Sodium-Glucose Cotransporter 2 Inhibitors: Possible Anti-Atherosclerotic Effects Beyond Glucose Lowering

The new drug for type 2 diabetes, the sodium-glucose cotransporter 2 (SGLT-2) inhibitor, is reversible inhibitor of SGLT-2, leading to reduction of renal glucose reabsorption and decrease of plasma glucose, in an insulin-independent manner. In addition to glucose control, the management of coronary risk factors is very important for patients with diabetes. Here we reviewed published articles about the possible anti-atherosclerotic effects beyond glucose lowering of the SGLT-2 inhibitors. We searched by using Pubmed, and found 770 published articles about SGLT-2 inhibitors. Among 10 kinds of SGLT-2 inhibitors, the number of published articles about dapagliflozin was the greatest among SGLT-2 inhibitors. Since SGLT-2 inhibitors have similar chemical structures, we concentrated on the published articles about dapagliflozin. SGLT-2 inhibitors are proved to be significantly associated with weight loss and reduction of blood pressure by a relatively large number of studies. The studies investigating effects of dapagliflozin on visceral fat, insulin sensitivity, serum lipids, inflammation and adipocytokines are very limited. An influence of increase in glucagon secretion by SGLT-2 inhibitors on metabolic risk factors remains unknown.


Introduction
Sodium-glucose cotransporter 2 (SGLT-2) mediates approximately 90% of active renal glucose reabsorption in the proximal tubule of the kidney [1]. Recently, the new drug for type 2 diabetes, the SGLT-2 inhibitor was developed. The SGLT-2 inhibitor is reversible inhibitor of SGLT-2, leading to reduction of renal glucose reabsorption and decrease of plasma glucose, in an insulin-independent manner [2]. Diabetes is a strong independent risk factor for cardiovascular diseases (CVDs) [3]. Compared with subjects without diabetes, the relative risk for CVD is 2 -3 times greater in men with diabetes and 3 -4 times greater in women with diabetes [4][5][6][7][8][9][10]. In addition to glucose control, the management of coronary risk factors is very important for patients with diabetes. Here we reviewed published articles about the possible anti-atherosclerotic effects beyond glucose lowering of the SGLT-2 inhibitors.

The Search Strategy for Published Articles About the Anti-Atherosclerotic Effects Beyond Glucose Lowering of the SGLT-2 Inhibitors
We searched by using Pubmed (Table 1), and found 770 published articles about SGLT-2 inhibitors. Ten kinds of SGLT-2 inhibitors were detected, and we searched the published articles about each SGLT-2 inhibitor. The number of published articles about dapagliflozin was the greatest among SGLT-2 inhibitors. Since SGLT-2 inhibitors have similar chemical structures, we concentrated on the published articles about dapagliflozin.

Glucose, Body Weight and Blood Pressure Lowering Effects of Dapagliflozin
Dapagliflozin also reduces renal glucose reabsorption and decrease of plasma glucose, in an insulin-independent manner [2], which induces reduction of body weight and blood pressure. Reduction of body weight and blood pressure by SGLT-2 inhibitors is also induced by osmotic diuretics [11]. There were 106 published articles about "dapagliflozin and body weight" and 78 articles about "dapagliflozin and blood pressure".
Matthaei et al studied effects of dapagliflozin 10 mg/day or placebo for 52 weeks on metabolic parameters in patients with type 2 diabetes using sulphonylurea and metformin [12], HbA1c and fasting plasma glucose levels showed greater improvement from baseline with dapagliflozin (-0.8% and -1.5 mmol/L) than with placebo. Dapagliflozin was associated with greater reductions in body weight and systolic blood pressure (-2.9 kg and -1.0 mm Hg) compared with placebo. Dapagliflozin was administered as monotherapy (n = 249) or combination therapy (n = 479) with existing antihyperglycemic agents to Japanese patients with diabetes for 52 weeks [13]. In patients receiving dapagliflozin as monotherapy or combination therapy, reductions from baseline were observed in HbA1c (-0.7% in both groups), weight (-2.6 and -2.1 kg, respectively), and systolic blood pressure (-5.2 and -3.9 mm Hg). Dapagliflozin reduced body weight and blood pressure by both monotherapy and add-on therapy.
In a meta-analysis including all trials with a duration of at least 12 weeks, comparing an SGLT-2 inhibitor with a non-SGLT-2 inhibitor agent in type 2 diabetes, SGLT-2 inhibitors are effective in the treatment of type 2 diabetes, providing additional benefits, such as weight loss, reduction of blood pressure [14].

