The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes

Abstract

BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity.This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS:Patients with obesity (BMI, 35-50 kg/m 2 ) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 − 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE 24 ) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY 3-36 , and GIP), insulin and glucagon.RESULTS: Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC 0-4h ) and suppressed insulin by 90% (P < 0.01; incremental AUC 0-4h ). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24-hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE 24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP-1 by 54% (P < 0.001) and PYY 3-36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12-week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%-43% with licogliflozin vs 9%-11% with placebo in the 12-week study) were among the other gastrointestinal events reported. CONCLUSION: Licogliflozin treatment (1-84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes. K E Y W O R D S clinical trial, continuous glucose monitoring (CGM), incretins, obesity therapy, phase I-II study, weight control

Investigation and Management of Stool Frequency and Consistency Associated With SGLT1 Inhibition by Reducing Dietary Carbohydrate: A Randomized Trial

“…We hypothesized that this could be due to complete inhibition of SGLT1 in the gut. 12 Our study demonstrates, we believe for the first time, that the stool changes associated with SGLT1 inhibition by licogliflozin can be alleviated by reducing the percentage carbohydrate in the breakfast meal (around the time of licogliflozin administration), and can be completely abolished by reducing carbohydrates to 0%. This is the first demonstration that the stool changes caused by an inhibitor of SGLT1 (licogliflozin) can be managed similarly to those of an SGLT1 inactivating mutation.…”

“…A recently developed selective and potent dual SGLT1/2 inhibitor, licogliflozin, has been shown to reduce dietary glucose absorption, increase renal glucose excretion, and lead to weight loss. 12 This was, however, accompanied by more frequent bowel movements and loose stool adverse events (AEs), 12 which were probably related to the complete inhibition of SGLT1 in the gut. 12,13 In addition, licogliflozin is currently under investigation as a potential treatment option for non-alcoholic steatohepatitis.…”

“…12 This was, however, accompanied by more frequent bowel movements and loose stool adverse events (AEs), 12 which were probably related to the complete inhibition of SGLT1 in the gut. 12,13 In addition, licogliflozin is currently under investigation as a potential treatment option for non-alcoholic steatohepatitis. 14 Loose stools observed in patients with SGLT1 inactivating mutations can be managed with elimination of glucose and galactose from the diet.…”

“…We have demonstrated that licogliflozin reduces body weight by ~ 6% after a 12-week treatment in a previous clinical proofof-concept study. 12 However, the potential impact of modifying the carbohydrate load (%) in the meal on the weight loss effect of licogliflozin remains to be investigated. SGLT1 is not only present in the gastrointestinal tract, but also plays an important role in glucose reabsorption by the kidneys, especially when SGLT2 is inhibited.…”

Obesity phenotypes are preserved in intestinal stem cell enteroids from morbidly obese patients

“…Inhibition of either SGLT1 or GLUT2 significantly decreases glucose absorption, indicating that these transporters might be potential targets for hyperglycemia in the BMI obese GA high subset of obese patients. Recent clinical studies using licogliflozin, a dual SGLT1/2 inhibitor that targets both the intestinal and renal glucose absorption, have shown promising results in decreasing blood glucose and body weight of obese patients [53].…”