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Aims/Introduction: To assess whether the sodium–glucose cotransporter 2 inhibitor, henagliflozin, improves cognitive impairment in patients with type 2 diabetes. Materials and Methods: We carried out a prospective study on 290 patients with type 2 diabetes and cognitive impairment. Montreal Cognitive Assessment scores and plasma phosphorylated tau181 levels were used to assess cognition. The association between henagliflozin use and changes in cognition was examined using multivariable logistic regression analysis. Results: Montreal Cognitive Assessment scores at enrollment and after 6 months were 21 (interquartile range [IQR]19–23) versus 22 (IQR 20–25; P < 0.0001) in all patients, 21 (IQR 19–23) versus 24 (IQR 22–26; P < 0.0001) in the henagliflozin group and 21 (IQR 19–22) versus 21 (IQR 19–23; P > 0.05) in the non‐sodium–glucose cotransporter 2 inhibitor group. Logistic regression analysis showed that henagliflozin treatment was associated with Montreal Cognitive Assessment score improvement independent of potential confounders (odds ratio [OR] 3.670, 95% confidence interval [CI] 2.224–6.056, P < 0.0001). Additionally, plasma phosphorylated tau181 levels significantly decreased at 6‐month follow up in all patients (OR 11.5, 95% CI 9.9–13.7 vs OR 10.1, 95% CI 7.8–12.9, P < 0.0001) and in the henagliflozin group (OR 11.5, 95% CI 10.3–13.0 vs OR 9.2, 95% CI 7.1–10.7, P < 0.0001), but not in the non‐sodium–glucose cotransporter 2 inhibitor group. Henagliflozin treatment was independently associated with decreased phosphorylated tau181 levels (OR 3.670, 95% CI 1.598–4.213, P < 0.0001). Conclusions: Henagliflozin treatment was independently associated with improvements in Montreal Cognitive Assessment scores and plasma phosphorylated tau181 levels, indicating significant beneficial effects on cognitive impairment in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract Aims/Introduction To assess whether the sodium–glucose cotransporter 2 inhibitor, henagliflozin, improves cognitive impairment in patients with type 2 diabetes. Materials and Methods We carried out a prospective study on 290 patients with type 2 diabetes and cognitive impairment. Montreal Cognitive Assessment scores and plasma phosphorylated tau181 levels were used to assess cognition. The association between henagliflozin use and changes in cognition was examined using multivariable logistic regression analysis. Results Montreal Cognitive Assessment scores at enrollment and after 6 months were 21 (interquartile range [IQR]19–23) versus 22 (IQR 20–25; P 0.05) in the non‐sodium–glucose cotransporter 2 inhibitor group. Logistic regression analysis showed that henagliflozin treatment was associated with Montreal Cognitive Assessment score improvement independent of potential confounders (odds ratio [OR] 3.670, 95% confidence interval [CI] 2.224–6.056, P

Qian Chen,1,2 Chengyin Yu,1,2 Qingqing Wu,1,2 Rong Song,1,2 Ye Liu,1,2 Sheng Feng,3 Chen Yu,1,2 Jingying Jia1,2 1Center Laboratory, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China; 2Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, People’s Republic of China; 3Jiangsu Hengrui Pharmaceuticals Co., Ltd, Lianyungang, Jiangsu, People’s Republic of ChinaCorrespondence: Jingying Jia, Center Laboratory, Shanghai Xuhui Central Hospital, No. 966, Huaihai Road (M), Shanghai, People’s Republic of China, Tel/Fax +86-21-54030254, Email jyjia@shxh-centerlab.comPurpose: Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ.Methods: This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated.Results: The 90% CI of the ratio of geometric means (combination: monotherapy) for AUCτ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80– 1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported.Conclusion: Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing.Trial Registration: ClinicalTrials.gov NCT06083116.Keywords: henagliflozin, drug-drug interaction, hydrochlorothiazide, pharmacokinetics, tolerability, pharmacodynamics, selective sodium-glucose cotransporter 2

Henagliflozin proline and metformin hydrochloride sustained‐release tablets (HR20033) are a fixed‐dose combination of the novel, highly selective, and effective sodium‐glucose cotransporter‐2 inhibitor henagliflozin, with a metformin sustained‐release layer for the treatment of type 2 diabetes mellitus in conjunction with dietary control and exercise. The aims of this study were to investigate the effect of a high‐fat diet on the pharmacokinetics of henagliflozin and metformin after a single administration of HR20033 and the effect of repeated oral administration of HR20033 on their pharmacokinetics in healthy volunteers. The food‐effect clinical study involved 18 healthy subjects randomized to receive either HR20033 in the fasted condition followed by HR20033 in the fed condition or the reverse schedule, with the two doses separated by a washout period of at least 7 days. The multiple‐dose clinical study was conducted on 10 healthy subjects. In the food‐effect study, compared with those in the fasted condition, the area under the blood concentration curve (AUC) and peak concentration (Cmax) of henagliflozin decreased by 12.64% and 40.89%, respectively, while the AUC of metformin increased by 31.13% and Cmax decreased by 7.09% in the fed state. There was no significant accumulation of HR20033 in the body after multiple oral doses. No serious adverse event was observed in either of the two clinical studies. Food did not have a clinically meaningful effect on the absorption of HR20033. [ABSTRACT FROM AUTHOR]

