Investigational Drug Details
| Drug ID: | D122 |
| Drug Name: | Empagliflozin |
| Synonyms: | (1S)-1,5-anhydro-1-(4-chloro-3-{4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}phenyl)-D-glucitol; 1-chloro-4-(glucopyranos-1-yl)-2-(4-(tetrahydrofuran-3-yloxy)benzyl)benzene; Empagliflozin |
| Type: | Chemical drug |
| DrugBank ID: | DB09038 |
| DrugBank Description: | Empagliflozin is an inhibitor of sodium-glucose co-transporter-2 (SGLT2), the transporters primarily responsible for the reabsorption of glucose in the kidney. It is used clinically as an adjunct to diet and exercise, often in combination with other drug therapies, for the management of type 2 diabetes mellitus. The first known inhibitor of SGLTs, phlorizin, was isolated from the bark of apple trees in 1835 and researched extensively into the 20th century, but was ultimately deemed inappropriate for clinical use given its lack of specificity and significant gastrointestinal side effects. Attempts at overcoming these limitations first saw the development of O-glucoside analogs of phlorizin (e.g. ), but these molecules proved relatively pharmacokinetically unstable. The development of C-glucoside phlorizin analogs remedied the issues observed in the previous generation, and led to the FDA approval of in 2013 and both and empagliflozin in 2014. As the most recently approved of the "flozin" drugs, empagliflozin carries the highest selectivity for SGLT2 over SGLT1 (approximately 2700-fold). |
| PubChem ID: | 11949646 |
| CasNo: | 864070-44-0 |
| Repositioning for NAFLD: | Yes |
| SMILES: | O[C@H]1[C@H](c2cc(Cc3ccc(cc3)O[C@H]3CCOC3)c(cc2)Cl)O[C@@H]([C@H]([C@@H]1O)O)CO |
| Structure: |
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| InChiKey: | OBWASQILIWPZMG-QZMOQZSNSA-N |
| Molecular Weight: | 450.915 |
| DrugBank Targets: | Sodium/glucose cotransporter 2 inhibitor |
| DrugBank MoA: | The vast majority of glucose filtered through the glomerulus is reabsorbed within the proximal tubule, primarily via SGLT2 (sodium-glucose linked co-transporter-2) which is responsible for ~90% of the total glucose reabsorption within the kidneys. Na<sup>+</sup>/K<sup>+</sup>-ATPase on the basolateral membrane of proximal tubular cells utilize ATP to actively pump Na+ ions into the interstitium surrounding the tubule, establishing a Na<sup>+</sup> gradient within the tubular cell. SGLT2 on the apical membrane of these cells then utilize this gradient to facilitate secondary active co-transport of both Na+ and glucose out of the filtrate, thereby reabsorbing glucose back into the blood – inhibiting this co-transport, then, allows for a marked increase in glucosuria and decrease in blood glucose levels. Empagliflozin is a potent inhibitor of renal SGLT2 transporters located in the proximal tubules of the kidneys and works to lower blood glucose levels via an increase in glucosuria. Empagliflozin also appears to exert cardiovascular benefits - specifically in the prevention of heart failure - independent of its blood glucose-lowering effects, though the exact mechanism of this benefit is not precisely understood. Several theories have been posited, including the potential inhibition of Na<sup>+</sup>/H<sup>+</sup> exchanger (NHE) 1 in the myocardium and NHE3 in the proximal tubule, reduction of pre-load via diuretic/natriuretic effects and reduction of blood pressure, prevention of cardiac fibrosis via suppression of pro-fibrotic markers, and reduction of pro-inflammatory adipokines. |
| DrugBank Pharmacology: | Empagliflozin lowers blood glucose levels by preventing glucose reabsorption in the kidneys, thereby increasing the amount of glucose excreted in the urine. It has a relatively long duration of action requiring only once-daily dosing. Patients should be monitored closely for signs and symptoms of ketoacidosis regardless of blood glucose level as empagliflozin may precipitate diabetic ketoacidosis in the absence of hyperglycemia. As its mechanism of action is contingent on the renal excretion of glucose, empagliflozin may be held in cases of acute kidney injury and/or discontinued in patients who develop chronic renal disease. The overexcretion of glucose creates a sugar-rich urogenital environment which increases the risk of urogenital infections - including urosepsis, pyelonephritis, mycotic infections, and even Fournier's gangrene - in both male and female patients - monitor closely for signs and symptoms of developing infection. |
| DrugBank Indication: | Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes. It is also indicated to reduce the risk of cardiovascular death in adult patients with both type 2 diabetes mellitus and established cardiovascular disease. Empagliflozin is also available as a combination product with either metformin and linagliptin as an adjunct to diet and exercise in the management of type 2 diabetes mellitus in adults. An extended-release combination product containing empagliflozin, metformin, and linagliptin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise. Empagliflozin is also approved to reduce the risk of cardiovascular mortality and hospitalization in adults with heart failure with reduced ejection fraction regardless of whether or not the patient has concomitant diabetes. Empagliflozin is not approved for use in patients with type 1 diabetes. |
| Targets: | SLC5A2 inhibitor; SGLT-2 inhibitor |
| Therapeutic Category: | Improve insulin resistance |
| Clinical Trial Progress: | Clinical trial completed (NCT02686476: When included in the standard treatment for type 2 diabetes, empagliflozin reduces liver fat and improves ALT levels in patients with type 2 diabetes and NAFLD.) |
