The findings from our research affirm the significant contribution of GLP-1RAs in the treatment approach for patients with T2DM, especially among individuals grappling with overweight and obesity, which are closely linked to heightened cardiovascular risks [14]. In our population study we observed, as expected, a significant weight loss. It is well-established that weight loss alone can enhance various metabolic functions and contribute to a decrease in cardiovascular risk [15]. However, in this study the weight loss was not associated with a significant change in the percentages of fat mass and lean mass.
To our knowledge, this is the first study to have observed a reduction in the ratio of android fat to gynoid fat in patients treated with GLP-1RAs. This finding suggests a reduction in the percentage of adipose tissue with a visceral distribution, which it is known to be strongly linked to increased cardiovascular risk [16]. The reduction of visceral fat could potentially be a mechanism to account for the observed cardiovascular benefits in past trials involving liraglutide among individuals diagnosed with type 2 diabetes [9]. Therefore, GLP-1RAs, being able to induce both weight loss and a reduction in visceral fat, would seem to play a dual role in cardiovascular prevention.
Another favorable result which underlines the contribute of GLP-1RAs in the improvement of cardio metabolic risk is represented by the significant reduction in serum values of both LDL-cholesterol and triglycerides after one year of therapy with GLP-1RAs despite the absence of changes in lipid-lowering treatment compared to baseline. These results regarding the impact of GLP-1RAs on lipid parameters appear to be in agreement with several previous studies [17, 18]. The important effect of GLP-1RAs on lipid metabolism could open a new perspective for their use in hepatic steatosis which is a frequent complication of T2DM and represents an important cardiovascular risk factor in both diabetic and non-diabetic populations [19].
A statistically significant reduction in microalbuminuria levels was also observed in our study population; this data is also of considerable importance: microalbuminuria is considered a marker of vascular dysfunction and atherogenesis and it is an independent risk factor for all cardiovascular diseases [20, 21]. Therefore, the reduction of microalbuminuria observed in our patients after one year treatment with GLP-1RAs would be the mirror of a reduction of vascular inflammation and atherosclerosis. Another result which would confirm this reduction of vascular inflammation and the proinflammatory state is the increase in adiponectin levels after 12 months of GLP-1RAs therapy [22]. Furthermore, in our study population the increase in adiponectin was greater in the group of patients who presented a weight loss > 5%. Adiponectin is a secretory product of adipocytes of white adipose tissue, which, unlike other adipokines, is produced and secreted at higher rates in the presence of a low white (in particular, visceral) adipose tissue mass [23]. Its role involves directing triglyceride storage toward subcutaneous adipose tissue, thereby reducing lipid overload and the associated lipotoxicity and dysfunction in muscle, liver, and the pancreas [23]. The elevation of adiponectin levels plays a positive role in reducing cardiovascular risk. In fact, low levels of adiponectin are linked to an increased cardiovascular risk and greater insulin resistance [24, 25].
Patients affected by T2DM who are overweight or obese have reduced serum adiponectin values which however present a significant increase in the presence of adequate weight loss [10]. Literature data indicate that GLP-1RAs increase adiponectin levels presumably through a direct effect on adipocytes [26, 27]. A recent meta-analysis has highlighted that the increase in adiponectin induced by GLP-1RAs depends on the potency and dose of the drugs, being modest and inconsistent with exenatide and much more marked with liraglutide and semaglutide [10, 22]. The role of adiponectine on insulin resistance in our study could be also perfectly pointed out by the statistically significant inverse correlation between adiponectin and blood fasting glucose values and glycated hemoglobin [19, 21, 22].
This is the first "in vivo" study that has analyzed the changes in serum myostatin induced by GLP-1RAs therapies, reporting a reduction in myostatin at the end of 12 months of therapy, although it did not reach statistical significance. However, this data may represent a stimulus for further studies aimed at evaluating the effect of GLP-1RAs on myostatin and diabetic muscular atrophy [12]. At baseline, our patients with type 2 diabetes and an average disease duration of over 13 years exhibited average IMT values elevated and indicative of carotid atherosclerosis. In agreement with some previous reports our study highlighted that one-year treatment with GLP-1RAs determined a statistically significant reduction in carotid IMT, a surrogate marker of atherosclerosis [28, 29]. Although the mechanisms by which GLP-1RAs drugs determine an antiatherosclerotic effect have not yet been well defined, it is conceivable that the improvement of the lipid profile, the reduction of inflammation and the modifications of the cytokine profile play an important role [30, 31]. This data, contributes to underlining the favorable role of GLP-1RAs in reducing the risk of major cardiovascular events.
Our study presents some limitations. Firstly, the number of patients enrolled in the present study is relatively small. Secondly, the absence of a control group undergoing weight loss solely through lifestyle modifications prevents us from determining whether the alterations in both IMT and biochemical parameters are due to the direct effects of GLP-1RAs or to weight loss. However, this study also has several strengths, including its longitudinal design, a prolonged duration of follow-up, and the assessment of intima-media thickness at a single center by a skilled operator who was external to the study.