What is known and objective: Henagliflozin is a novel selective sodium‐glucose co‐transporter 2 (SGLT2) inhibitor with similar inhibitory effect to ertugliflozin. Glimepiride is widely used to treat type 2 diabetes mellitus (T2DM) with few cardiovascular side effects. In the present study, we aimed at evaluating the pharmacokinetic (PK) interactions between henagliflozin and glimepiride. Methods: An open‐label, single‐centre, single‐arm, 3‐period, 3‐treatment, self‐control study was conducted in twelve healthy Chinese male subjects. During each study period, subjects received a single oral dose of glimepiride 2 mg, multiple oral doses of henagliflozin 10 mg or a combination of the two drugs. Serial blood samples were collected 24 h post‐dosing for PK analyses. Finger‐tip blood glucose was also tested for safety evaluation. Results and discussion: Co‐administration of henagliflozin with glimepiride did not affect their plasma PK profiles. For henagliflozin, the 90% confidence intervals for the geometric mean ratio (GMR) for the maximum plasma concentrations at steady‐state (Cmax ss) and the area under the plasma concentration–time curve during a dosing interval at steady‐state (AUCτ, ss) of combination therapy to henagliflozin alone were 1.00 (0.93–1.08) and 1.00 (0.98–1.02), respectively. For glimepiride, the corresponding values of combination therapy to glimepiride alone were 1.00 (0.88–1.13) for maximum plasma concentrations (Cmax), 0.91 (0.84–0.99) for the area under the plasma concentration–time curve from 0–24 h (AUC0‐24h) and 0.91 (0.83–1.00) for the plasma concentration–time curve from 0 h to infinite (AUC0‐inf), respectively. All values fell within the equivalence range of 0.8–1.25. All monotherapies and combination therapy led to no serious adverse events and were well tolerated. What is new and conclusion: Multiple doses of henagliflozin did not exert a significant change on glimepiride PK profiles and a single dose of glimepiride had little effect on henagliflozin blood concentration. Thus, henagliflozin can be co‐administered with glimepiride without dose adjustment of either drug. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of henagliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin. Material and Methods: This multicentre phase 3 trial included a 24‐week randomized, double‐blind, placebo‐controlled period, followed by a 28‐week extension period. Patients with a glycated haemoglobin (HbA1c) level of 7.0% (53 mmol/mol) to 10.5% (91 mmol/mol) were randomized and treated with once‐daily placebo (n = 161), henagliflozin 5 mg (n = 162), or henagliflozin 10 mg (n = 160). After 24 weeks, patients on placebo were switched to 5 mg or 10 mg henagliflozin for the additional 28‐week treatment, and patients on henagliflozin during 24‐week treatment period maintained this initial therapy. The primary endpoint was change in HbA1c from baseline to Week 24. Results: At Week 24, the least squares mean HbA1c changes versus placebo from baseline were − 0.76% (−8.3 mmol/mol) and − 0.80% (−8.7 mmol/mol) for henagliflozin 5 and 10 mg, respectively (all P < 0.0001). Compared with the placebo group, both doses of henagliflozin lowered fasting plasma glucose, 2‐hour postprandial plasma glucose, body weight and blood pressure, and increased the proportions of patients achieving HbA1c <7.0% (53 mmol/mol) at Week 24. The trends in these improvements were sustained over an additional 28 weeks. Slightly higher proportions of ketosis and presence of urine ketone bodies were observed in patients treated with henagliflozin compared to placebo at Week 24. No diabetic ketoacidosis or episodes of severe hypoglycaemia were reported. Conclusions: Henagliflozin 5 mg or 10 mg as add‐on therapy to metformin provided a new therapeutic option for the treatment of T2DM patients who have inadequate glycaemic control with metformin alone, and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Aim: To evaluate henagliflozin, a novel sodium‐glucose co‐transporter‐2 inhibitor, as monotherapy in patients with type 2 diabetes and inadequate glycaemic control with diet and exercise. Materials and Methods: This multicentre trial included a 24‐week, randomized, double‐blind, placebo‐controlled period, followed by a 28‐week extension period. Four hundred and sixty‐eight patients with an HbA1c of 7.0%–10.5% were randomly assigned (1:1:1) to receive once‐daily placebo, or 5 or 10 mg henagliflozin. After 24 weeks, patients on placebo were switched to 5 or 10 mg henagliflozin, and patients on henagliflozin maintained the initial therapy. The primary endpoint was the change in HbA1c from baseline after 24 weeks. Results: At Week 24, the placebo‐adjusted least squares (LS) mean changes from baseline in HbA1c were −0.91% (95% CI: −1.11% to −0.72%; P <.001) and −0.94% (−1.13% to −0.75%; P <.001) with henagliflozin 5 and 10 mg, respectively; the placebo‐adjusted LS mean changes were −1.3 (−1.8 to −0.9) and −1.5 (−2.0 to −1.1) kg in body weight, and −5.1 (−7.2 to −3.0) and −4.4 (−6.5 to −2.3) mmHg in systolic blood pressure (all P <.05). The trends of these improvements were sustained for an additional 28 weeks. Adverse events occurred in 81.0%, 78.9% and 78.9% of patients in the placebo, henagliflozin 5 and 10 mg groups, respectively. No diabetic ketoacidosis or major episodes of hypoglycaemia occurred. Conclusions: Henagliflozin 5 mg and 10 mg as monotherapy provided effective glycaemic control, reduced body weight and blood pressure, and was generally well tolerated. [ABSTRACT FROM AUTHOR]

