Background

Dapagliflozin is a once-daily prescription pill that is FDA-approved to treat Type 2 diabetes and reduce risk of heart failure in people with diabetes. It belongs to the gliflozin class of glucose-lowering agents that includes empagliflozin. These drugs inhibit the sodium-glucose cotransporter-2 (SGLT2), which is responsible for 90 percent of glucose reabsorption in the kidney. As a result, glucose is secreted via the urine. This lowers blood glucose, thus alleviating glucose toxicity, improving insulin sensitivity, and promoting weight loss. In clinical trials, dapagliflozin also reduced the chance of hospitalization for heart failure 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 testing of multiple classes of diabetes drug for the treatment or prevention of AD (for example, see nasal insulin, pioglitazone, metformin, liraglutide and semaglutide).

There is no published data on dapagliflozin in preclinical Alzheimer’s models. In rats and mice rendered obese and diabetic by high-fat diets, dapagliflozin reportedly improved cognition, as well as brain mitochondrial function, insulin signaling, neurogenesis, synaptic density, and hippocampal synaptic plasticity (Sa-Nguanmoo et al., 2017; Millar et al., 2017).

In a large Danish epidemiological study, use of SGLT2 inhibitors and other diabetes drugs reduced the risk of dementia in diabetics (Wium-Andersen et al., 2019).

Findings

In January 2019, a study began at the University of Kansas Medical Center to test dapagliflozin’s effect on brain metabolic markers in people with AD. The trial is enrolling 48 people with a clinical diagnosis of probable AD and a Mini-Mental State Exam score of 15 to 26. Participants may have diabetes, if they have been treated only with metformin. They will be randomized 2:1 to receive 10 mg dapagliflozin daily or placebo for 12 weeks. The primary outcome is change in brain n-acetyl aspartate (NAA), measured by magnetic resonance spectroscopy. NAA is synthesized in mitochondria, and its levels are reduced in many neurological conditions, including Alzheimer’s disease; the investigators are using it as a proxy for mitochondrial mass. Other endpoints include NAA levels in blood and urine, FDG-PET, markers of systemic glucose and fat metabolism, mitochondrial function, and inflammation, as well as cognitive measures and safety and tolerability. The trial will run through October 2020. It is funded by AstraZeneca.

In May 2019, a trial at Nanjing University Hospital began comparing dapagliflozin to liraglutide, and to the anti-diabetic medication acarbose, for their respective effects on cognitive and olfactory function in 87 overweight people whose Type 2 diabetes is poorly controlled with metformin alone. Outcome measures of this 16-week trial include fMRI of odor-induced brain activity, change on the MoCA cognition screen, and an odor-detection test. This trial is set to end in February 2021. 

Dapagliflozin is also being studied in Type 1 diabeties, kidney diseases, hepatitis, and other conditions. For details, see clinicaltrials.gov.