Treatment of HFpEF beyond the SGLT2-Is: Does the Addition of GLP-1 RA Improve Cardiometabolic Risk and Outcomes in Diabetic Patients?
Abstract
:1. Introduction
2. Phenotyping Aspects and the Burden of Cardio-Nephro-Metabolic Risk in HFpEF
3. Cardiovascular Effects of GLP-1 RAs in T2DM
4. The SGLT2-Is Effects on Cardio-Renal Axis
Sodium-glucose cotransporter 2 belongs to a family of glucose transporter proteins localized in the first segment of the proximal renal tubule and responsible for the majority of filtered glucose and sodium reabsorption. SGLT2-Is are a novel class of drugs for the treatment of T2DM and HF [80,81,82].Maximal glucose tubular transport (TmG) in healthy adult men is approximately 375 mg/min, which corresponds to 300 mg of glucose per day [83,84,85]. Because glucose filtration rate is lower than TmG under normoglycemic and hypoglycemic conditions, filtered glucose is completely reabsorbed in proximal convoluted tubules by SGLT2 receptor; conversely, glycosuria occurs when glycemia exceeds the threshold of 180 mg/day.
CV beneficial effects of SGLT2-Is include positive hemodynamic effects with a reduction in preload and afterload and improved cardiac contractility, related not only to the increased diuresis and natriuresis, but also to nephron remodeling, endothelial function improvement and, through glycosuria, also loss of body weight and adipose tissue with reduced insulin resistance [87,97,98]. A systematic review of preclinical studies showed that SGLT2-Is attenuated vascular dysfunction through a combination of mechanisms that appear to act independently of glucose-lowering benefits [99]. SGLT2-Is reduce blood pressure also in the absence of an increased heart rate, suggesting that these agents may lead to a reduction in sympathetic nervous system (SNS) activity [100,101]. As HF progresses, a continual decline in mitochondrial oxidative metabolism occurs; SGLT2-Is were shown to increase circulating ketone levels, secondary to mobilizing adipose tissue fatty acids, which are then used by the liver for ketogenesis [102]. These ketones have been proposed to improve cardiac energetics and cardiac efficiency [103,104].
5. The Rationale for the Use of GLP-1RAs and SGLT2-Is in T2DM Patients with HFpEF
6. Discussion
7. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Agent | SGLT2 Inhibitors | GLP-1 Agonists | Combination Therapy | |
---|---|---|---|---|
Effects | ||||
Oxidative stress | ||||
Inflammation | ||||
Endothelial dysfunction | ||||
Natriuresis | ||||
Diuresis | ||||
Plaque stability | ||||
Blood pressure | ||||
Body weight | ||||
Lipid profile | ||||
Epicardial fat | ||||
Myocardial fibrosis | ||||
Insulin resistance | ||||
Beta cell function |
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Belli, M.; Barone, L.; Bellia, A.; Sergi, D.; Lecis, D.; Prandi, F.R.; Milite, M.; Galluccio, C.; Muscoli, S.; Romeo, F.; et al. Treatment of HFpEF beyond the SGLT2-Is: Does the Addition of GLP-1 RA Improve Cardiometabolic Risk and Outcomes in Diabetic Patients? Int. J. Mol. Sci. 2022, 23, 14598. https://doi.org/10.3390/ijms232314598
Belli M, Barone L, Bellia A, Sergi D, Lecis D, Prandi FR, Milite M, Galluccio C, Muscoli S, Romeo F, et al. Treatment of HFpEF beyond the SGLT2-Is: Does the Addition of GLP-1 RA Improve Cardiometabolic Risk and Outcomes in Diabetic Patients? International Journal of Molecular Sciences. 2022; 23(23):14598. https://doi.org/10.3390/ijms232314598
Chicago/Turabian StyleBelli, Martina, Lucy Barone, Alfonso Bellia, Domenico Sergi, Dalgisio Lecis, Francesca Romana Prandi, Marialucia Milite, Chiara Galluccio, Saverio Muscoli, Francesco Romeo, and et al. 2022. "Treatment of HFpEF beyond the SGLT2-Is: Does the Addition of GLP-1 RA Improve Cardiometabolic Risk and Outcomes in Diabetic Patients?" International Journal of Molecular Sciences 23, no. 23: 14598. https://doi.org/10.3390/ijms232314598