SGLT Inhibitors

Back in the late 1800’s, a compound called phlorizin, found in the bark of apple trees, was isolated by French chemists.

Since then it has been put to use in multiple ways, but most notably in the physiological research of renal function because of its ability to cause glucosuria. Various studies of phlorizin through the decades showed that the transporters are located in the brush border cells, that sodium is required as a co-transporter for the reabsorption of glucose, and that phlorizin is a competitive inhibitor of glucose transport. Phlorizin is non-selective, inhibiting both SGLT1 and SGLT2, so it has not held an interest as an anti-diabetic agent. It is hydrolyzed to phloretin in the gastrointestinal tract giving it poor oral bioavailability and it is potentially toxic. Fortunately, clinical studies are currently underway for selective SGLT2 inhibitors for their use as antidiabetic agents.

How they work and what they do as a new drug class

There are two primary membrane transporters that reabsorb glucose back into the blood stream. They are sodium-glucose co-transporter 1 (SGLT1) and sodium-glucose co-transporter 2 (SGLT2). SGLT1 is a high affinity, low capacity transporter requiring 1 glucose and 2 sodium molecules. Found throughout the body SGLT1 can be located in the brain, skeletal muscle, intestine, lungs, liver, and kidney. In the kidney, SGLT1 is located in the S3 segment of the proximal renal tubule contributing to less than 10% of the renal reabsorption of glucose. SGLT1 is the primary transporter of glucose in the gastrointestinal tract making it necessary for the normal absorption of dietary glucose.

SGLT2 is a low affinity, high capacity transporter requiring 1 glucose and 1 sodium molecule. It is almost exclusively found in the S1 segment of the proximal renal tubule and accounts for about 90% of the renal reabsorption of glucose. SGLT2 would be the better target to create glucosuria. There are various moieties of SGLT2 inhibitors being researched, but the two farthest along in clinical studies are C-glucosides and O-glucosides. Both of these glucoside versions are based off of the glucoside ring in phlorizin which is responsible for binding to the SGLT2 transporter. The O- and C-linked phenolic distal rings are accountable for the inhibitory properties. The addition of lipophilic groups to the distal ring enhances the transporter inhibition and increases selectivity for SGLT2 over SGLT1. The enzyme, beta-glucosidase, has a greater affinity towards the O-glucoside linked ring leading to a higher risk of hydrolysis. It is essential for the O-glucoside SGLT2 inhibitors to be developed as pro-drug esters to avoid breakdown by beta-glucosidase in the small intestine after administration. On the other hand, the C-glucoside SGLT2 inhibitors tend to be more metabolically stable, compared to the O-glucosides, and were developed to address that potential therapeutic limitation. Researchers looked at the O-glucosides, changing the bond between glucose and the agylcone moiety to a carbon-carbon bond creating the C-glucosides, making them unsusceptible to beta-glucosidase. Alternative SGLT2 inhibitors include N-glucosides, modified sugar rings, bridged ketal rings, and antisense oligonucleotides. The antisense oligonucleotides inhibit the expression of SGLT2 by binding synthesized strands of nucleic acid to the SGLT2 messenger RNA. Administration of ISIS 388626 once weekly caused an 80% reduction in renal SGLT2 mRNA expression in animal models.

Hardman TC, Dubrey SW. Development and Potential Role of Type-2 Sodium-Glucose Transporter Inhibitors for Management of Type 2 Diabetes. Diabetes Therapy (2011) 2(3):133-145.

Long-term HbA1c levels may not significantly be lowered in the clinical setting. Modest HbA1c lowering capabilities of 0.5%-0.9% would be comparable to currently marketed agents for glucose lowering capacity. Due to the nature of glucose excretion by blocking reabsorption, it remains to be seen whether this will result in long term benefits such as metabolic balance or weight loss. The greatest benefit appears to be when the plasma glucose concentrations are highest, for instance, during post-prandial hyperglycemia. The SGLT2 inhibitors have the potential to block 90% of glucose reabsorption by the kidney, so there is the clinical potential to excrete 160 g of glucose each day. However, the trend in the clinical studies appears to only be excreting half that amount per day. There are possible compensating mechanism theories, but the true reasoning behind this is uncertain.

