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'''Gliflozin''' drugs are a class of medications that inhibit [[renal glucose reabsorption|reabsorption of glucose in the kidney]] and therefore lower [[blood sugar]].<ref name=Shubrook2015>{{cite journal |
'''Gliflozin''' drugs are a class of medications that inhibit [[renal glucose reabsorption|reabsorption of glucose in the kidney]] and therefore lower [[blood sugar]].<ref name=Shubrook2015>{{cite journal |doi=10.2147/DDDT.S69926 }}</ref> They act by inhibiting [[sodium-glucose transport protein 2]] (SGLT2), and are therefore also called '''SGLT2 inhibitors'''. Gliflozins are used in the treatment of [[type II diabetes mellitus]] (T2DM). Apart from glycemic control, gliflozins have been shown to provide significant cardiovascular benefit in T2DM patients.<ref>{{cite journal |doi=10.1177/2047487318755531 }}</ref> Several drugs of this class have been approved or are currently under development.<ref>{{cite journal |doi=10.1007/s40265-014-0337-y }}</ref> |
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In studies on [[canagliflozin]], a member of this class, the drug was found to enhance blood sugar control as well as reduce [[body weight]] and systolic and diastolic [[blood pressure]].<ref name="HaasEckstein2014">{{cite journal |
In studies on [[canagliflozin]], a member of this class, the drug was found to enhance blood sugar control as well as reduce [[body weight]] and systolic and diastolic [[blood pressure]].<ref name="HaasEckstein2014">{{cite journal |doi=10.1038/nutd.2014.40 }}</ref> |
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==Medical uses== |
==Medical uses== |
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The gliflozins are used to treat [[type 2 diabetes mellitus]] but are most often used as second- or third-line agents instead of first-line because there are other drugs on the market that have much longer safety record and are less expensive than gliflozins. |
The gliflozins are used to treat [[type 2 diabetes mellitus]] but are most often used as second- or third-line agents instead of first-line because there are other drugs on the market that have much longer safety record and are less expensive than gliflozins.<ref>{{cite journal |doi=10.1136/bmjopen-2012-001007 }}</ref> |
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Gliflozins may be a good option for patients who are failing with metformin monotherapy, especially if weight is part of the underlying treatment. |
Gliflozins may be a good option for patients who are failing with metformin monotherapy, especially if weight is part of the underlying treatment.<ref>{{cite journal |doi=10.2147/DDDT.S50773 }}</ref> |
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They are often used in combination therapy, for example the dual therapy [[metformin]] plus gliflozin and the triple therapy metformin, [[sulphonylurea]] and gliflozin.<ref> |
They are often used in combination therapy, for example the dual therapy [[metformin]] plus gliflozin and the triple therapy metformin, [[sulphonylurea]] and gliflozin.<ref>{{cite journal |doi=10.1136/bmjopen-2012-001007 }}</ref> |
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A recent 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.<ref>{{cite journal |
A recent 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.<ref>{{cite journal |doi=10.1001/jama.2018.3024 }}</ref> |
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==Adverse effects == |
==Adverse effects == |
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Genital infections seem to be the most common [[adverse effect]] of gliflozins. In [[clinical trials]] [[mycotic infections]], [[urinary tract infections]] and [[osmotic diuresis]] were higher in patients treated with gliflozins. |
Genital infections seem to be the most common [[adverse effect]] of gliflozins. In [[clinical trials]] [[mycotic infections]], [[urinary tract infections]] and [[osmotic diuresis]] were higher in patients treated with gliflozins. |
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In May 2015 FDA issued a warning that gliflozins can increase risk of [[diabetic ketoacidosis]] (DKA).<ref> |
In May 2015 FDA issued a warning that gliflozins can increase risk of [[diabetic ketoacidosis]] (DKA).<ref name=pmid27898586>{{cite journal |doi=10.1097/MED.0000000000000311 }}</ref> By reducing glucose blood circulation, gliflozins cause less stimulation of endogenous [[insulin]] secretion or lower dose of exogenous insulin that results in diabetic ketoacidosis (DKA). They can also contribute euglycemic DKA (euDKA) because of the renal tubular absorption of ketone bodies.<ref>{{cite journal |doi=10.1111/imj.13442 }}</ref> |
