Pharmacokinetic and Pharmacodynamics of YG1699 in Patients With Diabetes and Kidney Dysfunction

Background

Diabetic kidney disease (DKD), as one of the most common and serious complications of diabetes, has become the leading cause of end-stage renal disease (ESRD) worldwide. A domestic epidemiological survey shows that the prevalence of DKD in community patients was 30%-50% from 2009 to 2012, and accounted for about 40% in hospitalized patients in China. At present, the treatment of DKD is the comprehensive management of blood glucose, blood pressure and blood lipid. Nevertheless, about one-third of patients with type 1 diabetes mellitus (T1DM) and nearly half of patients with type 2 diabetes mellitus (T2DM) will progress to ESRD. Patients with DKD have higher complication rates and mortality. Studies have shown that the mortality rate of patients with diabetes complicated with DKD is 3 to 12 times higher than that of patients with simple diabetes. Although blood glucose is actively controlled and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) are used to control hypertension in the treatment of diabetes, the progression of DKD is still inevitable. Much more clinical needs are still present. Sodium-glucose co-transporter inhibitors (SGLT2i) are new hypoglycemic drugs discovered in recent years. They play their hypoglycemic roles by inhibiting glucose reabsorption in renal tubules and increasing urinary glucose excretion. More clinical studies have found that SGLT2s not only the hypoglycemic effect, but also has the effect of delaying the progression of DKD and improving the prognosis of heart failure, and is recommended by international authoritative guidelines with class IA evidence for cardiorenal organ protection.

Glucose cannot freely pass through the cell membrane and must rely on glucose transporter proteins on the cell membrane. Sodium-dependent glucose cotransporters (SGLTs) are an important family of transporter proteins that regulate glucose absorption and excretion. SGLT1 and SGLT2 are the most well studied members of this family and are both major glucose transporter proteins. SGLT1 is expressed in various tissues such as the small intestine, heart and kidney. SGLT2 is mainly expressed in segment S1 of the proximal convoluted tubule of the kidney.

In the renal tubules, 95% of glucose is reabsorbed through SGLT2, and 5% of glucose is reabsorbed through SGLT1. When SGLT2 is inhibited, the glucose reabsorbed through SGLT1 significantly increases to 50%, so the hypoglycemic effect of SGLT2 inhibitors may be weakened. The dual effects of SGLT1 and SGLT2 inhibitors can bring more potential benefits for treatment, including continuing to maintain the effectiveness of SGLT2 selective inhibitors; inducing intestinal cells to secrete endogenous glucagon-like peptide-1 (GLP-1) and YY peptide (PYY); reducing the adverse reactions of SGLT2 inhibition, such as genitourinary tract infections and constipation; blocking or delaying the absorption of glucose by the gastrointestinal tract.

Sotagliflozin is a SGLT2i with partial SGLT1 inhibitory activity. It was approved by the European Medicines Agency (EMA) in 2019 for adjuvant treatment of T1DM complicated with obesity. Recently, the sotagliflozin heart failure protection study was terminated in the middle stage due to the excellent effect of improving the outcome of heart failure. And it has a good effect of reducing proteinuria in patients with DKD. This suggests that SGLT1/2 dual-channel blockers may have better hypoglycemic and organ protection effects.