Dapagliflozin treatment is associated with a reduction of epicardial adipose tissue thickness and epicardial glucose uptake in human type 2 diabetes

Abstract

Objective We recently demonstrated that treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) leads to an increase in myocardial flow reserve in patients with type 2 diabetes (T2D) with stable coronary artery disease (CAD). The mechanism by which this occurs is, however, unclear. One of the risk factors for cardiovascular disease is inflammation of epicardial adipose tissue (EAT). Since the latter is often increased in type 2 diabetes patients, it could play a role in coronary microvascular dysfunction. It is also well known that SGLT-2i modify adipose tissue metabolism. We aimed to investigate the effects of the SGLT-2i dapagliflozin on metabolism and visceral and subcutaneous adipose tissue thickness in T2D patients with stable coronary artery disease and to verify whether these changes could explain observed changes in myocardial flow. Methods We performed a single-center, prospective, randomized, double-blind, controlled clinical trial with 14 T2D patients randomized 1:1 to SGLT-2i dapagliflozin (10 mg daily) or placebo. The thickness of visceral (epicardial, mediastinal, perirenal) and subcutaneous adipose tissue and glucose uptake were assessed at baseline and 4 weeks after treatment initiation by 2-deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography/Computed Tomography during hyperinsulinemic euglycemic clamp. Results The two groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, BMI, renal and heart function). Dapagliflozin treatment significantly reduced EAT thickness by 19% (p = 0.03). There was a significant 21.6% reduction in EAT glucose uptake during euglycemic hyperinsulinemic clamp in the dapagliflozin group compared with the placebo group (p = 0.014). There were no significant effects on adipose tissue thickness/metabolism in the other depots explored. Conclusions SGLT-2 inhibition selectively reduces EAT thickness and EAT glucose uptake in T2D patients, suggesting a reduction of EAT inflammation. This could explain the observed increase in myocardial flow reserve, providing new insights into SGLT-2i cardiovascular benefits.

Dapagliflozin promotes white adipose tissue browning though regulating angiogenesis in high fat induced obese mice

“…Recently, the regulatory effect of dapagliflozin on WAT is also gaining increasing attention by researchers. Clinical studies have shown that treatment with dapagliflozin might improve systemic metabolic parameters and decrease the epicardial adipose tissue (EAT) volume in diabetes mellitus patients [ 18 , 19 ]. Eva Kralova et al found that dapagliflozin influenced visceral fat gene expression in streptozotocin-induced diabetes mellitus Wistar rats.…”

Cholesin receptor signalling is active in cardiovascular system-associated adipose tissue and correlates with SGLT2i treatment in patients with diabetes

“…Animal model studies aimed to explain these effects through inhibition of peroxisomal factors like DGAT2, PPARG1 and PPARG2, but no clear mechanism linking the SGLT2i to these pathways was thus far identified [21][22][23]. Furthermore, reduction of epicardial fat volumes after SGLT2i treatment was described consistently across multiple studies [3,24,25], but the exact mechanism remained elusive. Here, we show that peroxisomal pathways are associated with GPR146 expression and suppressed by SGLT2i treatment.…”

Influence of dapagliflozin on cardiovascular remodeling in hypertensive patients with accompanying type 2 diabetes

“…Ці дані збігаються з результатами дослідження H. Tanaka et al [21], які встановили: дапагліфлозин асоціюється з покращенням поздовжньої функції міокарда ЛШ, а також наступним поліпшенням діастолічної функції ЛШ у хворих на ЦД 2 типу зі стабільною СН. Song X. et al повідомляли про збільшення глобального поздовжнього стрейну (GLS) та зниження товщини епікардіального жиру через 6 місяців після додавання дапагліфлозину до схеми лікування [22]. Інші дослідники встановили, що інгібітори SGLT2 мають сприятливіший вплив на діастолічну функцію ЛШ у пацієнтів із ЦД 2 типу і стабільною СН, ніж інші методи лікування, особливо у хворих із супутньою дисліпідемією [23].…”