Efficacy of metformin combined with liraglutide on the glucose and lipid metabolism, vascular endothelial function, and oxidative stress of patients with T2DM and metabolic syndrome

Objective: This study evaluates the impact of metformin combined with liraglutide on the glucose and lipid metabolism, oxidative stress, and vascular endothelium of patients with type-2 diabetes mellitus (T2DM) and metabolic syndrome. Methods: Medical records of 78 patients with T2DM and metabolic syndrome, admitted to Caoxian People’s Hospital from July 2021 to July 2022, were retrospectively analysed. Thirty five patients were treated with metformin (control group), and 43 patients were treated with metformin combined with liraglutide (observation group). Indexes of glucose and lipid metabolism, function of vascular endothelium and the oxidative stress of both groups were compared before and after the treatment. Results: There was a significant decrease in the levels of fasting plasma glucose (FPG), Glycosylated Hemoglobin A1c (HbA1c), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP) and waist circumference in both groups three months after the treatment, These indexes were significantly lower in the observation group compared to the control group (P<0.05). High-density lipoprotein cholesterol (HDL-C) levels were higher in the observation group (P<0.05). There was a significant improvement in the levels of nitric oxide (NO), endothelin-1 (ET-1), superoxide dismutase (SOD), and malondialdehyde (MDA) after the treatment, and these indexes were markedly better in the observation group compared to the control group (P<0.05). Conclusions: Metformin combined with liraglutide treatment is associated with better outcomes than metformin alone in patients with T2DM and metabolic syndrome. Combined treatment results in improved glucose and lipid metabolism, vascular endothelial function, and oxidative stress index values.

development of a vicious cycle. 5,6Clinical treatment of patients with T2DM and metabolic syndrome mainly includes hypoglycaemic drugs, such as metformin, and lifestyle changes.Metformin can promote insulin sensitivity, improve pancreatic islet β cells function, inhibit liver glycogen outputs, and reduce serum glucose levels.However, TD2M combined with the metabolic syndrome is challenging to treat with just one agent. 7Liraglutide is a glucagon like peptide-1 receptor agonist that reduces glucagon secretion, blood glucose drift and improves blood glucose levels.Liraglutide also induces β cell proliferation by inhibiting insulin secretion. 8Recent studies attempted to explore the efficiency of combined liraglutide and metformin treatment in obese patients with T2DM.However, the effect of the combined therapy on glucose and lipid metabolism, vascular endothelial function, and oxidative stress is still unclear. 9,10The aim of this study was to compare the clinical effect of metformin alone with the regimen of metformin combined with liraglutide in patients with T2DM and metabolic syndrome.

METHODS
Clinical data of 78 patients with T2DM and metabolic syndrome, treated in Caoxian People's Hospital from July 2021 to July 2022, were collected retrospectively.According to the treatment records, the patients were divided into the following two groups: the control group (n=35, patients who received oral metformin (Shanghai Squibb Pharmaceutical, H20023370), 0.5 g three times/day), and the observation group (n=43, patients who were treated with metformin and subcutaneous liraglutide injections (Novo Nordisk, Denmark, J20160037), 0.6 g once a day).All patients received the appropriate treatment for 3 months.

Inclusion Criteria:
• Patients met the diagnostic criteria for T2DM and metabolic syndrome according to the American Diabetes Association guideline.a xanthine oxidase method to quantify the levels of SOD and a thio-barbituric acid method to quantify the levels of MDA.The kits were purchased from Wuhan Bode Biotechnology.Statistical analysis: Categorical variables were expressed as n (%), and compared via Fisher's exact or Chi-squared tests.Normally distributed continuous variables were expressed as means ± SDs (standard deviations) and compared by Student's t-tests, while non-normally distributed continuous variables were expressed as median (interquartile range) and compared via Mann-Whitney U tests.P<0.05 was statistically significant.SPSS v26.0 (SPSS, Chicago, IL, USA) was used for all statistical analyses.