| Latest Progress: | Under clinical trials |
| Trial ID | Source ID | Phases | Status | Study Results | Start Date | Last Update Posted | |
|---|---|---|---|---|---|---|---|
| L0050 | NCT03646292 | Phase 4 | Recruiting | No Results Available | December 19, 2018 | October 19, 2020 | Details |
| L0056 | NCT04642261 | Phase 4 | Recruiting | No Results Available | January 1, 2021 | April 28, 2021 | Details |
| L0062 | NCT03867487 | Phase 2 | Active, not recruiting | No Results Available | May 1, 2019 | March 4, 2022 | Details |
| L0084 | NCT02686476 | Not applicable | Completed | No Results Available | March 2016 | August 15, 2019 | Details |
| L0113 | NCT04976283 | Phase 4 | Recruiting | No Results Available | September 15, 2021 | March 18, 2022 | Details |
| L0141 | NCT02637973 | Phase 4 | Completed | No Results Available | December 2015 | January 14, 2019 | Details |
| L0162 | NCT04639414 | Phase 4 | Recruiting | No Results Available | March 26, 2021 | January 20, 2022 | Details |
| L0233 | IRCT20190122042450N3 | Phase 2/Phase 3 | Not Recruiting | No Results Available | 24/05/2019 | 26 August 2019 | Details |
| L0345 | NCT05232071 | Phase 2 | Not yet recruiting | No Results Available | June 1, 2022 | March 2, 2022 | Details |
| L0348 | NCT02964715 | Phase 4 | Unknown status | No Results Available | November 2016 | May 31, 2017 | Details |
| L0350 | NCT04702490 | Phase 2 | Active, not recruiting | No Results Available | December 15, 2020 | June 1, 2021 | Details |
| L0373 | NCT05147090 | Phase 4 | Not recruiting | No Results Available | 22/11/2021 | 21 December 2021 | Details |
| L0374 | IRCT20210922052550N1 | Phase 3 | Recruiting | No Results Available | 07/11/2021 | 7 February 2022 | Details |
| L0384 | NCT04910178 | Phase 4 | Recruiting | No Results Available | 25/05/2021 | 17 August 2021 | Details |
| L0404 | IRCT20190122042450N5 | Phase 2 | Recruiting | No Results Available | 29/11/2020 | 5 January 2021 | Details |
| L0435 | IRCT20200128046294N1 | Phase 3 | Not Recruiting | No Results Available | 22/02/2020 | 21 June 2021 | Details |
| L0466 | IRCT20190122042450N1 | Phase 2/Phase 3 | Not Recruiting | No Results Available | 13/05/2019 | 21 May 2019 | Details |
| L0703 | KCT0004923 | Not applicable | Recruiting | No Results Available | 16/04/2020 | 21 April 2020 | Details |
| Strategy ID | Strategy | Synonyms | Related Targets | Related Drugs | |
|---|---|---|---|---|---|
| S08 | Lifestyle measures | Lifestyle intervention; weight loss; diet adaptation; dietary interventions; lifestyle modifications; Exercise | -- | -- | Details |
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Article ID | PMID | Source | Title | |
|---|---|---|---|---|
| A00249 | 35166009 | Diabetes Obes Metab | Effects of empagliflozin on markers of liver steatosis and fibrosis and their relationship to cardiorenal outcomes. | Details |
| A00609 | 35030323 | Lancet Gastroenterol Hepatol | Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: a systematic review. | Details |
| A00714 | 34992540 | Front Pharmacol | Transcriptomic Analysis Reveals the Protective Effects of Empagliflozin on Lipid Metabolism in Nonalcoholic Fatty Liver Disease. | Details |
| A00775 | 34971904 | Biochem Biophys Res Commun | Hepatoprotective effects of gemigliptin and empagliflozin in a murine model of diet-induced non-alcoholic fatty liver disease. | Details |
| A01378 | 34768942 | Int J Mol Sci | In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia. | Details |
| A02192 | 34466320 | Cureus | The Effect of Empagliflozin on Liver Fat in Type 2 Diabetes Mellitus Patients With Non-Alcoholic Fatty Liver Disease. | Details |
| A02915 | 34199317 | Int J Mol Sci | Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH. | Details |
| A04359 | 33648515 | Cardiovasc Diabetol | Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study. | Details |
| A04362 | 33647823 | Int Immunopharmacol | The SGLT2 inhibitor empagliflozin negatively regulates IL-17/IL-23 axis-mediated inflammatory responses in T2DM with NAFLD via the AMPK/mTOR/autophagy pathway. | Details |
| A04530 | 33586120 | Diabetes Ther | Empagliflozin Improves Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. | Details |
| A04884 | 33467546 | Int J Mol Sci | Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE(-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis. | Details |
| A05042 | 33396949 | Metabolites | Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. | Details |
| A05705 | 33148902 | J Med Invest | Long-term empagliflozin therapy improves levels of hepatic fibrosis marker in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus. | Details |
| A06190 | 32975679 | Adv Ther | Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial. | Details |
| A07203 | 32583961 | Clin Transl Sci | Evolving Role for Pharmacotherapy in NAFLD/NASH. | Details |
| A08737 | 32006266 | Adv Exp Med Biol | Glucose Lowering Efficacy and Pleiotropic Effects of Sodium-Glucose Cotransporter 2 Inhibitors. | Details |
| A09583 | 31686884 | Diabetes Metab Syndr Obes | Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Clinician's Guide. | Details |
| A09969 | 31540903 | Diabetes Care | Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial. | Details |
| A10234 | 31419466 | Mol Cell Endocrinol | Empaglifozin mitigates NAFLD in high-fat-fed mice by alleviating insulin resistance, lipogenesis and ER stress. | Details |
| A11204 | 31000862 | J Pak Med Assoc | Expert Opinion: Use of sodium glucose co-transporter type-2 inhibitors in South Asian population -The Pakistan perspective. | Details |