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

Abstract

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 H₃ )-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 H₂ )-glucose and (1,1,2,3,3-² H₅ )-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.

Keywords: LDL cholesterol; apolipoprotein B; dapagliflozin; glucose; insulin sensitivity; lipolysis; sodium-glucose co-transporter-2 inhibitor; type 2 diabetes.

Figure 1

Overview of (A) study protocol and individual study days, (B) two‐step hyperinsulinemic euglycaemic clamp day, and (C) overview of very low‐density lipoprotein (VLDL)‐HDL kinetics. REE, resting energy expenditure

Figure 2

The effect of dapagliflozin on lipid and glucose metabolism. (A) Individual apolipoprotein B (apoB) concentrations before and after dapagliflozin treatment are shown. Wilcoxon signed rank tests were used to compare time points. (B) Labelled leucine incorporation into apoB in very low‐density lipoprotein (VLDL)1 (squares; grey before, black after) and VLDL‐2 (triangles; grey before, black after) over time. (C) Fasting endogenous glucose production (EGP) in μmol kg⁻¹ min⁻¹. (D) Hepatic insulin sensitivity quantified as percentage of EGP suppression during hyperinsulinemia. (E) Peripheral insulin sensitivity quantified as peripheral glucose uptake (μmol kg⁻¹ min⁻¹) during hyperinsulinemia. (F) Peripheral lipolysis measured as rate of glycerol appearance (μmol kg⁻¹ min⁻¹). Mean ± SD are shown in (B) and individual data points are shown in all other panels. The two time points were compared using Wilcoxon signed rank tests. Significant differences are indicated in bold. Ra, rate of appearance; Rd, rate of disappearance; MPE, molar percentage ratio