Sivilangam et al have generated disappointing results, as they show in the LIRAFLAME study a placebo controlled study against Liraglutide improves only one out of multiple measures of cardiac autonomic neuropathy and PET marker of aortic and carotid inflammation in a cohort of patients with T2DM.

They show an association between CART’s and CACS score.

Was the inability to show an improvement after the intervention because of:

1. Inadequate trial design: Short duration of intervention. Did they really expect a 26 week intervention to improve CAN (26 weeks)?

2. Inadequately sensitive end-points for assessing cardiac autonomic neuropathy. This is an issue that his bedevilled multiple clinical trials in diabetic neuropathy.

3. Inadequate power, as the LIRA FLAMESTUDY was powered to the primary end-point not the quaternary end points.

4. In short of 6 cardiac autonomic neuropathy tests, only two show a difference compared to the placebo. Even here the significant difference in 30: 15 ratio and was driven by a decrease in the placebo group with no change in the liraglutide group. The E/I ratio increased in both the liraglutide and placebo group, just more so in the liraglutide group.

5. The significant increase in the placebo group in both the 30:15 ratio and E/I ratio make no physiological sense, unless there was a massive improvement in the risk factors for CAN.

6. What is the effect of the increased heart rate of ~4 beats/minute in the Liraglutide group?

Thank you for addressing my concerns.