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|Objective:||To investigate the effect of treatment with steady-state liraglutide 1.8 mg versus placebo on postprandial lipaemia (triglycerides and apolipoprotein [apo]B48) concentrations following a standardized high-fat meal in patients with type 2 diabetes|
|Study design:||Randomized, double-blind, placebo-controlled, cross-over trial|
Twenty patients with type 2 diabetes (11 male and 9 female, aged 53–73 years, body mass index 24–39 kg/m2)
|Primary variable:||Total area under the postprandial triglycerides concentration–time curve from meal-time until 8 hours (AUC0-8h), measured after 3 weeks treatment with liraglutide 1.8 mg/day. The incremental AUC0-8h (iAUC0-8h) was defined as the AUC 08h above the fasting value (15 minutes prior to the meal).|
Patients were randomized to treatment with once-daily subcutaneous liraglutide (starting dose 0.6 mg/day, weekly dose escalation 0.6 mg) followed by placebo for 3 weeks, or the reverse treatment order. Patients administered liraglutide or placebo before bedtime on Days 1–16 and between 21:00 and 22:00 hours on Days 17–21. There was a washout period of 3-9 weeks between the two treatment periods.
Postprandial lipaemia (AUC0-8h and iAUC0-8h for triglycerides and apoB48), non-esterified fatty acids, glucose, insulin, C-peptide and glucagon, and gastric emptying measures were assessed at the end of each 3-week treatment period.
After 3 weeks, postprandial lipaemia (triglycerides and apoB48) was substantially lower with liraglutide compared with placebo. There were significant decreases in mean postprandial triglycerides (AUC0-8h liraglutide/placebo treatment-ratio 0.72, 95% CI 0.62–0.83, p=0.0004). The mean iAUC0-8h for triglycerides was reduced by 57% with liraglutide versus placebo (Fig 1).
For apoB48, the AUC0-8h liraglutide/placebo treatment-ratio was 0.65 (95% CI 0.58-0.73, p<0.0001). The mean iAUC0-8h for apoB48 were was 57% lower, with liraglutide versus placebo. These effects were independent of gastric emptying.
Reductions in postprandial glucose and glucagon responses, as well as in low-density lipoprotein and total cholesterol concentrations were also observed with liraglutide versus placebo.
In patients with type 2 diabetes, liraglutide treatment significantly reduced postprandial excursions of triglycerides and apoB48 after a fat-rich meal, independently of gastric emptying.
Postprandial hypertriglyceridaemia is a risk factor for cardiovascular disease.1 This is attributed to increased exposure to atherogenic, intestinally-derived triglyceride-rich lipoprotein remnants containing apoB48, which can penetrate and deposit into the arterial wall.2 It is thought that impairment of the incretin secretion and/or response, as in insulin-resistant conditions, leads to a loss of glucagon-like peptide-1 (GLP-1)-mediated control of postprandial chylomicron production.3 As a result, there is an increase in the atherogenic apoB48 load, which potentially contributes to the increased risk for cardiovascular disease in these individuals.
Thus, pharmacological agents that target GLP-1 may not only improve glucose homeostasis, but may also have beneficial effects on postprandial hypertriglyceridaemia. This has already been shown for the GLP-1 receptor agonist exenatide.4,5 The current study now extends these findings to liraglutide, a human GLP-1 analogue. In addition to positive and durable benefits on glycaemic control and body weight,6 the results of this study suggest potential for liraglutide to reduce the high residual risk of cardiovascular disease in patients with type 2 diabetes receiving best standards of care. This is currently being tested in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation) trial,7 with results expected in 2016.
1. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299-308.
postprandial lipaemia; triglycerides; apolipoprotein B48; glucagon-like peptide-1; liraglutide