Anti-Atherosclerotic Effects Beyond Glucose Lowering of Dapagliflozin
Improvement in glucose control, body weight and blood pressure by dapagliflozin was almost confirmed by a relatively large number of studies. We hypothesized the underlying mechanisms for possible anti-atherosclerotic effects beyond glucose lowering of SGLT-2 inhibitors (Fig. 1). We searched the published articles about the effects of dapagliflozin on metabolic risk factors by using Pubmed (Table 2). In this search, we excluded "Original Articles using animals or cells", "Narrative Reviews" and "Expert Opinions", and we considered "Original Articles", Systematic Reviews" and "Meta-analysis" as important information.

The effect of dapagliflozin on visceral or body fat
Patients (N = 182) were randomly assigned to receive dapagliflozin 10 mg/day or placebo added to open-label metformin

The effect of dapagliflozin on insulin sensitivity
We selected "Original Articles" which evaluated insulin sensitivity using the euglycemic hyperinsulinemic clamp. Twentyfour subjects with diabetes received dapagliflozin (n = 16) or placebo (n = 8) for 2 weeks, and the euglycemic hyperinsulinemic clamp was performed before and after treatment [17]. Dapagliflozin significantly improved whole-body insulin sensitivity. In another study, 18 diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks [18]. Improvement in muscle insulin sensitivity by dapagliflozin was observed by using the euglycemic hyperinsulinemic clamp. Forty-four subjects were randomized to receive dapagliflozin 5 mg or matching placebo once daily for 12 weeks [19]. Insulin sensitivity was assessed by measuring the glucose disappearance rate during the last 40 min of a 5-h euglycemic hyperinsulinemic clamp. Dapagliflozin treatment improved insulin sensitivity.

The effect of dapagliflozin on inflammation and adipocytokines
In the review which critically assessed the results of up-todate clinical trials with dapagliflozin [21], it was described that high sensitivity C-reactive protein levels were decreased in dapagliflozin-treated patients. We could not find published articles about effects of dapagliflozin on adipocytokines including interleukin-6, tumor necrosis factor alpha and adiponectin.

The effect of dapagliflozin on glucagon secretion
In the study by Merovci et al [18], insulin-mediated tissue glucose disposal increased by approximately 18% after 2-week dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Following dapagliflozin treatment, an increase in fasting plasma glucagon concentration was observed. Glucagon is associated with insulin resistance [22]. An influence of increase of glucagon secretion by SGLT-2 inhibitors on insulin resistance or metabolic risk factors should be carefully observed.

Conclusion
SGLT-2 inhibitors seem to be associated with weight loss and reduction of blood pressure by a relatively large number of studies. However, the studies that investigated effects of dapagliflozin on visceral fat, insulin sensitivity, serum lipids, inflammation and adipocytokines are very limited. Furthermore, an influence of increase in glucagon secretion by SGLT-2 inhibitors on metabolic risk factors remains unknown. The glucose lowering effect in an insulin-independent manner of SGLT-2 inhibitors prevents hyperinsulinemia, which may also contribute to anti-atherogenesis. Very recently, Zinman et al showed that the addition of another SGLT-2 inhibitor, empagliflozin, reduced rates of death from cardiovascular causes (38% relative risk reduction), hospitalization for heart failure (35%), and death from any cause (32%) [23], suggesting a possible anti-atherosclerotic effect of SGLT-2 inhibitors. However, further studies should be performed to elucidate anti-atherosclerotic effect of SGLT-2 inhibitors.