1. Henagliflozin is a novel sodium-glucose transporter 2 inhibitor and presents a complementary therapy to metformin for patients with T2DM due to its insulin-independent mechanism of action. This study evaluated the potential pharmacokinetic drug-drug interaction between henagliflozin and metformin in healthy Chinese male subjects. 2. In open-label, single-center, single-arm, two-period, three-treatment self-control study, 12 subjects received 25 mg henagliflozin, 1000 mg metformin or the combination. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination: monotherapy being within the range of 0.80-1.25. 3. Co-administration of henagliflozin with metformin had no effect on henagliflozin area under the plasma concentration-time curve (AUC0–24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (Cmax) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC0–24(GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metforminCmax(GRM 1.12; CI 1.02, 1.23). All monotherapies and combination therapy were well tolerated. 4. Henagliflozin can be co-administered with metformin without dose adjustment of either drug. [ABSTRACT FROM PUBLISHER]

• A total 8 metabolites of henagliflozin were observed in humans for the first time via UPLC/Q-TOF MS. • Henagliflozin mainly undergoes glucuronidation and O -deethylation in humans. • Avalidated LC–MS/MS method was developed for simultaneous determination of 3 major metabolites of henagliflozinin human plasma. • Three analytes, as well as three isomers, were separated on a common C 18 column by an optimized gradient elution procedure. Henagliflozin is a highly specific inhibitor of sodium-glucose co-transporter-2 (SGLT2) proposed as a more efficient medication for type 2 diabetes mellitus (T2DM). In this work, henagliflozin metabolic profile was investigated in human plasma and urine samples using a newly developed high-performance liquid chromatography coupled with time-of-flight mass spectrometry (HPLC/Q-TOF MS) method. A total of 8 metabolites were observed, while the structures of four major metabolites, including M1 (O -deethylation metabolite), M5-1 (2- O -β-glucuronide conjugate), M5-2 (6- O -β-glucuronide conjugate), and M5-3 (3- O -β-glucuronide conjugate) were confirmed in our study after comparison with the reference standards. The principal henagliflozin metabolic pathways were identified as glucuronidation and O -deethylation in humans. The principal form of henagliflozin in human plasma was parent drug, followed by M5-1; while it was M5-3 and M5-1 in urine. Subsequently, an accurate and simple LC–MS/MS method was developed for simultaneously determine M5-1, M5-2, and M5-3 in human plasma. After optimization of this method, three M5 isomers were successfully separated and quantified using chromatography. Acetonitrile-induced protein precipitation method was adapted for extracting the analytes from human plasma. Separation was conducted using Gemini C 18 column under gradient elution with 5 mM aqueous ammonium acetate (A) and acetonitrile (B) mobile phases. Negative electrospray ionization was conducted using a selective reaction monitoring with the same transition of m/z 629→321 for detection of three M5 isomers. The method showed good linearities for M5-1, M5-2, and M5-3 within the range of 1.00−150 ng/mL, 0.500–75.0 ng/mL, and 1.00−150 ng/mL, respectively. Conclusively, the method has been applied successfully to assess phase I henagliflozin pharmacokinetics and pharmacodynamics and providing effective safety evaluations. [ABSTRACT FROM AUTHOR]