DISCUSSION
Our results showed that liraglutide combined with metformin is more effective than metformin alone in improving glucose and lipid metabolism, vascular endothelial function, and oxidative stress response in patients with T2DM and metabolic syndrome.Our results confirm previous study by Keskin et al 9 and Anholm et al 12 , but are different from the conclusions of the pilot study by Liu et al 10 .Zeraattalab-Motlagh S et al. 13 showed that the occurrence of T2DM is closely associated with dietary habits, lifestyle, and physical activity.The pathological mechanisms of T2DM include insulin secretion dysfunction, lipid metabolism disorders, and other factors that lead to the accumulation of multiple risk factors that may cause the metabolic syndrome, which in turn may aggravate insulin resistances and increases the incidence of diabetes complications.Therefore, a combination of T2DM with metabolic syndrome makes it difficult to control blood sugar. 14,15ote: compared with value before treatment, a P < 0.05.
We selected glucose and lipid metabolism (FPG, HbA1c, TG, TC), vascular endothelial function (NO, ET-1), and oxidative stress indicators (SOD, MDA) as the observation markers.FPG, HbA1c, TG, and TC are commonly used in clinical practice to assess lipid metabolism status of the patients. 16NO and ET-1 are synthesized by vascular endothelial cells, and serve as clinical markers of endothelial cell damage. 17NO is a vasodilator that effectively promotes relaxation of vascular smooth muscle, and ET-1 is an endogenous vasoconstrictor that promotes inflammatory reactions and proliferation of vascular smooth muscle cells.Tanaka A et al 18 showed that patients with T2DM and metabolic syndrome are in a state of long-term hyperglycaemia and lipid metabolism imbalance that can lead to vascular endothelial dysfunction with abnormal vasoconstriction, vasospasms, etc. Groeneveld ON et al. 19 also showed that patients with T2DM and metabolic syndrome are in a state of oxidative stress (as measured by levels of SOD and MDA).This, in turn, leads to further damage to the the vascular endothelium.SOD can promote the metabolism of oxygen-free radicals 20, and MDA reflect the level of peroxidation. 20,21ur results show that a combined metforminliraglutide regimen led to significant improvement in all indicators after three months of treatment compared to metformin treatment alone.
Our findings are similar to the results of Dahl K et al, 22 who showed that patients with T2DM and metabolic syndrome, treated with a combination of metformin and liraglutide, have better glucose and lipid metabolism, vascular endothelial function, and oxidative stress responses compared to patients treated with metformin alone. 7,22he increased efficiency of the combined treatment may be explained by the different mechanism of action of these two agents.Metformin acts by inhibiting liver gluconeogenesis, reducing liver glucose outputs, increasing insulin sensitivity in peripheral tissues, and thereby, reducing blood sugar levels. 7Moreover, metformin can reduce the formation of free fatty acids, promote lipoprotein activity, and regulate lipid metabolism disorders. 23Liraglutide, on the other hand, is a glucagon-like peptide-1 receptor agonist that simulates the physiological function of glucagon-like peptide-1 and reduces blood sugar levels, thus improving metabolic disorder, lowering blood pressure, and inhibiting inflammation. 24iraglutide contains a C-16 palmitic acid that can replace lysine, and reversibly binds plasma albumin to form a slowly dissolving repository, prolonging its action time and its half-life, which can reach 13 hours.Therefore, liraglutide can effectively stabilize blood glucose levels throughout the day and prevents fluctuations in blood glucose levels. 24,25Therefore, a regimen that combines metformin and liraglutide can have a synergistic effect in patients with T2DM and metabolic syndrome, and more effectively control blood glucose level, improve metabolic state, reduce organ damage caused by hyperglycemia and dyslipidemia, protect vascular endothelium, reduce oxidative stress, and enhance the overall clinical efficiency of the treatment compared to metformin alone. 22,24,25mitations of the study: This study was retrospective in nature, with a small sample size and a short follow-up of only three months.That may make our conclusions subjective and one-sided.Further multicentre studies with larger sample sizes and longer follow-ups are needed to confirm our results.

CONCLUSION
Liraglutide combined with a metformin treatment can improve the effects of the treatment on glucose and lipid metabolism, vascular endothelial function, and oxidative stress indexes in patients with T2DM • Patients with duration of T2DM less than two years • Patients aged 18-75 with no restriction on gender.•Patients with complete medical records.
• Oxidative stress indicators levels, as measured by study.There were 20 males and 15 females in the control group, with an average age of 49.88±7.68years.The observation group included 22 males and 21 females with an average age of 50.58 ± 8.27 years.General characteristics of the patients, such

Table - I
: Comparison of General Data of Two Groups.
observation group were significantly higher than in the control group (P<0.05).Levels of ET-1 and MDA decreased after the treatment in both groups and were significantly lower in the observation group compared to the control group (P<0.05;Table-III).There were no reports of adverse drug reactions in either group during the treatment.

Table -
II: Comparison of blood lipid metabolism indexes and basic physiological indicators between the two groups ().

Table -
III: Comparison of vascular endothelial function and oxidative stress indicators between the two groups ( ).Note: compared with values before treatment, a P < 0.05.