First-in-Human Study of Dual Inhibitor Licogliflozin Showed Significant Weight Loss in Obese Patients

Licogliflozin, a dual sodium glucose co-transporter 1/2 inhibitor, helped obese patients lose more than 5% of their body weight in 12 weeks and improved key health measures in those with type 2 diabetes, according to results of a first-in-human study released earlier this spring and published this week in the journal Diabetes Obesity and Metabolism.

So-called dual inhibitors, which target both the SGLT1 protein and the SGLT2 protein in the digestive and renal systems, work to help patients discharge nearly all glucose through the urine. Dual inhibitors are being studied in patients with both type 1 (T1D) and type 2 diabetes (T2D) because they not only help patients achieve glycemic control and lose weight, but they also help reduce glycemic variability, the “roller coaster” effect that patients with T1D in particular experience throughout the day.

The first dual inhibitor, sotagliflozin, received approval in the European Union for certain patients with T1D who cannot achieve glycemic control on insulin alone. However, the FDA issued a complete response letter for the drug earlier this year after a split vote by an advisory committee.

The current study of licogliflozin was not limited to patients with diabetes, however. A total of 130 patients took part in the study; 88 took part in a 12-week study to evaluate the effect of licogliflozin on obesity, while 42 with T2D enrolled in a separate, 2-part study: (1) 30 patients took part in a 14-day multiple-dose study, and 12 patients took part in the single-dose crossover study.

Licogliflozin Helps Those With Obesity Lose Weight

Those in the obesity study were between 18 and 65 years of age and had a body mass index (BMI) between 35 and 50 kg/m². After 12 weeks, those who took 150 mg of the study drug once a day lost 5.7% of their body weight on average compared with those taking placebo (80% CI, -6.52%, -4.87%; P < .001). The average amount of weight loss was 6.4 kg with licogliflozin (80% CI, -7.11, -5.72), compared with 0.24 kg with placebo (80% CI, -0.46, 0.94); P < .00001. Those taking licogliflozin also saw significant reductions in waist circumference and postprandial glucose excursion, and postprandial insulin levels were significantly suppressed compared with placebo.

Use of CGM in Study on Patients with T2D

Patients in the T2D studies were 18 to 65 years of age and had glycated hemoglobin of 6.5% to 10.0%. Researchers gave T2D patients in the single-dose study a baseline evaluation, including urine collection and an oral glucose tolerance test (OGTT). Researchers used OGTT after morning doses of the study drug, collected urine at intervals, and used continuous glucose monitoring (CGM) to track blood glucose levels. Researchers reported the following:

• Plasma glucose excursion following an OGTT was maximally reduced 48% with a single dose of licogliflozin 300 mg (morning) compared to placebo (P < .001). This reduction was statistically significant for all doses of licogliflozin relative to placebo.
• Insulin levels were suppressed following a morning dose of licogliflozin compared with placebo, while almost no difference in insulin levels was seen after an evening dose compared with placebo.
• CGM results showed that average glucose levels were reduced by 19% over 24 hours compared with baseline for on day 1 and remained reduced over a 14-day period following a 15 mg a day dose.
• After 14-day dosing with licogliflozin at 15 mg average glucose levels over 24 hours were reduced by 26% compared to baseline.
• Measures of urine and glucagon-like peptide-1 (GLP-1) confirmed the mechanistic effects of both SGLT2 and SGLT1 inhibition.

The most common adverse event (AE) reported was diarrhea, with 90% of patients taking licogliflozin reporting this, compared with 25% of those taking placebo. Less common AEs were flatulence, abdominal pain, and abdominal distension. Notably, no AEs related to ketosis of metabolic acidosis were reported, although researchers noted longer trials are needed to confirm this finding. Concern about the risk of diabetic ketoacidosis led to the divided FDA panel vote on sotagliflozin earlier this year.

Novartis Institutes for Biomedical Research funded the study.

Reference

He YL, Haynes W, Meyers CD, et al. The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes. Diabetes Obes Metab. 2019;21:1311-1321. doi:10.1111.dom.13654.