Therapeutics

Empagliflozin

Overview

Name: Empagliflozin
Synonyms: Jardiance, BI-10773
Chemical Name: (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Boehringer Ingelheim, Eli Lilly & Co.
Approved for: Type 2 Diabetes, Cardiovascular disease

Background

Empagliflozin is a once-daily prescription pill that is FDA-approved to treat Type 2 diabetes and reduce risk of cardiovascular death in adults with the illness (2016 FDA press release).

Empagliflozin belongs to the gliflozin class of glucose-lowering agents that includes dapagliflozin. These drugs inhibit the sodium-glucose cotransporter-2 (SGLT2), which is responsible for 90 percent of glucose reabsorption into the kidney. As a result, excess glucose is secreted via the urine, helping reduce blood glucose, alleviate glucose toxicity, improve insulin sensitivity, and promote weight loss. Empagliflozin also lowers the risk of death from heart attack and stroke in people with Type 2 diabetes and cardiovascular disease.

Type 2 diabetes is a risk factor for developing dementia, and people with Alzheimer’s disease display signs of insulin resistance in the brain. These findings have spurred evaluation of multiple classes of diabetes drug for the treatment or prevention of AD (for example, see nasal insulin, pioglitazone, metformin, liraglutide, semaglutide).

There are no published data on empagliflozin in preclinical Alzheimer’s models.

In a large Danish epidemiological cohort, use of SGLT2 inhibitors, among other diabetes drugs, reduced the risk of dementia in people with Type 2 diabetes (Wium-Andersen et al., 2019).

Besides lowering glucose, SGLT2 inhibitors increase production of ketone bodies. Formed by the breakdown of fatty acids, ketone bodies provide an alternative to glucose as a fuel source in the brain. Because brain glucose metabolism is impaired in AD, there has been interest in ketogenic food products or diets as potential treatments (e.g., tricaprilinTaylor et al., 2018). Empagliflozin may offer an additional way to induce moderate chronic ketosis.

An excess of ketone bodies can cause a life-threating acidification of the blood. Occurrence of this ketoacidosis was negligible in empagliflozin trials, but has since been reported in some people taking the drug (Yamamoto et al., 2019McGill and Subramian, 2019Kaku et al., 2020).

Findings

In March 2019, a Phase 1 proof-of-concept study started up at the National Institute on Aging’s Clinical Trials Unit in Baltimore. It tests empagliflozin’s effect on ketone body production in adults older than 55 without diabetes. One hundred participants will undergo a two-week observation period, followed by two weeks of taking 25 mg empagliflozin per day. Investigators will measure ketone bodies, insulin, glucose, glucagon, and fatty acids in blood; markers of ketone body metabolism in blood exosomes; and brain metabolism by magnetic resonance spectroscopy (MRS), before and after treatment. The study will run through 2022.  

Empagliflozin is also being trialed for the treatment of Type 1 diabetes, diabetic kidney disease, and congestive heart failure. For details on empagliflozin trials for Alzheimer’s disease, see clinicaltrials.gov.

Last Updated: 09 Mar 2020

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References

Therapeutics Citations

  1. Dapagliflozin
  2. Nasal Insulin
  3. Pioglitazone
  4. Metformin
  5. Liraglutide
  6. Semaglutide
  7. Tricaprilin

Paper Citations

  1. . Antidiabetic medication and risk of dementia in patients with type 2 diabetes: a nested case-control study. Eur J Endocrinol. 2019 Nov;181(5):499-507. PubMed.
  2. . Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer's disease. Alzheimers Dement (N Y). 2018;4:28-36. Epub 2017 Dec 6 PubMed.
  3. . [Risk of Euglycemic Diabetic Ketoacidosis Due to Low-carbohydrate Diet While Taking Empagliflozin: a Case Report]. Yakugaku Zasshi. 2019;139(11):1479-1483. PubMed.
  4. . Safety of Sodium-Glucose Co-Transporter 2 Inhibitors. Am J Cardiol. 2019 Dec 15;124 Suppl 1:S45-S52. PubMed.
  5. . Safety and effectiveness of empagliflozin in Japanese patients with type 2 diabetes: interim analysis from a post-marketing surveillance study. Expert Opin Drug Saf. 2020 Feb;19(2):211-221. Epub 2019 Nov 26 PubMed.

External Citations

  1. clinicaltrials.gov
  2. 2016 FDA press release

Further Reading

No Available Further Reading