Since the target of SGLT2 inhibitors is so specific and the membrane transporter itself is almost exclusively known to reside in the renal tubules, the potential for cross-reaction should be low. It is unlikely SGLT2 inhibitors will induce hypoglycemia. If the plasma glucose levels are low only a small amount of glucose will be excreted in the urine. SGLT2 works independently of insulin and can be used with other antidiabetic medications with minimal risk of hypoglycemia. Even if the SGLT2 transporters are completely blocked, the SGLT1 transporters are available with a degree of glucose recovery. Due to the nature of the SGLT2 inhibitors to cause glucosuria there is the potential for increased risk of urinary tract infections (UTI). The likelihood of individuals experiencing a higher rate of UTI while on SGLT2 inhibitors needs to be looked into further. A larger amount of glucose in the urine also raises the probability of increased urine flow due to the osmotic diuretic effect.This could lead to modest reductions in blood pressure; however concerns of dehydration and loss of solutes are just as plausible. The effects look to be lower than that of loop diuretics. It is speculated that simple hydration maintenance may be all that is needed to overcome this obstacle. There is also a rare group of people with a genetic mutation that blocks the SGLT2 transporter partially or in whole. These individuals do not seem to endure any poor consequences, suggesting T2DM patients that use the SGLT2 inhibitors would not pose an immediate risk.

Current SGLT2 inhibitor clinical studies according to Clinicaltrials.gov

None of the SGLT2 inhibitors are currently approved by the Food and Drug Administration (FDA) but several companies are in the process of submitting New Drug Applications (NDA) to the FDA. Below are some press releases from the companies developing these agents.

1. Janssen Research & Development Submits New Drug Application to U.S. FDA for Canagliflozin to Treat Patients with Type 2 Diabetes: May 31, 2012. Janssen Research & Development, LLC (Janssen), announced today that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for the use of canagliflozin, an investigational, oral, once-daily, selective sodium glucose cotransporter 2 (SGLT2) inhibitor, for the treatment of adult patients with type 2 diabetes. (Janssen)
2. AstraZeneca and Bristol-Myers Squibb receive complete response letter from US Food and Drug Administration for dapagliflozin: January 19, 2012. The complete response letter requests additional clinical data to allow a better assessment of the benefit-risk profile for dapagliflozin. This includes clinical trial data from ongoing studies and may require information from new clinical trials. AstraZeneca and Bristol-Myers Squibb will work closely with the FDA to determine the appropriate next steps for the dapagliflozin [NDA] application and are in ongoing discussions with health authorities in Europe and other countries as part of the application procedures. (AstraZeneca)
3. FORXIGA (dapagliflozin) receives positive CHMP opinion in the European Union for the treatment of type 2 diabetes: April 20, 2012. AstraZeneca and Bristol-Myers Squibb Company today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended the approval of FORXIGA (dapagliflozin) tablets for the treatment of type 2 diabetes, as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products including insulin, and as a monotherapy in metformin intolerant patients. (AstraZeneca)
4. 90-week data suggest sustained glucose reduction and weight loss with investigational SGLT-2 inhibitor, empagliflozin: June 9, 2012. Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company (NYSE: LLY) presented results that showed empagliflozin (BI 10773), alone or as an add-on to metformin, reduced hemoglobin A1c (HbA1c or A1C) levels, fasting plasma glucose (FPG) levels and body weight when given to adults with type 2 diabetes for up to 90 weeks. A1C is measured in people with diabetes to provide an index of blood glucose control for the previous two to three months. The new data, from a phase 2b open-label extension study, were presented during a late-breaking session at the American Diabetes Association’s (ADA’s) 72nd Scientific Sessions®. (Lilly)

1. Hardman TC, Dubrey SW. Development and Potential Role of Type-2 Sodium-Glucose Transporter Inhibitors for Management of Type 2 Diabetes. Diabetes Therapy (2011) 2(3):133-145.
2. Nair S, Wilding JP. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab 95: 34 –42.
3. Sodium-Glucose Transporter 2 Inhibitors: New Therapeutic Targets, New Therapeutic Options in the Treatment of Type 2 Diabetes Mellitus. Medscape Diabetes & Endocrinology © 2008.
4. AstraZeneca andBristol-Myers Squibb receive complete response letter from US Food and Drug Administration for dapagliflozin. AstraZeneca Media Press releases. January 19,2012.
5. Janssen Research & Development Submits New Drug Application to U.S. FDA for Canagliflozin to Treat Patients with Type 2 Diabetes. Janssen News Releases. May 31, 2012.
6. 90-week data suggest sustained glucose reduction and weight loss with investigational SGLT-2 inhibitor, empagliflozin. Lilly newsroom. June 9, 2
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8. From Diabetesincontrol.com, Erica Paul, PharmD, Graduate Intern University of Florida College of Pharmacy
9. Nyhetsinfo
10. www red DiabetologNytt