Potential contribution of haemoconcentration to changes in lipid variables with empagliflozin in patients with type 2 diabetes: A post hoc analysis of pooled data from four phase 3 randomized clinical trials.

Aims: The selective sodium-glucose cotransporter 2 inhibitor empagliflozin increases urinary glucose, sodium excretion, and urinary volume, and reduces plasma glucose in type 2 diabetes mellitus (T2DM) patients. Changes in lipids with empagliflozin have also been observed. We examined the association between changes in lipids and markers of haemoconcentration (haematocrit and serum albumin) with empagliflozin, using pooled data from four phase-3 randomized trials. Materials and Methods: T2DM patients received placebo (n = 825), empagliflozin 10 mg (n = 830) or 25 mg (n = 822) for 24 weeks. In post hoc mediation analyses, we assessed total changes in LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein (Apo) B, and Apo A-I, and changes in these parameters associated with, and independent of, changes in haematocrit and serum albumin at week 24 using ANCOVA models. Results: Empagliflozin versus placebo increased serum LDL-cholesterol, HDL-cholesterol, and Apo A-I, decreased triglycerides (empagliflozin 10 mg only), and (non-significantly) increased Apo B. Empagliflozin modestly increased haematocrit and serum albumin. In mediation analyses, haematocrit changes (increases) with empagliflozin were associated with significant changes (increases) in all lipid parameters, including Apo B. Except for triglycerides (non-significant), similar lipid parameter associations were observed with serum albumin changes. Haematocrit- and serum albumin-independent changes in lipids with empagliflozin were significant for HDL-cholesterol (increases), mostly significant for triglycerides (decreases), and less so for other lipid fractions. Conclusion: Haematocrit and serum albumin increases were associated with increases in lipid fractions with empagliflozin. Empagliflozin-associated changes in serum lipids, particularly LDL-cholesterol increases, may be partly due to haemoconcentration resulting from increased urinary volume and subsequent volume contraction.