Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy: a randomized clinical trial

JAMA Ophthalmol. 2014 May;132(5):535-43. doi: 10.1001/jamaophthalmol.2014.93.


Importance: Inflammation may contribute to the pathogenesis of diabetic retinopathy (DR).

Objectives: To investigate, in a proof-of-concept clinical trial, whether low-dose oral doxycycline monohydrate can (1) slow the deterioration of, or improve, retinal function or (2) induce regression or slow the progression of DR in patients with severe nonproliferative DR (NPDR) or non-high-risk proliferative (PDR), and to determine the potential usefulness of visual function end points to expedite the feasibility of conducting proof-of-concept clinical trials in patients with DR.

Design, setting, and participants: We conducted a randomized, double-masked, 24-month proof-of-concept clinical trial. Thirty patients (from hospital-based retina practices) with 1 or more eyes with severe NPDR or PDR less than Early Treatment Diabetic Retinopathy Study-defined high-risk PDR.

Interventions: Patients were randomized to receive 50 mg of doxycycline monohydrate or placebo daily for 24 months.

Main outcomes and measures: Change at 24 months compared with baseline in functional factors (frequency doubling perimetry [FDP], Humphrey photopic Swedish Interactive Thresholding Algorithm 24-2 testing, contrast sensitivity, dark adaptation, visual acuity, and quality of life) and anatomic factors (Early Treatment Diabetic Retinopathy Study DR severity level, area of retinal thickening, central macular thickness, macular volume, and retinal vessel diameters).

Results: From baseline to month 24, mean FDP foveal sensitivity decreased in the placebo group (-1.9 dB) and increased in the doxycycline group (+1.8 dB) (P = .02). A higher mean FDP foveal sensitivity in the doxycycline group compared with the placebo group was detected at 6 months (P = .04), and this significant difference persisted at 12 and 24 months. A difference between the groups was not detected with respect to the other visual function outcomes and all anatomic outcomes assessed.

Conclusions and relevance: 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. Oral doxycycline may be a promising therapeutic strategy targeting the inflammatory component of DR. Furthermore, study results suggest that FDP, which primarily measures inner retinal function, is responsive to intervention and may be a useful clinical trial end point for proof-of-concept studies in patients with DR.

Trial registration: clinicaltrials.gov Identifier: NCT00511875.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Ocular
  • Adult
  • Aged
  • Anti-Bacterial Agents / administration & dosage
  • Contrast Sensitivity*
  • Diabetic Retinopathy / complications
  • Diabetic Retinopathy / drug therapy*
  • Diabetic Retinopathy / physiopathology
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Doxycycline / administration & dosage*
  • Feasibility Studies
  • Female
  • Fluorescein Angiography
  • Follow-Up Studies
  • Fundus Oculi
  • Humans
  • Male
  • Middle Aged
  • Retina / drug effects
  • Retina / pathology
  • Retina / physiopathology*
  • Retrospective Studies
  • Surveys and Questionnaires
  • Time Factors
  • Treatment Outcome
  • Visual Field Tests
  • Visual Fields*
  • Vitreoretinopathy, Proliferative / drug therapy*
  • Vitreoretinopathy, Proliferative / etiology
  • Vitreoretinopathy, Proliferative / physiopathology
  • Young Adult


  • Anti-Bacterial Agents
  • Doxycycline

Associated data

  • ClinicalTrials.gov/NCT00511875