Abstract
The role of the autonomic nervous system in the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with type 1 diabetes is unknown. We assessed the association between autonomic function and weight loss induced by the GLP-1 RA liraglutide.Methods: Lira-1 was a randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of 1.8 mg liraglutide once-daily for 24 weeks in overweight patients with type 1 diabetes. Autonomic function was assessed by heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio), to the Valsalva maneuver and resting heart rate variability (HRV) indices. Associations between baseline the cardiovascular autonomic neuropathy (CAN) diagnosis (> 1 pathological non-resting test) and levels of test outcomes on liraglutide-induced weight loss was assessed by linear regression models.Results: Ninety-nine patients with mean age 48 (SD 12) years, HbA1c 70 (IQR 66;75) mmol/mol and BMI of 30 (SD 3) kg/m2 were assigned to liraglutide (N = 50) or placebo (N = 49). The CAN diagnosis was not associated with weight loss. A 50% higher baseline level of the 30/15 ratio was associated with a larger weight reduction by liraglutide of −2.65 kg during the trial (95% CI: −4.60; −0.69; P = 0.009). Similar significant associations were found for several HRV indices.Conclusions: The overall CAN diagnosis was not associated with liraglutide-induced weight loss in overweight patients with type 1 diabetes. Assessed separately, better outcomes for several CAN measures were associated with higher weight loss, indicating that autonomic involvement in liraglutide-induced weight loss may exist.
Highlights
Glucagon-like peptide-1 (GLP-1) is a gut-derived hormone with anorexigenic properties [1]
Of the 100 patients enrolled in the Lira-1 trial, one patient in the placebo group had no usable cardiovascular autonomic neuropathy (CAN) measures, leaving 50 patients in the liraglutide and 49 patients in the placebo arm for analysis
Sex, (N/%) Age HbA1c HbA1c (%) Bodyweight Body mass index Diabetes duration Insulin dose per kilo per day Total cholesterol HDL cholesterol LDL cholesterol Systolic blood pressure Diastolic blood pressure Beta blocker (N/%) Diuretics (N/%) ACE inhibitor (N/%) ARBs (N/%) CAN diagnosis (N/%) Early CAN (N/%) Pathological E/I ratio (N/%) Pathological 30/15 ratio (N/%) Pathological Valsalva (N/%) E/I ratio 30/15 ratio Valsalva standard deviation of normal-to-normal intervals (SDNN) RMSSD High frequency power Low frequency power Total power LF/HF ratio Heart rate
Summary
Glucagon-like peptide-1 (GLP-1) is a gut-derived hormone with anorexigenic properties [1]. Activation of GLP1 receptors in peripheral vagal neurons [6, 7] seems to be involved, suggesting that dysfunction of the vagal nerve may affect the body weight-reducing effect of liraglutide in patients. If this is the case, a substantial subset of people with diabetes may experience a reduced effect of treatment as autonomic neuropathy is a common complication to diabetes. We hypothesize that autonomic dysfunction might be expected to influence the efficacy of GLP-1RAs in type 1 patients. We explored the possible association between CAN measures and liraglutideinduced weight loss, insulin requirements and gastric emptying rate in patients with type 1 diabetes
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