Summary: In adults with type 2 diabetes, empagliflozin reduced total-body norepinephrine (NE) turnover rate at both 1 day and 12 weeks, even as hepatic glucose production (HGP) increased. The fall in NE turnover inversely correlated with the rise in HGP, so sympathetic activation does not appear to explain the sustained increase in glucose production. The abstract reports directional findings only; no effect sizes, confidence intervals, or p values were provided.
PICO Summary
| Element | Detail |
|---|---|
| Population | Adults with type 2 diabetes (single-country mechanistic study, USA). Exact enrolled n is not stated in the abstract. |
| Intervention | Empagliflozin (an SGLT2 inhibitor) started and continued for 12 weeks, with hepatic glucose production and total-body norepinephrine turnover rate measured at 1 day and 12 weeks. Arm n not reported in the abstract. |
| Comparison | Randomized trial design; the specific comparator (placebo versus another arm) and arm n are not specified in the abstract. |
| Outcome | Total-body NE turnover rate decreased at 1 day and at 12 weeks after starting empagliflozin, despite an increase in hepatic glucose production. The magnitude of the decrease in NE turnover inversely correlated with the increase in HGP. No effect estimates, 95% CIs, p values, or ARR/NNT are reported in the abstract; this is a mechanistic study with no efficacy outcome. |
Expert Commentary
This randomized mechanistic study addresses a specific physiological puzzle rather than a clinical endpoint, and the verdict is that it reframes, rather than confirms, an earlier hypothesis. SGLT2 inhibitors are known to raise hepatic glucose production, and an acute (within four hours) rise in norepinephrine turnover had previously been proposed as the driver. Here the longer-term picture is reversed: norepinephrine turnover was found to fall at both 1 day and 12 weeks, and the size of that fall was inversely related to the rise in glucose production. The interpretation is therefore that sustained sympathetic activation is unlikely to be the mechanism behind the long-lasting increase in glucose output. The principal limitation is that the abstract reports only the direction of effect, with no sample size, effect estimates, confidence intervals, or p values, so the strength and precision of these findings cannot be judged from the published summary alone. Can I use this with my patients? Not yet; this is hypothesis-shaping physiology with no glycaemic or clinical outcome, and it changes nothing about prescribing for a person with type 2 diabetes today. The full paper should be read for the comparator, sample size, and quantitative results before any inference is drawn, and replication with reported effect sizes would be welcome.
References
Abdelgani S, Khattab A, Adams JM, Al-Mulla F, Abu-Farha M, Baskoy G, et al. Empagliflozin Enhances Hepatic Glucose Production and Reduces Total-Body Norepinephrine Turnover Rate: A Randomized Trial. Diabetes. 2025;74(9):1480-1488. doi:10.2337/db25-0210