Fluoroquinolone alterations on glucose homeostasis

April 2005

The fluoroquinolone sales market has been highly competitive over the past decade. Each manufacturer has been trying to find an advantage for their respective fluoroquinolone to gain market share.

One of the more recent marketing techniques has been to focus on patient safety issues. For example, if quinolone A is used the patient is more likely to experience an adverse effect, then if quinolone B is used. Therefore use of quinolone A will drive-up health care costs. It is interesting that the pharmaceutical manufactures are jumping on the patient-safety bandwagon in their marketing plans.

However, one needs to wonder what the true differences are between the individual fluoroquinolones and what is a class effect. The two safety issues that seem to be at the forefront are the likely hood of an agent to induce C. difficile diarrhea and effects on glucose homeostasis.

Glycemic control

The glycemic control issues with the fluoroquinolones came to the forefront in 2002 when Bristol Myers Squibb strengthened the language in the gatifloxacin package insert regarding hypo- and hyperglycemic adverse reactions. Although most of the attention for effects on glucose homeostasis has revolved around gatifloxacin, it should be noted that all of the major fluoroquinolones have been reported to cause either hypoglycemia or hyperglycemia or both. It is not clear as to whether one agent is more or less likely to effect glucose homeostasis.

Serum glucose is one of the most highly controlled substances in humans. It is regulated by complex interactions between insulin release and action, and the counterregulatory hormones, glucagon, epinephrine, cortisol and growth hormone.

The adverse consequences of hyperglycemia have gained attention within the health care community. There is a growing body of literature documenting the increased complication rates, and increased utilization of health care resources in patients with short-term and long-term hyperglycemia. Additionally, the literature is also documenting the positive effects of tightly controlled glucose in various disease states, including sepsis and surgical wound infections. Therefore, health-systems have been instituting aggressive hyperglycemia management protocols in an effort to improve patient and economic outcomes.

With the increased focus on tight glycemic control it is likely that an increased incidence of drug induced hypoglycemia will occur. Drug induced hypoglycemia is most commonly encountered with the use of exogenously administered insulin and the sulfonylureas.

The antimicrobial agents most associated with alterations in glucose homeostasis are pentamidine and the protease inhibitors. However, more recently fluoroquinolone associated alterations in glucose homeostasis is getting increasing attention, despite hypoglycemia and hyperglycemia being rare adverse events related to fluoroquinolone use.

The exact mechanisms for fluoroquinolone-induced alterations in glucose homeostasis are not fully known. However, the hypoglycemic effects tend to occur more frequently at the beginning of treatment and conversely hyperglycemia is more prominent at the end of treatment.

Hypoglycemia appears to be due to an increase in insulin release from the pancreas. In rat pancreatic islet cells, fluoroquinolones increased insulin release by blocking the K⁺-ATP channels on the ß-islet cell membranes. In patients with non-insulin dependent diabetes mellitus maintained on diet and exercise, gatifloxacin was found to increase serum insulin levels 1-hour after a dose, but this did not have a significant effect on serum glucose; there was no effect on ß-cell function or on fasting glucose levels. The magnitude of insulin release following a dose of gatifloxacin decreased with subsequent doses. This may in part explain why hypoglycemia tends to occur earlier in the treatment course.

The mechanism for hyperglycemia is unknown, and is unclear if it is due to a direct drug effect on glucose metabolism or is a result of uncovering pre-existing diabetic disease. It is well known that the presence of an infection may stimulate a hyperglycemic episode in known diabetics. Therefore, hyperglycemia during fluoroquinolone therapy may be a function of a disease state effect and not related to a direct drug effect.

However in animals given higher than normal doses of a fluoroquinolone, there were decreased secretory granules found in the pancreatic ß-cells after prolonged dosing. This resulted in decreased serum insulin levels with a reciprocal increase in glucose levels. One may postulate that this same effect could be seen in humans with high serum concentrations of a fluoroquinolone for a long period of time. This could explain the findings of hyperglycemia tending to occur later in a course of therapy.

Patient adverse event reporting

Whenever a patient experiences an adverse event, the patient’s medication profile should be evaluated for the possibility of a drug interaction. Drug interactions between the fluoroquinolones and oral diabetic agents are not listed in the prescribing information of the fluoroquinolones or in standard reference resources. However, there are a few case reports in the literature describing patients with resistant hypoglycemia receiving concurrent glyburide and ciprofloxacin. The mechanism of the drug interaction is postulated to be inhibition of glyburide metabolism resulting in increased glyburide serum concentrations.

Alterations in glucose homeostasis have become a marketing point for the fluoroquinolone manufactures despite hypoglycemia and hyperglycemia being rare adverse reactions. There does not appear to be a difference between the agents in causing glycemic control problems. However with the increased focus on tight glycemic control, it is likely that the incidence of drug induced hypoglycemia will increase.

For more information:

• Chan JCN, Cockram CS, Critchley JA. Drug-induced disorders of glucose metabolism. Drug Saf. 19896;15:135-157.
• Gajjar DA, LaCreta FP, Kollia GD, et al. Effect of multiple-dose gatifloxacin or ciprofloxacin on glucose homeostasis and insulin production in patients with noninsulin-dependent diabetes mellitus maintained with diet and exercise. Pharmacotherapy. 2000;20(6Pt2):76S-86S.
• Roberge RJ, Kaplan R, Frank R, Fore C. Glyburide-ciprofloxacin interaction with resistant hypoglycemia. Ann Emerg Med. 2000;36:160-163.

• Marianne Billeter, PharmD, BCPS, Clinical Pharmacology Specialist, Infectious Diseases, Ochsner Clinic Foundation, New Orleans.