Could SGLT2 inhibitors eventually be approved as a type 1 diabetes treatment?

Jack Woodfield
By Jack Woodfield
1st August 2016
In Depth, Opinion
 
16365

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a relatively new drug class for treating type 2 diabetes, and while they have significant benefits, they also carry significant risks and side effects. It is therefore intriguing that SGLT2s are being investigated as a type 1 diabetes treatment, but will the side effects of the drugs outweigh any benefits that could be attained?

SGLT2 inhibitors were approved for treating type 2 diabetes in 2013 – specifically, in patients with high blood glucose levels who cannot tolerate metformin and a sulfonylurea or pioglitazone is not appropriate.  [1]

The drugs can lower blood glucose levels and have benefits for weight loss, making them a valuable treatment for type 2 diabetes. One SGLT2 drug, Jardiance (empagliflozin), has also showed promise for cardiovascular health: in 2015 it reduced the risk of risk of cardiovascular death by 38 per cent in people with type 2 diabetes, compared to placebo.

It is not surprising, consequently, that SGLT2s are being investigated in type 1 diabetes research.

Despite the benefits, SGLT2s have their problems. They have been associated with increased incidences of diabetic ketoacidosis (DKA), a dangerous short-term complication, to risks of acute kidney failure. Furthermore, long-term side effects of the drugs remain unclear.

Considering SGLT2 inhibitors have been the subject of numerous health warnings in recent years, you’d forgive people with type 1 diabetes for possibly grimacing in fear when talk of SGLT2 research occurs.

But a number of studies have shown that SGLT2 drugs such as Forxiga (dapagliflozin) and Invokana (canagliflozin) could improve blood sugar control in adults with type 1 diabetes who struggle to do so with insulin.

On the face of it, adding SGLT2s as an adjunct (additional treatment) to insulin could lead to benefits in type 1 diabetes management. Given the risks, though, there is a surplus of safety reassurances that will have to be made before the drugs are ever green lighted.

The mechanism of how SGLT2 inhibitors work in the body (www.sironabiochem.com)

The mechanism of how SGLT2 inhibitors work in the body (www.sironabiochem.com)

Type 1 diabetes treatment trials

A significant trial investigating SGLT2 drugs in type 1 diabetes was reported on in September 2014, when San Diego researchers concluded “dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability” and “may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes.” [2]

No incidences of DKA were observed in the study, and participants experienced reductions in 24-hour daily average blood glucose levels, glycemic variability, and total daily insulin doses. However, the two-week study period meant that no substantial long-term, or even short-term conclusions, could be feasibly deduced.

Dr Robert R Henry, MD, was a senior author on this paper, and he has continued to pursue this research.

In a phase II study, published in October 2015, Henry and colleagues found over 18 weeks that canagliflozin led to increased DKA in type 1 patients, but all cases occurred in the presence of precipitating factors, such as insulin pump failure, skipped insulin dose, or concurrent illness. [3]

Henry et al concluded: “(M)itigation strategies to reduce the risk of DKA in patients with type 1 diabetes treated with canagliflozin will be needed for use in future clinical trials.” These proposed strategies included “more frequent monitoring of ketones, interruption of treatment during periods of stress or illness, and use of lower canagliflozin doses.”

Benefits were again observed following SGLT2 treatment: canagliflozin patients had improved glycemic control and reduced body weight compared with placebo, and the drug was not associated with an increased risk of hypoglycemia.

Then, SGLT2s received a major endorsement as a type 1 diabetes treatment.

Rosenstock and Ferrannini highlighted the importance of euglycemic diabetic ketoacidosis (euDKA) in SGLT2 research. This is the name given for very high ketone levels alongside normal blood glucose levels, and it could explain elevated rates of DKA in SGLT2-treated patients.

Late in 2015, Texas researcher Dr Julio Rosenstock and Dr Ele Ferrannini, from Italy, reported that the risk of DKA should be manageable in people with type 1 diabetes. [4]

“We submit that this potential complication (DKA) related to SGLT2 inhibition is predictable, detectable, and preventable (or mitigable) so that the balance of benefits and risks favours the use of SGLT2 inhibitors in the T1D population, which is in desperate need of adjunct therapies,” they wrote.

