SAN DIEGO — Discussing data on the investigational oral agent sotagliflozin — a first-in-class, oral dual inhibitor of both sodium-glucose cotransporter types 1 and 2 (SGLT1 and SGLT2) — for the treatment of type 1 diabetes, doctors at the American Diabetes Association (ADA) 2017 Scientific Sessions last week said the agent looks promising but there remain some lingering concerns about side effects.
Sotagliflozin was originated by Lexicon Pharmaceuticals, which is now working with Sanofi to develop the product.
Three phase 3 trials of the agent have been completed, all of which have reported top-line results, with one study being presented in detail at the ADA meeting.
The aim for sotagliflozin is that it can be given as an oral adjunct to insulin in type 1 diabetes. The findings of the trials so far indicate that the agent lowers HbA1c by about 0.5%, as well as reducing blood pressure and inducing some weight loss.
John B Buse, MD, PhD, of University of North Carolina School of Medicine, Chapel Hill, who presented results from the inTandem1 study with sotagliflozin here last week, told Medscape Medical News: "Type 1 diabetes is a tough disease because there is only insulin, and most patients actually aren't well controlled — in the best practices, only about 50% are probably adequately controlled."
Sotagliflozin therefore "has the potential of bringing another 30% or so of patients into the [glycemic] range where we don't expect disabling complications over decades," he added.
The results of inTandem1 showed that sotagliflozin "significantly reduced HbA1c in the setting of optimized insulin therapy" and is "the first report of a successful phase 3 trial of an oral antidiabetic as adjunct to insulin therapy for type 1 diabetes," Dr Buse told meeting attendees.
However, 1.1% of patients taking the 200-mg dose of sotagliflozin and 3.3% of those taking the higher 400-mg dose developed diabetic ketoacidosis (DKA) during the 24-week trial, compared with no one in the placebo group. And a higher rate of DKA was observed in those patients using insulin pumps, he noted.
Asked for comment, Partha Kar MD, FRCP, clinical director of diabetes at Portsmouth Hospitals NHS Trust, United Kingdom, who was not involved in the trials, told Medscape Medical News: "These were encouraging data, with some caveats. Sotagliflozin definitely does what it says on the tin — which is to drop the A1c, drop weight, and have a very good impact on blood pressure. There also didn't seem to be an increase in severe hypoglycemia."
However, "the flag is the 1% to 3% risk of diabetic ketoacidosis" with sotagliflozin, he observed.
"I would say that is what the company now needs to look at — can you earmark people who are at higher risk [of DKA], or are we saying that anybody who goes on this with type 1 diabetes just needs better monitoring — should we give them ketone meters?"
SGLT-1 and 2 Inhibition: A Logical Choice for Type 1 Diabetes?
Currently, a number of SGLT2 specific inhibitors are on the market for the treatment of type 2 diabetes, and these are being used off-label in the treatment of type 1 diabetes by some doctors.
But these agents have been plagued by a rash of side effects, including the risk of diabetic ketoacidosis, and so there have been warnings by some experts to avoid their use in type 1 diabetes for this reason. But others say the risk can be minimized using careful selection of patients and dose titration, along with meticulous monitoring of ketones.
Various series of data have shown a real-world doubling of the risk of DKA when type 2 diabetes patients start on SGLT2 inhibitors as opposed to other glucose-lowering agents, but the overall risk is still very low. One recent estimate puts the risk at between five and eight patients per 1000 initiating SGLT2 inhibitors who will go on to develop DKA.
Both Drs Kar and Buse say they currently employ SGLT2 inhibitors off-label in certain type 1 patients.
"I do use SGLT2 inhibitors off-label in the setting of type 1 diabetes to great benefit, but it's based on individual assessment of the risk for a patient and their willingness to engage in a conversation about how to mitigate that risk. The most common patient profile for me [to use SGLT2 inhibitors in type 1 diabetes] would be a middle-aged patient with an A1c above 7.5% and often overweight," Dr Buse told Medscape Medical News.
The hope therefore is that a dual inhibitor of SGLT 1 and 2 will prove superior or at least equivalent to SGLT2 inhibitors in helping to control HbA1c in type 1 diabetes and drop BP and weight with less risk of DKA.
SGLT1 acts on glucose absorption in the gastrointestinal tract, while SGLT2 affections glucose reabsorption by the kidney, so by inhibiting both of these pathways, sotagliflozin helps control blood glucose levels.
Using a dual inhibitor of SGLT1 and 2 in type 1 diabetes therefore "physiologically makes a lot of sense," Dr Kar told Medscape Medical News. "If you've got extra glucose in your system, it will tip it out."
Strict Monitoring for DKA in inTandem1 Trial
At ADA, Dr Buse reported detailed 24-week data from inTandem1—top-line results for which were already released by the company last September.
The trial involved a total of 793 type 1 diabetes patients in North America with mean age in their mid-40s and mean diabetes duration 24 years. About two-thirds used insulin pumps, and the rest multiple daily injections.
After 6 weeks of insulin optimization, during which their average HbA1c levels dropped from a mean of about 8.2% to 7.6%, they then stayed on the insulin regimen while they were randomized to sotagliflozin in 200 mg or 400 mg daily doses or to placebo for 24 weeks.
For the primary end point, percentage reduction in HbA1c from baseline after 24 weeks of treatment, results were 0.08%, 0.43%, and 0.49% for placebo, 200-mg sotagliflozin, and 400-mg sotagliflozin, respectively. The difference compared with placebo for patients treated with sotagliflozin 200 mg and 400 mg once daily were 0.36% and 0.41%, respectively (P < .001 for both doses).
Body weight was significantly decreased in both the 200-mg and 400-mg sotagliflozin arms, and there was no increase in severe hypoglycemic events during the 24-week treatment period (18, 11, and 12 events in the placebo, 200-mg dose, and 400-mg dose arms, respectively).
The number of patients positively adjudicated with DKA events during the 24-week treatment period was 0 (0.0%), three (1.1%), and eight (3.1%) in the placebo, 200-mg dose, and 400-mg dose arms, respectively.
These DKA events were more common among patients on insulin pumps compared with patients using multiple daily injections; 0 pump users (0.0%) for placebo, compared with two pump users (1.3%) and six pump users (3.8%) for the 200-mg dose and 400-mg dose, respectively.
Dr Buse observed that monitoring for DKA events in this trial was very strict. "We did a pretty good job of educating the patients to be wary, to check for ketones; I think there were patients who probably caught themselves before they got far out of bounds," he told Medscape Medical News.
Top-line results from inTandem2, a very similar trial but this time conducted in Europe and Israel, were reported in December and are broadly in line with those of inTandem1.
And Lexicon Pharmaceuticals also announced top-line results for a third trial, inTandem3, last week.
This is a global trial in 1400 type 1 diabetes patients treated with sotagliflozin 400 mg once daily or placebo added to insulin therapy, but with no insulin optimization prior to randomization. Findings were again broadly in line with those of the other two trials; a full analysis of the results, including safety data, "will be submitted for publication in a peer-reviewed journal," the company noted in a press release.
Dr Kar is on advisory boards for Novo Nordisk, Sanofi, and Lilly.
American Diabetes Association 2017 Scientific Sessions. June 10, 2017; San Diego, California. Abstract 69-OR
Medscape Medical News © 2017
Cite this: SGLT1/2 Inhibitor Sotagliflozin 'Encouraging' in Type 1 Diabetes - Medscape - Jun 22, 2017.