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In September 2015 FDA issued a warning related to canagliflozin (Invokana®) and canagliflozin/metformin (Invokmet®) 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 T2BM such as sulfonylureas and insulin. |
In September 2015 FDA issued a warning related to canagliflozin (Invokana®) and canagliflozin/metformin (Invokmet®) 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 T2BM such as sulfonylureas and insulin.<ref name=pmid27898586/> |
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<ref>Daniel S Hsia, Owen Grove, William T Cefalu, [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028052/"An Update on SGLT2 Inhibitors for the Treatment of Diabetes Mellitus"], ''Curr Opin Endocrinology Diabetes Obes'', February 2017</ref> |
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Increased risk of lower [[limb amputation]] is associated with canagliflozin but further data is needed to confirm this risk associated with different gliflozins. |
Increased risk of lower [[limb amputation]] is associated with canagliflozin but further data is needed to confirm this risk associated with different gliflozins.<ref>{{cite journal |doi=10.1111/dom.13255 }}</ref> |
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== Interactions == |
== Interactions == |
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Interactions are important for SGLT2 inhibitors because most T2DM patients are taking many other medications. Gliflozins can increase the diuretic effect of [[thiazides]], [[loop diuretics]] and related [[diuretics]] and therefore increase the risk of [[dehydration]] and [[hypotension]].<ref>BMJ Group, ''BNF 73'', march-september 2017</ref> It is important to adjust the dose of antidiabetics if the treatment is combination therapy to avoid hypoglycemia. For example interactions with sulfonylureas have lead to severe hypoglycemia presumably due to [[cytochrome P450]].<ref> |
Interactions are important for SGLT2 inhibitors because most T2DM patients are taking many other medications. Gliflozins can increase the diuretic effect of [[thiazides]], [[loop diuretics]] and related [[diuretics]] and therefore increase the risk of [[dehydration]] and [[hypotension]].<ref>BMJ Group, ''BNF 73'', march-september 2017{{full}}</ref> It is important to adjust the dose of antidiabetics if the treatment is combination therapy to avoid hypoglycemia. For example interactions with sulfonylureas have lead to severe hypoglycemia presumably due to [[cytochrome P450]].<ref>{{cite journal |doi=10.1007/s40262-013-0128-8 }}</ref> |
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A study has shown that it is safe to consume dapagliflozin along with [[pioglitazone]], metformin, [[glimepiride]], or [[sitagliptin]] and dose adjustment is unnecessary for either drug.<ref name=Bhartia,2011 /> It is unlikely that food intake has clinical meaningful impact on the efficacy of dapagliflozin, therefore it can be administered without regard to meals.<ref name=Bhartia,2011 /><ref name="Yang, 2013" /> |
A study has shown that it is safe to consume dapagliflozin along with [[pioglitazone]], metformin, [[glimepiride]], or [[sitagliptin]] and dose adjustment is unnecessary for either drug.<ref name=Bhartia,2011 /> It is unlikely that food intake has clinical meaningful impact on the efficacy of dapagliflozin, therefore it can be administered without regard to meals.<ref name=Bhartia,2011 /><ref name="Yang, 2013" /> |
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* [[Ertugliflozin]] was approved in the United States under the brand name Steglatro in December 2017.<ref>{{Cite web|url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=209803|title=Drugs@FDA: FDA Approved Drug Products|website=www.accessdata.fda.gov|access-date=2017-12-21}}</ref> |
* [[Ertugliflozin]] was approved in the United States under the brand name Steglatro in December 2017.<ref>{{Cite web|url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=209803|title=Drugs@FDA: FDA Approved Drug Products|website=www.accessdata.fda.gov|access-date=2017-12-21}}</ref> |
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* [[Ipragliflozin]] (ASP-1941), produced by the Japanese company [[Astellas Pharma]] Inc. under the brand name Suglat; approved in Japan in January 2014.<ref name=pharma-share>[http://www.pharma-share.com/sglt-2-inhibitor-approval-race-%E2%80%93-astrazeneca-bristol-myers-squibb-home-gold-dapagliflozin SGLT2 inhibitor approval race]</ref><ref>{{cite web|title=Approval of Suglat® Tablets, a Selective SGLT2 Inhibitor for Treatment of Type 2 Diabetes, in Japan|url=http://www.astellas.com/en/corporate/news/detail/approval-of-suglat-tablets-a-s.html|date=January 17, 2014}}</ref> |
