Empagliflozin

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Empagliflozin
Empagliflozin.svg
Names
Trade namesJardiance, others
Other namesBI-10773
  • (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol
Clinical data
Drug classSodium-glucose cotransporter-2 (SGLT2) inhibitor[1]
Pregnancy
category
  • AU: D[2]
  • US: N (Not classified yet)[2]
Routes of
use
By mouth
Defined daily dose17.5 mg[3]
External links
AHFS/Drugs.comMonograph
MedlinePlusa614043
Legal
License data
Legal status
  • UK: POM (Prescription only) [4][5]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Chemical and physical data
FormulaC23H27ClO7
Molar mass450.91 g·mol−1
3D model (JSmol)
  • C1COCC1OC2=CC=C(C=C2)CC3=C(C=CC(=C3)C4C(C(C(C(O4)CO)O)O)O)Cl
  • InChI=1S/C23H27ClO7/c24-18-6-3-14(23-22(28)21(27)20(26)19(11-25)31-23)10-15(18)9-13-1-4-16(5-2-13)30-17-7-8-29-12-17/h1-6,10,17,19-23,25-28H,7-9,11-12H2/t17-,19+,20+,21-,22+,23-/m0/s1
  • Key:OBWASQILIWPZMG-QZMOQZSNSA-N

Empagliflozin, sold under the brand name Jardiance among others, is a medication used together with diet and exercise to treat type 2 diabetes.[1][6] It is less preferred than metformin and sulfonylureas.[7] It may be used together with other medications such as metformin or insulin.[1][6] It is not recommended for type 1 diabetes.[1] It is taken by mouth.[1]

Common side effects include urinary tract infections, fungal infections of the groin, and joint pains.[1] Rarer but more serious side effects include a skin infection of the groin called Fournier's gangrene and a form of diabetic ketoacidosis with normal blood sugar levels.[1][8] Use in pregnancy and breastfeeding is not recommended.[7] Use is not recommended in those with significant kidney disease, though it may help slow the progression of mild kidney problems.[1][6] Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), and works by increasing sugar lost in the urine.[1]

Empagliflozin was approved for medical use in the US and in the European Union in 2014.[1][9][10][11] It is on the World Health Organization's List of Essential Medicines.[12] A month supply in the UK costs the NHS about GB£36.59 as of 2019.[7] In the US, the wholesale cost of this amount is about US$442.[13] In 2017, it was the 228th most commonly prescribed medication in the United States, with more than two million prescriptions.[14][15]

Medical use

Beneficial effects of empagliflozin administration[16]

Type 2 diabetes

Empagliflozin is used in combination with proper diet and exercise to help people with type 2 diabetes lower their blood sugar levels.[17] It can be used alongside other medications for type 2 diabetes such as metformin, sulfonylureas, and insulin.[18] When compared to a placebo, empagliflozin led to a drop of 0.7% in hemoglobin A1c, a long-term marker of blood glucose levels.[19]

Weight and blood pressure

Empagliflozin causes moderate reductions in blood pressure and body weight. These effects are likely due to the excretion of glucose in the urine and a slight increase in urinary sodium excretion.[20][19] In clinical trials, patients taking empagliflozin lost an average of 2% of their baseline body weight.[21] A higher percentage of people taking empagliflozin achieved weight loss greater than 5% from their baseline.[19] The medication reduced systolic blood pressure by 3 to 5 millimeters of mercury (mmHg).[19] The effects on blood pressure and body weight are generally viewed as favorable, as many patients with type 2 diabetes have high blood pressure or are overweight or obese.[22][23]

Heart and kidney disease

SGLT2 inhibitors, including empagliflozin, appear to reduce the likelihood of hospitalization for heart failure or progression of chronic kidney disease in persons with type 2 diabetes. Empagliflozin may reduce the likelihood of death due to cardiovascular causes in people with type 2 diabetes who have known cardiovascular disease.[24][25][26] One concern regarding the trial on which these claims are based is that the different arms received different amounts of other medications; thus, the reduced risk cannot necessarily be attributed to empaglifozin.[27] In some countries it has also been approved to reduce the risk of death from cardiovascular causes in people with type 2 diabetes and heart disease.[26]

Treatment guidelines

Guidelines by the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommend SGLT-2 inhibitors like empagliflozin as second-line medications after metformin for type 2 diabetes in people with heart failure or chronic kidney disease.[6] For type 2 diabetes with established cardiovascular disease, the guidelines recommend either a SGLT-2 inhibitor or a GLP-1 agonist as second-line medications after metformin. In all other type 2 diabetes cases, SGLT-2 inhibitors like empagliflozin can be appropriate second-line options if blood glucose control or weight loss are treatment priorities. They are less appropriate if cost is a major factor.[6]

In the United Kingdom empagliflozin is typically only recommended together with metformin if a sulfonylurea cannot be taken.[18]

