Diabetic Retinopathy: Beneficial Effects Shown in Experimental Model with Linagliptin

Value-Based Care in Cardiometabolic Health August 2012, Vol 1, No 2
Mary Mosley

The dipeptidyl peptidase (DPP)-4 inhibitor linagliptin was shown to have a protective effect on the microvasculature of the diabetic retina, most likely as a result of a combined effect on the neurovascular unit, according to data presented at the 2012 ADA annual meeting by Hans-Peter Hammes, MD, PhD, of the University of Heidelberg, Germany.

The effect of DPP-4 inhibitors on the diabetic vasculature is still being studied. DPP-4 inhibition could have effects on oxidation, apoptosis, and vasoprotection, but it has also been shown to be proangiogenic, which could be an untoward effect in the diabetic eye.

Glucose and hemoglobin (Hb) A1c levels were reduced by 10% to 15% with linagliptin in the diabetic rats.  Diabetes was induced in the rats with streptozotocin. One group of diabetic rats was fed food containing linagliptin (0.083 g/kg) for 26 weeks, and another diabetic group and the control group were fed regular food.

DPP-4 activity was reduced by 75% with linagliptin. Surprisingly, active glucagon-like peptide (GLP)-1 was increased by more than 12-fold with linagliptin; Dr Hammes said that this may contribute to the benefits seen in this study.

Methylglyoxal, a major factor in the reduction of vascular damage, was significantly reduced by 50% in the diabetic rats receiving linagliptin compared with a 4-fold increase in the diabetic rats who did not (P = .01).

Regarding the retinal morphology, for the first time, the researchers discriminated between the superficial layer of the retina and the layer proximal to the large vessels. Notably, they found a >80% reduction of acellular capillaries with linagliptin, primarily in the deep capillary layer proximal to the photoreceptors. In neurodegenerative models, this layer is the site where capillary degeneration starts. Diabetic retinopathy is thought to be a neurodegenerative disease.

Dr Hammes and colleagues established 4 years ago that pericyte loss occurs in the diabetic retina of most models of hyperglycemia, and that pericyte migration is an important contributing mechanism to this loss. In the present study, the usual 25% rate of pericyte loss was found in the diabetic rats, but this was normalized with linagliptin. Pericyte migration, which occurs when endothelial cells are damaged, was normalized.

No proangiogenic effect of lina­gliptin was found in the diabetic retina. Stromal-derived factor concentrations were not changed, indicating that there was no signal to recruit more stem cells to the diabetic retina for repair.

The major effect of DPP-4 inhibition on the vasculature was seen in the ganglion-cell layer, the location of the large neurons, of the diabetic retina. Linagliptin increased active GLP-1 and phospho-Akt and reduced capillary damage. The reduction in reactive oxygen species and methylglyoxal found in the present study has since been confirmed by the investigators in another experimental model that contained only neurons.

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