* [[Ipragliflozin]] (ASP-1941), produced by the Japanese company [[Astellas Pharma]] Inc. under the brand name Suglat; approved in Japan in January 2014.<ref name=pharma-share>[http://www.pharma-share.com/sglt-2-inhibitor-approval-race-%E2%80%93-astrazeneca-bristol-myers-squibb-home-gold-dapagliflozin SGLT2 inhibitor approval race]</ref><ref>{{cite web|title=Approval of Suglat® Tablets, a Selective SGLT2 Inhibitor for Treatment of Type 2 Diabetes, in Japan|url=http://www.astellas.com/en/corporate/news/detail/approval-of-suglat-tablets-a-s.html|date=January 17, 2014}}</ref> |
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* [[Luseogliflozin]] was approved in March 2014 in Japan under the brand name Lusefi and was developed by Taisho Pharmaceutical. |
* [[Luseogliflozin]] was approved in March 2014 in Japan under the brand name Lusefi and was developed by Taisho Pharmaceutical.<ref>{{cite journal |doi=10.1007/s40265-014-0230-8 }}</ref> |
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* [[Remogliflozin etabonate]] (BHV091009) discontinued in clinical trials. |
* [[Remogliflozin etabonate]] (BHV091009) discontinued in clinical trials.<ref>{{cite journal |doi=10.1039/c8md00183a }}</ref> |
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* [[Sergliflozin etabonate]] discontinued after Phase II trials. |
* [[Sergliflozin etabonate]] discontinued after Phase II trials. |
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* [[Sotagliflozin]] is a dual SGLT1/SGLT2 inhibitor in phase III trials under the brand name Zynquista. Developed by Lexicon pharmaceuticals. If approved, sotagliflozin would be the first oral treatment in combination with insulin to treat type 1 diabetes mellitus. |
* [[Sotagliflozin]] is a dual SGLT1/SGLT2 inhibitor in phase III trials under the brand name Zynquista. Developed by Lexicon pharmaceuticals. If approved, sotagliflozin would be the first oral treatment in combination with insulin to treat type 1 diabetes mellitus.<ref>{{ClinicalTrialsGov|NCT02531035|A Phase 3 Study to Evaluate the Safety of Sotagliflozin in Patients With Type 1 Diabetes Who Have Inadequate Glycemic Control With Insulin Therapy Alone (inTandem3)}}</ref> |
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* [[Tofogliflozin]] was approved in March 2014 in Japan under the brand names Apleway and Deberza developed by [[Sanofi]] and [[Kowa Pharmaceutical]]<ref>{{cite journal |
* [[Tofogliflozin]] was approved in March 2014 in Japan under the brand names Apleway and Deberza developed by [[Sanofi]] and [[Kowa Pharmaceutical]]<ref>{{cite journal |doi=10.1007/s40265-014-0229-1 }}</ref> |
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<ref>https://www.ncbi.nlm.nih.gov/pubmed/24848755</ref> |
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== Mechanism of action == |
== Mechanism of action == |
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SGLTs are responsible for mediating glucose [[reabsorption]] in the kidneys, as well as in the gut and the [[heart]]. SGLT-2 is primarily expressed in the kidney on the [[epithelial]] cells lining the first segment of the [[proximal convoluted tubule]]. It is the major [[transport protein]] that promotes reabsorption from the [[glomerular filtration]] glucose back into circulation and is responsible for approximately 90% of the kidney's glucose reabsorption.<ref name=Shubrook2015/> |
SGLTs are responsible for mediating glucose [[reabsorption]] in the kidneys, as well as in the gut and the [[heart]]. SGLT-2 is primarily expressed in the kidney on the [[epithelial]] cells lining the first segment of the [[proximal convoluted tubule]]. It is the major [[transport protein]] that promotes reabsorption from the [[glomerular filtration]] glucose back into circulation and is responsible for approximately 90% of the kidney's glucose reabsorption.<ref name=Shubrook2015/> |
||
By inhibiting SGLT-2, medications of the gliflozin class 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).<ref name="Anderson og Marrs, 2012">{{cite journal |
By inhibiting SGLT-2, medications of the gliflozin class 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).<ref name="Anderson og Marrs, 2012">{{cite journal |doi=10.1345/aph.1Q538 }}</ref><ref name="Li o.fl., 2011">{{cite journal |doi=10.1016/j.bmcl.2011.02.056 }}</ref> |
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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 [[glycemic control|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 drugs]]. Functional pancreatic [[Beta cell|β-cell]]s are not necessary for the activity of the drug so it is convenient for patients with diminished β-cell function.<ref name="Anderson og Marrs, 2012" /><ref name="Li o.fl., 2011" /> |
