Recurrent Antibiotic Use Linked to Risk of Type 2 Diabetes

Commentary by Kristian Mikkelsen, MD; Yu-Xiao Yang, MD, MSCE; and Ben Boursi, MD

Pharmacist Filling a PrescriptionRecurrent use of antibiotics has been linked to the risk for type 2 diabetes in a population-based, case-control study. It is unclear whether antibiotics are directly linked to type 2 diabetes or if patients requiring repeated antibiotic use have undiagnosed diabetes, placing them at increased risk of infections, the authors noted in the October issue of the European Journal of Endocrinology.

Previous studies have suggested that certain antibiotics causing insulin resistance or increased adiposity, explained Kristian Mikkelsen, MD, a researcher and doctoral student at the University of Copenhagen, Hellerup, Denmark.

“We here report an association between use of antibiotics in general and development of type 2 diabetes, with a rather homogenous signal seen for all of the commonly prescribed antibiotics,” Dr. Mikkelsen said. “If antibiotics should play a causal role in development of type 2 diabetes, our results points toward a general phenomenon of antibiotics, rather than an effect limited to one or a few groups of antibiotics. However, as we cannot infer causality based on these observational data, more studies are needed to make this conclusion,” Dr. Mikkelsen noted.

The researchers analyzed data from the Danish National Registry of Patients, the Danish National Prescription Registry, and the Danish Person Registry to identify patients with a first-ever prescription of a noninsulin glucose-lowering agent. Patients with a diagnosis of diabetes before being prescribed a noninsulin glucose-lowering agent were excluded from the study to ensure consistency in the timing of the diabetes diagnosis and treatment of cases.

The researchers identified 170,504 persons prescribed a noninsulin glucose-lowering agent who met exclusion criteria between January 1 and December 31, 2012. These cases were matched to 1,364,008 control persons without diabetes.

Increasing Use of Antibiotics Linked to Greater Risk for Diabetes
The adjusted odds ratio for type 2 diabetes with use of any antibiotic increased from 1.21 for 2 to 4 prescriptions to 1.53 for ≥5 prescriptions, compared with 0 to 1 prescriptions. Slightly higher odds ratios were found for narrow-spectrum antibiotics (1.22 and 1.55 for 2–4 and ≥5 prescriptions, respectively) and bacteriostatic types of antibiotics (1.31 and 1.39 for 2–4 and ≥5 prescriptions, respectively).

The association between increased use of antibiotics and risk for type 2 diabetes was found up to 15 years before the diagnosis as well as after the diagnosis. 

“It is generally assumed that having type 2 diabetes is a risk factor for acquisition of infections,” Dr. Mikkelsen explained. “In accordance, we found that patients diagnosed with type 2 diabetes had an increased use of antibiotics compared with controls. However, cases with type 2 diabetes also had an increased exposure to antibiotics already 15 years before time of diagnosis. It remains uncertain whether patients already at this point should have an increased risk of infections, and it could therefore be speculated, that antibiotics exposure contributes to the development of type 2 diabetes,” Dr. Mikkelsen said.

COMMENTARY

Yu-Xiao Yang, MD, MSCE
Associate Professor of Medicine
Associate Professor of Epidemiology in Biostatistics and Epidemiology
University of Pennsylvania

Ben Boursi, MD
Postdoctoral Fellow
University of Pennsylvania

The nationwide case-control study from Denmark by Mikkelsen et al was able to show similar results to those reported recently by Boursi et al1 in a population representative database from the United Kingdom. Both studies demonstrated an association between recurrent antibiotic exposure and type 2 diabetes risk.

The risk reported in both studies was similar, mainly with recurrent use of penicillins and macrolides, and was stable even for prescriptions up to 10 years before diabetes was diagnosed, pointing against possible reverse causality as an explanation for the results. The study by Boursi et al also was able to adjust for important anthropomorphic risk factors such as body mass index (BMI), and to show no similar association with other medications, such as antivirals and antifungals.

The two studies support previous data, mainly in animal models, demonstrating dysbiosis (change in the microbiota composition and diversity) in response to antibiotic exposure and secondary increase in the risk of obesity, insulin resistance, and other metabolic disorders. Although both studies were observational and had no data regarding the microbiota composition, they emphasize a possible intriguing role for the microbiota in the pathogenesis of type 2 diabetes.

While over-prescription of antibiotics and increased bacterial resistance is already a problem around the world, these studies serve as a warning sign for both patients and clinicians to reduce unnecessary antibiotic treatments that might cause diseases in ways not fully appreciated.

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