Novel SGLT Inhibitor Adds Benefit to Insulin in Type 1 Diabetes

Miriam E Tucker

September 13, 2016

Top-line results show some promise for a completely new, but still investigational, oral agent, sotagliflozin, in people with type 1 diabetes.

Sotagliflozin is a first-in-class, oral dual inhibitor of both sodium-glucose cotransporter types 1 and 2 (SGLT1 and SGLT2), with SGLT1 acting on glucose absorption in the gastrointestinal tract in addition to SGLT2's glucose reabsorption by the kidney. The drug's mechanisms are independent of insulin.

It was developed by Lexicon, which licensed it to Sanofi in November 2015. If eventually approved, sotagliflozin would be the first-ever oral agent approved for people with type 1 diabetes as an adjunct to insulin.

In an investor call last week, Lexicon officials presented top-line results from a randomized, placebo-controlled, phase 3 trial, inTandem1, in which all study subjects underwent a period of "optimized" insulin therapy before randomization.

"It's an important design because it means any efficacy of sotagliflozin is beyond what can be done by insulin alone," pointed out Pablo Lapuerta, MD, Lexicon executive vice president and chief medical officer.

Dr Lapuerta explained that the SGLT1 inhibition with sotagliflozin results in lower glucose levels in the intestinal tract, thereby reducing postprandial glucose levels and elevating gastrointestinal hormones associated with metabolic benefits.

Chair of the sotagliflozin type 1 diabetes steering committee, Anne Peters, MD, director of the clinical diabetes programs at the University of Southern California, told Medscape Medical News, "The reduction in HbA1c [in inTandem1], which was the primary end point, seems quite encouraging, especially along with a trend toward reduction in episodes of severe hypoglycemia."

Asked to comment, Simeon I Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, agreed.

He told Medscape Medical News: "When this study is viewed on a stand-alone basis, it is impressive that sotagliflozin delivered a clinically meaningful improvement in glycemic control with an apparent decrease in the risk of severe hypoglycemia."

However, he expressed some concerns about the side-effect profile.

Will Side Effects Be an Issue?

Because sotagliflozin is less selective than the currently available SGLT2 inhibitors, adverse effects may be an issue. While the overall discontinuation rate due to adverse events was low in the study, it was higher with sotagliflozin compared with placebo, and rates of diabetic ketoacidosis (DKA) rose at the higher sotagliflozin dose used in the trial (400 mg). And, as expected with the mechanism of SGTL1 inhibition, diarrhea also increased dose-dependently.

Dr Taylor pointed out that the "optimized insulin" background for all the study groups may have resulted in higher rates of hypoglycemia but lower rates of DKA than might occur in clinical practice.

"It would be interesting to see if the safety profile might deteriorate if used in 'real world' rather than in a clinical trial.…The reported data may be the best-case scenario."

Indeed, Dr Peters noted, "We await further results, including data on weight change, episodes of mild hypoglycemia, and much further characterization of the episodes of DKA."

Reduced HbA1c on Top of "Optimized" Insulin

The inTandem1 trial involved a total of 793 type 1 diabetes 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.

They first underwent a 6-week period of insulin optimization, during which their average hemoglobin HbA1c levels dropped from a mean of about 8.2% to 7.6%. After that, they 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

By week 24, HbA1c levels — the primary end point — were 7.17% in the 200-mg sotagliflozin group and 7.08 with the 400-mg dose, compared with minimal change (7.5%) with placebo.

The HbA1c reductions from baseline were statistically significant for all three groups (P = .027 placebo and <0.001 for the 200- and 400-mg sotagliflozin doses), as was the difference between the two doses and placebo (both P < .001).

The 0.35 and 0.41 percentage point differences in HbA1c from baseline meet the US FDA's threshold of 0.3 percentage points for clinically meaningful change, Dr Lapuerta noted.

Adverse Events Low Overall, but Greater With Sotagliflozin

Treatment-emergent adverse events occurred in 67.5%, 67.3%, and 71.0% of the placebo, 200-mg, and 400-mg groups, respectively. Serious adverse events occurred in 1.5%, 1.1%, and 3.8%, respectively. There were no deaths.

Diarrhea occurred in 5.6%, 7.2%, and 9.9%, respectively, with discontinuations due to diarrhea of 0.4%, 0.0%, and 0.4%. Genital mycotic infections arose in 3.4%, 6.1%, and 10.3%, respectively, with discontinuations in 0.0%, 0.4%, and 0.0%.

Diabetic ketoacidosis developed in zero, three, and eight patients, respectively, with percentages of 0%, 1.1%, and 3.1%. Discontinuations due to DKA were 0%, 0.4%, and 0.8%.

Severe hypoglycemia occurred in 18, 11, and 12 patients in the placebo, 200-mg, and 400-mg groups, or 6.7%, 4.2%, and 4.6%. The only discontinuations for hypoglycemia were from the placebo group, 0.4%.

Overall, "we are encouraged by these results," Dr Lapuerta said.

The inTandem1 trial is the first of three phase 3 studies on sotagliflozin in type 1 diabetes patients.

Lexicon is currently conducting another similar pivotal phase 3 clinical trial predominantly in Europe (inTandem2), with top-line results expected by the end of the year. The third trial, inTandem3, is also under way globally, with approximately 1400 type 1 diabetes patients treated with sotagliflozin 400 mg once daily or placebo added to insulin therapy, but with no optimization prior to randomization.

In addition, Sanofi is expected to begin phase 3 clinical trials for sotagliflozin in patients with type 2 diabetes by the end of the year.

Dr Lapuerta is an employee of Lexicon Pharmaceuticals. Dr Peters has served as director, officer, partner, employee, advisor, consultant, or trustee for Amylin Pharmaceuticals, Eli Lilly, and Novo Nordisk; served as a speaker or member of a speaker's bureau for Amylin, Eli Lilly, Novo Nordisk, and Takeda Pharmaceuticals North America; and served as a consultant or ad hoc speaker/consultant for AstraZeneca, Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Dexcom, Medtronic MiniMed, Merck, Roche, and Sanofi. Dr Peters also serves on the advisory board of Medscape Diabetes & Endocrinology. Dr Taylor was previously employed by Bristol-Myers Squibb (2002–2013) but has sold all of his Bristol-Myers Squibb stock. He currently consults for Ionis Pharmaceuticals and Aegerion Pharmaceuticals and owns stock in Gilead, Celgene, and Akorn, and United Healthcare.

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