SGLT2 Inhibitors: good news for diabetes

Reviewed by Professor Anthony Barnett, Institute of Metabolism and Systems Research, University of Birmingham, UK.

SGLT2 Inhibitors: good news for diabetes

Within the last 3 years, the biggest development in treatment options for Type 2 Diabetes has been the emergence of sodium-glucose co-transporter 2 (SGLT2) inhibitors known as gliflozins. Inhibiting SGLT2 (the transporter responsible for most of the glucose reabsorption in the kidney) allows these medications to prevent around 25-30% of the kidneys' reuptake of glucose. This promotes glucose excretion in the urine and ultimately reduction of glucose in the blood. Glucose loss via the urine causes weight loss and the subsequent diuresis lowers blood pressure. The insulin independent mechanism of action dramatically reduces risk of hypoglycaemia and means that these agents can be successfully combined with any other anti-diabetes drug, including insulin, at any stage in the disease.

Potential blockbusters

The first SGLT2 inhibitor approved for Type 2 Diabetes anywhere in the world was AstraZeneca’s Forxiga (dapagliflozin), when the European Medicines Agency gave it approval in 2012. This once-a-day oral medication was approved as a monotherapy, and as a supplement to other anti-diabetes drug treatments, and subsequently approved in the US in 2014 as Farxiga. Since then it has also been approved as the combination drug Xigduo (dapagliflozin and metformin).

Janssen Pharmaceuticals came a close second behind AstraZeneca with its own gliflozin, canagliflozin, which was approved in the US and EU as Invokana in 2013. That made Invokana the first SGLT2 drug approved in the key US market, where it has made huge strides in sales since 2014. Invokamet (combined canagliflozin with metformin) has yet to be approved by the FDA, however EU approval has been granted, and alongside Invokana (US and EU), it was widely used during the first quarter of 2015.

Meanwhile Boehringer and Eli Lilly have their own competitor with Jardiance (empagliflozin), approved in both the US and EU in 2014. Of the gliflozins, empagliflozin has the highest specificity for SGLT2 inhibition. Jardiance is also the first anti-diabetes drug to display positive long term cardiovascular endpoint data (in the EMPA-REG study involving patients with Type 2 Diabetes and established cardiovascular disease). These included a dramatic effect on CV deaths, demonstrating a 38% risk reduction for this endpoint and similar reduction for overall mortality and heart failure. This is particularly significant because approximately three quarters of deaths among people with Type 2 Diabetes are due to CV disease. The company argues that this effect is specific to empagliflozin although it may well be a class effect (this is being tested in similar studies on-going with the other SGLT2 inhibitors), the FDA has recently accepted a supplemental New Drug Application for Jardiance based on cardiovascular risk reduction data. The EMPA-REG results may have had an impact on sales, as Jardiance has begun gaining traction on Invokana and Farxiga, and now accounts for 25 percent of new US patients taking SGLT2 inhibitors.

Boehringer and Eli Lilly were the first to get US approval for a combination of SGLT2 inhibitor with DPP-4 inhibitor with Glyxambi (empagliflozin plus linagliptin) in 2015. Glyxambi may soon have a competitor, as AstraZeneca is working on a combination treatment and filed Saxa Dapa FDC (saxagliptin, dapagliflozin, metformin) with the FDA at the end of 2015. This was rejected at the first instance, and the company has received a complete response from the agency meaning further work is required before approval can be given. Meanwhile a combination of Pfizer's developmental SGLT2 inhibitor ertugliflozin with Merck's DPP-4 inhibitor Januvia (sitagliptin) is also in late-stage testing.

Next generation treatments

There have also been several SGLT2 inhibitor approvals in Japan. Suglat (ipragliflozin), produced by Astellas Pharma, was approved in Japan in 2014 but is not likely to be marketed in the EU or US. Sanofi and Takeda Pharmaceutical have their own therapy: Deberza / Apleway (tofogliflozin), which was approved in Japan in 2014. Similarly, the Novartis SGLT2 inhibitor drug Lusefi (luseogliflozin) was also approved in Japan in 2014.

There are a number of other SGLT2 inhibitor therapies on the horizon, with about half a dozen currently in trials. Merck and Pfizer are co-developing MK 8835 (ertugliflozin) in phase III trials, both as a single therapy and in combination with metformin and with sitagliptin. Another treatment in Phase III trials is THR 1442 (bexagliflozin), from Theracos. Interestingly, THR1442 produced no increase in genital infection rates relative to the placebo, unlike other SGLT2 therapies. BHV Pharma’s remogliflozin is currently in Phase IIb trials in the US. BHV and Islet Sciences have developed a novel once-daily bi-phasic formulation that the companies hope will combine the efficacy of conventional twice-daily dosing, with the improved safety and tolerability profile demonstrated with once-daily dosing.

