March 13, 2014

Low-Dose Doxycycline May Slow Diabetic Retinopathy

This article by Veronica Hackethal, MD appeared in Medscape, Mar 13, 2014

Low-dose doxycycline could slow the progression of diabetic retinopathy (DR), according to a small proof-of concept study by a group of researchers in the United States and Denmark, published online March 6 in JAMA Ophthalmology.

"To our knowledge, this is the first observation suggesting a link between a low-dose oral anti-inflammatory agent and subclinical improvement in inner retinal function," write Ingrid U. Scott, MD, MPH, from the Penn State Hershey Eye Center and the Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania, and colleagues.

At this time, no established therapy exists to slow the progression of nonproliferative DR, the stage of retinopathy that affects most people with diabetes, according to Thomas Gardner, MD, professor of ophthalmology and visual sciences at the University of Michigan Medical School, Ann Arbor, and senior author of the article. Vascular endothelial growth factor inhibitors may slow progression of DR but are not widely used and require multiple intraocular injections. The idea in this study was that low-dose tetracycline could be used to suppress the neuroinflammatory component of DR, Dr. Gardner told Medscape Medical News. Tetracycline has been shown to reduce inflammation, although the exact mechanism is unclear.

The study was a 24-month randomized, double-masked, clinical trial involving 30 participants from hospital-based retina clinics in Pennsylvania and Denmark. Participants received financial compensation and were recruited from October 1, 2008, to May 31, 2010. They had either type 1 or type 2 diabetes mellitus and 1 or more eyes affected by nonproliferative DR or non-high-risk proliferative DR, defined according to the Early Treatment Diabetic Retinopathy Study criteria.

Participants were randomly assigned in a 1:1 fashion to receive either low-dose (50 mg) doxycycline monohydrate or placebo for 24 months. Investigators, clinical coordinators, photographers, and patients were masked to therapeutic group. The investigators determined adherence using pill counts and monthly telephone calls made by the clinical coordinator.

The researchers measured retinal vessel diameters and performed complete ocular exams at baseline. They assessed retinal function using 6 different measurements.

The authors hypothesized that frequency-doubling perimetry would provide the best estimate of treatment effect, as it primarily indicates inner retinal function. The researchers conducted follow-up ophthalmic exams every 3 months and performed retinal function testing and quality-of-life assessments every 6 months. Fluorescein angiography was done at 24 months. Hemoglobin A1C level, serum cholesterol level, creatinine level, pregnancy tests (when appropriate), blood pressure, and body mass index were measured at baseline and every 3 months. The researchers assessed progression to high-risk DR using changes in Early Treatment Diabetic Retinopathy Study severity level or need for photocoagulation.

Eighty-three percent of initial enrollees finished the study. The groups were similar in most baseline characteristics, except that diabetes duration was shorter in the doxycycline group compared with the placebo group (19.6 vs 27.2 years; P = 0.03). Starting at 6 months, the doxycycline group had a significantly higher mean frequency-doubling perimetry foveal sensitivity compared with placebo (P = 0.04), a difference that remained significant at 12 (P = 0.04) and 24 (P = 0.02) months. At 24 months, mean frequency-doubling perimetry foveal sensitivity remained increased in the doxycycline group (+1.8 dB) and decreased in the placebo group (−1.9 dB). This difference remained significant after adjusting for duration of diabetes (P = 0.03). There were no differences between groups regarding other visual function and anatomical outcomes.

Three serious adverse events occurred (motor vehicle accident, elevated serum creatinine, and vitreous hemorrhage), of which none were thought to be related to doxycycline. A minor adverse event (nausea) also could have been related to the study drug.

Limitations included the inability to detect significant differences between groups resulting from small sample size, which may have been compounded by 4 losses to follow-up and insufficient data in 1 patient, all in the treatment group.

"The significance of the work is the potential ability to treat [DR] with a safe, [US Food and Drug Administration]-approved oral agent and to avoid the necessity for intraocular injections," Dr. Gardner emphasized. "The current study is a proof-of-concept study and requires confirmation in larger studies, plans for which are under discussion."

Of particular interest, Andrew Hendrick, MD, assistant professor of medicine at Emory University School of Medicine, Atlanta, Georgia, told Medscape Medical News, is the use of frequency-doubling perimetry as a surrogate for typical ophthalmic outcomes to assess worsening diabetic retinal damage. Larger-scale clinical trials have looked at slowing the progression of DR using other drugs but have failed to find clinical benefit, Dr. Hendrick said.

"The difference this study implemented is the use of a different outcome measure [that was more] sensitive to detecting a lower threshold of purported preclinical disease state," Dr. Hendrick explained, "[Frequency-doubling perimetry] is not a commonly used technique."

This drug is not likely to come into use in clinical practice any time soon, as large-scale investigations will be needed to confirm the findings, Dr. Hendrick noted. Concerns regarding treatment with low-dose doxycycline mostly include gastrointestinal discomfort, although at higher doses there may be a risk for cutaneous light sensitivity and drug-induced pseudotumor cerebri, Dr. Hendrick added.

"[DR] is the leading cause of blindness in patients younger than 55 [years]," Dr. Hendrick emphasized. "This research demonstrates the potential benefit of a medication that is fairly well-tolerated in patients with severe nonproliferative and early proliferative [DR], disease states for which our [current] standard is [limited] to recommending improved blood pressure and glycemic control."

Dr. Jackson reports being an investor and employee of MacuLogix Inc, the maker of AdaptDx. The other authors and Dr. Hendrick have disclosed no relevant financial relationships.

JAMA Opthalmol. Published online March 6, 2014. Abstract
Article: Low-Dose Doxycycline May Slow Diabetic Retinopathy. Medscape. Mar 13, 2014.

Last Modified: Friday, 21-Mar-2014 15:10:43 EDT