SGLT2 inhibition, circulating proteins, and insomnia: A mendelian randomization study

Area of Science:

• Pharmacology
• Genetics
• Sleep Medicine

Background:

• Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are primarily oral antidiabetic medications with known pleiotropic effects.
• Insomnia is a widespread and impactful sleep disorder with unclear links to SGLT2i.
• This research investigates the causal relationship between SGLT2 inhibitors and insomnia.

Purpose of the Study:

• To ascertain the causal effect of SGLT2 inhibition on insomnia and sleep duration.
• To identify circulating proteins that mediate the relationship between SGLT2 inhibition and insomnia.
• To explore the role of SGLT2 inhibition-driven plasma proteins in causing insomnia.

Main Methods:

• A two-sample Mendelian Randomization (MR) analysis was performed to assess the causality of SGLT2 inhibition on insomnia and sleep duration.
• A two-step and proteome-wide MR analysis investigated the causal link between SGLT2 inhibition and 4907 circulating proteins.
• Mediation analyses identified plasma proteins mediating the effects of SGLT2 inhibition on insomnia, with FDR correction applied.

Main Results:

• SGLT2 inhibition showed a significant negative correlation with insomnia (OR=0.791, P=5.579*10^-6) and a positive correlation with sleep duration (β=0.186, P=0.004).
• Diadenosine tetraphosphatase (Ap4A) was identified as a plasma protein associated with both SGLT2 inhibition and insomnia.
• Mediation analysis revealed that Ap4A partially mediates the effect of SGLT2 inhibition on insomnia (β=-0.018, P=0.023), accounting for 7.7% of the effect.

Conclusions:

• The study establishes a causal link between SGLT2 inhibition and a reduced risk of insomnia.
• Plasma Ap4A is identified as a potential mediator in the relationship between SGLT2 inhibitors and insomnia.
• These findings suggest SGLT2 inhibitors may offer therapeutic benefits for insomnia through Ap4A modulation.