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. 2024 Jan 13;76(Suppl 1):S86–S89. doi: 10.1016/j.ihj.2024.01.010

Dyslipidemia and peripheral arterial disease

Ajay Yadav a,∗, Vivek Sawant a, Varinder Singh Bedi a, Kanupriya Yadav b
PMCID: PMC11019313  PMID: 38224837

Abstract

Peripheral arterial disease (PAD) affects 12 % of adult population and is increasing globally and in India. Peripheral arterial disease when associated with atherosclerosis in two or more other arterial beds such as coronary artery disease (CAD), mesenteric/renal artery and cerebrovascular disease (CVD), is known as polyvascular disease. The Reduction of Atherothrombosis for Continued Health (REACH) registry reported that 1 out of 6 patients had multi-vascular bed involvement. Progression of PAD to critical limb ischaemia (CLI) is seen in 1 % of affected patients per year, but patients who progress to CLI may have a 10- to 15-fold increased risk of cardiovascular death.

The 2019 ECS/EAS guidelines for the management of dyslipidaemias have suggested that for primary or secondary prevention in very high risk, patients should follow a therapeutic regimen that achieves >50 % LDL-C reduction from baseline and an LDL-C goal of <55 mg/dl. High Intensity Statin is mainstay of treatment but optimal management is inadequate. Statin treatment reduces all-cause mortality by 39 %, CV death by 41 %, CV outcomes by 34 %, ischaemic stroke by 28 %, acute limb ischaemia by 30 % and amputations by 35 %. Ezetimibe when added to statins in IMPROVE-IT trial, showed significant reduction of MACE. PCSK9 inhibitor (FOURIER TRIAL) showed reduction in primary end point in PAD vs Non PAD patients (3.5 % vs 1.6 %).

There is a critical need for an Indian multi-disciplinary task force for research on the direct impact of lipid-lowering agents on limb salvage rates and major limb-related events in PAD patients.

Keywords: Dyslipidaemia, Peripheral arterial disease, Ezetimibe, Polyvascular disease, LDL-C goal of <55 mg/dl

1. Introduction

Peripheral arterial disease (PAD), characterised by occlusion or narrowing of the arteries supplying the lower extremities, has recently been estimated to affect approximately 240 million people worldwide, a large section (about 70 %) of whom reside in low- or middle-income countries.1 Peripheral arterial disease reportedly affects up to 12 % of the adult population in Western countries, and the incidence increases with age to as high as 29 % for those aged >70 years.2 Peripheral arterial disease prevalence data for India is sparse and one study from Kerala reported a rate of nearly 27 %.3

Peripheral arterial disease is a manifestation of atherosclerosis and is associated with an elevated risk of myocardial infarction and cardiovascular deaths. Peripheral arterial disease when associated with atherosclerosis in two or more other arterial beds such as coronary artery disease (CAD), mesenteric/renal artery and cerebrovascular disease (CVD), is known as polyvascular disease.4 The Reduction of Atherothrombosis for Continued Health (REACH) registry reported that 1 out of 6 patients had multi-vascular bed involvement. Subsequent studies have largely verified this prevalence of PAD in the population of patients with stable CAD.5, 6, 7 The REACH study demonstrated that major adverse cardiac event rates are significantly higher (nearly three-fold cumulative increase) among patients with PAD compared with those with single vascular bed disease or those with only risk factors for atherosclerotic disease. Recent analyses of randomised trials geared towards secondary prevention in patients with CAD have shown up to 50 % of major adverse cardiac events (MACE) in patients with PAD.8,9

Progression of PAD to critical limb ischaemia (CLI) is seen in 1 % of affected patients per year, but patients who progress to CLI may have a 10- to 15-fold increased risk of cardiovascular death.10

1.1. Dyslipidaemia

Dyslipidaemia (especially high LDL cholesterol) predicts the risk of cardiovascular events, and PAD patients are more likely to have higher rates of hyperlipidaemia and other risk factors.

