The Effects of Cardioprotective Antidiabetic Therapy on Microbiota in Patients with Type 2 Diabetes Mellitus—A Systematic Review

Abstract

As the pathophysiologic mechanisms of type 2 diabetes mellitus (T2DM) are discovered, there is a switch from glucocentric to a more comprehensive, patient-centered management. The holistic approach considers the interlink between T2DM and its complications, finding the best therapies for minimizing the cardiovascular (CV) or renal risk and benefitting from the treatment‘s pleiotropic effects. Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) fit best in the holistic approach because of their effects in reducing the risk of CV events and obtaining better metabolic control. Additionally, research on the SGLT-2i and GLP-1 RA modification of gut microbiota is accumulating. The microbiota plays a significant role in the relation between diet and CV disease because some intestinal bacteria lead to an increase in short-chain fatty acids (SCFA) and consequent positive effects. Thus, our review aims to describe the relation between antidiabetic non-insulin therapy (SGLT-2i and GLP-1 RA) with CV-proven benefits and the gut microbiota in patients with T2DM. We identified five randomized clinical trials including dapagliflozin, empagliflozin, liraglutide, and loxenatide, with different results. There were differences between empagliflozin and metformin regarding the effects on microbiota despite similar glucose control in both study groups. One study demonstrated that liraglutide induced gut microbiota alterations in patients with T2DM treated initially with metformin, but another failed to detect any differences when the same molecule was compared with sitagliptin. The established CV and renal protection that the SGLT-2i and GLP-1 RA exert could be partly due to their action on gut microbiota. The individual and cumulative effects of antidiabetic drugs on gut microbiota need further research.

Interactions between Gut Microbiota and Oral Antihyperglycemic Drugs: A Systematic Review

“…Conversely, SGLT2 inhibitors and TZDs have been suggested to have less pronounced effects on gut microbiota and microbial metabolites compared to other treatments [ 124 ]. Although the exact microbial patterns linked to individual antidiabetic drugs are unknown, understanding how these treatments affect the gut microbiota might be essential in identifying their potential mechanisms and improving their efficacy.…”

Gut–Kidney–Heart: A Novel Trilogy

“…Lee et al demonstrated that treatment with Dapagliflozin can reduce the Firmicutes:Bacteroidetes ratio and increased the Akkermansia muciniphila population [174]. Treatment with Empagliflozin increases SCFA-producing species, such as Eubacterium, Roseburia, and Faecalibacterium [176]. However, dapagliflozin concurrently elicits potential side effects.…”

Antidiabetic Drug Efficacy in Reduction of Mortality during the COVID-19 Pandemic

“…Furthermore, metformin inhibits fructose-1,6-bisphosphatase by a hepatic AMPK-independent mechanism [33]. It changes the composition of the microbiota [5], thus reducing inflammation. In addition, it downregulates the expression of genes encoding pro-inflammatory cytokine production [15], significantly decreasing excessive inflammatory responses and thus slowing disease progression [4].…”

“…These figures indicate that diabetes is causing high mortality rates globally, hence the need for requisite interventions to handle the growing number of affected individuals worldwide [4]. Diabetes leads to non-traumatic lower extremity amputations, end-stage renal disease, and adult-onset blindness [5]. These complications cause severe disabilities and chronic disorders [2] among affected individuals.…”

“…The Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are classified as anti-diabetic drugs, which function by inhibiting the resorption of glucose and sodium in the proximal convoluted tubule of the kidney [53], thus improving glycemic control [54]. They are found to significantly improve the quality of life and reduce mortality rates among diabetes patients infected with COVID-19 [3], as well as have important renal protective [55] and cardiovascular benefits [5]. A meta-analysis by Nguyen et al (2022) has found that treatment with SGLT-2i resulted in lower mortality rates (OR 0.60, 95% CI 0.40-0.88) [12].…”