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Autonomic neuropathy is associated with the lack of glucagon-like peptide-1 receptor agonists treatment efficacy in patients with type 2 diabetes

While glucagon-like peptide-1 receptor agonists (GLP-1 RA) are widely used in the treatment of type 2 diabetes (T2DM), factors contributing to the lack of their efficacy have not been fully elucidated. We investigated the potential influence of cardiac autonomic neuropathy (CAN) in patients not responding to GLP1-RA. Two hundred and 14 patients with T2DM ; 142 (66%) on liraglutide and 72 (34 %) on exenatide, both added to co-existing antidiabetic therapy, were divided into 2 groups ( GLP-1 RA responders and non-responders) and followed for 40 months. Non-responding was defined by switching to insulin therapy at any time after intervention during 40 months treatment. Testing of CAN was carried out on VAGUS 2100 (Sigma Medizin Technik, Thum, Germany) using a standard battery of cardiovascular tests based on heart rate variation (HRV): HRV at rest, HRV during deep breathing, Valsalva maneuver, active orthostatic test and blood pressure response to standing. The statistical data were processed by standard, vector and spectral analysis and following parameters were obtained: the coefficient of variation at rest (HRV-CV), the spectrum of low frequency power (LF) and high frequency power (HF), the coefficient of variation during deep breathing (dbHRV-CV), E / I ratio, 30 : 15 ratio and the Valsalva ratio. The resulting parameters were compared with normal values for the appropriate age, and a pathological finding of two or more parameters was considered as CAN. Non-responders (n=47), compared to responders (n=167), were older (62 vs 59 years, p=0.002), had longer diabetes duration o (14.9 vs 12.7 years, p<0.001), higher systolic (147.5 vs 143.3 mmHg, p=0.001), diastolic blood pressure (88.1 vs 86.4 mmHg, p= 0.002) and heart rate (81.1 vs 71.7 beats per minute, p=0.001). The non-responders group compared to responders showed increased CAN presence (9.4% vs 4.7% and 53.1% vs 19.2%, p<0.001): significantly lower HRV-CV at rest, dbHRV-CV and Valsalva ratio, a significant attenuation for both LF and HF bands indicating lower parasympathetic or higher sympathetic nerve activity. The Cox regression model including the possible confounding variables revealed that higher HRV-CV, dbHRV-CV, E/I ratio, LF and LF/HF were associated with GLP-1 RA therapy success. Lack of GLP1-RA efficacy appears to be associated with CAN leading to the shortening of the time of insulin dependency in T2DM. As autonomic dysfunction could represent a significant factor leading to treatment failure, early identification of the CAN presence might be of special clinical interest. The predictive value of the relationship between GLP-1 RA efficacy and autonomic disbalance merits to be further investigated.

autonomic neuropathy, GLP-1 receptor agonists

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