Weight Loss Drugs Show Promise for Secondary Prevention in PAD

New data on patients with diabetes and a history of peripheral vascular events suggest that glucagon-like peptide-1 (GLP-1) receptor agonists may have limb-protective benefits, including reducing the risk of amputation.

Those on a GLP-1 also had reduced risks of MACE, CV death, all-cause death, and progression to dialysis compared with patients who were on other oral glucose-lowering medications. Peripheral revascularization rates were not significantly different.

The study is one of the first to evaluate GLP-1 therapies from the perspective of secondary prevention for major adverse limb events in high-risk patients, say the authors. More than half of those studied had a prior revascularization and chronic limb-threatening ischemia, and about 25% had a prior amputation.

The authors, led by Fu-Chih Hsiao, MD (Chang Gung Memorial Hospital, Taoyuan, Taiwan), say the data support prioritizing GLP-1s in those with established CVD, including prior limb events.

“The observed benefits likely stem from synergistic systemic and direct vascular mechanisms,” the researchers write in their study published last week in JAMA Network Open. The antiatherogenic properties of GLP-1 agents together with promotion of angiogenesis and preservation of endothelial integrity “provide a coherent biological basis for the reduced cardiovascular and limb events observed in this high-risk population,” they suggest.

Commenting for TCTMD, Sahil Parikh, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), said while the STRIDE trial and others also support the idea that GLP-1 agents are associated with some CV and limb benefits, no proof of a putative mechanism has been shown.

“Without a mechanism there’s still a little bit of a doubt,” he said. The doubt is compounded by the expense of GLP-1s and concerns about adding to the already significant polypharmacy burden of high-risk peripheral vascular disease patients.

Even though this study was positive, further research is needed “because what we may learn is that there are even better ways to achieve these endpoints,” he added. “The phenomenology all seems to be pointing in the same direction, but I would love to see even more understanding of the mechanisms to know if we can further leverage them. It makes you feel more confident that when you write a script that you’re really helping your patients.”

Fewer Overall and Major Amputations

The analysis included 17,288 patients (mean age 70.7 years; 42% women) enrolled in the Taiwan National Health Insurance Research Database. GLP-1 agents were being taken by 1,583 patients and consisted of dulaglutide (Trulicity; Eli Lily; n = 981), liraglutide (Victoza; Novo Nordisk; n = 590), and semaglutide (Wegovy; Novo Nordisk; n = 12). The remainder of the patients were on one of five different dipeptidyl peptidase-4 (DPP-4) inhibitors. Compared with those on a DDP-4, users of GLP-1 medications had longer duration of diabetes (13.2 vs. 11.9 years).

Over a mean follow-up of 4 years, the rate of lower limb revascularization and nontraumatic major and minor amputation (primary composite outcome) was 42.4 events per 1,000 person-years in the GLP-1 group and 42.7 events per 1,000 person-years in the DPP-4 inhibitor group. The subdistribution hazard ratio, which adjusts for the competing risks of death, was 0.90 (95% CI 0.83-0.97).

The difference in the observed benefit in the primary outcome was driven by lower risk of overall and major amputation among the GLP-1 group, with 12 events per 1,000 person-years versus 13.2 in the DPP-4 inhibitor group (subdistribution HR 0.86; 95% CI 0.75-0.98). For major amputation, the incidence was 4.4 versus 7.2 events per 1,000 person-years, respectively (subdistribution HR 0.59; 95% CI 0.47-0.73)

Additionally, GLP-1 users had a lower incidence of MACE at 65.8 events per 1,000 person-years compared with 103.1 in the DPP-4 group (HR 0.62; 95% CI 0.58-0.65), with each component of the MACE endpoint significantly lower in the GLP-1 group. All-cause mortality and progression to dialysis were each reduced by nearly 40% in those on a GLP-1 versus DPP-4.

Hsiao and colleagues say the association between GLP-1 use and reduced risk of MACE, CV mortality, and all-cause mortality is consistent with trials such as LEADER, SUSTAIN-6, and REWIND. This study adds evidence suggesting that the CV outcome benefits may be greater in higher-risk patients. Furthermore, the delayed progression to dialysis aligns with what has been shown in the FLOW trial, in which diabetic patients with kidney disease had a 24% reduction in major kidney disease events on semaglutide compared with placebo in addition to less risk of MACE.

Parikh noted that the data that have emerged on GLP-1s are welcome given the lack of treatment innovation in peripheral vascular care for decades, but said the cost of being on all guideline-recommended drugs plus a pricy weight-loss medication may be a bridge too far in high-risk PAD.

“I think that’ll be the next thing: to show an economic value proposition,” he said. “That maybe will induce payers to really start thinking about prevention as opposed to treatment for these patients.”

For now, Hsiao and colleagues suggest that the data are hypothesis-generating, adding that one other concern about prescribing GLP-1 medications in this population could be the risk of weight loss compromising nutritional reserves necessary for healing.

“Thus, while GLP-1 RAs appear robust for preventing initial major amputations, their efficacy in patients with established major limb loss remains uncertain and warrants prospective investigation,” they conclude.