Cardiovascular Benefits of Empagliflozin Are Associated With Gut Microbiota and Plasma Metabolites in Type 2 Diabetes

Xinru Deng; Chenhong Zhang; Pengxu Wang; Wei Wei; Xiaoyang Shi; Pingping Wang; Junpeng Yang; Limin Wang; Shasha Tang; Yuanyuan Fang; Yalei Liu; Yiqi Chen; Yun Zhang; Qian Yuan; Jing Shang; Quane Kan; Huihui Yang; Hua Man; Danyu Wang; Huijuan Yuan

Disclosures

J Clin Endocrinol Metab. 2022;107(7):1888-1896. 

In This Article

Abstract and Introduction

Abstract

Context: Cardiovascular benefits of empagliflozin in patients with type 2 diabetes mellitus (T2DM) have been reported; however, the underlying mechanism remains unknown.

Objective: We hypothesized that the cardiovascular benefits of empagliflozin are associated with altered gut microbiota and plasma metabolites, and that empagliflozin may be used as an initial treatment for patients with T2DM at risk of cardiovascular diseases (CVDs).

Methods: This randomized, open-label, 3-month, 2-arm clinical trial included 76 treatment-naïve patients with T2DM and risk factors for CVD who were treated with either empagliflozin (10 mg/d, n = 40) or metformin (1700 mg/d, n = 36). We investigated changes in clinical parameters related to glucose metabolism and CVD risk factors, gut microbiota using 16S rRNA gene sequencing, and plasma metabolites using LC-MS.

Results: We found significant and similar reduction in HbA1c levels and alleviation of glucose metabolism in both groups. However, only empagliflozin improved CVD risk factors. Empagliflozin significantly reshaped the gut microbiota after 1 month of treatment; this alteration was maintained until the end of the trial. Empagliflozin increased the levels of plasma metabolites such as sphingomyelin, but reduced glycochenodeoxycholate, cis-aconitate, and uric acid levels. Concurrently, empagliflozin elevated levels of short-chain fatty acid-producing bacteria such as species from Roseburia, Eubacterium, and Faecalibacterium, and reduced those of several harmful bacteria including Escherichia-Shigella, Bilophila, and Hungatella.

Conclusion: Empagliflozin may be a superior initial therapy for patients with T2DM at risk of CVDs; its cardiovascular benefits may be associated with shifts in gut microbiota and plasma metabolites.

Introduction

Empagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2i), reduces hyperglycemia in patients with type 2 diabetes mellitus by decreasing renal glucose reabsorption and elevating urinary glucose excretion.[1] Furthermore, treatment with empagliflozin not only improves hyperglycemia, but also results in body-weight loss, a reduction in blood pressure, and a decrease of cardiovascular events and mortality.[2] Therefore, the Food and Drug Administration has added an indication for empagliflozin, as the first antihyperglycemic medication to reduce the risk of major adverse cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular diseases (CVDs).[3] However, almost all guidelines from the American Diabetes Association, International Diabetes Federation, and World Health Organization (WHO) on the management of type 2 diabetes recommend metformin as an initial therapy for patients with no contraindications.[4–6] Given the cardiovascular benefit of empagliflozin, we hypothesized that it may be a better initial therapy for patients with type 2 diabetes at risk of CVDs.

Moreover, the mechanisms underlying the effects of empagliflozin on the cardiovascular system remain unclear. A previous study in animal models suggested that, in addition to empagliflozin-related diuresis, the antioxidant, anti-inflammatory, and anti-apoptotic effects of empagliflozin may also contribute to its cardiovascular benefits.[7] Besides, emerging evidence indicates that the gut microbiota modulates metabolism as well as oxidative and inflammatory activities in the host, thereby significantly influencing the pathogenesis of type 2 diabetes and CVDs.[8–10] Recently, an animal study suggested that another SGLT2i, dapagliflozin, subtly alters the composition of the gut microbiota in mice with type 2 diabetes.[11] It has also been reported that several antidiabetic drugs such as metformin, acarbose, and liraglutide partly achieve their glucose-lowering effects and additional metabolic improvements by modulating the gut microbiota and its metabolites.[12–15] However, it remains unknown whether treatment with empagliflozin alters the gut microbiota in patients with type 2 diabetes; furthermore, the relationship between the gut microbiota and CVDs-related beneficial effects of empagliflozin remains elusive.

Herein, we investigate the clinical benefits of empagliflozin and possible associations between its cardiovascular benefits and alterations in plasma metabolites and the gut microbiota in patients with type 2 diabetes and at risk of CVDs. To this end, we conducted a randomized, open-label, two-arm clinical trial on treatment-naïve patients with type 2 diabetes and risk factors for CVDs treated with either empagliflozin or metformin for 3 months.

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