Peripheral arterial occlusive disease (PAOD) is one of the most common ischemic vascular diseases besides coronary heart disease (CHD). A new study shows that proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9 inhibitors) significantly reduce the risk of PAOD. The effect could be mediated by the reduction of lipoprotein(a).
More than 200 million people worldwide suffer from PAOD. Affected patients are severely restricted in their quality of life. Even the covering of short distances can bring unbearable pain. Long-term nicotine consumption, diabetes mellitus, and high blood pressure are the biggest risk factors for the development of PAOD. Furthermore, increased lipid levels seem to play a role.
In addition to high low-density lipoprotein cholesterol (LDL-C), previous studies have associated high lipoprotein(a) levels with an increased risk of PAOD. Lipoprotein(a) is considered the "little brother" of LDL. It is structured like an LDL particle, but there is an additional protein, apoprotein(a), on the surface of the LDL particle, which hangs like a "molecular tail".
Lipoprotein(a) has thrombogenic, atherogenic, and pro-inflammatory properties and is an important risk factor for cardiovascular disease. Unlike LDL-C, the level of lipoprotein(a) in the blood cannot be changed by a change in lifestyle. Rather, the lipoprotein(a) concentration is genetically determined.
Although the statins used as a standard in PAOD lower the LDL-C level, they have no effect on the concentration of lipoprotein(a) in the blood. Therefore, new drugs are needed that can specifically lower the lipoprotein(a) level. PCSK9 inhibitors, a new class of lipid-lowering drugs, have been on the market for around four years. In addition to a marked reduction in LDL-C, the antibodies also lead to an approximately 20-25% decrease in lipoprotein(a) in the blood. The question arises whether they can thereby also significantly reduce the risk of developing PAOD events.
A team led by Prof. Gregory Schwartz (University of Colorado, USA) therefore conducted a post hoc analysis of the double-blind randomized ODYSSEY study, which tested the efficacy of the PCSK9 inhibitor alirocumab in about 19,000 test subjects with the acute coronary syndrome. All subjects in this study received maximum statin therapy and had suffered from acute coronary syndrome.
The ODYSSEY study was designed so that one-half of the patients received an injection of alirocumab 75mg or 150mg every two weeks, while the other half received a placebo injection. The average age of the study participants was 59 years and about 75% of them were male. In both groups, about 4% of the participants were suffering from PAOD at baseline. The average duration of the study was 2.8 years. During this time, the research team recorded the number of all newly occurring PAOD events, which were defined as circulatory disorders of the legs, peripheral revascularization, and amputation. At the same time, the LDL-C and lipoprotein(a) levels in the blood were measured. Prior to the start of therapy, the mean lipoprotein(a) level was 21 mg/dl while the LDL-C level averaged 75 mg/dl.
During the observation period of the ODYSSEY study, 246 subjects (1.3%) suffered a PAOD event. In the first step, the researchers investigated whether the risk of suffering a PAOD event correlated with baseline LDL-C or lipoprotein(a) levels. As already known from preliminary studies, lipoprotein(a) in particular seemed to be a decisive risk factor. Thus, an elevated lipoprotein(a) above 60 mg/dl was associated with an approximately twice as high risk for PAOD events. In contrast, high LDL-C levels did not significantly increase the risk of PAOD (P = 0.06).
In a second step, the researchers investigated whether treatment with alirocumab reduced the risk of PAOD events. As described in previous studies, the bi-weekly administration of alirocumab reduced LDL-C by 71% and lipoprotein(a) by 24%. Participants with higher baseline lipoprotein(a) showed a greater reduction in lipoprotein(a). Alirocumab therapy reduced the relative risk for PAOD events by 31% compared to the placebo group. In subjects with previously known PAOD, the relative risk reduction was as high as 41%, which corresponds to an absolute risk reduction of 8.6% to suffer a PAOD event within 3 years. Interestingly, the risk reduction was greatest in those participants in whom lipoprotein(a) was most strongly reduced by PCSK9 inhibitor therapy. A 1 mg/dl lower lipoprotein(a) was associated with a 0.9% risk reduction.
The study data show that regular administration of alirocumab leads to a significant reduction of PAOD events, which is particularly beneficial in subjects with already known PAOD. Furthermore, the results suggest that lipoprotein(a) could play a causal role in the development of PAOD. Thus, those study participants showed the strongest risk reduction in which the lipoprotein(a) reduction by alirocumab was also strongest. Currently, these findings are not yet reflected in the guidelines of the European Society of Cardiology. If the results are confirmed in further studies, an increased risk of PAOD could possibly represent a separate indication for treatment with a PCSK9 inhibitor. This is because these are currently the only drugs that can effectively lower the lipoprotein(a) level in the blood.