The effect of dapagliflozin on apolipoprotein B and glucose fluxes in patients with type 2 diabetes and well‐controlled plasma LDL cholesterol

AIM: To dissect the effects of the sodium‐glucose linked transporter 2 inhibitor dapagliflozin on lipid metabolism and assess whether these effects could potentially offset cardiovascular benefit with this drug‐class. MATERIALS AND METHODS: We assessed the effect of dapagliflozin on lipid metabolism in 11 adults with uncomplicated type 2 diabetes. After 4 weeks of statin wash‐out and 4 weeks of rosuvastatin 10 mg treatment, participants were treated with dapagliflozin 10 mg once‐daily for 5 weeks. Before and after dapagliflozin, plasma lipids were measured and very low‐density lipoprotein (VLDL)‐1 and VLDL‐2 apolipoprotein (Apo)B fluxes were assessed using (5.5.5‐(2)H(3))‐leucine tracer infusion. In addition, hepatic and peripheral insulin sensitivity as well as insulin‐mediated inhibition of peripheral lipolysis were measured during a two‐step hyperinsulinemic‐euglycaemic clamp using (6,6‐(2)H(2))‐glucose and (1,1,2,3,3‐(2)H(5))‐glycerol tracers. RESULTS: Rosuvastatin decreased all plasma lipids significantly: total cholesterol from 4.5 (3.2–6.2) to 3.1 (2.5–3.8) mmol/L, LDL cholesterol from 2.6 (1.7–3.4) to 1.5 (1.1–2.2) mmol/L, HDL cholesterol from 1.34 (0.80–2.02) to 1.19 (0.74–1.89) mmol/L and triglycerides from 0.92 (0.31–3.91) to 0.79 (0.32–2.10) mmol/L. The addition of dapaglifozin to rosuvastatin did not raise either LDL cholesterol or total cholesterol, and only increased HDL cholesterol by 0.08 (−0.03–0.13) mmol/L (P = 0.03). In line with this, dapagliflozin did not affect VLDL‐1 or VLDL‐2 ApoB fluxes. Fasting endogenous glucose production tended to increase by 0.9 (−3.4–3.1) μmol kg(−1) min(−1) (P = 0.06), but no effect on hepatic and peripheral insulin sensitivity or on peripheral lipolysis was observed. CONCLUSIONS: Dapagliflozin has no effect on plasma LDL‐cholesterol levels or VLDL‐apoB fluxes in the context of optimal lipid‐lowering treatment, which will thus not limit cardiovascular benefit when lipids are adequately controlled.