Canagliflozin: A novel SGLT2 inhibitor for type 2 diabetes mellitus

Kaushal, Shaveta; Singh, Harmanjit; Thangaraju, Pugazhenthan; Singh, Jasbir

doi:10.4103/1947-2714.128471

Cited by 27 publications

(6 citation statements)

References 40 publications

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“…[12] CYP3A4-mediated metabolism of canagliflozin is minimal in humans, hence it is least likely to result in significant drug interactions. [15] The tacrolimus levels were not affected in our subjects.…”

Section: Discussionmentioning

confidence: 80%

Efficacy and safety of canagliflozin in kidney transplant patients

et al. 2019

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Introduction: There is no report of efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor in post kidney transplant patients with diabetes. Materials and Methods: A pilot study was undertaken in stable renal transplant recipients with preexisting diabetes or new onset diabetes after transplantation (NODAT) to look at the efficacy of SGLT2 inhibitor, cangliflozin. With the introduction of canagliflozin (100 mg), the dose of insulin and/or other oral hypoglycemic agents was reduced if the blood sugar control improved. The parameters monitored were body weight, blood pressure (BP), serum creatinine, HbA1c, and tacrolimus trough level. Safety was assessed by adverse event (AE) reports. Each patient was followed for a minimum period of 6 months. Results: The study included 24 (23 males and 1 females) stable kidney transplant patients with diabetes. The mean age of the patients was 53.8 ± 7.12 years. The mean body weight of study subjects was 78.6 ± 12.1 kg before and 76.1 ± 11.2 kg 6 months after starting canagliflozin ( P < 0.05). The mean systolic and diastolic BP (mm Hg) was 142 ± 21 and 81 ± 9 before and 134 ± 17 and 79 ± 8, 6 months after starting canagliflozin, respectively ( P < 0.05 for systolic BP). There was no significant change in creatinine level (mg/dL). It was 1.1 ± 0.2 before and 1.1 ± 0.3 after starting canagliflozin. The tacrolimus level (ng/mL) was 6.7 ± 3.7 before and 6.1 ± 2, 6 months after starting canagliflozin. The mean HbA1c before was 8.5 ± 1.5%. At 6 months, it was 7.6 ± 1%. Hypoglycemia was not seen. There was no increase in infections. Conclusion: Canagliflozin provided reductions in body weight, BP, HbA1c, and the requirement of other hypoglycemic agents without any hypoglycemic episodes and without significant AEs.

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Section: Discussionmentioning

confidence: 80%

Efficacy and safety of canagliflozin in kidney transplant patients

et al. 2019

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“…The FDA approved canagliflozin, an SGLT2 inhibitor, for use in T2DM treatment in 2013 [ 38 ]. In the present study, canagliflozin was used as a positive control against SGLT2.…”

Section: Resultsmentioning

confidence: 99%

Biocomputational Prediction Approach Targeting FimH by Natural SGLT2 Inhibitors: A Possible Way to Overcome the Uropathogenic Effect of SGLT2 Inhibitor Drugs

et al. 2021

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The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium–glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2 inhibitor drugs are under evaluation due to their associative side effects, such as urinary tract and genital infection, urinary discomfort, diabetic ketosis, and kidney problems. Even clinicians have difficulty in recommending it to diabetic patients due to the increased probability of urinary tract infection. In our study, we selected natural SGLT2 inhibitors, namely acerogenin B, formononetin, (−)-kurarinone, (+)-pteryxin, and quinidine, to explore their potential against an emerging uropathogenic bacterial therapeutic target, i.e., FimH. FimH plays a critical role in the colonization of uropathogenic bacteria on the urinary tract surface. Thus, FimH antagonists show promising effects against uropathogenic bacterial strains via their targeting of FimH’s adherence mechanism with less chance of resistance. The molecular docking results showed that, among natural SGLT2 inhibitors, formononetin, (+)-pteryxin, and quinidine have a strong interaction with FimH proteins, with binding energy (∆G) and inhibition constant (ki) values of −5.65 kcal/mol and 71.95 µM, −5.50 kcal/mol and 92.97 µM, and −5.70 kcal/mol and 66.40 µM, respectively. These interactions were better than those of the positive control heptyl α-d-mannopyranoside and far better than those of the SGLT2 inhibitor drug canagliflozin. Furthermore, a 50 ns molecular dynamics simulation was conducted to optimize the interaction, and the resulting complexes were found to be stable. Physicochemical property assessments predicted little toxicity and good drug-likeness properties for these three compounds. Therefore, formononetin, (+)-pteryxin, and quinidine can be proposed as promising SGLT2 inhibitors drugs, with add-on FimH inhibition potential that might reduce the probability of uropathogenic side effects.

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“…Canagliflozin was approved by the FDA in 2013 and is used in the treatment of type II diabetes. This drug is a C-glycosyl derivative compound and acts as a sodium-glucose transport protein subtype 2 (SGLT2) inhibitor (Kaushal et al., 2014 ). Muscle loss is common in patients with type II diabetes, therefore Canagliflozin has been found to have a positive effect on the cardiovascular system in clinical trials in the following years.…”

Section: Resultsmentioning

confidence: 99%

Targeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: an in silico structure-based approach

Mutlu

Ugurel

Sarıyer

et al. 2020

Journal of Biomolecular Structure and Dynamics

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In this study, the Nsp12-Nsp8 complex of SARS-CoV-2 was targeted with structure-based and computer-aided drug design approach because of its vital role in viral replication. Sequence analysis of RNA-dependent RNA polymerase (Nsp12) sequences from 30,366 different isolates were analysed for possible mutations. FDA-approved and investigational drugs were screened for interaction with both mutant and wild-type Nsp12-Nsp8 interfaces. Sequence analysis revealed that 70.42% of Nsp12 sequences showed conserved P323L mutation, located in the Nsp8 binding cleft. Compounds were screened for interface interaction, any with XP GScores lower than À7.0 kcal/mol were considered as possible interface inhibitors. RX-3117 (fluorocyclopentenyl cytosine) and Nebivolol had the highest binding affinities in both mutant and wild-type enzymes, therefore they were selected and resultant protein-ligand complexes were simulated for analysis of stability over 100 ns. Although the selected ligands had partial mobility in the binding cavity, they were not removed from the binding pocket after 100 ns. The ligand RX-3117 remained in the same position in the binding pocket of the mutant and wild-type enzyme after 100 ns MD simulation. However, the ligand Nebivolol folded and embedded in the binding pocket of mutant Nsp12 protein. Overall, FDA-approved and investigational drugs are able to bind to the Nsp12-Nsp8 interaction interface and prevent the formation of the Nsp12-Nsp8 complex. Interruption of viral replication by drugs proposed in this study should be further tested to pave the way for in vivo studies towards the treatment of COVID-19.

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Canagliflozin: A novel SGLT2 inhibitor for type 2 diabetes mellitus

Cited by 27 publications

References 40 publications

Efficacy and safety of canagliflozin in kidney transplant patients

Efficacy and safety of canagliflozin in kidney transplant patients

Biocomputational Prediction Approach Targeting FimH by Natural SGLT2 Inhibitors: A Possible Way to Overcome the Uropathogenic Effect of SGLT2 Inhibitor Drugs

Targeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: an in silico structure-based approach

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