Glucose Homeostasis Abnormalities and Fluoroquinolones: A Canadian Thought-Leader Perspective From Stephen D. Shafran, MD, FRCPC

Stephen D. Shafran, MD, FRCPC

Introduction
Although the product inserts of all fluoroquinolones indicate that hypoglycemia and hyperglycemia are possible adverse effects, these were thought to be rare events until relatively recently. Despite many years of ciprofloxacin use in more than 500 million patients, reports of symptomatic hypoglycemia were rare and believed to be due to a drug-drug interaction with glyburide.[1] (Ciprofloxacin is an inhibitor of cytochrome P450 [CYP] 3A4 that metabolizes most oral hypoglycemics, whereas gatifloxacin, levofloxacin, and moxifloxacin do not inhibit CYP 3A4 and thus do not alter the metabolism of oral hypoglycemic agents.)

Glucose Homeostasis Abnormalities: An Emerging Concern With Gatifloxacin
In 2002, 2 groups reported severe, symptomatic hypoglycemia related to gatifloxacin use in patients with type 2 diabetes mellitus who received oral hypoglycemic agents.[2,3] Additional reports of symptomatic hypoglycemia associated with gatifloxacin followed,[4-6] as well as reports of symptomatic, severe hyperglycemia.[5-9] These published reports and other unpublished cases reported to regulatory agencies led to modifications of the product labeling, as well as a report in the Canadian Adverse Reaction Newsletter.[10] In Japan, regulators required labeling to state that gatifloxacin is contraindicated in patients with diabetes mellitus.[11]

At the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in Washington, DC, from October 30 to November 2, 2004, Dr. Richard Frothingham from the Division of Infectious Diseases and International Health at Duke University presented 2 studies on the issue of glucose homeostasis abnormalities (GHA) that contribute significant information to our understanding of this topic. Dr. Frothingham used the US Freedom of Information Act to obtain all spontaneous adverse drug effect (ADE) reports filed with the US Food and Drug Administration (FDA) for the fluoroquinolones ciprofloxacin, gatifloxacin, levofloxacin, and moxifloxacin from November 1997 to September 2003.[12] There were a total of 568 GHA reports, of which 25 indicated a fatality. Gatifloxacin was associated with 80% of all GHA reports and 68% of GHA reports indicating a fatality, despite the fact that it accounted for only 6.6% of the prescriptions for the 4 fluoroquinolones examined. The incidence of GHA reports filed with the FDA was 477 per 10 million scripts for gatifloxacin compared with 8 per 10 million scripts for the 3 other fluoroquinolones combined (P < .001), which amounts to a 56-fold difference. GHA accounted for 24% of all ADEs reported with gatifloxacin compared with </= 1.6% of ADEs reported with any of the other 3 fluoroquinolones examined. The majority of patients with fluoroquinolone-associated hypoglycemia were elderly diabetic patients receiving oral hypoglycemic agents. The patients who developed fluoroquinolone-associated hyperglycemia were also usually elderly, but were usually not diabetic.

Dr. Frothingham presented a second study,[13] entitled "Glucose Homeostasis and Fluoroquinolones: Are There Differences Among Drugs?" He reviewed the published literature as well as his study based on spontaneous ADE reporting to the FDA. He pointed out that relatively rare but serious ADEs have been recognized for several fluoroquinolones only after licensure and once these agents were used in large numbers of subjects with a wide range of ages, comorbidities, and concomitant medications. Temafloxacin, trovafloxacin, sparfloxacin, and grepafloxacin all demonstrated significant toxicities after licensure that led to either their withdrawal from the market or marked restriction in their use. Hence, not all toxicities of fluoroquinolones can be considered class effects. Some ADEs occur uniquely or disproportionately often with 1 fluoroquinolone. It now appears that this holds true for gatifloxacin and GHA. A PubMed search at the time of ICAAC 2004 revealed 15 published cases of GHA and fluoroquinolones, of which 13 were associated with gatifloxacin, 2 with ciprofloxacin, and none with either levofloxacin or moxifloxacin. Subsequent to ICAAC 2004, 4 additional cases of GHA associated with gatifloxacin have been published.[6,8]

