medwireNews: The only notable short-term differences in the effects of sotagliflozin and empagliflozin occur in glucose metabolism after breakfast, show findings from a randomized trial.
These differences, all observed in people with type 2 diabetes, “waned” at lunch and the evening meal, say Niklas Walther (Charité Research Organisation GmbH, Berlin, Germany) and co-researchers.
The study participants undertook a breakfast time mixed-meal tolerance test (MMTT) before and toward the end of 8 weeks of taking either sotagliflozin 400 mg/day or empagliflozin 25 mg/day. During the first 3 hours of the test, the glucose area under the curve (AUC) was 3.2 mmol/L per hour lower on treatment than at baseline in people taking sotagliflozin and 1.7 mmol/L per hour lower in those taking empagliflozin.
This amounted to a significant difference of 1.5 mmol/L per hour between the groups in favor of sotagliflozin.
In addition, the AUCs for insulin and C-peptide across the first 5 hours were reduced significantly more from baseline with sotagliflozin than empagliflozin, and the proinsulin AUC was reduced significantly more within the first 3 hours.
The phase 2a study involved 41 people diagnosed with type 2 diabetes at least 1 year previously, treated with metformin only. They stayed in the study unit for 6 days at baseline and another 6 days at the end of the 8-week double-blind, double-dummy treatment period.
The researchers attribute the differences observed to sotagliflozin’s dual inhibition of sodium-glucose cotransporter (SGLT)1, which is present largely in the gastrointestinal tract, and SGLT2, which is found mostly in the kidneys.
Sotagliflozin can therefore inhibit glucose absorption at two sites, whereas the SGLT2 inhibitor empagliflozin can influence just one.
In line with this, the team found differences in intestinal peptide responses between the two medications. Sotagliflozin use resulted in significant increases in active and total glucagon-like peptide (GLP)-1 throughout the first 5 hours after the breakfast MMTT versus no changes with empagliflozin. And the reduction in glucose-dependent insulinotropic polypeptide (GIP) AUC was significantly greater with sotagliflozin than empagliflozin throughout the 5-hour post-breakfast monitoring period.
In almost all other respects, however, the two medications produced nearly identical effects. Levels of acetate decreased across the 8-week treatment period in people taking sotagliflozin and increased in those taking empagliflozin to give a significant between-group difference. But there were no significant differences between the two for changes in other metabolites, in blood pressure or cardiovascular markers, in kidney function, in urinary or fecal markers, or in glycemic control.
“For the most part, the current study was unable to identify obvious features that would convincingly relate to a different clinical impact of dual versus single SGLT inhibition,” write the researchers in Diabetes Care.
However, they highlight the effect of the two SGLT inhibitors, particularly sotagliflozin, on GIP levels, noting that recent research suggests that GIP inhibition may be cardioprotective, contrary to the development of GLP-1/GIP co-agonists to treat type 2 diabetes.
Walther and team suggest this paradox may be explained if GIP agonists work by “desensitizing” the GIP receptor, leading to a decrease rather than an increase in GIP receptor signaling.
“[T]he potential benefit of lower GIP levels on cardiovascular outcomes suggests the need for additional studies to determine if prolonged sotagliflozin-mediated lowering of plasma GIP levels contributes to improved cardiovascular outcomes observed with this drug,” they conclude.
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