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Dual SGLT inhibitor boosts insulin efficacy in type 1 diabetes
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ORLANDO, Fla. — Adults with type 1 diabetes treated with an investigational dual inhibitor of SGLT1 and SGLT2, together with optimized insulin therapy saw greater reductions at 52 weeks in HbA1c, fasting plasma glucose and body weight compared with optimized insulin therapy alone, according to data from the inTandem1 trial.
First-in-class oral sotagliflozin (Zynquista, Lexicon/Sanofi), accepted for review by the FDA in May, acts on SGLT1 in the gastrointestinal tract and on SGLT2 in the kidney, according to John Buse, MD, PhD, director of the Diabetes Center, director of the North Carolina Translational and Clinical Sciences Institute and executive associate dean for clinical research at the University of North Carolina School of Medicine in Chapel Hill.
“Inhibition of SGLT1 blunts and delays the rise in glucose after meals. SGLT2, on the other hand, is the primary glucose transporter in the kidney, where it reabsorbs 90% of the filtered glucose,” Buse said during a press briefing. “There is about 180 g per day of glucose that’s filtered through the kidney, so arguably, the kidney is as important an organ for glucose metabolism as the GI tract. ... In fact, the amount of carbohydrate that passes through the GI tract and the kidneys is more or less similar.”
In a phase 3, randomized, double-blind, controlled clinical trial, Buse and colleagues assigned
793 adults with type 1 diabetes receiving optimized insulin therapy (mean age, 45 years; mean BMI, about 30 kg/m2; mean HbA1c, 7.5%; mean daily insulin dose .74 units/kg per day; 60% using an insulin pump) to daily 200 mg sotagliflozin, 400 mg sotagliflozin or placebo in addition to their insulin. Primary endpoint was change in HbA1c from baseline to week 24. Participants experienced a 3.6% reduction in HbA1c during insulin intensification prior to baseline, Buse said.
At 24 weeks following the addition of sotagliflozin, those in the 200-mg and 400-mg groups had HbA1c –0.36% and –0.41% lower, respectively, than the placebo group and –0.25% and –0.31% lower, respectively, at week 52 (P < .001 for all comparisons).
At week 52, 26.6% of those in the 200-mg group and 32.4% of those in the 400-mg group achieved HbA1c less than 7% without severe hypoglycemia or diabetic ketoacidosis vs. 19% in the placebo group. Participants in the sotagliflozin groups also experienced greater reductions in fasting plasma glucose and body weight vs. placebo at 52 weeks, according to Buse.
Similar numbers of total treatment-emergent adverse events and events leading to discontinuation occurred in all three groups, Buse said.
“The major focus in the development of SGLT inhibitors in the setting of type 1 diabetes regarding safety has been around diabetic ketoacidosis,” Buse said. A small increase in diabetic ketoacidosis was seen in the 200-mg (3.4%) and 400-mg (4.2%) groups vs. placebo (0.4%).
Fewer participants in the sotagliflozin groups experienced at least one severe hypoglycemic event (6.5% in each group) vs. placebo (9.7%).
The sotagliflozin groups experienced a modest increase in diarrhea — likely driven by local SGLT1 inhibition in the intestine, Buse said — as well as genital mycotic infections related to the glucose in the urinary tract typically seen with these agents.
“There was a significant difference from placebo in patient-reported outcomes related to treatment satisfaction, and that was maintained at 52 weeks,” Buse said. “The small but increased risk of diabetic ketoacidosis can be potentially mitigated with proper education and ketone monitoring. Thus, we believe that sotagliflozin is effective in subjects with type 1 diabetes and has an acceptable risk-benefit profile.” – by Jill Rollet
Reference:
Buse JB, et al. 212-OR. Presented at: American Diabetes Association 78th Scientific Sessions; June 22-26, 2018; Orlando, Fla.
Disclosure: Buse reports he has financial ties with the ADA, Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly and Company, Fractyl Laboratories, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Metavention, National Center for Advancing Translational Sciences, National Institute of Environmental Health Sciences, NHLBI, NovaTarg, Novo Nordisk, Patient-Centered Outcomes Research Institute, Sanofi, Shenzhen Hightide Biopharmaceutical, Theracos and vTv Therapeutics.