Here, we confirm that chronic GLP-1R agonist administration increases HR, according to a previously available meta-analysis 22. Systematically, the HR increase after chronic GLP-1R agonist administration is evident in five of six included trials. Indeed, only one study found no significant changes in HR after GLP-1R agonist administration, but, differently from the others, authors used a short-acting GLP-1R agonist, such as exenatide, for much longer time 28. Thus, we could speculate that the GLP-1R agonist effect on HR could depend on the molecule used and the duration of the administration. Moreover, together with the HR increase, no significant change in other ANS-related parameters is evident in our meta-analysis. This result suggests that the chronic GLP-1R agonist administration may not influence the sympathetic and parasympathetic functions. Thus, we could speculate that the HR modifications induced by GLP-1R agonist is not consequence of sympathetic or parasympathetic stimulation, but other mechanisms should be involved.
GLP-1R agonists are increasingly used in clinical practice in diabetes, considering the wide range of positive effects on glucose homeostasis, body weight, BP and the low risk of hypoglycaemia. However, an overall GLP-1R agonist effect on ANS is far from being elucidated, even with the meta-analytic approach. Considering each study separately, interesting results could be extracted. Jaiswal et al. did not detect any change in autonomic function after 18 months of treatment with the short-acting GLP-1R agonist exenatide in patients with T2DM, evaluating either the gold-standard CARTs, such as DB and VM or measures of HRV, such as HR, LF/HF, SDNN, RMSSD 28. In particular, that study was characterized by different follow-up length (18 months) than other studies included in the analysis (range 12–26 weeks). Therefore, we could not exclude that this difference represents a confounding factor, or a determinant of a kind of mitigation of HR increase over time. On the contrary, Kumarathurai et al. reported detrimental reductions in several HRV indices in T2DM patients treated with liraglutide for 12 weeks 31. In particular, liraglutide decreased SDNN, RMSSD and HF without changes in LF/HF ratio compared to placebo 31. This SDNN decrease persisted despite body weight loss and metabolic parameter improvement, suggesting an impairment in vagal activity after treatment 31. Moreover, in order to elucidate the role of the cardiac sympatho-vagal balance as a possible mediator of the reported HR increase in GLP-1R agonist treatment, Cacciatori et al. performed CARTs and power spectral analysis of HRV in 28 T2DM patients after exenatide extended-release administration 26. The main result of this study is an expected HR increase together with an unexpected LF/HF decrease, suggesting the existence of a compensatory mechanism 26. This phenomenon is characterized by a “shift” of the sympatho-vagal balance with reduction of the LF component and no change in parasympathetic tone (HF) 26. In contrast, Nystrom et al. demonstrated the absence of changes in sympathetic or parasympathetic activity evaluated by HRV in 62 T2DM individuals receiving 1.8 mg liraglutide once daily in comparison with 4 mg glimepiride once daily 30. Similarly, in the context of type 1 DM (T1DM), changes neither in the HRV domains, nor in cardiac vagal tone and cardiac sensitivity to the baroreflex were observed in 19 patients treated with liraglutide for 26 weeks 25. This result was confirmed by the post-hoc analysis of Hansen et al., showing no changes in CAN measures after liraglutide 1.8 mg once-daily for 24 weeks. In this study, the E/I ratio declined significantly in both liraglutide and placebo groups 27.
Accordingly, our findings show no difference in the LF/HF ratio after treatment, considering both different molecules (exenatide and/or liraglutide) and both type of diabetes (T1DM and/or T2DM). Moreover, others HRV measures, such as SDNN and RSMSSD, do not change after chronic GLP-1R agonist administration. These results are confirmed considering liraglutide and exenatide separately, suggesting no differences between molecules. LF/HF ratio represents an index widely used in clinical practice for CAN evaluation in diabetic patients, providing information about autonomic - parasympathetic and sympathetic - modulation of the cardiovascular system. Even if considered among the methods of investigation for cardiac autonomic dysfunction in human research studies 24, LF/HF ratio from HRV study confirms to be a measure not accurate and not directly related to sympatho-vagal balance, according to previous studies 32,33. Among CARTs measurements, representing the gold standard for the diagnosis of CAN, the only parameter that seems to be influenced by GLP-1R agonist administration is the 30:15 ratio, which decreases after treatment. However, the strength of this result is limited by the small number of trials reporting this parameter. Thus, our meta-analysis suggests that chronic GLP-1R agonist treatment does not influence the sympatho-vagal balance in people with diabetes. Hence, the HR increase could depend on different mechanisms.
In animal models, GLP-1 engages GLP-1R in central, peripheral, and autonomic nervous systems, enhancing the sympathetic nervous system activity, and reducing the parasympathetic nervous system activity 34. In this regard, Baggio et al. suggested that the GLP-1R agonist-related HR increase is the final effect of direct chronotropic action, which is attenuated by propanolol but not by atropine 34. Moreover, the in vivo GLP-1R agonist administration induces c-fos expression - a marker of neuronal activity - in the adrenal medulla, activates neurons involved in autonomic control in the brain, and activates tyrosine hydroxylase transcription in brainstem catecholamine neurons 35. These findings suggest that the central GLP-1 action could be involved in the regulation of the sympathetic pathway 35. However, the identification of GLP-1R expression in mouse atria 36 and in monkey sinoatrial node 37 raised the additional possibility that GLP-1 may directly modulate HR through the cardiac GLP-1R. Moreover, Berkelaar et al. evaluated 130 healthy participants undergoing hyperglycaemic clamps and acute exposure to GLP-1 during hyperglycaemia, showing a small acute HR increase without an acute decrease in cardiac vagal control, measured by HRV 38. In this setting, serum insulin was positively associated with HR 38, suggesting that GLP-1 effect could be mediated by GLP1-driven increase in endogenous insulin 39. Again, other experimental trials suggested the sympathetic nervous system activation after GLP-1R agonist infusion in healthy individuals 40,41. All these examples demonstrate that the action of GLP-1R agonist on the sympathetic and parasympathetic systems must be both direct and indirect but this should be further studied with properly designed clinical and experimental trials. Indeed, even the present meta-analytical approach is not able to reach conclusive results, since it is still based on a limited number of studies with small sample size. Thus, the lack of significant effects of GLP-1R agonist chronic administration on ANS might be related to the limited amount of data available so far.