Rosenstock and Ferrannini highlighted the importance of euglycemic diabetic ketoacidosis (euDKA) in SGLT2 research. This is the name given for very high ketone levels alongside normal blood glucose levels, and it could explain elevated rates of DKA in SGLT2-treated patients.

Rather than being caused by hyperglycemia, they reported that DKA amongst SGLT2 treated type 1s is commonly caused by factors such as insulin reductions, low caloric and fluid intake and alcohol use.

“We believe that euDKA is in fact easily detectable because reliable tools are currently available to monitor ketonuria and ketonemia and should be recommended to be used at any time an SGLT2 inhibitor–treated patient feels unwell regardless of the ambient glucose levels,” the authors said.

They added that regularly testing ketones, particularly when patients feel unwell, should be part of any educational element for those with type 1 who are treated with an SGLT2 inhibitor.

While these findings provide a sense of optimism regarding future treatment, they will need to be verified in multiple, larger studies.

The side effects of SGLT2 drugs

SGLT2 drugs can provide a valuable tool in diabetes care: in 2015, William T. Cefalu and Matthew C. Riddle wrote: “This class of drugs (SGLT2s) has a novel mode of action that appears capable of adding a further glucose-lowering effect in combination with many other classes.”

But there is reason for caution. SGLT2s carry a lot of side effects, including urinary tract infections, thrush, polyuria, genital pain and low blood pressure.

Furthermore, this list isn’t exhaustive; each SGLT2 drug possesses additional side effects as well as stricter criterion regarding one’s eligibility to take the drugs.

The FDA has released several health warnings about SGLT2 inhibitors

The FDA has released several health warnings about SGLT2 inhibitors

Longer-term studies are continuing to uncover additional side effects of SGLT2 drugs and these could have stark implications for people with diabetes.

During the last 18 months, the US Food and Drug Administration (FDA) has released a multitude of safety announcements regarding SGLT2s: in May 2015, it warned that SGLT2s can lead to DKA that may require hospitalisation; in April 2016 it strengthened its warning about the risk of acute kidney injury for canagliflozin and dapagliflozin; and in May 2016, it reported on increased leg and foot amputations among patients taking canagliflozin.

SGLT2 inhibitors are the new kids on the block, so to speak. Because of their modernity, the duration of studies available is limited. As a result “the balance of benefits versus risks is still not well understood and it will take time to fully evaluate this issue,” according to Cefalu and Riddle.

But in a statement earlier this year, the European Medicines Agency (EMA) said that “the benefits of SGLT2 inhibitors continue to outweigh their risks in the treatment of type 2 diabetes”.

The EMA subsequently urged GPs to pay attention to symptoms of DKA in type 2 diabetes patients taking SGLT2 drugs, stressing that treatment should be immediately discontinued if patients show these signs, but concluded that episodes of DKA were often “atypical, with patients not having blood sugar levels as high as expected” (this refers to euDKA).

So, what’s the latest?

Research continues. Earlier this year, Anne L Peters stressed that DKA still requires “mitigation strategies in future clinical trials”, but suggested that people with type 1 diabetes may need a lower dose of SGLT2 drugs (canagliflozin was evaluated in this study) compared to people with type 2 diabetes in order for treatment to be successful. [5]

The scope of research is also expanding. In February, a UK-based member of our Diabetes Forum wrote about how he was recruited for a trial investigating the efficacy of SGLT2s in type 1 diabetes.

However, it doesn’t appear that SGLT2s will be approved by official regulators for type 1 diabetes any time soon.

A multitude of trials will still need to be conducted that consider several aspects – such as drug safety, dosage and monitoring of blood sugar and ketones – to establish effective treatment strategies, which will have to be individualised to patients’ requirements.

Furthermore, it still remains to be seen whether SGLT2 drugs will be safe enough for people with type 1 diabetes. This is a critical requirement, and it is one that has not yet come anywhere near close enough to being resolved.

Main image: http://www.diasporanews.com/

[1] https://www.nice.org.uk/guidance/ta390/chapter/1-Recommendations

[2] http://care.diabetesjournals.org/content/early/2014/08/07/dc13-2955.abstract

[3] http://care.diabetesjournals.org/content/38/12/2258.full

[4] http://care.diabetesjournals.org/content/38/9/1638

[5] http://care.diabetesjournals.org/content/39/4/532

What do you think?