Recent GHA Data on Gemifloxacin and Other Fluoroquinolones
Also at ICAAC, Iannini and colleagues[14] presented an analysis of GHA from the phase 3 studies of gemifloxacin of all patients who received a hypoglycemic agent combined with either gemifloxacin or a comparator antibiotic. The incidence of hyperglycemia and hypoglycemia was 4.5% and 0%, respectively, for gemifloxacin vs 5.3% and 2.3%, respectively, for the comparator. A pooled analysis of phase 2 and 3 studies of moxifloxacin[15] reported no drug-related hypoglycemic adverse events in 8474 moxifloxacin-treated subjects. Drug-related hyperglycemic adverse events were reported in 7 (< 0.1%) moxifloxacin and 1 (< 0.1%) comparator-treated patients; none of these cases was considered serious, and 6 of the 7 moxifloxacin cases were graded as mild and required no intervention. Data from 5 moxifloxacin postmarketing studies in 46,130 subjects[15] reported no episodes of hypoglycemia and 2 hyperglycemic episodes that were not drug-related.

A differential effect of individual fluoroquinolones on GHA is supported by experimental animal data.[15-17] Maeda and coworkers[16] demonstrated that quinolones increase insulin release from rat pancreatic islets via a blockade of adenosine triphosphate (ATP)-sensitive potassium channels, and that lomefloxacin and sparfloxacin could do so at concentrations more than 33-fold lower than either enoxacin or tosufloxacin. Saraya and associates[17] demonstrated that gatifloxacin and tosufloxacin stimulated insulin secretion and inhibited potassium ATP channel currents in a dose-dependent manner, whereas levofloxacin had only a small effect. Gavin and colleagues[15] demonstrated that gatifloxacin, but not levofloxacin or moxifloxacin, lowered glucose and insulin in rats in a dose-dependent manner.

Discussion
It is quite possible that the propensity for GHA to occur in the elderly is explained by the fact that the elderly experience an age-related decline in renal function and usually have significantly higher serum concentrations of renally excreted drugs compared with younger adults. Since gatifloxacin is renally excreted, higher serum concentrations will be achieved in the elderly and this will likely increase the risk of GHA, given the concentration-dependent effect of gatifloxacin on insulin release in experimental animals.

The data on the incidence of GHA with specific fluoroquinolones are imperfect because they are based mainly on spontaneous reporting that is subject to underreporting, and there is also the possibility that there has been ascertainment bias in the cases of gatifloxacin. However, the risk of GHA for gatifloxacin relative to the other fluoroquinolones is so high (56-fold), and a differential risk for GHA among fluoroquinolones is supported by experimental animal data.[15-17] Although the cumulative global experience with moxifloxacin is still somewhat limited, the global experience with ciprofloxacin and levofloxacin includes hundreds of millions of individuals treated with each drug. It is difficult to believe that GHA related to ciprofloxacin and levofloxacin could have been missed with so many exposed individuals, particularly severe transient hyperglycemia in nondiabetics, as this cannot be ascribed to background disease as might occur with hypoglycemia in patients receiving concomitant oral hypoglycemics. These data in the aggregate strongly suggest that gatifloxacin is causally associated with GHA, and whereas GHA might occasionally occur with other fluoroquinolones, it occurs much more frequently with gatifloxacin.

The critical question is what this all means for clinical practice, given that the absolute incidence of GHA is quite low, even with gatifloxacin. I believe that there are 3 possible approaches. One is to avoid gatifloxacin altogether, since it has not been demonstrated to be superior to any other fluoroquinolone for any indication. A second approach is to avoid gatifloxacin in diabetic patients receiving oral hypoglycemic therapy. The third approach is to avoid gatifloxacin in all diabetic patients (the approach favored by the Japan Health Authority) regardless of whether the patient is receiving oral hypoglycemic therapy. The latter 2 approaches will reduce the risk of hypoglycemia in diabetic patients, but won't avoid the possibility of hyperglycemia in nondiabetic patients.

