significant bias may occur, because of the spontaneous and voluntary reporting of ADRs. Media attention and recent publication of an ADR in the literature might affect the reporting behaviors. FAERS data cannot be used to estimate risks. The signals detected by FAERS should be further investigated with future studies. Despite the limitations, FAERS has a large sample size and is suitable for discovering new and rare drug-ADR associations.

5. Conclusion

Many patients on antibiotics, including fluoroquinolones, are associated with hypoglycemia when they are also taking sulfonylureas or meglitinides. Patients on cefditoren, tigecycline, ertapenem, and clarithromycin are associated with hypoglycemia even if they are not taking sulfonylureas or meglitinides. The association between ertapenem and hypoglycemia has not been previously reported. Finally, patients taking concomitant clarithromycin and repaglinide have much higher association with hypoglycemia than those taking clarithromycin without repaglinide.

Key points:

1. Many patients on antibiotics, including fluoroquinolones, are associated with hypoglycemia when they are also taking sulfonylureas or meglitinides.

2. Patients on cefditoren, tigecycline, ertapenem, and clarithromycin are associated with hypoglycemia even if they are not taking sulfonylureas or meglitinides.

3. Patients taking concomitant clarithromycin and repaglinide have much higher association with hypoglycemia than those taking clarithromycin without repaglinide.