Combined Intervention With Pioglitazone and n-3 Fatty Acids in Metformin-treated Type 2 Diabetic Patients

Improvement of Lipid Metabolism

Jiri Veleba; Jan Kopecky Jr.; Petra Janovska; Ondrej Kuda; Olga Horakova; Hana Malinska; Ludmila Kazdova; Olena Oliyarnyk; Vojtech Skop; Jaroslava Trnovska; Milan Hajek; Antonin Skoch; Pavel Flachs; Kristina Bardova; Martin Rossmeisl; Josune Olza; Gabriela Salim de Castro; Philip C. Calder; Alzbeta Gardlo; Eva Fiserova; Jørgen Jensen; Morten Bryhn; Jan Kopecky Sr.; Terezie Pelikanova


Nutr Metab. 2015;12(52) 

In This Article


The complex etiology of type 2 diabetes (T2D) prompts for the use of a combination therapy to target multiple underlying mechanisms. Indeed, standards of medical care in diabetes recommend the combination therapy of metformin and other anti-diabetic drugs, next to metformin monotherapy.[1] Major effects of metformin include the lowering of hepatic glucose production and fasting glycemia and reduced risk of cardiovascular events,[2] as well as an independent anti-inflammatory action[3] and amelioration of the oxidative stress.[4] The combination of metformin and the peroxisome proliferator-activated receptor (PPAR) γ agonist pioglitazone, a drug from the thiazolidinedione family, provided superior clinical outcomes to metformin alone.[5] In spite of the beneficial effects of thiazolidinediones on glycemic control, insulin sensitivity, inflammation and oxidative stress,[2,4,5] as well as their triacylglycerol-lowering effect in both humans[5] and mice,[6,7] clinical use of pioglitazone has declined recently due to the risk of its side-effects (reviewed in[1,8]). However, this risk could be outweighed by the benefits of pioglitazone in prevention of cardiovascular disease,[9] the leading cause of death in patients with T2D.[10] Indeed, pioglitazone is associated with a relatively low risk of all-cause mortality (reviewed in[8]).

Dietary interventions represent an important part of any management or treatment strategy for patients with T2D. Naturally occurring long-chain n-3 polyunsaturated fatty acids, namely eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3), are considered to be healthy dietary constituents in diabetics.[11] These fatty acids exert anti-inflammatory and hypolipidemic effects, while increasing catabolism of lipids via a PPARα-mediated mechanism.[11,12] At a daily dose of 4 g, EPA + DHA are approved for the treatment of hypertriacylglycerolemia[13] and could ameliorate non-alcoholic fatty liver disease.[14] Even modest consumption of EPA + DHA (0.25–0.5 g/day) helps to prevent cardiovascular disease,[15] reflecting probably the stabilization of atherosclerotic plaques.[16] The hypolipidemic effect of n-3 fatty acids could also be involved, since increased postprandial triacylglycerolemia represents an independent risk factor for cardiovascular disease in T2D patients.[10,17] In contrast with the earlier clinical trials, most of the recent studies did not show a benefit of EPA + DHA in the secondary prevention of cardiovascular disease (reviewed in[11]). Importantly, in patients with T2D within a large cohort, positive cardiovascular effects of n-3 fatty acids were observed.[18] Regarding the effects of EPA + DHA on glycemic control and insulin sensitivity, positive results have been obtained in animal models (reviewed in[11]), and in the prevention of T2D in obese children and young overweight/obese individuals.[19] Mixed results were obtained with respect to prevention of T2D by EPA + DHA in adult humans; in patients with T2D, either no or detrimental effects on glucose homeostasis were found in older studies, while more recent studies mostly showed neutral effects.[11]

Our experiments in mice with diet-induced obesity[6,7,20] demonstrated additive beneficial effects of a combined intervention using EPA + DHA and thiazolidinediones on insulin sensitivity, glucose tolerance, metabolic flexibility, lipid metabolism, hepatic steatosis, inflammation and obesity. These effects were observed in both the prevention[6,7,20] and reversal[7] of obesity-associated phenotypes. Therefore, in this study, we sought to examine whether EPA + DHA, at a dose of ~2.8 g/day (i.e., 5 g EPA + DHA concentrate/day), could modulate the effects of pioglitazone in overweight and obese patients with T2D, specifically in well-controlled patients treated with metformin. In order to unmask potential additive effects, pioglitazone was used at a relatively low dose of 15 mg/day, which is the initial recommended dose for treatment. The major goal of the study was to characterize the effect of the combined intervention on glucose homeostasis and lipid metabolism.