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Effects of 6 Months of Dapagliflozin Treatment on Metabolic Profile and Endothelial Cell Dysfunction for Obese Type 2 Diabetes Mellitus Patients without Atherosclerotic Cardiovascular Disease

Background Sodium-glucose cotransporter 2 inhibitors reduce the risk of cardiovascular death in individuals with type 2 diabetes mellitus (T2DM) and cardiovascular disease, but the effect of these inhibitors on early cardiovascular disease remains unknown. This study evaluated the effect of dapagliflozin on the metabolic profiles and endothelial cell function in obese patients with T2DM without established cardiovascular disease. Methods We enrolled 140 patients with a mean age, weight, and body mass index (BMI) of 47 years, 83 kg, and 30.3 kg/m2, respectively. Dapagliflozin (10 mg daily for 6 months) was administered to obese patients with T2DM without established cardiovascular disease. Participants’ weight, BMI, body fat mass (BFM), muscle mass, glycosylated hemoglobin (HbA1c), lipid profile, waist to hip ratio (WHR), and pulse wave velocity (PWV) were measured at baseline and after 6 months. Results Participants experienced statistically significant reductions in their HbA1c, fasting plasma glucose, low-density lipoprotein cholesterol, total cholesterol, body weight, BMI, WHR, BFM, and aortic PWV, without a significant change in their muscle mass, extracellular fluid, or intracellular volume. Statistically significant reductions in aortic PWV were associated with a decrease in BFM, visceral fat, WHR, and homeostatic model assessment of insulin resistance. Conclusion Dapagliflozin may be beneficial in preventing early cardiovascular disease in obese patients with T2DM without established cardiovascular disease.


INTRODUCTION
Type 2 diabetes mellitus (T2DM) patients are at a high risk for cardiovascular diseases. Atherosclerotic cardiovascular disease (AS-CVD) is the major cause of morbidity and mortality in T2DM patients. 1 Although diabetes poses a substantial independent risk for cular disease and all-cause mortality. 4 The Look AHEAD (Action for Health in Diabetes) trial failed to show that lifestyle management alone reduces cardiovascular events in patients with T2DM. 5 Thus, medications associated with weight loss and other beneficial effects are recommended for patients with T2DM and a BMI > 27 kg/m 2 . 4 Metabolic abnormalities such as hyperglycemia, excess free fatty acids, inflammation, and insulin resistance can lead to the suppression of nitric oxide production and activation of the renin-angiotensin-aldosterone system. This leads to oxidative stress and endothelial dysfunction that contribute to the development of cardiovascular diseases. 6 Endothelial dysfunction promotes the development of hypertension, contributing to cardiovascular damage. This may lead to increased arterial stiffness, related vascular calcification, or collagen accumulation. 7 Arterial stiffness, which can be assessed by measuring pulse pressure, is a powerful predictor of early cardiovascular disease. 8 Notably, early treatment of endothelial dysfunction can reverse the condition. Therefore, early treatment is crucial.
Cardiovascular disease is the main cause of mortality among patients with T2DM. Although strict glycemic control can reduce microvascular complications, the effect of glycemic control on macrovascular complications remains controversial. [9][10][11][12] The EMPA-REG OUTCOME study showed that empagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT-2), reduced the rate of primary composite cardiovascular outcomes among patients with T2DM who have a history of ASCVD. 13 Randomized controlled studies such as CANVAS-R and DECLARE showed some secondary preventative effects of SGLT-2 inhibitors in reducing the risk of myocardial infarction recurrence, cardiovascular death, and allcause death in T2DM patients with a history of ASCVD. 14,15 However, limited data are available to verify whether any of the SGLT-2 inhibitors have a primary preventative effect on early cardiovascular disease in patients with T2DM who have no history of ASCVD.
Further studies are needed to evaluate the primary preventative effects of SGLT-2 inhibitors.
Dapagliflozin is an oral selective SGLT-2 inhibitor. Since SGLT-2 is found exclusively in the proximal tubule of the kidney, the mode of action of dapagliflozin involves blocking glucose and sodium reabsorption. Dapagliflozin may affect blood glucose control, blood pressure, and body weight (BW), all of which are cardiovascular disease risk factors. Dapagliflozin induces glucose excretion in the urine and has been reported to induce weight loss by increasing calorie loss and reducing blood pressure through diuretic action.

Statistical analysis
Statistical analyses were conducted using R version 3.2 (R Foundation, Vienna, Austria), and a Cronbach's alpha value of P < 0.05 was considered statistically significant. Clinical and anthropometric data are expressed as the mean and standard deviation. The values at baseline and after 6 months of treatment were compared using paired t-tests. To evaluate the PWV aorta factors, we used linear regression analysis.

Baseline characteristics
The demographic characteristics and baseline metabolic parameters of the 140 study subjects are shown in Table 1. The mean age of the subjects was 47.0 ± 10.6 years, and the mean duration of diabetes was 6.0 ± 3.1 years, with a mean HbA1c of 7.56% ± 1.25%.

Effects of 6 months of dapagliflozin treatment on glycemic values and metabolic profiles
After 6 months of dapagliflozin treatment, HbA1c levels significantly decreased from 7.56% ± 1.25% at baseline to 7.14% ± 1.02% at 6 months (P< 0.01). FPG levels also decreased (P< 0.01) ( Table   2). There were significant decreases in the levels of TC and LDL-C, but levels of TG and HDL-C did not significantly change.

