Chemistry:SGLT2 inhibitor
SGLT2 inhibitors, also called gliflozins or flozins, are a class of medications that inhibit sodium-glucose transport proteins in the nephron (the functional units of the kidney), unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar.[1] They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes.[2][3] (As of 2014), several medications of this class had been approved or were under development.[4] In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.[5]
Medical uses
The 2022 ADA standards of medical care in diabetes include SGLT2 inhibitors as a first line pharmacological therapy for type 2 diabetes (usually together with metformin), specifically in patients with chronic kidney disease, cardiovascular disease or heart failure.[6]
A systematic review and network meta-analysis comparing SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors demonstrated that use of SGLT2 inhibitors was associated with a 20% reduction in death compared with placebo or no treatment.[7] Another systematic review discussed the mechanisms by which SGLT-2 inhibitors improve cardio-renal function in patients with type 2 diabetes, emphasizing the impacts in improving neural tone.[8]
A meta-analysis including 13 cardiovascular outcome trials found that SGLT-2 inhibitors reduce the risk for three-point MACE, especially in subjects with an estimated glomerular filtration rate (eGFR) below 60 ml/min, whereas GLP-1 receptor agonists were more beneficial in persons with higher eGFR.[9] Likewise, the risk reduction due to SGLT-2 inhibitors was larger in populations with a higher proportion of albuminuria, but this relationship was not observed for GLP-1 receptor agonists. This suggests a differential use of the two substance classes in patients with preserved and reduced renal function or with and without diabetic nephropathy, respectively.[9]
Two reviews have concluded that SGLT2 inhibitors benefit patients with atherosclerotic major adverse cardiovascular events (MACE).[10][11] One of those studies defined MACE as the composite of myocardial infarction, stroke, or cardiovascular death.[10]
Adverse effects
Genital infections seem to be the most common adverse effect of gliflozins. In clinical trials fungal infections, urinary tract infections and osmotic diuresis were higher in patients treated with gliflozins.[citation needed]
In May 2015, the FDA issued a warning that gliflozins can increase risk of diabetic ketoacidosis (DKA, a serious condition in which the body produces high levels of blood acids called ketones).[12] By reducing glucose blood circulation, gliflozins cause less stimulation of endogenous insulin secretion or lower dose of exogenous insulin that results in diabetic ketoacidosis. They can specifically cause euglycemic DKA (euDKA, DKA where the blood sugar is not elevated) because of the renal tubular absorption of ketone bodies.[13] A particularly high risk period for ketoacidosis is the perioperative period. SGLT2 inhibitors may need to be discontinued before surgery, and only recommended when someone is not unwell, is adequately hydrated and able to consume a regular diet.[14] Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.[15] To lessen the risk of developing ketoacidosis after surgery, the FDA has approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Canagliflozin, dapagliflozin, and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery.[15]
In September 2015, the FDA issued a warning related to canagliflozin (Invokana) and canagliflozin/metformin (Invokamet) due to decreased bone mineral density and therefore increased risk of bone fractures. Using gliflozins in combination therapy with metformin can lower the risk of hypoglycemia compared to other type 2 diabetes treatments such as sulfonylureas and insulin.[12]
Increased risk of lower limb amputation is associated with canagliflozin but further data is needed to confirm this risk associated with different gliflozins.[16] A European Medicines Agency review concluded that there is a potential increased risk of lower limb amputation (mostly affecting the toes) in people taking canagliflozin, dapagliflozin and empagliflozin.[17]
In August 2018, the FDA issued a warning of an increased risk of Fournier gangrene in patients using SGLT2 inhibitors.[18] The absolute risk is considered very low.[19]
In the FDA Adverse Event Reporting System an increase was reported in events of acute kidney injury associated with SGLT2 inhibitors,[20][21] though data from clinical trials actually showed a reduction in such events with SGLT-2 treatment.[22]
Interactions
Interactions are important for SGLT2 inhibitors because most people with type 2 diabetes are taking many other medications. Gliflozins appear to increase the diuretic effect of thiazides, loop diuretics and related diuretics and may increase the risk of dehydration and hypotension.[23] It is important to adjust the dose of antidiabetics if the treatment is combination therapy to avoid hypoglycemia. For example, interactions with sulfonylureas have led to severe hypoglycemia presumably due to cytochrome P450.[24]
Members
These are the known members of the gliflozin class:
- Bexagliflozin was approved in the United States under the brand name Brenzavvy in January 2023.[25]
- Canagliflozin was the first SGLT2 inhibitor to be approved for use in the United States. It was approved in March 2013, under the brand name Invokana and it was also marketed throughout the EU under the same name.[26][27]
- Dapagliflozin, approved under the name Forxiga, was approved by the EU in 2012, the first SGLT2 inhibitor approved anywhere.[28] It was approved for use in the United States under the brand name Farxiga by the FDA in January 2014.[29] It was the first oral treatment, in combination with insulin, to treat type 1 diabetes in the UK and EU.
