A team of researchers from the University of Florida and the Erasmus Medical Center in the Netherlands have demonstrated that a drug cocktail of the blood pressure medication irbesartan and the anti-diarrheal agent thiorphan reduced symptoms and slowed progression of diabetic retinopathy in a rat model.
The experiment follows previous investigations that showed combinations of angiotensin receptor blockers and neprilysin inhibitors – which block the breakdown of diuretic and vasodilating natriuretic peptides – are more effective at lowering blood pressure, reducing risk of heart failure and improving cardiovascular outcomes in diabetic patients than use of renin-angiotensin system (RAS) inhibition alone.
Long term use of neprilysin inhibitors in the eye has not yet been evaluated, and the possible chronic effects must be understood before this treatment can advance to human testing. Future research will also need to assess whether the beneficial effects of ARNI are independent of the blood-pressure lowering effect.
Yet the authors are optimistic that the drug cocktail could someday be a promising option for managing diabetic retinopathy.
“The two drugs did not completely reverse the effects of diabetic retinopathy, but they slowed it in the animal models,” said co-author Tuhina Prasad, PhD. "If you can decrease that inflammation, it protects the retinal cells and delays the progression of the disease.”
In the study, published in Investigative Ophthalmology & Visual Science, diabetic rats were given ibesartan alone (ARB), ibesartan+thiorphan (ARNI) or vehicle via an osmotic minipump, and followed for either 5 or 12 weeks. After 5 weeks, both the ARB and ARNI groups displayed less capillary loss, gliosis and apoptotic cell death than the vehicle-treated rats.
The superiority of the cocktail over the single agent was pronounced in the 12-week group, with ARNI rats showing 51% and 68% reductions in the amount of cell death and capillary loss compared to control, respectively, whereas ARB rats showed decreases of 25% and 43%.
In addition, retinal expression levels of inflammatory cytokines and angiogenic factors were significantly lower in the ARB and ARNI eyes compared with controls after both 5 and 12 weeks, and levels in ARNI eyes were consistently lower than those that received ARB alone.
As expected, rats receiving ARB and ARNI showed significantly reduced mean arterial blood pressure, though weight and blood glucose levels were not affected.