Digest 27-1: “An injection a day may keep CLI away?”

Welcome to another diabetic foot digest commentary. Hopefully there will be a few abstracts that may catch your interest. 

The focus paper is an open-label randomised controlled study from a group in Naples, Italy. Its main objective was to investigate the effect of liraglutide, a glucagon-like peptide 1 receptor agonist (GLP-1RA), on peripheral arterial perfusion, measured as peripheral transcutaneous oxygen pressure (TcPO₂) in individuals with type 2 diabetes and existing mild peripheral artery disease (PAD). The authors screened 89 subjects with type 2 diabetes with an HbA_1c of 6.5–8% and PAD, recruiting 55 people. Inclusion criteria included GLP-1RA naïve or not taken for 3+ months, TcPO₂ 30–49 mmHg (foot dorsum). PAD diagnosis was determined by Doppler ultrasonography, CT angiography, or angiography within 12 months. 

The authors randomised 27 subjects to target daily dose 1.8 mg of subcutaneous liraglutide titrated 0.6 mg weekly to target (LG) and 28 to control group (CG) for 6 months. Primary outcomes were a change from baseline TcPO₂ between groups and proportional comparison of subjects who reached 10% increase from baseline TcPO₂ in each group. 

The mean age was 67.5 (SD ± 8.5) years; 78% (n=43) were male. The median HbA_1c was 6.9% (range 6.5–7.8%) and the mean TcPO₂ was 40.3 (± 5.7) mmHg. 

The 10% increase of TcPO₂ occurred in 24 participants (89%) in LG and 13 (46%) in CG (relative risk 1.91; 95% CI 1.26–2.90; p<0.001). However, overall, there was a TcPO₂ increase at follow-up in both groups, but with a significant difference favouring the LG (difference of 11.2 mmHg; 95% CI 8.0–14.5 mmHg; p<0.001). Compared with CG, individuals in LG had a significant reduction of C-reactive protein (−0.4 mg/dl; 95% CI −0.7, −0.07; p=0.02), urinary albumin:creatinine ratio (−119.4 mg/g; 95% CI −195.0, −43.8; p=0.003), and improvement of 6-minute walking distance (25.1 m; 95% CI 21.8–28.3 m; p<0.001). 

There have been several previous studies indicating that GLP-1RAs have a potentially beneficial role in reducing PAD progression (SUSTAIN-6, EXSCEL and LEADER trials), but this study is the first to measure tissue perfusion which is important because it a physiological measurement of tissue oxygen levels. Of course, there are potential confounders of TcPO₂,  namely oedema and inflammation. There was no account of these in the study design. 

There was no record of activity, which may explain the fact that both groups had an increase in TcPO₂ levels by developing increased collateral supply. The study had a short follow-up period of only 6 months, a longer-term follow-up would be required to see if these results were sustained or changed. Additionally, the sample size was small, and being open labelled this study could be prone to high bias. It would also perhaps have benefitted from also using other comparative assessment methods e.g. waveform analysis, digital PPG, etc. 

However, this study suggests that perhaps liraglutide could be used to prevent the clinical progression of PAD in individuals with type 2 diabetes.