What’s New on the Horizon?
Sodium-glucose co-transporter 2 (SGLT2) inhibitors, the first drugs to actually eliminate glucose from the body, are paving the way for a new wave of diabetes treatment options. Canagliflozin (Invokana®) took the U.S. market by storm when it became the first in class SGLT2 inhibitor to be approved by the U.S. Food and Drug Administration (FDA) in March 2013 but other drug companies are doing their best to bring their products to market as quickly as possible. Sitting in the pipeline are AstraZeneca/Bristol-Meyers Squibb’s dapagliflozin (Forxiga®) which has been approved in Europe since 2012 and has an advisory committee meeting set with the FDA on December 12, 2013; Eli Lilly and Boehringer Ingelheim’s empagliflozin which has a NDA with the FDA and is currently in phase III trials; and Pfizer and Merck’s ertugliflozin (PF-04971729) which is ready for phase III studies….
See more SGLT-2 Resources
So why the expansion of SGLT2 inhibitor-containing combination drugs? One reason is that SGLT2 inhibitors are currently recommended as an add-on treatment and making a combination drug could allow for decreased pill burden and improved efficacy. A second reason is that these combinations could move the SGLT2 inhibitors towards a place in the primary therapy option lineup. A third intriguing reason in this push toward combination is that although the effects of inhibiting the SGLT2 in the kidney bring a novel way of getting glucose out of the body, the SGLT2 inhibitors have not always proven to be as effective as research has posited they could be. Blocking the SGLT2 inhibitor was the main target that drug companies looked at for a new class in diabetes drugs because it is the high capacity glucose transporter in the proximal renal tubule. Basic anatomy and physiology made this transporter seem like the ideal target. The SGLT2 is located more proximal in the renal tubule than the SGLT1 and has a higher capacity for filtering glucose load. Previous research indicated that the SGLT1 was only responsible for reabsorbing approximately 20% of the glucose load while the SGLT2 reabsorbs about 80% – 90% of the glucose load, based on normal blood glucose levels. However, we are not seeing as much of an effect from SGLT2 inhibitors as expected. If they were truly blocking reabsorption of 80% of the glucose load, we would see a more significant glycosuria and most likely a larger drop in blood sugars as well as a larger impact on weight loss. However, recent new research has demonstrated that the SGLT1 can up-regulate its re-absorptive capacity when faced with higher glucose loads. In fact, research based on SGLT2 knockout mice indicated that up to 70% of filtered glucose load was still reabsorbed and when SGLT2/SGLT1 knockout mice were assessed, the glucosuric effect was tripled1,2.
In order to improve their place on the market and to provide more efficacy, SGLT2 inhibitors may be seen in more and more combination drugs. Currently, AstraZeneca/Bristol-Meyers Squibb’s Xigduo (dapagliflozin/metformin combo drug), which will come in 2 fixed dosages of film-coated tablets: 5-mg dapagliflozin/850-mg metformin, and 5-mg/1000-mg, with twice a day dosing recommendations, has received positive feedback for approval in the European Union by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). Also, Merck and Pfizer may team up to provide a Januvia/ertugliflozin combination pending ertugliflozin’s approval for use in the U.S. and on the forefront of SGLT1/SGLT2 inhibitor combination drugs, Lexicon Pharmaceuticals is showing promise with their pipeline agent, LX4211, which is currently in phase IIb studies. Preliminary data from their phase IIb studies in type 2 diabetes patients indicated that HbA1C was reduced by up to 1.25%; half of the patient’s HbA1C decreased to <7%; and other cardio-metabolic improvements were also noted including weight loss, reduced blood pressure and decreased triglycerides3.
Right now, we only have canagliflozin (Invokana) approved for use in the U.S. as an add-on treatment to current diabetes management but it appears we may have a flood of new products hit the market in the next several years which contain SGLT2 inhibiting effects as long as manufacturers can safely find a way of combining these agents.
- Powell, DR et al. Improved Glycemic Control in mice lacking SGLT1 and SGLT2. American Journal of Physiology Endocrinology Metabolism 2013; 304:E414 – E423.
- Abdul-Ghani, M. et al. Novel Hypothesis to Explain Why SGLT2 Inhibitors Inhibit only 30 – 50% of Filtered Glucose Load in Humans. Diabetes 2013; 62: 3324 – 3328, 2013
- LX4211. Clinical Trials Pipeline. Lexicon Pharmaceuticals Online; Accessed 10 December 2013: http://www.lexgen.com/pipeline/lx4211.html
- SGLT2 Drugs. Fierce Biotech: The Biotech Industry’s Daily Monitor. 2013 FierceMarkets. Accessed 10 December 2013. http://www.fiercebiotech.com/tags/sglt2-drugs