Discussion
obesity, late renal disease, diabetes-related complications, atherosclerosis, T2DM, diabetes
OBESITY, ATHEROSCLEROSIS, DISEASE, OXIDATIVE STRESS, CARDIOVASCULAR COMPLICATIONS, DIABETES
This study demonstrates a reduction in cardiovascular risk indicators AGE and AGE/s-RAGE ratio achieved by therapeutic intervention with both pioglitazone and glimepiride, in combination with metformin, independent of glycemic control. Patients on pioglitazone achieved a greater benefit, likely related to the characteristic effect of the drug on PARPγ receptors that activates antioxidant enzymes, including glutathione peroxidase, which contributes to the decrease in oxidative stress (Several studies have shown that patients at higher cardiovascular risk (including subjects with T2DM) present a higher AGE/s-RAGE ratio than controls (Elevated s-RAGE level is associated with the development of early and late renal disease both in the population not affected by diabetes (In the present study, despite a modest significant increase of body weight and BMI at the end of the 5-year period in the group treated with pioglitazone, no correlation was observed in the entire cohort between Δ BMI and the glyco-oxidation parameters of the AGE/RAGE axis. Indeed, several studies have been conducted to investigate the functioning of the AGE/RAGE axis in relation to body composition, weight and BMI, and the impact that weight, dietary and bariatric surgery interventions may have on cardiovascular risk reduction. Although there is still no conclusive evidence to support the cause-and-effect relationship between obesity and high AGE levels, a close association between AGEs and caloric intake has been reported (Studies that evaluated the impact of diet and bariatric surgery demonstrated, during follow-up of bariatric surgery, an increase in s-RAGE of 20% (A key question remains whether interventions to modulate AGE-RAGE axis might provide a protection against atherosclerosis progression. However, a major strength of this study consists in its structure as a longitudinal observation that permitted a five-year duration, in order to investigate specific glyco-oxidation parameters which are usually evaluated by cross-sectional studies only.Our data exclude a correlation of the calculated 10-year ASNCVD risk with ΔAGE-RAGE parameters; interestingly, while in the literature a correlation is highlighted between AGE-RAGE axis and several cardiovascular risk factors when considered separately (The present study has limitations, in particular linked to the small sample size and the follow-up limited to 5 years, all factors that depends on the fact that the research was derived from a main project multicenter clinical trial (TOSCA.IT) with strict limitations of the protocol. The same protocol did not involve a control group. The data here observed, although significant, should be in the future straightened with longer follow-up under the two treatment regimens, including a placebo group, regarding the values of AGE, s-RAGE and AGE/s-RAGE ratio, also in relation to the possible occurrence of related cardiovascular complications.In conclusion, the present study evaluated the AGE/s-RAGE ratio in a cohort of patients with T2DM on different oral hypoglycaemic therapies: metformin in combination with pioglitazone or glimepiride. Taking into consideration both the entire cohort of patients and the groups separately, the AGE/s-RAGE ratio was significantly reduced, a result that, in agreement with what is reported in the literature (The indications arising from the present research suggest future directions of investigation that include a careful re-evaluation of the benefits of antidiabetic therapy with classical drugs of known and proven hypoglycaemic properties. Possible pleiotropic actions, although still hidden, may reveal their usefulness in counteracting the onset of diabetes-related complications, especially with the aim of containing the cardiovascular risk associated with the disease. The usefulness of the AGE/s-RAGE ratio for disease monitoring might suggest to examine its use as an additional parameter to be added to the current panel of biohumoral markers of diabetes control.