- Empagliflozin, approved in the United States in August 2014, under the brand name Jardiance by Boehringer Ingelheim.[30] Of the gliflozins, empagliflozin and tofogliflozin have the highest specificity for SGLT2 inhibition.[1] This oral medicine for type 2 diabetes has been shown to reduce the risk of cardiovascular death.[31]
- Ertugliflozin was approved in the United States under the brand name Steglatro in December 2017.[32]
- Ipragliflozin, produced by the Japanese company Astellas Pharma Inc. under the brand name Suglat, approved in Japan January 2014.[33][34]
- Luseogliflozin, developed by Taisho Pharmaceutical, was approved in Japan in March 2014 under the brand name Lusefi.[35]
- Remogliflozin etabonate was commercially launched first in India by Glenmark in May 2019.
- Sergliflozin etabonate discontinued after Phase II trials.[36]
- Sotagliflozin (Inpefa) is a dual SGLT1/SGLT2 inhibitor approved by the FDA in May 2023, to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure or type 2 diabetes, chronic kidney disease, and other cardiovascular risk factors.[37][38]
- Tofogliflozin, developed by Sanofi and Kowa Pharmaceutical, was approved in Japan in March 2014, under the brand names Apleway and Deberza.[39]
- Henagliflozin, selective SGLT2 inhibitor. Approved in China.
- Janagliflozin.
- Mizagliflozin
- Velagliflozin Proline hydrate
- Enavogliflozin
Mechanism of action
Sodium Glucose cotransporters (SGLTs) are proteins that occur primarily in the kidneys and play an important role in maintaining glucose balance in the blood.[40] SGLT1 and SGLT2 are the two most known SGLTs of this family. SGLT2 is the major transport protein and promotes reabsorption from the glomerular filtration glucose back into circulation and is responsible for approximately 90% of the kidney's glucose reabsorption.[1] SGLT2 is mainly expressed in the kidneys on the epithelial cells lining the first segment of the proximal convoluted tubule. By inhibiting SGLT2, gliflozins prevent the kidneys' reuptake of glucose from the glomerular filtrate and subsequently lower the glucose level in the blood and promote the excretion of glucose in the urine (glucosuria).[41][42]
The mechanism of action on a cellular level is not well understood. Work is underway to define this mechanism as a prodiuretic with great promise. However, it has been shown that binding of different sugars to the glucose site affects the orientation of the aglycone in the access vestibule. So when the aglycone binds it affects the entire inhibitor. Together these mechanisms lead to a synergistic interaction. Therefore, variations in the structure of both the sugar and the aglycone are crucial for the pharmacophore of SGLT inhibitors.[43]
Dapagliflozin is an example of an SGLT-2 inhibitor, it is a competitive, highly selective inhibitor of SGLT. It acts via selective and potent inhibition of SGLT-2, and its activity is based on each patient's underlying blood sugar control and kidney function. The results are decreased kidney reabsorption of glucose, glucosuria effect increases with higher level of glucose in the blood circulation. Therefore, dapagliflozin reduces the blood glucose concentration with a mechanism that is independent of insulin secretion and sensitivity, unlike many other antidiabetic medications. Functional pancreatic β-cells are not necessary for the activity of the medication so it is convenient for patients with diminished β-cell function.[41][42]
Sodium and glucose are co-transported by the SGLT-2 protein into the tubular epithelial cells across the brush-border membrane of the proximal convoluted tubule. This happens because of the sodium gradient between the tubule and the cell and therefore provides a secondary active transport of glucose. Glucose is later reabsorbed by passive transfer of endothelial cells into the interstitial glucose transporter protein.[41][42][44]
SGLT | Expressed in human tissues |
---|---|
SGLT1 | Intestine, trachea, kidney, heart, brain, testis, prostate |
SGLT2 | Kidney, brain, liver, thyroid, muscle, heart |
Ratios of activity between SGLT1 and SGLT2 may be helpful in defining expression.
