Slowing of Peripheral Artery Disease: Another Liraglutide Benefit?

Liraglutide (Victoza), a type 2 diabetes drug, may help prevent peripheral artery disease (PAD) progression, the small, open-label STARDUST trial suggested.

Over 6 months, adults with type 2 diabetes on subcutaneous liraglutide had a significantly greater increase of transcutaneous oxygen pressure (TcPO2) compared with conventional treatment (14.2 mmHg vs 2.9 mmHg, estimated treatment difference 11.2 mmHg, 95% CI 8.0-14.5 mmHg), according to Maria Ida Maiorino, PhD, of the University of Campania Luigi Vanvitelli in Naples, Italy, and colleagues.

A total of 89% of liraglutide patients achieved the coprimary endpoint — a 10% increase of TcPO2 from baseline — versus only 46% of the control group (relative risk 1.91, 95% CI 1.26-2.90), the researchers reported in JAMA Network Open.

“According to these data, we could expect that the administration of GLP-1 RAs [receptor agonists] may represent a proper strategy in patients with PAD and diabetes, determining a reduction or a delay of the onset of lower-extremity complications,” they wrote. “This finding may be relevant in the prevention of PAD clinical progression because the diagnosis of PAD often occurs with the appearance of critical limb ischemia or gangrene, which usually result in lower-extremity amputation.”

PAD-related amputation in people with diabetes commonly leads to permanent disability and adds a significant economic burden to the healthcare system, they pointed out.

The researchers noted that the increase in TcPO2 “was consistent over time within the liraglutide group, with significant differences compared with the individuals randomized to the control group,” adding that this was the first trial of patients with type 2 diabetes and PAD to show that liraglutide increased peripheral perfusion.

“Liraglutide, as well as other GLP-1 RAs, may determine its effect on peripheral perfusion through both microvascular and macrovascular mechanisms,” they wrote. “Liraglutide is effective on glycometabolic outlook, which affects the cardiovascular risk profile.”

First established for type 2 diabetes, GLP-1 RAs have recently become popular for weight management. Liraglutide was initially approved by the FDA in 2010 at the 1.8-mg dose for type 2 diabetes. At the 3-mg dose, liraglutide (Saxenda) was approved for chronic weight management in 2014 for adults, which was extended to teens in 2020.

More recently, this class of agents has moved into the cardiovascular protection space, with the GLP-1 receptor agonist semaglutide (Wegovy) approved to reduce the risk of cardiovascular death, heart attack, and stroke in adults with cardiovascular disease and either obesity or overweight.

In the STARDUST study, Maiorino’s group noted several other significant mean changes from baseline after 6 months of treatment:

• HbA1c: -0.4% for the liraglutide group vs -0.02 for the control group
• Body weight: -2.3 kg (5.1 lb) vs -1.2 kg (2.6 lb)
• BMI: -1.1 vs -0.3
• Systolic blood pressure: -5.4 mmHg vs -5.3 mmHg
• C-reactive protein: -0.4 mg/dL vs -0.03 mg/dL
• Urine albumin to creatinine ratio: -90.5 mg/g vs 28.8 mg/g
• 6-minute walking test: 364.0 m vs 340.1 m

Compared with the control group, liraglutide-treated patients had significantly greater drops in C-reactive protein, interleukin 6, luteinizing hormone, urine albumin to creatinine ratio, and 6-minute walking distance.

The researchers said these results “suggest a potential beneficial effect of liraglutide in improving endothelial function in people with type 2 diabetes and PAD,” but also noted that the two groups didn’t differ much in glycometabolic status by the end of the trial.

The final analysis assessed 55 participants (27 randomized to liraglutide and 28 to the control group) who were enrolled between February 2021 and June 2022 in Italy. The average age at baseline was 67.5 and 78% were male.

Median HbA1c levels were 6.9% and average TcPO2 levels were 40.3 mmHg. All patients had to have TcPO2 of the foot between 49 to 30 mmHg at the screening visit, plus an HbA1c between 6.5% to 8% while on stable glucose-lowering medication doses. Patients were excluded if they had used a GLP-1 receptor agonist in the prior 3 months.

Patients in the liraglutide group were started on a 0.6-mg once-daily liraglutide subcutaneous injections at approximately the same time each day, titrated up on a weekly schedule by a 0.6-mg increase to a target dose of 1.8 mg or the maximum tolerated. Patients in the control group received conventional treatment of cardiovascular risk factors. Patients in both groups were given tailored therapeutic prescriptions to manage blood glucose levels and cardiovascular risk factors.

The small sample size and small number of women — though PAD epidemiology tends to be male-centric — were noted as limitations of the trial.

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