This pilot study shows, for the first time, that liraglutide has desirable effect on carotid IMT in patients with T2DM after 8 months of therapy. This effect seems to be achieved by mechanisms independent of induced changes in plasma glucose and lipid concentrations. This is somewhat consistent to a very recent study, where GLP-1 analogue therapy reduced several inflammatory markers, independently of the glycaemic or body weight effects induced by the GLP-1 analogue . Pioglitazone therapy also slowed progression of carotid atherosclerosis in subjects with prediabetes, independently of changes in cardio-metabolic risk factors .
Although not yet directly demonstrated, it is possible that liraglutide has beneficial effects on the process of atherosclerotic plaque formation. Pre-clinical data have shown that liraglutide is able to reduce infarct size in mice with experimental myocardial infarction , while exenatide, a synthetic GLP-1 receptor agonist, reduced intimal hyperplasia in insulin resistant rats . Further, in patients with type-2 diabetes, the stimulation of GLP-1 secretion seems to have a significant impact on cardiovascular risk . Yet, in a recent study a 6-month GLP-1 receptor agnist treatment did not modulate vascular function, despite significant improvements in body composition and glycaemic control .
Regarding other liraglutide effects found in the present study, body weight significantly reduced after 4 months of therapy but we found no further change after 8 months of treatment. In another study , liraglutide induced significant and persistent weight loss up to 6 months of follow-up in obese Japanese patients with type 2 diabetes. In the present study liraglutide treatment was also able to significantly reduce plasma total- and LDL-cholesterol concentrations; further, LDL-cholesterol was the only variable showing an independent associations with decreased carotid IMT at multivariate analysis. Yet, in a recent study performed in subjects with type-2 diabetes , apolipoprotein B and not LDL-cholesterol was able to predict subclinical carotid atherosclerosis.
Further, a large number of our patients were under cardiovascular drugs; yet, we did not find any significant relationship between the use of cardiovascular medications and carotid IMT. This finding may be potentially explained by: a) the relative small numbers of patients receiving each individual class of drugs; b) the very common use in our patients of multiple cardiovascular therapies, which therefore limits the identification of the effect of a specific class of drug.
Our findings on the beneficial effect of liraglutide on carotid IMT may be linked to the improved endothelial function by incretin-based therapies, and GLP-1 in particular (as reviewed in ). Indeed, using different methodologies, it has been shown that GLP-1 improves endothelial function in patients with type-2 diabetes or the metabolic syndrome; such methodologies included strain-gauged plethysmography and flow-mediated dilation [19–21]. Further, in pre-clinical studies, liraglutide improved endothelial function and inhibited the progression of vascular disease via the effects on plaque stability and endothelial function [22, 23].
Previous studies have investigated the effects of anti-diabetic agents on carotid IMT. For instance, the CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) trial  was a randomized, double-blind, multicenter study, which evaluated the effect of pioglitazone vs glimepiride on changes in carotid IMT in patients with type-2 diabetes. In this study, after 18 months of treatment, the change from baseline in carotid IMT (e.g., the prespecified primary end point) was -0.001 mm in the pioglitazone group and +0.012 mm in the glimepiride group. By contrast, in a very recent study , vildagliptin was able to reduce carotid IMT by about 0.10 mm after only 3 months of therapy in 90 patients with type-2 diabetes. This finding is somewhat consistent to our finding of a reduction of 0.15 mm after 4 months of liraglutide therapy.
Although our findings regarding changes in carotid IMT are of considerable interest, the impact of liraglutide on clinical cardiovascular outcomes is unknown, and further studies are needed to investigate its athero-metabolic actions. The very recent data on the cardiovascular outcome with the use of saxagliptin and alogliptin highlight the need of more studies for incretin-based therapies [26, 27], including the GLP-1 analogues. It is hoped that the ongoing international LEADER study will provide useful answers in this regard .
A limitation of the present study is the lack of the placebo (control) arm. Such control group had to include patients undergoing metformin therapy only, e.g. without liraglutide. Although we did not investigate the effect of metformin alone on carotid IMT, previous studies have shown that metformin therapy has mild or null effects on carotid IMT [28–30]. It is therefore unlikely that metformin was responsible for the strong and significant decrease in carotid IMT that we have found after 4 and 8 months of therapy. Also, it needs to be highighted that in the present study we administered liraglutide as add-on therapy in patients who were already receiving metformin therapy. Finally, the statistical analysis revealed that the effect of liraglutide on several parameters (including carotid IMT) was very strong and highly significant; therefore, the probabilty of the occurrence of our findings by chance alone is extremely low.
Strengths of the study include the blinded measurements of carotid intima-media thickness as well as the excellent adherence to treatment. To our knowledge, the present study is the first one to examine the effects of liraglutide on carotid IMT.