Remaining challenges

Which will be most successful? Research suggests that empagliflozin has the highest degree of selectivity for the SGLT2 receptors, followed by tofogliflozin, dapagliflozin, ipragliflozin and canagliflozin. However, in clinical practice, it is side effects which may prove the biggest challenge. In particular, SGLT2 inhibitors have been shown to lead to increased genital infections including thrush (which occurs more commonly in women), a possible increase in urinary tract infections, increased urination (which is rarely a problem or even noticed), small elevations in LDL cholesterol (perhaps mitigated by a corresponding increase in HDL-cholesterol), and episodes of low blood pressure. In practice genital infection is easily treated and rarely recurrent, and other side-effects mentioned are rare, with suitable cautions existing on the label of these drugs to ensure appropriate/safe usage. More serious concerns have been flagged up too; approval of dapagliflozin by the FDA in 2014 was accompanied by a demand for six post-marketing studies to investigate: CV impact, risk of liver and bladder cancers, effects on paediatric patients, and liver abnormalities and pregnancy outcomes.

In June 2015 the European Medicines Agency started a review of canagliflozin, dapagliflozin and empagliflozin. The aim was to evaluate the risk of diabetic ketoacidosis (DKA), a serious condition that usually develops in people with type 1 diabetes when insulin levels are too low. A total of 101 cases of DKA in patients treated with SGLT2 inhibitors for type 2 diabetes were reported worldwide in EudraVigilance as of 19 May 2015. Many cases were serious and required hospitalisation. Although DKA is usually accompanied by high blood glucose levels, in a number of these reports blood glucose was only moderately raised. These uncharacteristic findings could potentially delay diagnosis and treatment. It is important to recognise several important facts in the context of these reports:

1. These reports must be balanced against the fact that exposure to these medicines is over half a million patient years.

2. The massive (around 18,500 patient) database of clinical trials for canagliflozin reported only 12 cases of DKA, and on further analysis 6 of these had slowly progressive Type 1 Diabetes (Latent Autoimmune Diabetes of Adults-LADA).

3. Many of the reports of DKA have been associated with off label use of these drugs in Type 1 Diabetes.

4. Even patients with true Type 2 Diabetes, but who are not on these medications can develop DKA; where reported rates are not very different from those reported specifically in association with SGLT2 inhibitors.

5. Most case reports in those who do not have Type 1 Diabetes have been in longstanding insulin treated type 2 patients, who have insulin deficiency and often another acute problem such as a viral illness or are peri-operative.  This is clearly an issue that requires further research at present.

SGLT2 inhibitor drugs also face a challenge from competitors with other mechanistic effects. Incretin based therapies stimulate insulin and inhibit glucagon secretion in a glucose dependent manner, thereby reducing blood glucose when this is high but  “switching off” as glucose levels fall and normalise. For these reasons they rarely provoke hypoglycaemia, and are weight neutral or cause weight loss. There are two classes of such agents: orally active DPP-4 inhibitors which are extremely well tolerated, weight neutral and with low risk of hypoglycaemia and GLP-1 receptor agonists. One of the latter is the injectable Victoza (liraglutide) from Novo Nordisk. In 2015 Novo Nordisk unveiled a new meta-analysis, showing that it was more effective at reducing HbA1c (a measure of long term glycaemic control) than SGLT2 drugs. The analysis of 17 controlled trials suggested that patients using Victoza had a better chance of meeting their HbA1c targets.

SGLT2 inhibitors are oral agents (GLP-1 RAs are injected) and as well as lowering blood glucose, they can stimulate weight loss - unlike DPP-4 inhibitors. SGLT2 inhibitors are significantly cheaper than GLP-1 RAs, and are similarly priced to DPP-4 inhibitors. In addition, SGLT2 inhibitors are the only anti-diabetes agents which have been shown to improve cardiovascular outcomes (including cardiovascular mortality, total mortality and heart failure) – although this has only been demonstrated in a single trial to date.

Future drugs

As well as a range of new combination treatments that are possible as a result of SGLT2 drugs, there are other variations which could prove promising. For example, Sanofi’s LX 4211 (sotagliflozin) is an orally-delivered medication currently in Phase II trials. It inhibits both the renally expressed SGLT2 receptors, and the SGLT1 receptor found in the GI tract, thus preventing glucose re-absorption in both the GI tract and kidneys, with potential for greater weight loss and reduction in blood glucose (but perhaps more side-effects). The developer of the drug, Lexicon, believes that sotagliflozin may be useful in renally-impaired diabetic patients. Development of single tablet combination SGLT2 plus DPP4 therapies are also underway, with the first already approved (see above). Results with triple therapy (SGLT2 + DPP4 + metformin) are promising. In one trial the proportion of patients achieving HbA1c less than 7% was 41% with triple therapy,18% with saxagliptin plus metformin and 22% with dapagliflozin plus metformin. A further exciting aspect of SGLT2 inhibitor use is that these therapies appear effective for use in combination with insulin therapy in Type 2 Diabetes. Studies to see if this applies to Type 1 Diabetes are underway.

Further Reading

The Mechanisms and Therapeutic Potential of SGLT2 Inhibitors in Diabetes Mellitus. Volker V.  Annual Review of Medicine, January 2015 Vol. 66: 255-270

SGLT2 Inhibitors: The Latest “New Kids on the Block”. Cefalu WT, Riddle MC. Diabetes Care, March 2015 vol. 38 no. 3 352-354

Future glucose-lowering drugs for type 2 diabetes. Bailey CJ, Tahrani AA, Barnett AH. Lancet Diabetes Endocrinol 2016 Published Online January 22, 2016.