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Cardiovascular protection by SGLT2 inhibitors - Do anti-inflammatory mechanisms play a role?
Asmaa Elrakaybi1, Katharina Laubner2, Qian Zhou3
1Division of Endocrinology and Diabetology, Department of Medicine II, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Department of Clinical Pharmacy, Ain Shams University, 11566 Cairo, Egypt.
Background:
Metabolic syndrome and related metabolic disturbances represent a state of low-grade inflammation, which accelerates insulin resistance, type 2 diabetes (T2D) and cardiovascular disease (CVD) progression. Among antidiabetic medications, sodium glucose co-transporter (SGLT) 2 inhibitors are the only agents which showed remarkable reductions in heart failure (HF) hospitalizations and major cardiovascular endpoints (MACE) as well as renal endpoints regardless of diabetes status in large randomized clinical outcome trials (RCTs). Although the exact mechanisms underlying these benefits are yet to be established, growing evidence suggests that modulating inflammation by SGLT2 inhibitors may play a key role.
Scope Of Review:
In this manuscript, we summarize the current knowledge on anti-inflammatory effects of SGLT2 inhibitors as one of the mechanisms potentially mediating their cardiovascular (CV) benefits. We introduce the different metabolic and systemic actions mediated by these agents which could mitigate inflammation, and further present the signalling pathways potentially responsible for their proposed direct anti-inflammatory effects. We also discuss controversies surrounding some of these mechanisms.
Major Conclusions:
SGLT2 inhibitors are promising anti-inflammatory agents by acting either indirectly via improving metabolism and reducing stress conditions or via direct modulation of inflammatory signalling pathways. These effects were achieved, to a great extent, in a glucose-independent manner which established their clinical use in HF patients with and without diabetes.
Insights
Sodium glucose co-transporter (SGLT) 2 inhibitors demonstrate anti-inflammatory effects, potentially explaining their cardiovascular benefits. These benefits occur independently of glucose levels, supporting their use in heart failure patients with or without diabetes.
Area of Science:
- Cardiovascular Medicine
- Endocrinology
- Pharmacology
Background:
- Metabolic syndrome and related disturbances promote inflammation, accelerating insulin resistance, type 2 diabetes (T2D), and cardiovascular disease (CVD).
- Sodium glucose co-transporter (SGLT) 2 inhibitors uniquely reduce heart failure hospitalizations, major cardiovascular endpoints (MACE), and renal events, irrespective of diabetes status.
- Modulating inflammation is a proposed mechanism for the cardiovascular benefits of SGLT2 inhibitors.
Purpose of the Study:
- To review the anti-inflammatory effects of SGLT2 inhibitors as a mechanism for their cardiovascular benefits.
- To explore metabolic and systemic actions of SGLT2 inhibitors that mitigate inflammation.
- To present signaling pathways involved in the direct anti-inflammatory effects of SGLT2 inhibitors and discuss controversies.
Main Methods:
- Literature review of randomized clinical outcome trials (RCTs) and mechanistic studies.
- Analysis of metabolic and systemic actions of SGLT2 inhibitors.
- Examination of proposed direct anti-inflammatory signaling pathways.
Main Results:
- SGLT2 inhibitors possess anti-inflammatory properties, acting both indirectly through metabolic improvements and directly on inflammatory pathways.
- These anti-inflammatory effects contribute to the observed reductions in cardiovascular and renal endpoints.
- Significant benefits were noted in a glucose-independent manner, supporting their use in heart failure patients with or without diabetes.
Conclusions:
- SGLT2 inhibitors show promise as anti-inflammatory agents, mediating cardiovascular benefits through both direct and indirect mechanisms.
- Their anti-inflammatory actions, particularly in a glucose-independent fashion, are crucial for their established clinical efficacy in heart failure.
- Further research into specific signaling pathways will elucidate the full therapeutic potential of SGLT2 inhibitors.
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