Drugs for Diabetes: Part 8 SGLT2 Inhibitors

Alison MacEwen; Gerard A McKay; Miles Fisher

Disclosures

Br J Cardiol. 2012;19(1):26-29. 

In This Article

Pharmacology

Under normal physiological conditions, approximately 180 g of glucose is filtered by the kidney daily. Almost all of this is re-absorbed into the circulation via sodium glucose co-transporters (SGLTs). SGLTs transport sodium and glucose into cells using the sodium gradient created by sodium/potassium ATPase pumps at the basolateral cell membranes. Glucose is then transported passively by GLUT2 along its concentration gradient into the interstitium. Approximately 10% of renal glucose re-absorption occurs via SGLT1, and the remaining 90% occurs via SGLT2, which is found in the early proximal tubule.[8]

Phlorizin, a bitter white glycoside isolated from apple tree bark by French chemists in 1835, is a naturally occurring inhibitor of both SGLT1 and SGLT2 and was used for the treatment of diabetes in the pre-insulin era. Its use was limited by poor oral bioavailability and side effect profile. SGLT1 is expressed in the intestinal mucosa as well as the kidney. Its use as a therapeutic target is limited by side effects from malabsorption of glucose and galactose in the small intestine.[8]

Several specific SGLT2 inhibitors are currently under development including dapagliflozin, canagliflozin, empagliflozin, ipragliflozin and tofogliflozin. These work independently of insulin to prevent glucose re-absorption from the glomerular filtrate resulting in a reduced renal threshold for glucose, glycosuria and net calorie loss (Figure 1).[8]

Figure 1.

SGLT2, a high-capacity, low-affinity transporter of glucose and sodium is found in high concentration at the brush border membrane of the S1 and S2 segment of the proximal convoluted tubule (PCT). SGLT2 binds to sodium and glucose in the filtrate and these compounds are translocated across the apical cell membrane, an active process driven by the electrochemical sodium gradient between tubular filtrate and the cell. The second stage of re-absorption is the transport of glucose through the utilisation of GLUT2 transporters in the basolateral membrane. In poorly controlled diabetes, the threshold for re-absorption is exceeded resulting in glycosuria. By blocking the SGLT2 transporter, re-absorption of glucose is reduced resulting in glycosuria and a reduction in blood glucose levels

Of the SGLT2 inhibitors under development, dapagliflozin is furthest along in development. Phase I clinical data indicate that dapagliflozin has a pharmacokinetic profile of a once-daily drug with good oral bioavailability. It produces glycosuria in a dose-dependent fashion with a maximum plasma concentration within two hours and a mean half-life ranging from 11 to 17 hours.[9]

In phase IIa studies, dapagliflozin administered at 5 mg, 25 mg and 100 mg doses inhibits approximately 40% of renal glucose re-absorption when compared with baseline resulting in excretion of up to 70 g of glucose per day.[10] Overall, dapagliflozin was well tolerated. Reported side effects include a higher incidence of genital fungal infections, particularly at higher doses.

Less published data are currently available on canagliflozin. A phase I study has recently reported that canagliflozin also produces glycosuria in a dose-dependent fashion and is well tolerated in healthy euglycaemic subjects.[11]

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