Type 1 diabetes

Empagliflozin is not recommended for type 1 diabetes.[1] One trial studied its use in addition to insulin in people with type 1 diabetes.[28] The medications delivered modest improvements in blood glucose control and body weight but were associated with an increased risk of diabetic ketoacidosis, a dangerous complication of diabetes.[28] Empagliflozin is not approved by the U.S. Food and Drug Administration (FDA) for use in type 1 diabetes.[17]

Dosage

The defined daily dose is 17.5 mg by mouth.[3]

Side effects

Common

  • Empagliflozin increases the risk of genital fungal infections. The risk is highest in people with a prior history of genital fungal infections.[19]
  • Urinary tract infections (UTIs) may be more common with empagliflozin. Certain individual clinical trials have demonstrated an increase risk but cumulative data across multiple trials show no increase in UTI risk.[21][19][22]
  • Empagliflozin reduces systolic and diastolic blood pressure and can increase the risk of low blood pressure, which can cause fainting and/or falls.[19] The risk is higher in older people, people taking diuretics, and people with reduced kidney function.[19]
  • Slight increases in LDL cholesterol can be seen with empagliflozin, in the range of 2% to 4% from baseline.[19]

Serious

  • Diabetic ketoacidosis (DKA), a rare but potentially life-threatening condition, may occur more commonly with empagliflozin and other SGLT-2 inhibitors.[29][30] While DKA is usually associated with elevated blood glucose levels, in people taking SGLT-2 inhibitors DKA may be seen with uncharacteristically normal blood glucose levels, a phenomenon called euglycemic ketoacidosis.[29] The absence of elevated blood glucose levels in people on an SGLT-2 inhibitor may make it more difficult to diagnose DKA. The risk of empagliflozin-associated DKA may be higher in the setting of illness, dehydration, surgery, and/or alcohol consumption.[29] It is also seen in type 1 diabetes who take empagliflozin, which notably is an unapproved or "off-label" use of the medication.[30] To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high levels of blood acids called ketones) 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. Empagliflozin should each be stopped at least three days before scheduled surgery.[31] Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.[31]
  • Fournier's gangrene, a rare but serious infection of the groin, occurs more commonly in people taking empaglflozin and other SGLT-2 inhibitors.[8][1] Symptoms include feverishness, a general sense of malaise, and pain or swelling around the genitals or in the skin behind them. The infection progresses quickly and urgent medical attention is recommended.[8]
  • Empagliflozin can increase people' risk of low blood sugar when it is used together with a sulfonylurea or insulin.[32] When used by itself or in addition to metformin it does not appear to increase the risk of hypoglycemia.[22]

Contraindications

Mechanism of action

Biochemical mechanisms of empagliflozin in heart failure.[33]

Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), which is found almost exclusively in the proximal tubules of nephronic components in the kidneys. SGLT-2 accounts for about 90 percent of glucose reabsorption into the blood. Blocking SGLT-2 reduces blood glucose by blocking glucose reabsorption in the kidney and thereby excreting glucose (i.e., blood sugar) via the urine.[34][35][36]

History

It was developed by Boehringer Ingelheim and Eli Lilly and Company. It is also available as the combination empagliflozin/linagliptin, empagliflozin/metformin, or empagliflozin/linagliptin/metformin.

Regulatory status

As of May 2013, Boehringer and Lilly had submitted applications for marketing approval to the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA).[37] The drug was approved in Europe in May 2014,[11] and was approved by the FDA in August 2014.[9][38] The FDA required four postmarketing studies: a cardiovascular outcomes trial, two studies in children, and a toxicity study in animals related to the pediatric trials.[38]

Society and culture

Cost

A month supply in the UK costs the NHS about GB£36.59 as of 2019.[7] In the US, the wholesale cost of this amount is about US$442.[13] In 2017, it was the 228th most commonly prescribed medication in the United States, with more than two million prescriptions.[14][15]

References

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  2. 2.0 2.1 "Empagliflozin (Jardiance) Use During Pregnancy". Drugs.com. 30 August 2018. Archived from the original on 5 August 2019. Retrieved 10 February 2020.
  3. 3.0 3.1 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 17 May 2021. Retrieved 8 September 2020.
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  7. 7.0 7.1 7.2 7.3 British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 691. ISBN 9780857113382.
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  23. "Obesity and overweight fact sheet" (PDF). World Health Organization. Archived (PDF) from the original on 23 January 2019. Retrieved 23 March 2019.
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  25. Usman MS, Siddiqi TJ, Memon MM, Khan MS, Rawasia WF, Talha Ayub M, Sreenivasan J, Golzar Y (March 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.
  26. 26.0 26.1 "FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes" (Press release). U.S. Food and Drug Administration (FDA). 6 December 2016. Archived from the original on 11 February 2020. Retrieved 12 December 2016.
  27. "EMPA-REG Outcome trial: What does it mean?" (PDF). Therapeutics Initiative. July–August 2017. Archived (PDF) from the original on 31 March 2018. Retrieved 21 December 2018.
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