Pharmacology
The elimination half-life, bioavailability, protein binding, the blood concentration Cmax at time tmax, and other pharmacokinetic parameters of various medications of this class are present in table 2. These medications are excreted in the urine as inactive metabolites.[44][45][46][47]
Name of drug | Bioavailability | Protein binding | tmax (hours) | t1/2 (hours) | Cmax | SGLT2 selectivity over SGLT1 |
---|---|---|---|---|---|---|
Canagliflozin | 65% (300 mg dose) | 99% | 1–2 | 10.6 (100 mg dose); 13.1 (300 mg dose) | 1096 ng/mL (100 mg dose); 3480 ng/mL (300 mg dose) | 250 fold |
Dapagliflozin | 78% | 91% | 1–1.5 | 12.9 | 79.6 ng/mL (5 mg dose); 165.0 ng/mL (10 mg dose) | 1200 fold |
Empagliflozin | 90–97% (mice); 89% (dogs); 31% (rats) | 86.20% | 1.5 | 13.2 (10 mg dose); 13.3h (25 mg dose) | 259nmol/L (10 mg dose); 687nmol/L (25 mg dose) | 2500 fold |
Ertugliflozin | 70-90% | 95% | 0.5-1.5 | 11-17 | 268 ng/mL (15 mg dose) | 2000 fold |
Ipragliflozin (50 mg) | 90% | 96.30% | 1 | 15–16 (50 mg dose) | 975 ng/mL | 360 fold |
Luseogliflozin | 35.3% (male rats); 58.2% (female rats); 92.7% (male dogs) | 96.0–96.3% | 0.625±0.354 | 9.24±0.928 | 119±27.0 ng/mL | 1650 fold |
Tofogliflozin (10 mg) | 97.50% | 83% | 0.75 | 6.8 | 489 ng/mL | 2900 fold |
- Cmax: Maximum serum concentration that drug achieves in body after the drug has been administered
- tmax: Time to achieve maximum plasma concentration
- t1/2: Biological half-life
In studies that were made on healthy people and people with type 2 diabetes, who were given dapagliflozin in either single ascending dose (SAD) or multiple ascending dose (MAD) showed results that confirmed a pharmacokinetic profile of the medication. With dose-dependent concentrations the half-life is about 12–13 hours, Tmax 1–2 hours and it is protein-bound, so the medication has a rapid absorption and minimal excretion by the kidney.[49]
Dapagliflozin disposition is not evidently affected by BMI or body weight, therefore the pharmacokinetic findings are expected to be applicable to patients with a higher BMI. Dapagliflozin resulted in dose-dependent increases excretions in urinary glucose, up to 47g/d following single-dose administration, which can be expected from its mechanism of action, dapagliflozin.[50]
Some studies found that dapagliflozin is associated with a decrease in body weight which is statistically superior compared to placebo or other active comparators.[50][44] It is primarily associated with caloric rather than fluid loss.[50][44]
In contrast with other anti-hyperglycemic diabetes medications, SGLT2 inhibitors enhance, rather than suppress, gluconeogenesis and ketogenesis.[51] Because SGLT2 inhibitors activate sirtuin 1 (and thus PGC-1α and FGF21), they are more cardioprotective than the other medications used to treat diabetes.[51]
Structure-activity relationship
The structure-activity relationship (SAR) of gliflozins is not fully understood.
The most common gliflozins are dapagliflozin, empagliflozin and canagliflozin. The differences in the structures is relatively small. The general structure includes a glucose sugar with an aromatic group in the β-position at the anomeric carbon. In addition to the glucose sugar moiety and the β-isomeric aryl substituent the aryl group is composed of a diarylmethylene structure.
