Licogliflozin (LIK066)

Licogliflozin versus placebo in women with polycystic ovary syndrome: A randomized, double-blind, phase 2 trial

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066 :TRPCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066 :TRPCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066 :TRPCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066 :TRPCB [MAXI]: 0·26; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066 :TRPCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.

Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that may advance to fibrosis and lead to mortality; however, no pharmacotherapy is currently available. We tested the hypothesis that inhibition of both the sodium-glucose cotransporters 1 and 2 with licogliflozin would lead to improvement in NASH. A total of 107 patients with phenotypic or histologic NASH were randomized (1:2:2) to receive oral administration of either placebo (n = 21), licogliflozin 30 mg (n = 43) or 150 mg (n = 43) once daily for 12 weeks. Licogliflozin 150 mg showed a significant 32% (80% confidence interval (CI): 21-43%; P = 0.002) placebo-adjusted reduction in serum alanine aminotransferase after 12 weeks of treatment, the primary endpoint of the study. However, the 30 mg dose of licogliflozin did not meet the primary endpoint (placebo-adjusted reduction 21% (80% CI: 7-32%; P = 0.061)). Diarrhea occurred in 77% (33 of 43), 49% (21 of 43) and 43% (9 of 21) of patients treated with licogliflozin 150 mg, 30 mg and placebo, respectively, which was mostly mild in severity. No other major safety concerns were identified. Treatment with 150 mg licogliflozin led to reductions in serum alanine aminotransferase in patients with NASH. Studies of longer duration and in combination with drugs that have different mechanisms of action are needed to validate these findings and to define a role of licogliflozin as a therapeutic option for NASH. ClinicalTrials.gov identifier: NCT03205150.

Dose-dependent reduction in body weight with LIK066 (licogliflozin) treatment in Japanese patients with obesity

Aims: LIK066 (licogliflozin) is a dual sodium glucose co-transporter 1/2 inhibitor with potential benefits in weight loss. This study evaluated the efficacy, tolerability and safety of licogliflozin in Japanese adults with obesity.
Materials and methods: This study was a randomized, double-blind, placebo-controlled, dose-finding study to evaluate the effect of licogliflozin (2.5, 10, 25 and 50 mg once daily) in 126 Japanese patients with obesity. The primary objective was to examine the dose-response relationship of licogliflozin treatment in body weight reduction relative to placebo at 12 weeks. The secondary objectives included assessment of responder rates, change in parameters related to complications, visceral and subcutaneous fat area, and safety during 12 weeks of treatment.
Results: The placebo-subtracted least square mean percentage change in body weight from baseline at week 12 was -1.99 (95% confidence interval -2.92, -0.21), -3.00 (-4.15, -1.70), -3.54 (-4.54, -2.26) and - 3.91% (-5.01, -2.77) in licogliflozin 2.5, 10, 25 and 50 mg once-daily dose groups, respectively. The proportion of responders with ≿% reduction in body weight in the licogliflozin 2.5, 10, 25 and 50 mg once-daily dose groups were 15.8%, 55.6%, 50.0% and 56.7%, respectively, versus placebo [7.1%; P ≿.002 for all except the 2.5 mg once-daily group (P = 0.39)]. Dose-dependent reductions were observed significantly in haemoglobin A1c, uric acid, fasting plasma glucose and potentially in the waist circumference, diastolic blood pressure and visceral fat area.
Conclusion: Dual inhibition of SGLT1/2 with licogliflozin treatment induced a dose-dependent reduction in body weight in Japanese patients with obesity. Treatment with licogliflozin was safe and well tolerated in this study. The study is registered with ClinicalTrials.gov (NCT03320941).

Licogliflozin effective in PCOS treatment

Effects of Sodium/Glucose Cotransporter 2 (SGLT2) Inhibitors and Combined SGLT1/2 Inhibitors on Cardiovascular, Metabolic, Renal, and Safety Outcomes in Patients with Diabetes: A Network Meta-Analysis of 111 Randomized Controlled Trials

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of anti-hyperglycemic drugs that has been steadily increasing in popularity due to its cardiovascular and renal benefits. Dual SGLT1/SGLT2 (SGLT1/2) inhibitors have potentially augmented anti-hyperglycemic action due to additional SGLT1 inhibition. This network meta-analysis aimed to compare the treatment effect across various outcomes between pure SGLT2 inhibitors and combined SGLT1/2 inhibitors in patients with diabetes.
Methodology: Four electronic databases (PubMed, Embase, Cochrane, and Scopus) were searched for randomized controlled trials published from inception to 15th January 2022. Frequentist network meta-analysis was conducted to summarize the treatment effects reported in individual trials, stratified by type 1 (T1DM) and type 2 diabetes mellitus (T2DM). This meta-analysis was registered on PROSPERO (CRD42020222031).
Results: Our meta-analysis included 111 articles, comprising a combined cohort of 103,922 patients. SGLT2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, and luseogliflozin) and SGLT1/2 inhibitors (licogliflozin and sotagliflozin) were compared. Frequentist network meta-analysis demonstrated that in T2DM patients, SGLT1/2 inhibitors led to a decreased hazard rate of myocardial infarction (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.56-0.98) and stroke (HR 0.65, 95% CI 0.47-0.92) compared with SGLT2 inhibitors. SGLT2 inhibitors achieved a greater hemoglobin A1c (HbA1c) reduction than SGLT1/2 inhibitors (0.16%, 95% CI 0.06-0.26). In patients with T2DM, the risk of diarrhea (risk ratio [RR] 1.42, 95% CI 1.07-1.88) and severe hypoglycemia (RR 5.89, 95% CI 1.41-24.57) were found to be higher with SGLT1/2 inhibitor use compared with SGLT2 inhibitor use. No differences were observed for cardiovascular, metabolic, and safety outcomes between SGLT1/2 inhibitors and SGLT2 inhibitors in patients with T1DM.
Conclusions: In patients with T2DM, compared with pure SGLT2 inhibitors, combined SGLT1/2 inhibitors demonstrated a lower risk of myocardial infarction and of stroke, but were associated with a higher risk of diarrhea and severe hypoglycemia.