The degree of heterotopic lipid deposition in T2DM patients is much higher than that in non-diabetic patients; this not only promotes insulin resistance, impairs pancreatic β-cell function, and aggravates metabolic disorder but also is an important pathological basis leading to the damage of target organ function. The accumulation of lipids in organs can lead to local lipotoxic injury. To date, a large number of studies have focused on the ectopic deposition of fat in the liver and pancreas, leading to the formation and progression of nonalcoholic fatty liver and promoting the damage of pancreatic β-cells. However, there is little research on renal lipid ectopic deposition. Some studies have confirmed that the accumulation of fat in the kidneys is also an independent risk factor for kidney injury. Therefore, reversing or reducing ectopic lipid deposition in the kidneys early on is an effective strategy for early kidney protection in patients with T2DM. A large pool of data from evidence-based medicine has proved that SGLT2 inhibitors are antihyperglycemic drugs of a cardiorenal risk-reducing agent [18, 19]. Previous studies have concluded the potential mechanisms that contribute to their protective effects on the kidney include (1) restoration of the tubuloglomerular feedback, (2) decreased activation of the intra-renal renin–angiotensin–aldosterone system, (3) increased production of ketone bodies, and (4) protection against oxidative stress, and fibrosis [20]. In addition, studies have confirmed that SGLT-2 inhibitors can lessen abdominal visceral fat content and liver fat accumulation in T2DM patients while simultaneously reducing their weight [21, 22]. These studies suggested that SGLT-2 inhibitors can display a renal-protection mechanism independent of its hypoglycemic, hypotensive, and tubuloglomerular feedback by reducing renal fat content. In this study, the findings suggested that weight loss can be achieved through short-term lifestyle intervention, but the extent to which fat content in the kidneys is reduced is limited. However, canagliflozin can significantly reduce the content of fat in the kidneys.

The accumulation of fat in the kidneys can not only lead to lipotoxic injury but also exacerbate renal hypoxia. Chronic renal hypoxia is also a common pathogenic pathway of kidney injury mediated by various pathogenic factors of diabetes, which is an important trigger that induces and aggravates oxidative stress injury [23]. BOLD MRI is currently the only noninvasive technique that can detect the oxygenation level of tissues in vivo, which can reflect the oxygen content and oxygen saturation of tissues so as to reflect the functional state of tissues, and it shows good consistency with the oxygen partial pressure measured directly by microelectrodes [24,25,26]. The kidney is a highly perfused organ, and the cortex–medulla pairing has a natural oxygen partial pressure gradient, making it an ideal organ for BOLD MRI examination. BOLD MRI can use deoxyhemoglobin as an endogenous contrast agent to indirectly reflect the partial pressure of local tissue oxygen without increasing the metabolic burden on the kidneys, evaluate the blood oxygen level of the tissue, and make it possible to reflect kidney function earlier than the morphological changes of the kidney [25, 26]. The measurement results of the BOLD MRI parameter R2* have high reliability. The results showed that canagliflozin can improve hypoxia of the renal cortex and medulla in newly diagnosed diabetic patients, which may confirm a protective effect of canagliflozin on the kidneys independent of lowering blood glucose. This phenomenon may be related to the mechanism that SGLT2 inhibitors could induce an overall metabolic shift toward a fasting state, characterized by the increased use of lipids and ketones as energy substrates, which may improve oxygen availability and attenuate renal hypoxia [27, 28]. Previous study also discovered that SGLT2 inhibitors could reduce HIF-1 activity and/or promote HIF-2α activity, increasing erythropoietin [29]. The latter increases hematocrit and improves O2 delivery to the kidney medulla and cortex [29]. This effect may be related to SGLT2 inhibitors’ ability to alleviate renal glycolipid toxicity, thereby reducing the inflammatory response. The results also suggested that canagliflozin may have a primary preventive effect against diabetic nephropathy.

Based on the aforementioned findings, the correlation between the reduction in renal FF and the improvement in hypoxia was further analyzed. A significant correlation between the decrease in renal FF and the oxygenation level of the renal cortex was found. These results suggested that the improvement of the renal cortex oxygenation level brought on by canagliflozin related to the reduction in renal fat deposition.

Moreover, canagliflozin can significantly improve renal medulla hypoxia, but the improvement in renal medulla oxygenation level showed no significant correlation with the reduction of renal FF. The reason for this trend may be that the R2* value of the renal medulla was higher than that of the renal cortex in T2DM patients with normal renal function in this study, whether at baseline or after treatment. Canagliflozin can improve renal cortex hypoxia by reducing the accumulation of renal fat, while the mechanism of renal medullary hypoxia and renal cortical hypoxia in T2DM is different. The renal medulla itself has a low oxygen content, but the renal tubule consumes much oxygen in the reabsorption process of macromolecular substances and ions. Such a physiological function of low oxygen and high load determines that the renal medulla is more susceptible to ischemia and hypoxia. Under the condition of glomerular hyperfiltration, the renal tubule reabsorption burden, sodium pump activity, and cell oxygen consumption all increased. Conversely, after treatment with canagliflozin, sodium uptake by renal tubules and oxygen consumption of cells decreased, thus alleviating hypoxia in the kidney medulla. Therefore, the improvement of renal medulla hypoxia caused by canagliflozin is related to the reduction of renal tubular reabsorption of sodium and glucose. Hesp et al. also speculated in their review that SGLT-2 inhibitors may play a protective role in the kidneys by improving hypoxia of the renal cortex in DKD patients [30]. Our research not only confirmed the hypothesis of Anne et al. in newly diagnosed diabetic patients but, also, the newly diagnosed T2DM patients enrolled in this study all had normal renal functions, so these patients were in diabetic CKD1 stage. The results also suggested that renal cortex and medullary hypoxia could occur in the early stage of DKD. Zanchi et al. did not observe the effect of empagliflozin on the oxygenation level of non-diabetic patients’ kidneys [31], which may be related to the fact that the kidneys of non-diabetic volunteers did not suffer from hypoxic damage. This study also confirmed the renal damage caused by chronic hypoxia in patients with T2DM from another perspective. Therefore, improving the hypoxia state of the kidneys early on is beneficial to inhibit the progression of DKD. Canagliflozin can protect the kidneys by improving the oxygenation level of newly diagnosed T2DM patients.

Moreover, in our study, only two patients experienced side effects of mild urinary tract infections, and four patients had mild urine ketone body positivity. We also did not observe any adverse reactions associated with interactions of canagliflozin and other drugs such as metformin. Canagliflozin performed a good safety profile in these newly diagnosed T2DM patients overall.

Limitations of this study include a relatively modest sample size, and this was a single-center study. The findings should be further verified in a larger, multicenter study, and the specific molecular mechanism needs further investigation. Meanwhile, long-term follow-up data are required to determine whether the observed beneficial effects of canagliflozin on renal outcomes are sustained over time.

To sum up, canagliflozin can reduce the ectopic deposition of renal lipids and improve chronic renal hypoxia in newly diagnosed T2DM patients with normal renal function. The use of SGLT-2 inhibitors during the early stages of T2DM may have an early renal benefit.