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 [[glycemic control|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 drugs]]. Functional pancreatic [[Beta cell|β-cell]]s are not necessary for the activity of the drug so it is convenient for patients with diminished β-cell function.<ref name="Anderson og Marrs, 2012" /><ref name="Li o.fl., 2011" /> |
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[[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.<ref name="Anderson og Marrs, 2012" /><ref name="Li o.fl., 2011" /><ref name="Plosker, 2012">{{cite journal |
[[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.<ref name="Anderson og Marrs, 2012" /><ref name="Li o.fl., 2011" /><ref name="Plosker, 2012">{{cite journal |doi=10.2165/11209910-000000000-00000 }}</ref> |
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The use of dapagliflozin with other oral antidiabetic agents act synergistically with virtually no increased risk of developing low blood sugar levels.<ref name="Anderson og Marrs, 2012" /><ref name="Li o.fl., 2011" /> |
The use of dapagliflozin with other oral antidiabetic agents act synergistically with virtually no increased risk of developing low blood sugar levels.<ref name="Anderson og Marrs, 2012" /><ref name="Li o.fl., 2011" /> |
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{| class="wikitable" |
{| class="wikitable" |
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|+ TABLE 1: PHARMACOKINETIC PARAMETERS OF VARIOUS SGLT-2 INHIBITORS<ref>{{ |
|+ TABLE 1: PHARMACOKINETIC PARAMETERS OF VARIOUS SGLT-2 INHIBITORS<ref>{{cite journal |doi=10.1016/j.ejps.2016.08.025 }}</ref> |
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|- |
|- |
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! Name of drug !! Bioavailability !! Protein binding !! tmax (hours) !! t1/2 (hours) !! Cmax !! Selectivity towards SGLT2 over SGLT1 |
! Name of drug !! Bioavailability !! Protein binding !! tmax (hours) !! t1/2 (hours) !! Cmax !! Selectivity towards SGLT2 over SGLT1 |
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[[File:Dapagliflozin structure.svg|thumb|Dapagliflozin]] |
[[File:Dapagliflozin structure.svg|thumb|Dapagliflozin]] |
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In studies that were made on healthy people and people with type II diabetes mellitus, who were given dapagliflozin in either single ascending dose (SAD) or multiple ascending dose (MAD) showed results that confirmed a [[pharmacokinetic profile]] of the drug. 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 [[renal excretion|excretion by the kidney]].<ref name=Bhartia,2011>{{cite journal |
In studies that were made on healthy people and people with type II diabetes mellitus, who were given dapagliflozin in either single ascending dose (SAD) or multiple ascending dose (MAD) showed results that confirmed a [[pharmacokinetic profile]] of the drug. 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 [[renal excretion|excretion by the kidney]].<ref name=Bhartia,2011>{{cite journal |doi=10.1900/RDS.2011.8.348 }}</ref> |
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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 [[Body mass index|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.<ref name="Yang, 2013">{{cite journal |
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 [[Body mass index|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.<ref name="Yang, 2013">{{cite journal |doi=10.1016/J.Clinthera.2013.06.017 }}</ref> |
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In some long term clinical studies that have been made on dapagliflozin, dapagliflozin was associated with a decrease in body weight which was statistically superior compared to placebo or other active comparators. It is primarily associated with caloric rather than fluid loss.<ref name="Yang, 2013" /><ref name="Plosker, 2012" /> |
In some long term clinical studies that have been made on dapagliflozin, dapagliflozin was associated with a decrease in body weight which was statistically superior compared to placebo or other active comparators. It is primarily associated with caloric rather than fluid loss.<ref name="Yang, 2013" /><ref name="Plosker, 2012" /> |
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== Alternative pharmacological actions == |
== Alternative pharmacological actions == |
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Gliflozins have been found to exhibit cardioprotective, renoprotective, anti‐hyperlipidemic, anti‐atherosclerotic, anti‐obesity, anti‐neoplastic, hepatoprotective, and renoprotective effects in ''in vitro'', pre‐clinical, and clinical studies. These 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 anti‐oxidative actions.<ref>{{ |
