Excretion of glucose analogue with SGLT2 affinity predicts response effectiveness to sodium glucose transporter 2 inhibitors in patients with type 2 diabetes mellitus

Abstract

Purpose Sodium-glucose cotransporter 2 inhibitor (SGLT2i) regulation, developed as treatment for patients with type 2 diabetes, can be imaged with the glucose analogue alpha-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside (Me4FDG), a positron emission tomography (PET) tracer with a high affinity for SGLT1 and SGLT2 proteins. With regard to therapy effectiveness, we aimed to investigate whether clinical parameters or Me4FDG excretion could predict response to SGLT2i in patients with type 2 diabetes. Methods In a longitudinal, prospective study, 19 patients with type 2 diabetes underwent Me4FDG combined PET and magnetic resonance imaging (PET/MRI) scans at baseline and 2 weeks after initiation of therapy with SGLT2i, accompanied by the collection of blood and urine samples. Me4FDG-excretion was determined from the Me4FDG uptake in the bladder. Long-term response was determined by HbA1c level after 3 months; a strong response to the therapy was defined as a reduction of HbA1c by at least 10% from baseline. Results SGLT2i resulted in significantly increased Me4FDG excretion (4.8 vs. 45.0, P < 0.001) and urine glucose (56 vs. 2806 mg/dl, P < 0.001). Baseline urine glucose and baseline Me4FDG excretion correlated both with long-term decline in HbA1c with r = 0.55 (P < 0.05). However, only Me4FDG excretion was a predictor of a strong response to SGLT2i (P = 0.005, OR 1.9). Conclusions Using Me4FDG-PET, we demonstrated for the first time renal SGLT2-related excretion before and after short-term SGLT2i treatment. In contrary to other clinical parameters, SGLT2-related excretion before treatment was a robust predictor of long-term HbA1c response in patients with type 2 diabetes, suggesting that therapy effectiveness is only dependent of endogenous SGLT2 processes.

In vivo assessment of safety, biodistribution, and radiation dosimetry of the [18F]Me4FDG PET-radiotracer in adults

“…Also recent findings in rodents suggest to use this tracer for renal examinations [ 19 ]. In particular, it was shown that renal uptake can be altered due to SGLT inhibition treatments, which was also already implied by our study [ 10 ]. Moreover, the animal data found that Me4FDG can be used to determine the effects of SGLT inhibition in the digestive tract [ 20 ], suggested to be used as patient selection tool for diabetic patients designated for SGLT inhibition therapy.…”

“…Herein, we investigated clinical safety, biodistribution and radiation dosimetry of [ 18 F]Me4FDG in 5 healthy adult volunteers with no history of oncologic or endocrinologic diseases While this tracer demonstrated no side effects in patients with type 2 diabetes in a 3-month longitudinal study [ 10 ], to our knowledge it has not yet been systematically studied in healthy volunteers.…”

“…While there are certain rare cancers [ 3 – 5 ] that warrant the application of this diagnostic tracer, it may also be of interest to utilize this tracer to understand the effects and consequences of SGLT1 inhibition therapies on the heart, where SGLT1 expression is associated with oxidative stress, inflammation and mitochondrial dysfunction [ 9 ]. As evidenced by the aforementioned study involving type 2 diabetes mellitus [ 10 ], Me4FDG may be able to be potentially employed to investigate the contribution of the renal system to obesity-related diseases, as Me4FDG is able to determine the threshold of renal glucose reabsorption, a process carried out exclusively by the two transporters SGLT1 and SGLT2.…”

“…Additionally, from the outcome of our earlier study, we are aware that the degree of washout of this tracer from the blood pool is comparable to that of [ 18 F]FDG, allowing static PET acquisition 60 min after tracer injection without expecting a high degree of tracer circulation in the blood pool [ 10 ].…”

“…Unlike [ 18 F]FDG, the tracer [ 18 F]Me4FDG is not phosphorylated but is effectively trapped, particularly in the kidneys, which have not only high SGLT2 but also SGLT1 expression levels [ 6 ], as well as in the heart [ 9 ] and in certain cancer cell types [ 5 ]. Due to its characteristics, this tracer is also of interest for patients suffering from diabetes type 2, where it has already been used in a study conducted at our institution [ 10 ]. Although we monitored the general health status and possible effects of toxicity of this tracer in all diabetic subjects during that study, this tracer was never investigated in healthy subject.…”