SGLT2 Inhibitor–Induced Low-Grade Ketonemia Ameliorates Retinal Hypoxia in Diabetic Retinopathy—A Novel Hypothesis

Abstract

Diabetic retinopathy (DR) is a well-recognized microvascular complication of diabetes. Growing evidence suggests that in addition to retinal vascular damage, there is significant damage to retinal neural tissue in DR. Studies reveal neuronal damage before clinically evident vascular lesions and DR is now classified as a neuro-vascular complication. Hyperglycemia causes retinal damage through complex metabolic pathways leading to oxidative stress, inflammation, vascular damage, capillary ischemia and retinal tissue hypoxia. Retinal hypoxia is further worsened by high oxygen consumption in the rods. Persistent hypoxia results in increases in vascular endothelial growth factor (VEGF) and other pro-angiogenic factors leading to proliferative DR/macular edema and progressive visual impairment. Optimal glucose control has favorable effects in DR. Other treatments for DR include laser photocoagulation, which improves retinal oxygenation by destroying the high oxygen consuming rods and their replacement by low oxygen consuming glial tissue. Hypoxia is a potent stimulator of VEGF, and intra-vitreal anti-VEGF antibodies are effective in regressing macular edema and in some studies, retinal neovascularization. In this review, we highlight the complex pathophysiology of DR with a focus on retinal oxygen/fuel consumption and hypoxic damage to retinal neurons. We discuss potential mechanisms through which SGLT2-inhibitors improve retinal hypoxia - through ketone bodies which are energetically as efficient as glucose and yield more ATP per molecule of oxygen consumed than fat, along with less oxidative stress. Retinal benefits would occur through improved fuel energetics, less hypoxia and through the anti-inflammatory/oxidative stress effects of ketone bodies. Well-designed studies are needed to explore this hypothesis.

Revealing the Angiopathy of Lacrimal Gland Lesion in Type 2 Diabetes

“…RI and PI are vital parameters for characterizing the arterial waveform and vascular resistance (Halpern et al, 1998 ; Bude and Rubin, 1999 ; Grenier et al, 2001 ; Heine et al, 2005 ). Increased vascular resistance along with tissue atrophy in diabetes indicated the occurrence of the hypoxia-ischemic syndrome in the tissue endings (Liu et al, 2017 ; Nilsson et al, 2020 ), which is a common mechanism of diabetic vascular complications (Fadini et al, 2010 ; Mudaliar et al, 2021 ).…”

Will GLP-1 Analogues and SGLT-2 Inhibitors Become New Game Changers for Diabetic Retinopathy?

“…SGLT-2 inhibitor-dependent low-grade hyperketonemia, resulting in shift of fuel metabolism from glucose and fat oxidation to more energy efficient and less oxidative stress producing ketone metabolism, has been suggested to account for the cardiorenal beneficial effects [ 70 ]. Since human retina is a highly oxygen-consuming unit, such a metabolic switch, together with the anti-inflammatory and anti-oxidative properties of ketones, could potentially exert a beneficial effect also for DR [ 71 ]. In a recent study conducted in a diabetic mice model this inhibition of oxidative stress and apoptosis, improvement of tight junction in the retina, reduction of inflammation and production of angiogenic factors was demonstrated for empagliflozin, suggesting its potential for the prevention of DR [ 72 ]…”

Risk of diabetic macular oedema with sodium‐glucose cotransporter‐2 inhibitors in type 2 diabetes patients: A multi‐institutional cohort study in Taiwan

“…42 Leukostasis leads to ischaemia, secretion of VEGF, neovascularization and DMO. 43 SGLT2 inhibitors decrease the cellular influx of sodium and glucose, 42 induce low-grade ketonaemia, ameliorate retinal hypoxia, 44 and lower the levels of proinflammatory cytokines 14,15 ; hence they could theoretically be beneficial with regard to DMO. In addition, very few laboratory animal models (eg, zebrafish, rodents and lagomorphs) can fully reproduce the macular oedema phenotype in humans, 17 so the exact mechanism of SGLT2 inhibitors on DMO may be hard to prove in animal models.…”