Efficacy of metformin on postprandial plasma triglyceride concentration by administration timing in patients with type 2 diabetes mellitus: A randomized cross-over pilot study

Abstract

Aims/introduction: Preprandial metformin administration significantly reduces postprandial plasma triglyceride levels in animal studies by reducing intestinal absorption through delayed gastric emptying. However, this effect has not been shown in a clinical study. Therefore, we planned to investigate the efficacy of preprandial metformin administration on postprandial hypertriglyceridemia and the related gastrointestinal effects in patients with type 2 diabetes mellitus.

Materials and methods: A total of 11 patients taking single-dose metformin at 500-1,000 mg, with non-fasting plasma triglyceride levels of 150-1,000 mg/dL, were recruited at a single university hospital. The difference between preprandial and postprandial metformin administration on postprandial hypertriglyceridemia was examined by a meal test. The gastrointestinal effects of metformin, including stomach heaviness, heartburn and satiety, were also assessed using a visual analog scale.

Results: The mean bodyweight of patients was 80.6 kg (body mass index 27.9 kg/m² ), and the mean non-fasting plasma triglyceride level was 275.9 ± 57.0 mg/dL. The area under the curve of triglyceride during the meal test was significantly lower in the preprandial protocol than in the postprandial protocol (P < 0.05). Compared with postprandial administration, preprandial administration of metformin increased satiety (P = 0.036) without stomach heaviness or heartburn.

Conclusions: Preprandial metformin administration significantly reduced plasma triglyceride level during meal testing without marked exacerbation of gastrointestinal adverse effects. The present results suggest that a simple change in the timing of metformin administration represents a novel approach for enhancing triglyceride-lowering strategies in patients with type 2 diabetes mellitus and postprandial hypertriglyceridemia.

Keywords: Gastric emptying; Metformin; Postprandial hypertriglyceridemia.

Figure 1

(a) Study design. (b) Meal tests under the preprandial metformin administration (pre‐Met; 500–1,000‐mg single dose) and postprandial metformin administration (post‐Met) protocols were carried out alternately. The participants ingested a cookie consisting of 75 g carbohydrate (flour starch and maltose) and 28.5 g fat. Blood was collected at fasting (−30, 0), 60, 120, 180 and 240 min after ingestion of the cookie. GLP‐1, glucagon‐like peptide‐1.

Figure 2

Effect of the preprandial metformin administration (pre‐Met) protocol on efficacy parameters in 11 patients with type 2 diabetes mellitus. Change in (a) plasma triglyceride (TG) levels, (b) blood glucose levels and (c) plasma insulin levels during the meal test. Data are the mean ± standard deviation. *P < 0.05 versus postprandial metformin administration (post‐Met) protocol by paired t‐test. Filled circle: pre‐Met protocol; open circle: post‐Met protocol. (d) Change in TG area under the curve for 0 to 4 h (AUC 0–4 h) under the pre‐Met and post‐Met protocols. (e) Change in glucose AUC 0–4 h under the pre‐Met and post‐Met protocols. Change in TG AUC 0–4 h and glucose AUC 0–4 h were analyzed using the Wilcoxon signed‐rank test. (f) Correlation between ΔTG AUC 0–4 h (pre‐Met protocol minus post‐Met protocol) and Δglucose AUC 0–4 h. The relationship between ΔTG AUC 0–4 h and Δglucose AUC 0–4 h was analyzed using Pearson's correlation coefficients.

Figure 3

Change in visual analog scale scores for gastrointestinal adverse effects of metformin. (a) Satiety, (b) stomach heaviness and (c) heartburn. Change in visual analog scale scores in preprandial metformin administration (pre‐Met) and postprandial metformin administration (post‐Met) protocols were analyzed using the Wilcoxon signed‐rank test. Filled circle: pre‐Met protocol; open circle: post‐Met protocol.

Figure 4

Correlation between the change in plasma‐active glucagon‐like peptide‐1 (GLP‐1) and triglyceride (TG) area under the curve for 0 to 4 h (AUC 0–4 h). (a) Change in plasma active GLP‐1 levels during the meal test. Data are the mean ± standard deviation. Filled circle: pre‐Met protocol; open circle: post‐Met protocol. (b) Correlation between ΔGLP‐1 AUC 0–1 h (pre‐Met protocol minus post‐Met protocol) and ΔTG AUC 0–4 h. The relationship between ΔGLP‐1 AUC 0–1 h and ΔTG AUC 0–4 h was analyzed using Pearson's correlation coefficients.