The synthesis of Gliflozins involves three general steps. The first one is the construction of the aryl substituent, the next one is the introduction of the aryl moiety onto the sugar or glucosylation of the aryl substituent and the last one the deprotection and modification of the arylated anomeric center of the sugar.[52]
Phlorizin was the first type of gliflozin and it was non-selective against SGLT2/SGLT1. It is a natural O-aryl glycoside composed of a d-glucose and an aromatic ketone.[53] However Phlorizin is very unstable, it is rapidly degraded by glucosidases in the small intestines, so it can not be used as an oral administration medication to treat diabetes. Structural modifications have been made to overcome this instability problem. The most efficient way was to conjugate aryl moiety with glucose moiety since C-glucosides are more stable in the small intestines than O-glucoside derivatives (C-C bond instead of C-O-C bond).[54]
In the sugar analogues of dapagliflozin, the β-C series are more active than α-C series so it is critical that the β-configuration is at C-1 for the inhibitory activity.[55] Both dapagliflozin and empagliflozin contain a chlorine (Cl) atom in their chemical structure. Cl is a halogen and it has a high electronegativity. This electronegativity withdraws electrons off the bonds and therefore it reduces the metabolism. The Cl atom also reduces the IC50 value of the medication so the medication has better activity. The carbon-fluorine bond (C-F) has also has a very low electron density.[55]
For example, in the chemical structure of canagliflozin a fluorine atom is connected to an aromatic ring then the compound is more stable and the metabolism of the compound is reduced. Empagliflozin contains a tetrahydrofuran ring but not canagliflozin nor dapagliflozin.[56]
In the development of gliflozins the distal ring contains a thiophene ring instead of an aromatic ring. However the final chemical structures of the marketing gliflozins does not contain this thiophene ring.[57]
History
Research
SGLT2 inhibitors increase circulating ketone body concentrations.[58] The cardioprotective effects of SGLT2 inhibitors have been attributed to the elevated ketone levels.[59]
Gliflozins have been posited to exhibit protective effects on the heart, liver, kidneys, anti‐hyperlipidemic, anti‐atherosclerotic, anti‐obesity, anti‐neoplastic effects in in vitro, pre‐clinical, and clinical studies. Pleiotropic effects of this class have been attributed to a variety of its pharmacodynamic actions such as natriuresis, hemoconcentration, deactivation of renin-angiotensin-aldosterone system, ketone body formation, alterations in energy homeostasis, glycosuria, lipolysis, anti‐inflammatory, and antioxidative actions.[60][3]
SGLT2 inhibitors have shown beneficial effects on liver function in clinical trials on individuals with NAFLD and type 2 diabetes, and also on those without type 2 diabetes.[61][62]
References
- ↑ 1.0 1.1 1.2 Shubrook, Jay; Baradar-Bokaie, Babak; Adkins, Sarah (2015). "Empagliflozin in the treatment of type 2 diabetes: Evidence to date". Drug Design, Development and Therapy 9: 5793–803. doi:10.2147/DDDT.S69926. PMID 26586935.
- ↑ Usman, Muhammad Shariq; Siddiqi, Tariq Jamal; Memon, Muhammad Mustafa; Khan, Muhammad Shahzeb; Rawasia, Wasiq Faraz; Talha Ayub, Muhammad; Sreenivasan, Jayakumar; Golzar, Yasmeen (2018). "Sodium-glucose co-transporter 2 inhibitors and cardiovascular outcomes: A systematic review and meta-analysis". European Journal of Preventive Cardiology 25 (5): 495–502. doi:10.1177/2047487318755531. PMID 29372664.
- ↑ 3.0 3.1 "Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence". Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 13: 161–174. 2020. doi:10.2147/DMSO.S233538. PMID 32021362.
- ↑ Scheen, André J. (2014). "Pharmacodynamics, Efficacy and Safety of Sodium–Glucose Co-Transporter Type 2 (SGLT2) Inhibitors for the Treatment of Type 2 Diabetes Mellitus". Drugs 75 (1): 33–59. doi:10.1007/s40265-014-0337-y. PMID 25488697.
- ↑ Haas, B.; Eckstein, N.; Pfeifer, V.; Mayer, P.; Hass, M D S. (2014). "Efficacy, safety and regulatory status of SGLT2 inhibitors: Focus on canagliflozin". Nutrition & Diabetes 4 (11): e143. doi:10.1038/nutd.2014.40. PMID 25365416.