Gliflozins have been found to exhibit cardioprotective, renoprotective, anti‐hyperlipidemic, anti‐atherosclerotic, anti‐obesity, anti‐neoplastic, hepatoprotective, and renoprotective effects in ''in vitro'', pre‐clinical, and clinical studies. These 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 anti‐oxidative actions.<ref>{{cite journal |doi=10.1111/1440-1681.12963 }}</ref> |
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==History== |
==History== |
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Revision as of 00:31, 1 October 2018
Gliflozin drugs are a class of medications that inhibit reabsorption of glucose in the kidney and therefore lower blood sugar.[1] They act by inhibiting sodium-glucose transport protein 2 (SGLT2), and are therefore also called SGLT2 inhibitors. Gliflozins are used in the treatment of type II diabetes mellitus (T2DM). Apart from glycemic control, gliflozins have been shown to provide significant cardiovascular benefit in T2DM patients.[2] Several drugs of this class have been approved or are currently under development.[3] In studies on canagliflozin, a member of this class, the drug was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.[4]
Medical uses
The gliflozins are used to treat type 2 diabetes mellitus but are most often used as second- or third-line agents instead of first-line because there are other drugs on the market that have much longer safety record and are less expensive than gliflozins.[5]
Gliflozins may be a good option for patients who are failing with metformin monotherapy, especially if weight is part of the underlying treatment.[6] They are often used in combination therapy, for example the dual therapy metformin plus gliflozin and the triple therapy metformin, sulphonylurea and gliflozin.[7]
A recent 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.[8]
Adverse effects
Genital infections seem to be the most common adverse effect of gliflozins. In clinical trials mycotic infections, urinary tract infections and osmotic diuresis were higher in patients treated with gliflozins.
In May 2015 FDA issued a warning that gliflozins can increase risk of diabetic ketoacidosis (DKA).[9] By reducing glucose blood circulation, gliflozins cause less stimulation of endogenous insulin secretion or lower dose of exogenous insulin that results in diabetic ketoacidosis (DKA). They can also contribute euglycemic DKA (euDKA) because of the renal tubular absorption of ketone bodies.[10]
In September 2015 FDA issued a warning related to canagliflozin (Invokana®) and canagliflozin/metformin (Invokmet®) 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 T2BM such as sulfonylureas and insulin.[9]
Increased risk of lower limb amputation is associated with canagliflozin but further data is needed to confirm this risk associated with different gliflozins.[11]
Interactions
Interactions are important for SGLT2 inhibitors because most T2DM patients are taking many other medications. Gliflozins can increase the diuretic effect of thiazides, loop diuretics and related diuretics and therefore increase the risk of dehydration and hypotension.[12] It is important to adjust the dose of antidiabetics if the treatment is combination therapy to avoid hypoglycemia. For example interactions with sulfonylureas have lead to severe hypoglycemia presumably due to cytochrome P450.[13]
A study has shown that it is safe to consume dapagliflozin along with pioglitazone, metformin, glimepiride, or sitagliptin and dose adjustment is unnecessary for either drug.[14] It is unlikely that food intake has clinical meaningful impact on the efficacy of dapagliflozin, therefore it can be administered without regard to meals.[14][15]
Members
These are the known members of the gliflozin class:
- 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.[16] [17]
- Dapagliflozin is the first SGLT2 inhibitor approved anywhere in the world, it happened in 2011 by the EU. It was approved for use in the United States under the brand name Forxiga by the Food and Drug Administration in January 2014.[18]
- Empagliflozin, approved in the United States in August 2014 under the brand name Jardiance by Boehringer Ingelheim.[19] Of the gliflozins, empagliflozin and tofogliflozin have the highest specificity for SGLT2 inhibition.[1] It is the only oral medicine for type 2 diabetes that has been shown to reduce the risk of cardiovascular death.[20]
- Ertugliflozin was approved in the United States under the brand name Steglatro in December 2017.[21]
- Ipragliflozin (ASP-1941), produced by the Japanese company Astellas Pharma Inc. under the brand name Suglat; approved in Japan in January 2014.[22][23]
- Luseogliflozin was approved in March 2014 in Japan under the brand name Lusefi and was developed by Taisho Pharmaceutical.[24]
- Remogliflozin etabonate (BHV091009) discontinued in clinical trials.[25]
- Sergliflozin etabonate discontinued after Phase II trials.
