Liraglutide treatment improves postprandial lipid metabolism and cardiometabolic risk factors in humans with adequately controlled type 2 diabetes: A single-centre randomized controlled study

Niina Matikainen, Sanni Söderlund, Elias Björnson, Kirsi Pietiläinen, Antti Hakkarainen, Nina Lundbom, Marja-Riitta Taskinen, Jan Borén, Niina Matikainen, Sanni Söderlund, Elias Björnson, Kirsi Pietiläinen, Antti Hakkarainen, Nina Lundbom, Marja-Riitta Taskinen, Jan Borén

Abstract

Aims: Patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) exhibit considerable residual risk for cardiovascular disease (CVD). There is, therefore, increasing interest in targeting postprandial lipid metabolism and remnant cholesterol. Treatment with the glucagon-like peptide 1 (GLP-1) analogue liraglutide reduces CVD risk by mechanisms that remain unexplained in part. Here we investigated the effects of liraglutide intervention on ectopic fat depots, hepatic lipogenesis and fat oxidation, postprandial lipid metabolism and glycaemia in humans with type 2 diabetes.

Methods: The effect of liraglutide was investigated in 22 patients with adequately controlled type 2 diabetes. Patients were randomly allocated, in a single-blind fashion, to either liraglutide 1.8 mg or placebo once daily for 16 weeks. Because liraglutide is known to promote weight loss, the study included dietary counselling to achieve similar weight loss in the liraglutide and placebo groups. Cardiometabolic responses to a high-fat mixed meal were measured before and at the end of the liraglutide intervention.

Results: Weight loss at Week 16 was similar between the groups: -2.4 kg (-2.5%) in the liraglutide group and -2.1 kg (-2.2%) in the placebo group. HBA1c improved by 6.4 mmol/mol (0.6%) in the liraglutide group (P = 0.005). Liver fat decreased in both groups, by 31% in the liraglutide group and by 18% in the placebo group, but there were no significant changes in the rate of hepatic de novo lipogenesis or β-hydroxybutyrate levels, a marker of fat oxidation. We observed significant postprandial decreases in triglycerides only in plasma, chylomicrons and VLDL, and remnant particle cholesterol after treatment in the liraglutide group. Fasting and postprandial apoCIII concentrations decreased after liraglutide intervention and these changes were closely related to reduced glycaemia. In relative importance analysis, approximately half of the changes in postprandial lipids were explained by reductions in apoCIII concentrations, whereas less than 10% of the variation in postprandial lipids was explained by reductions in weight, glycaemic control, liver fat or postprandial insulin responses.

Conclusions: Intervention with liraglutide for 16 weeks produces multiple improvements in cardiometabolic risk factors that were not seen in the placebo group, despite similar weight loss. Of particular importance was a marked reduction in postprandial atherogenic remnant particles. The underlying mechanism may be improved glycaemic control, which leads to reduced expression of apoCIII, a key regulator of hypertriglyceridaemia in hyperglycaemic patients.

Keywords: GLP-1-agonist; apolipoprotein C3; atherogenic dyslipidaemia; de novo lipogenesis; liraglutide; liver fat; postprandial lipids; remnant lipoproteins.

Conflict of interest statement

The authors report no duality of interest.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Responses of plasma glucose, insulin, β‐hydroxybutyrate and NEFA after a fat‐rich mixed meal before treatment (open squares) and at week 16 (filled squares) in patients with type 2 diabetes being treated with liraglutide (n = 15) or receiving placebo (n = 7). P values were calculated using the ANOVA repeated measures test for within‐group differences
Figure 2
Figure 2
Responses of plasma triglycerides (TG), chylomicron TG, VLDL1 TG and plasma apoB48 after a fat‐rich mixed meal before treatment (open squares) and at week 16 (filled squares) in subjects with type 2 diabetes treated with liraglutide (n = 15) or placebo (n = 7). P values were calculated using the ANOVA repeated measures test for within‐group differences
Figure 3
Figure 3
Responses of plasma apoCIII, remnant‐like particle cholesterol (RLP‐C) and triglyceride‐rich lipoprotein cholesterol (TRL‐C) after a fat‐rich mixed meal before treatment (open squares) and at week 16 (filled squares) in subjects with type 2 diabetes treated with liraglutide (n = 15) or placebo (n = 7). P values were calculated using the ANOVA repeated measures test for within‐group differences
Figure 4
Figure 4
Relative importance analysis demonstrating the percentage contribution of changes in various metabolic parameters to reduction (delta, Δ) in A, plasma TG area under the curve (AUC); B, plasma remnant‐like particle cholesterol (RLP‐C) AUC; C, triglyceride‐rich lipoprotein cholesterol (TRL‐C); and D, plasma apoCIII AUC. Height of bar shows the absolute percentage contribution, calculated using an average of four different methods (see the Material and Methods section). Variables to be included in the regression model were chosen based on hypothesized physiological relevance to the trait of interest. Exclusion of Matsuda index in favour of HOMA2‐IR did not significantly affect the results

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