- ↑ "9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022". https://diabetesjournals.org/care/article/45/Supplement_1/S125/138908/9-Pharmacologic-Approaches-to-Glycemic-Treatment.
- ↑ Zheng, Sean L.; Roddick, Alistair J.; Aghar-Jaffar, Rochan; Shun-Shin, Matthew J.; Francis, Darrel; Oliver, Nick; Meeran, Karim (2018). "Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors with All-Cause Mortality in Patients with Type 2 Diabetes". JAMA 319 (15): 1580–1591. doi:10.1001/jama.2018.3024. PMID 29677303.
- ↑ Nashawi, Mouhamed; Sheikh, Omar; Battisha, Ayman; Ghali, Abdullah; Chilton, Robert (May 2021). "Neural tone and cardio-renal outcomes in patients with type 2 diabetes mellitus: a review of the literature with a focus on SGLT2 inhibitors". Heart Failure Reviews 26 (3): 643–652. doi:10.1007/s10741-020-10046-w. ISSN 1573-7322. PMID 33169337. https://pubmed.ncbi.nlm.nih.gov/33169337/.
- ↑ 9.0 9.1 Sohn, M; Dietrich, JW; Nauck, MA; Lim, S (28 June 2023). "Characteristics predicting the efficacy of SGLT-2 inhibitors versus GLP-1 receptor agonists on major adverse cardiovascular events in type 2 diabetes mellitus: a meta-analysis study.". Cardiovascular Diabetology 22 (1): 153. doi:10.1186/s12933-023-01877-6. PMID 37381019.
- ↑ 10.0 10.1 "SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials". The Lancet 393 (10166): 31–39. 2019. doi:10.1016/S0140-6736(18)32590-X. PMID 30424892.
- ↑ "Sodium-Glucose Cotransporter-2 Inhibitor (SGLT2i) as a Primary Preventative Agent in the Healthy Individual: A Need of a Future Randomised Clinical Trial?". Frontiers in Medicine 8: 712671. 2021. doi:10.3389/fmed.2021.712671. PMID 34497814.
- ↑ 12.0 12.1 Hsia, Daniel S.; Grove, Owen; Cefalu, William T. (2016). "An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus". Current Opinion in Endocrinology, Diabetes and Obesity 24 (1): 73–79. doi:10.1097/MED.0000000000000311. PMID 27898586.
- ↑ Isaacs, Michelle; Tonks, Katherine T.; Greenfield, Jerry R. (2017). "Euglycaemic diabetic ketoacidosis in patients using sodium-glucose co-transporter 2 inhibitors". Internal Medicine Journal 47 (6): 701–704. doi:10.1111/imj.13442. PMID 28580740.
- ↑ Milder, D. A.; Milder, T. Y.; Kam, P. C. A. (August 2018). "Sodium-glucose co-transporter type-2 inhibitors: pharmacology and peri-operative considerations". Anaesthesia 73 (8): 1008–1018. doi:10.1111/anae.14251. PMID 29529345.
- ↑ 15.0 15.1 "FDA revises labels of SGLT2 inhibitors for diabetes to include warning". 19 March 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious.
This article incorporates text from this source, which is in the public domain.
- ↑ Khouri, Charles; Cracowski, Jean-Luc; Roustit, Matthieu (2018). "SGLT-2 inhibitors and the risk of lower-limb amputation: Is this a class effect?". Diabetes, Obesity and Metabolism 20 (6): 1531–1534. doi:10.1111/dom.13255. PMID 29430814.
- ↑ "SGLT2 inhibitors: information on potential risk of toe amputation to be included in prescribing information". 4 May 2017. https://www.ema.europa.eu/en/medicines/human/referrals/sglt2-inhibitors-previously-canagliflozin.
- ↑ "FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes". Center for Drug Evaluation and Research. 7 September 2018. p. Drug Safety and Availability. https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm.