- Sotagliflozin is a dual SGLT1/SGLT2 inhibitor in phase III trials under the brand name Zynquista. Developed by Lexicon pharmaceuticals. If approved, sotagliflozin would be the first oral treatment in combination with insulin to treat type 1 diabetes mellitus.[26]
- Tofogliflozin was approved in March 2014 in Japan under the brand names Apleway and Deberza developed by Sanofi and Kowa Pharmaceutical[27]
Mechanism of action
SGLTs are responsible for mediating glucose reabsorption in the kidneys, as well as in the gut and the heart. SGLT-2 is primarily expressed in the kidney on the epithelial cells lining the first segment of the proximal convoluted tubule. It is the major transport protein that promotes reabsorption from the glomerular filtration glucose back into circulation and is responsible for approximately 90% of the kidney's glucose reabsorption.[1] By inhibiting SGLT-2, medications of the gliflozin class 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).[28][29]
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 drugs. Functional pancreatic β-cells are not necessary for the activity of the drug so it is convenient for patients with diminished β-cell function.[28][29]
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.[28][29][30]
The use of dapagliflozin with other oral antidiabetic agents act synergistically with virtually no increased risk of developing low blood sugar levels.[28][29]
Pharmacology
The elimination half-life, bioavailability, protein binding, the blood concentration Cmax at time tmax, and other pharmacokinetic parameters of various drugs of this class are present in table 1. These drugs are excreted in the urine as inactive metabolites.[30][31][32][33]
| Name of drug | Bioavailability | Protein binding | tmax (hours) | t1/2 (hours) | Cmax | Selectivity towards SGLT2 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) | 1:414 |
| Dapagliflozin | 78% | 91% | 1–1.5 | 12.9 | 79.6 ng/mL (5 mg dose); 165.0 ng/mL (10 mg dose) | 1:1200 |
| 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) | 1:2500 |
| Ipragliflozin (50 mg) | 90% | 96.30% | 1 | 15–16 (50 mg dose) | 975 ng/mL | 1:360 |
| 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 | 1:1770 |
| Remogliflozin Etabonate | Almost complete | – | 0.5 | 0.39 | 39.0 ng/mL | 1:365 |
| Tofogliflozin (20 mg) | 97.50% | 82.3–82.6% | 1.10±0.431 | 5.40±0.622 | 509±108 ng/mL | 1:3000 |
- tmax: Time to achieve maximum plasma concentration
- t1/2: Biological half-life
In studies that were made on healthy people and people with type II diabetes mellitus, who were given dapagliflozin in either single ascending dose (SAD) or multiple ascending dose (MAD) showed results that confirmed a pharmacokinetic profile of the drug. 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.[14]
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.[15]
In some long term clinical studies that have been made on dapagliflozin, dapagliflozin was associated with a decrease in body weight which was statistically superior compared to placebo or other active comparators. It is primarily associated with caloric rather than fluid loss.[15][30]
Alternative pharmacological actions
Gliflozins have been found to exhibit cardioprotective, renoprotective, anti‐hyperlipidemic, anti‐atherosclerotic, anti‐obesity, anti‐neoplastic, hepatoprotective, and renoprotective effects in in vitro, pre‐clinical, and clinical studies. These 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 anti‐oxidative actions.[35]
History
Phlorizin is a molecule with SGLT inhibiting properties, and served an important role in the development of the gliflozin class of drugs.
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