Treatment of dyslipidaemia indirectly reduces cardiovascular mortality and morbidity in patients with PAD and should include lipid-lowering therapies. The 2019 ECS/EAS guidelines for the management of dyslipidaemias have suggested that for primary or secondary prevention in very high risk, patients should follow a therapeutic regimen that achieves >50 % LDL-C reduction from baseline and an LDL-C goal of <55 mg/dl.11

However, despite these recommendations as well as numerous studies showing the benefit of lipid-lowering treatment in PAD patients, optimal medical management remains inadequate.8,12,13 The ALLIANCE study noted less than half of patients presenting with PAD with ACS received the guideline-recommended medications.14 Zhang et al reported that asymptomatic patients with PAD as detected by ankle-brachial index (ABI) and transcranial doppler screening had higher rates of MACE at 4 years.13 Screening population with PAD for dyslipidaemia, which is a modifiable risk factor, can have a significant impact.

1.2. Management of dyslipidaemia

Diet is the first important and mandatory step for lowering serum cholesterol, along with medical therapy to achieve recommended LDL-C goals. A systematic review of 18 trials including 10,000 patients, with cholesterol levels ranging from normal to elevated, reported that lipid-lowering therapy in people affected by lower limb atherosclerosis was associated with a 20 % reduction in total CV events, together with a non-significant 14 % reduction in all-cause mortality.15

1.3. Role of statins

A meta-analysis including 18,686 patients with diabetes mellitus (DM) demonstrated that a statin-induced reduction of LDL-C by 1.0 mmol/l (40 mg/dl) was associated with a 9 % reduction in all-cause mortality and a 21 % reduction in the incidence of major CV events. In a meta-analysis of RCTs enrolling >90,000 patients on statin therapy, which considered mainly the extent of LDL-C reduction, showed a 21 % reduction in the incidence of all strokes in different populations.16In the Heart Protection Study, the need for non-coronary revascularisation was reduced by 16 % with statin therapy. Further, statin treatment has been reported to reduce all-cause mortality by 39 %, CV death by 41 %, CV outcomes by 34 % and ischaemic stroke by 28 %, but also reduced acute limb ischaemia by 30 % and amputations by 35 %.16

In non-cardiac vascular procedures, perioperative statin therapy significantly reduced the incidence of fatal and non-fatal cardiac events, congestive heart failure, stroke, vascular complications, length of stay, and the overall mortality rate.17, 18, 19 In contrast, perioperative discontinuation of statin therapy was associated with increased cardiac events.20

1.4. Impact on limb salvage

Patients who were receiving statin therapy at the time of endovascular intervention for CLI had improved patency, limb salvage, and overall survival.21 Statin therapy is associated with improved patency after infra-inguinal bypass graft surgery and improved outcomes after endovascular aortic aneurysm repair, carotid artery stenting.22

The Scandinavian Simvastatin Survival Study revealed a 38 % reduction in new and worsening intermittent claudication in addition to the already proven cardiovascular benefits in patients with CAD.23,24 Statins also improved ABI, walking distance, and pain-free walking distance. The HPS, a trial of simvastatin, 40 mg/day, versus antioxidant vitamins or placebo in 20,536 participants at high risk for a CHD event24 showed a 20 % reduction in non-coronary revascularisation, including a decrease in the number of carotid endarterectomies. The results of HPS which was a landmark trial supports the treatment of all patients with PAD with a statin agent for lipid-lowering therapy.25

The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) wherein high-risk elderly population (5800 patients with a history of pre-existing vascular disease, or at increased risk) was studied were randomised to 40 mg/day of pravastatin or placebo showed that need for peripheral vascular intervention requirement was less in treatment group compared to placebo group (HR 0.78, p = 0.25).23

1.5. Role of ezetimibe

IMPROVE-IT trial26 reported that in patients with PAD, ezetimibe had largest absolute risk reduction on MACE, possibly due to the higher risk of this subgroup.8,9,27 Ezetimibe has been proved to lower LDL-C when added to statins, which was assessed in patients with PAD.28 Evolution of atherosclerotic plaques in the superficial femoral artery was studied by using magnetic resonance imaging in patients with PAD, treated with statin or statin plus ezetimibe.21 Statin initiation, with/without ezetimibe, proved to stop the progression of atherosclerosis. Adding ezetimibe to patients previously treated only with statin surprisingly led to a progression in peripheral atherosclerosis, despite the 22 % decrease in LDL-C. These results correlate with those of a different study which compared the effects of niacin added to statin to ezetimibe added to statin therapy. Hence, role of ezetimibe in reducing risk of CLI in patients with PAD is not clear.

