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).

In a mixed mouse model of Alzheimer’s disease and Type 2 diabetes, treatment with empagliflozin for 22 weeks helped maintain insulin levels, reduced neuronal loss, microgliosis, amyloid load, and brain hemorrhage. The mice were reported to show improvement in cognitive deficits (Hierro-Bujalance et al., 2020).

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., tricaprilin; Taylor 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., 2019; McGill and Subramian, 2019; Kaku 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 tested empagliflozin’s effect on ketone body production in adults older than 55 without diabetes. Thirty-nine participants underwent a two-week observation period, followed by two weeks of taking 25 mg empagliflozin per day. Investigators planned to 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 was completed in December 2021.

In October 2021, a Phase 2 trial started to test empagliflozin alone or in combination with nasal insulin in people with AD. Empagliflozin was recently reported to improve the brain response to nasal insulin in people with prediabetes (Kullmann et al., 2022). The single-site study at Wake Forest University will enroll 60 participants with elevated brain amyloid and normal cognition, MCI, or early dementia. The four-arm protocol compares nasal insulin four times daily, one 10 mg empagliflozin pill daily, or both, to placebo. The primary outcome is safety; other outcomes include cognitive measures, CSF Aβ and tau, and brain blood flow. The study will run until 2028.

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.