Comparison between body-fat-lost and body-fat-gained groups and effects of 6 months of dapagliflozin treatment on vascular variables in the body-fat-lost group (n=80)
After 6 months of treatment with dapagliflozin, an improvement in arterial stiffness was observed along with a reduction in BW. We also investigated the difference between arterial stiffness, regional fat distribution and insulin resistance according to body fat changes. PWV, body fat mass, and homeostatic model assessment of insulin resistance scores were analyzed by dividing participants into two groups based on body fat changes after 6 months of dapagliflozin treatment: those who lost body fat (n = 80) and those who gained body fat (n = 20). Significant improvements were shown for aortic PWV, regional fat distribution, and insulin resistance in the group that lost body fat (P < 0.01). However, there was no significant relation between a reduction in aortic PWV and body fat mass or insulin resistance in the body-fat-gained group. Re-analysis according to BMI showed the same result.
Among the study participants, aortic PWV significantly improved from 7.33 ± 1.48 m/sec at baseline to 6.76 ± 1.51 m/sec after 6 months of treatment (P < 0.01) in only the BW reduction group. However, there was no significant improvement in PWV in the extremities (PWV ext) and PWV aorta (Table 4).

Association between PWV aorta and metabolic parameters
The association between PWV aorta and metabolic parameters are in Table 5. PWV aorta is significantly dependent on BW, body fat mass and WHR and slightly, but not significantly, dependent on BMI. This association is not significantly dependent on PWV ext.

DISCUSSION
Our study findings show the effects of dapagliflozin in reducing cardiovascular disease risk in obese T2DM patients with no history of cardiovascular disease. This 6-month trial of patients with T2DM who did not develop cardiovascular disease showed that daily oral dapagliflozin treatment reduced arterial stiffness and improved metabolic profiles as well as glycemic control. Over the duration of our clinical trial, dapagliflozin significantly reduced HbA1c by a mean absolute amount of 0.42 (data not shown).
Obesity is associated with hypertension, dyslipidemia, and cardiovascular disease as well as DM. Studies have shown a sustained reduction in cardiovascular risk when obese adults maintained weight loss of 10%-15%. 16 Among obese patients with T2DM, sustained weight loss has also been shown to improve glycemic control. However, several classes of anti-hyperglycemic agents are associated with weight gain or no change in weight. Therefore, weight loss medications are considered effective adjuncts to life-  To maintain healthy conditions while losing weight and reducing body fat, especially visceral fat, improving the metabolic profile such as blood glucose levels, blood pressure, and endothelial cell function is important. 17  patients with previous ASCVD. 13 However, the mechanism of action for the reduction in cardiovascular outcomes is not fully understood. One suggestion is that suppression of the renin-angiotensin-aldosterone system, activation of the sympathetic nervous system, and improvement in nitric oxide bioactivity could explain this cardiovascular protection. 18 However, some studies have shown that these neurohormonal pathways remain unchanged in response to SGLT-2 inhibitors. 18-20 Therefore, we suggest that a decrease in arterial stiffness with dapagliflozin plays a crucial role in explaining its cardiovascular benefit. Weight loss independently reduces arterial stiffness. 21 Aortic stiffness is associated with visceral adiposity, a key driver of cardiometabolic risk. Increased WC and TG levels are predictors of excess visceral adiposity. Several studies have explored positive relationships between PWV and WC; these are indicators of visceral fat, as well as WHR. Dapagliflozin was associated with a significant reduction in weight (an average loss of 3.8 kg) in our study. Since WC and WHR were also significantly reduced, this reduction in weight was probably due to central fat loss. As the result, significant improvements were shown for only aortic PWV, not PWV ext, so we supposed that the weight loss effect by SGLT-2 inhibitors is due to the fat loss effect rather than the muscle. This is more specific in abdominal fat and appears as a decrease in the cir-   22 Insulin sensitivity is determined by body fat distribution; those with a more peripheral distribution have more insulin sensitivity than those whose fat distribution is more central. 23 WHR is a marker of insulin resistance. 24 Visceral adipocytes have elevated lipolytic activity; this results in increased free fatty acid release in the portal vein with an accumulation in the liver and muscles, contributing to insulin resistance. 25 In this study, the weight loss group showed significant improvements in insulin resistance according to HOMA as compared with the weight gain group.
A series of studies have also demonstrated a positive relationship between the amount of visceral fat and PWV. 26 Aortic PWV is a predictor of cardiovascular disease. Cardiovascular events and allcause mortality are greater in patients with high aortic PWV than in those with low aortic PWV. 8 Several studies also show evidence that increased PWV indicates adverse macrovascular and microvascular outcomes in T2DM patients. 27 The present study had certain limitations that need to be acknowledged. First, as a retrospective study, this study has selection bias. Second, the study period was too short to evaluate the effects of dapagliflozin in primary prevention of a cardiovascular event. Third, the number of participants in the fat gain group was less than that in the fat loss group. Thus, further studies are required for the evaluation of the long-term effects of dapagliflozin treatment on overweight or obese T2DM patients.
In summary, we demonstrated that dapagliflozin administration for 6 months in T2DM patients with no history of cardiovascular disease resulted in improved glycemic control, lower aortic stiffness, and reduced BW and body fat, especially visceral fat without a loss in body muscle mass. When used in obese diabetic patients with no evidence of vascular disease, SGLT-2 inhibitors may help with initial vascular disease in addition to blood sugar control.

CONFLICTS OF INTEREST
The authors declare no conflict of interest.