1.6. Role of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor

In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial,29 patients with atherosclerotic disease on statin therapy were randomly assigned to a fixed dose of evolocumab or placebo. The PCSK9 inhibition led to a 47 % reduction in LDL-cholesterol despite on statin therapy. Evolocumab significantly reduced the MACE by 21 %, as well as the risk of MALE by 42 %.30 Thus the FOURIER was the first randomized trial to demonstrate that intensive LDL-C lowering was safe and effective in decreasing the risk of acute limb ischaemia.16 Similarly, in Alirucumab and cardiovascular outcome after acute coronary syndrome (ODYSSEY) trial wherein primary endpoint was composite death with a median follow up of 2.8 years. In this study, patients on high intensity statins were randomized to receive alirocumab or placebo with dose adjustment every 2 weeks. Results of ODYSSEY trial showed that primary event occurred in 9.5 % vs 11.1 % in alirocumab and placebo group respectively suggesting that risk of recurrent ischaemia is lower with aggressive statin therapy. A subgroup analysis of patients with history of PAD or VTE within ODYSSEY OUTCOMES on comparing with placebo demonstrated lower PAD related events in 2.5 % of patients.31 Larger population studies are required in order to assess their possible role in PAD.

2. Role of fibrates

Both the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)32 and ACCORD33 studies demonstrated that administration of fenofibrate on top of statins significantly reduced microvascular complications and carotid revascularisations. The fibrates, gemfibrozil and fenofibrate are peroxisome proliferator receptor-α agonists used for treating hypertriglyceridemia and to increase HDL-C.34 Fenofibrate reduced the risk of minor amputations without known large-vessel disease through non-lipid mechanisms.31

Triglyceride lowering with Pemafibrate to Reduce Cardiovascular Risk (PROMINENT trial) showed that among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels.

3. Role of icosapent ethyl

The Reduction of Cardiovascular Events with Icosapent Ethyl- Intervention Trial (REDUCE-IT), which enrolled more than 8000 patients for a time period of nearly 5 years showed that the patients receiving icosapent ethyl (2 gm BD with food) were 25 % less likely than placebo patients to experience cardiovascular death, nonfatal MI, stroke, coronary revascularization or unstable angina.35 Prescription omega-3 fatty acids (eicosapentanoic acid – EPA and/or docosahexaenoic acid- DHA) are indicated to treat severe hypertriglyceridemia (TG levels of 500 mg/dL or higher).36

4. Role of bempedoic acid

Bempedoic acid and cardiovascular outcomes in statin intolerant patients trial (CLEAR outcomes) published in 2023 showed that among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization).37

5. Role of inclisiran

Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol (ORION 10 & ORION 11 trials) showed that reductions in LDL cholesterol levels of approximately 50 % were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo.38

6. Conclusion

There is a critical need for Indian research data on the direct impact of lipid-lowering agents on limb salvage rates and major limb-related events in PAD patients. Adoption of specific risk assessment scores for PAD in dyslipidaemia that are tailored to the Indian population is urgent. A multidisciplinary task force is also required to develop guidelines for managing dyslipidaemia in Indians in order to reduce cardiovascular risk.

Anti-lipid agent Trials
Statins Heart Protection Study
Scandinavian Simvastatin Survival Study
PROSPER
Ezetimibe IMPROVE-IT
PCSK9 FOURIER
ODYSSEY
Fibrates FIELD
ACCORD
PROMINENT
Icosapent Ethyl REDUCE-IT
Bempedoic Acid CLEAR Outcomes
Inclisiran ORION 10 & ORION 11
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Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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