Supported by an independent educational grant from Janssen-Ortho.

References
Roberge RJ, Kaplan R, Frank R, Fore C. Glyburide-ciprofloxacin interaction with resistant hypoglycemia. Ann Emerg Med. 2000;36:160-163. Abstract
Menzies DJ, Dorsainvil PA, Cunha BA, Johnson DH. Severe and persistent hypoglycemia due to gatifloxacin interaction with oral hypoglycemic agents. Am J Med. 2002;113:232-234. Abstract
Baker SE, Hangii MC. Possible gatifloxacin-induced hypoglycemia. Ann Pharmacother. 2002;36:1722-1726. Abstract
LeBlanc M, Belanger C, Cossette P. Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy. Pharmacotherapy. 2004;24:926-931. Abstract
Biggs WS. Hypoglycemia and hyperglycemia associated with gatifloxacin use in elderly patients. J Am Board Fam Pract. 2003;16:455-457. Abstract
Khovidhunkit W, Sunthornyothin S. Hypoglycemia, hyperglycemia, and gatifloxacin. Ann Intern Med. 2004;141:969.
Donaldson AR, Vandiver JR, Finch CK. Possible gatifloxacin-induced hyperglycemia. Ann Pharmacother. 2004;38:602-605. Abstract
Happe MR, Mulhall BP, Maydonovitch CL, Holtzmuller KC. Gatifloxacin-induced hyperglycemia. Ann Intern Med. 2004;141:968-969. Abstract
Arce FC, Bhasin RS, Pasmantier R. Severe hyperglycemia during gatifloxacin therapy in patients without diabetes. Endocr Pract. 2004;10:40-44.
Letourneau G, Morrison H, McMorran M. Gatifloxacin (Tequin[TM]): hypoglycemia and hyperglycemia. Canadian Adverse Reaction Newsletter. 2003;13:1-2.
Japan Ministry of Health, Labor and Welfare. Gatiflo Dear Doctor Letter in Japan. PJB Publication Ltd; March 10, 2003.
Frothingham R. Gatifloxacin associated with a 56-fold higher rate of glucose homeostasis abnormalities than comparator quinolones in the FDA spontaneous reporting database. Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract A-1092.
Frothingham R. Glucose homeostasis and fluoroquinolones: are there differences among drugs? Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract A-1629.
Iannini P, Mandell L, Tillotson G. Influence of gemifloxacin on the incidence of blood glucose disturbances. Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract A-1094.
Gavin JR III, Kubin R, Choudhri S, et al. Moxifloxacin and glucose homeostasis: a pooled-analysis of the evidence from clinical and postmarketing studies. Drug Saf. 2004;27:671-686. Abstract
Maeda N, Tamagawa T, Niki I, et al. Increase in insulin release from rat pancreatic islets by quinolone antibiotics. Br J Pharmacol. 1996;117:372-376. Abstract
Saraya A, Yokokura M, Gonoi T, Seino S. Effects of fluoroquinolones on insulin secretion and beta-cell ATP-sensitive K+ channels. Eur J Pharmacol. 2004;497:111-117. Abstract




Stephen D. Shafran, MD, FRCPC, Professor and Director, Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada


Disclosure: Stephen D. Shafran, MD, FRCPC, has disclosed that he has received grants for clinical research from Pfizer, Schering, Roche, Valiant, GlaxoSmithKline, Novartis, Merck, and Abbott. He has received grants for educational activities from Janssen-Ortho, Bristol-Myers Squibb, Sanofi Aventis, Pfizer, Schering, Roche, and AstraZeneca. He has served as an advisor or consultant for Janssen-Ortho, Bristol-Myers Squibb, Sanofi Aventis, Pfizer, Schering, Novartis, and AstraZeneca.


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