- ↑ Bardia, Amit; Wai, Mabel; Fontes, Manuel L. (February 2019). "Sodium-glucose cotransporter-2 inhibitors: an overview and perioperative implications". Current Opinion in Anesthesiology 32 (1): 80–85. doi:10.1097/ACO.0000000000000674. PMID 30531609. http://insights.ovid.com/crossref?an=00001503-201902000-00014.
- ↑ "FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR)". U.S. Food and Drug Administration (FDA). 2019-02-09. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-kidney-warnings-diabetes-medicines-canagliflozin.
- ↑ Perlman, A.; Heyman, S. N.; Matok, I.; Stokar, J.; Muszkat, M.; Szalat, A. (2017-12-01). "Acute renal failure with sodium-glucose-cotransporter-2 inhibitors: Analysis of the FDA adverse event report system database". Nutrition, Metabolism and Cardiovascular Diseases 27 (12): 1108–1113. doi:10.1016/j.numecd.2017.10.011. ISSN 0939-4753. PMID 29174031. https://www.nmcd-journal.com/article/S0939-4753(17)30238-7/abstract.
- ↑ Neuen, Brendon L.; Young, Tamara; Heerspink, Hiddo J. L.; Neal, Bruce; Perkovic, Vlado; Billot, Laurent; Mahaffey, Kenneth W.; Charytan, David M. et al. (November 2019). "SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis". The Lancet. Diabetes & Endocrinology 7 (11): 845–854. doi:10.1016/S2213-8587(19)30256-6. ISSN 2213-8595. PMID 31495651. https://pubmed.ncbi.nlm.nih.gov/31495651/.
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- ↑ Scheen, André J. (2014). "Drug–Drug Interactions with Sodium-Glucose Cotransporters Type 2 (SGLT2) Inhibitors, New Oral Glucose-Lowering Agents for the Management of Type 2 Diabetes Mellitus". Clinical Pharmacokinetics 53 (4): 295–304. doi:10.1007/s40262-013-0128-8. PMID 24420910. http://orbi.ulg.ac.be/handle/2268/164207.
- ↑ "Novel Drug Approvals for 2023". U.S. Food and Drug Administration. 20 January 2023. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023.
- ↑ "Drug Approval Package: Invokana (canagliflozin) Tablets NDA #204042". 24 December 1999. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000TOC.cfm.
- ↑ "Invokana EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/invokana.
- ↑ "Forxiga EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/forxiga.
- ↑ "Drug Approval Package: Farxiga (dapagliflozin) Tablets NDA #202293". 24 December 1999. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000TOC.cfm.
- ↑ "FDA approves Jardiance (empagliflozin) tablets for adults with type 2 diabetes". Boehringer Ingelheim / Eli Lilly and Company. 1 August 2014. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/08-01-14-fda-approves-jardiance-empagliflozin-tablets-reduce-blood-sugar-levels-adults-type-2-diabetes.html.
- ↑ "FDA Advisory Committee recommends approval of Jardiance (empagliflozin) for cardiovascular indication in 12-11 vote". 28 June 2016. https://finance.yahoo.com/news/fda-advisory-committee-recommends-approval-222200556.html;_ylt=A0LEVrhllatXlP8AlncnnIlQ;_ylu=X3oDMTByOHZyb21tBGNvbG8DYmYxBHBvcwMxBHZ0aWQDBHNlYwNzcg--.
- ↑ "Steglatro (ertugliflozin), Steglujan (ertugliflozin and sitagliptin), Segluromet (ertugliflozin and metformin hydrochloride) Tablets". 5 March 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209803,209805,209806Orig1s000TOC.cfm.
- ↑ "Approval of Suglat® Tablets, a Selective SGLT2 Inhibitor for Treatment of Type 2 Diabetes, in Japan". January 17, 2014. http://www.astellas.com/en/corporate/news/detail/approval-of-suglat-tablets-a-s.html.
- ↑ Poole, Raewyn M.; Dungo, Rosselle T. (26 March 2014). "Ipragliflozin: First Global Approval". Drugs 74 (5): 611–617. doi:10.1007/s40265-014-0204-x. PMID 24668021.
- ↑ Markham, Anthony; Elkinson, Shelley (2014). "Luseogliflozin: First Global Approval". Drugs 74 (8): 945–950. doi:10.1007/s40265-014-0230-8. PMID 24848756.
- ↑ Da Silva, Paula Nogueira; Da Conceição, Raissa Alves; Do Couto Maia, Rodolfo; De Castro Barbosa, Maria Leticia (2018). "Sodium–glucose cotransporter 2 (SGLT-2) inhibitors: A new antidiabetic drug class". MedChemComm 9 (8): 1273–1281. doi:10.1039/c8md00183a. PMID 30151080.
- ↑ "Inpefa- sotagliflozin tablet". 5 June 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a46614e-05f6-421a-b6f4-d6f8760d643a.
- ↑ "Once-Daily Inpefa Approved for Treating Heart Failure" (in en). https://www.uspharmacist.com/article/oncedaily-inpefa-approved-for-treating-heart-failure.
- ↑ Poole, Raewyn M.; Prossler, Jennifer E. (2014). "Tofogliflozin: First Global Approval". Drugs 74 (8): 939–944. doi:10.1007/s40265-014-0229-1. PMID 24848755.
- ↑ Chao, E. C. (2014). "SGLT-2 Inhibitors: A New Mechanism for Glycemic Control". Clinical Diabetes 32 (1): 4–11. doi:10.2337/diaclin.32.1.4. PMID 26246672.
- ↑ 41.0 41.1 41.2 Anderson, Sarah L.; Marrs, Joel C. (2012). "Dapagliflozin for the Treatment of Type 2 Diabetes". Annals of Pharmacotherapy 46 (4): 590–598. doi:10.1345/aph.1Q538. PMID 22433611.
- ↑ 42.0 42.1 42.2 Li, An-Rong; Zhang, Jian; Greenberg, Joanne; Lee, Taeweon; Liu, Jiwen (2011). "Discovery of non-glucoside SGLT2 inhibitors". Bioorganic & Medicinal Chemistry Letters 21 (8): 2472–2475. doi:10.1016/j.bmcl.2011.02.056. PMID 21398124.
- ↑ Hummel, Charles S.; Lu, Chuan; Liu, Jie; Ghezzi, Chiari; Hirayama, Bruce A.; Loo, Donald D. F.; Kepe, Vladimir; Barrio, Jorge R. et al. (2012). "Structural selectivity of human SGLT inhibitors". American Journal of Physiology. Cell Physiology 302 (2): C373–C382. doi:10.1152/ajpcell.00328.2011. PMID 21940664.
- ↑ 44.0 44.1 44.2 44.3 Plosker, Greg L. (2012). "Dapagliflozin". Drugs 72 (17): 2289–2312. doi:10.2165/11209910-000000000-00000. PMID 23170914.
- ↑ "Jardiance". https://www.drugs.com/pro/jardiance.html.
- ↑ "Farxiga". https://www.drugs.com/pro/farxiga.html.
- ↑ "Invokana". https://www.drugs.com/pro/invokana.html.
- ↑ Madaan, Tushar; Akhtar, Mohd.; Najmi, Abul Kalam (2016). "Sodium glucose Co Transporter 2 (SGLT2) inhibitors: Current status and future perspective". European Journal of Pharmaceutical Sciences 93: 244–252. doi:10.1016/j.ejps.2016.08.025. PMID 27531551.
- ↑ Bhartia, Mithun; Tahrani, Abd A.; Barnett, Anthony H. (2011). "SGLT-2 Inhibitors in Development for Type 2 Diabetes Treatment". The Review of Diabetic Studies 8 (3): 348–354. doi:10.1900/RDS.2011.8.348. PMID 22262072.
- ↑ 50.0 50.1 50.2 Yang, Li; Li, Haiyan; Li, Hongmei; Bui, Anh; Chang, Ming; Liu, Xiaoni; Kasichayanula, Sreeneeranj; Griffen, Steven C. et al. (2013). "Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects". Clinical Therapeutics 35 (8): 1211–1222.e2. doi:10.1016/J.Clinthera.2013.06.017. PMID 23910664.
- ↑ 51.0 51.1 Packer M (2020). "Cardioprotective Effects of Sirtuin-1 and Its Downstream Effectors: Potential Role in Mediating the Heart Failure Benefits of SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors". Circulation: Heart Failure 13 (9): e007197. doi:10.1161/CIRCHEARTFAILURE.120.007197. PMID 32894987.
- ↑ LARSON, GERALD L. (March–April 2015). "The synthesis of gliflozins". Chimica Oggi - Chemistry Today 33 (2): 37–40. http://www.teknoscienze.com/getpdf.php?filename=Contents%2FRiviste%2FPDF%2FCO2_Oligos-Peptides_2015_RGB.pdf&beginpage=39&endpage=42&filetitle=The%20synthesis%20of%20gliflozins. Retrieved 1 October 2018.
- ↑ "Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice". Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 13: 739–751. 2020. doi:10.2147/DMSO.S242282. PMID 32231437.
- ↑ Chen, Zeng-Hao; Wang, Ruo-Wen; Qing, Feng-Ling (2012). "Synthesis and biological evaluation of SGLT2 inhibitors: Gem-difluoromethylenated Dapagliflozin analogs". Tetrahedron Letters 53 (17): 2171–2176. doi:10.1016/j.tetlet.2012.02.062.
- ↑ 55.0 55.1 Ng, Wai-Lung; Li, Ho-Chuen; Lau, Kit-Man; Chan, Anthony K. N.; Lau, Clara Bik-San; Shing, Tony K. M. (17 July 2017). "Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition". Scientific Reports 7 (1): 5581. doi:10.1038/s41598-017-05895-9. ISSN 2045-2322. PMID 28717146. Bibcode: 2017NatSR...7.5581N.
- ↑ "7.5: Electron Affinities". 18 November 2014. https://chem.libretexts.org/Textbook_Maps/General_Chemistry/Map%3A_Chemistry_-_The_Central_Science_(Brown_et_al.)/07._Periodic_Properties_of_the_Elements/7.5%3A_Electron_Affinities.
- ↑ Song, Kwang-Seop; Lee, Suk Ho; Kim, Min Ju; Seo, Hee Jeong; Lee, Junwon; Lee, Sung-Han; Jung, Myung Eun; Son, Eun-Jung et al. (2010). "Synthesis and SAR of Thiazolylmethylphenyl Glucoside as Novel C-Aryl Glucoside SGLT2 Inhibitors". ACS Medicinal Chemistry Letters 2 (2): 182–187. doi:10.1021/ml100256c. PMID 24900297.
- ↑ "Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics". Cell Metabolism 25 (2): 262–284. 2017. doi:10.1016/j.cmet.2016.12.022. PMID 28178565.
- ↑ "Ketone bodies: from enemy to friend and guardian angel". BMC Medicine 19 (1): 313. 2021. doi:10.1186/s12916-021-02185-0. PMID 34879839.
- ↑ "SGLT2 inhibitors in cardiovascular medicine". Eur Heart J Cardiovasc Pharmacother 7 (4): e67–e68. July 2021. doi:10.1093/ehjcvp/pvab039. PMID 33964138.
- ↑ Ratziu, Vlad; Francque, Sven; Sanyal, Arun (1 June 2022). "Breakthroughs in therapies for NASH and remaining challenges". Journal of Hepatology 76 (6): 1263–1278. doi:10.1016/j.jhep.2022.04.002. ISSN 0168-8278. PMID 35589249.
- ↑ Androutsakos, Theodoros; Nasiri-Ansari, Narjes; Bakasis, Athanasios-Dimitrios; Kyrou, Ioannis; Efstathopoulos, Efstathios; Randeva, Harpal S.; Kassi, Eva (13 March 2022). "SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection". International Journal of Molecular Sciences 23 (6): 3107. doi:10.3390/ijms23063107. ISSN 1422-0067. PMID 35328527.
External links
- "FDA revises label of diabetes drug canagliflozin". 15 January 2016. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-label-diabetes-drug-canagliflozin-invokana-invokamet.
- "FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR)". 18 May 2016. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-confirms-increased-risk-leg-and-foot-amputations-diabetes-medicine.
- "FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate". 9 May 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-interim-clinical-trial-results-find-increased-risk-leg-and-foot.
- "Warning use metformin in certain patients with reduced kidney function". 14 November 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-warnings-regarding-use-diabetes-medicine-metformin-certain.
- "Warning: infection of genital area with SGLT2 inhibitors for diabetes". 7 September 2018. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes.
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