Medical treatment of chronic lower limb ischaemia

Smoking cessation

Smoking is associated with worsening atherosclerosis, increases the risk of cardiovascular death, and accelerates bypass graft failure. ^, For patients with PAD, smoking cessation has been shown to reduce death from coronary disease, and decrease lower extremity interventions and amputations. Advising and assisting patients to quit smoking is a beneficial intervention that healthcare professionals can deliver in the population with PAD. Supplementing counselling on smoking cessation with nicotine replacement and the antidepressant bupropion has been shown to be most effective in 12-month abstinence from smoking rates compared to each alone. This has led some clinical guidelines to recommend prescribing pharmacological interventions such as varenicline, bupropion and nicotine replacement to assist in smoking cessation.

Management of dyslipidaemia

Elevated total cholesterol concentrations, increased levels of low-density lipoprotein cholesterol (LDL-c), triglycerides and decreased high-density lipoprotein (HDL) levels are independent risk factors for the development of PAD. The term dyslipidaemia refers to abnormal concentrations in LDL, HDL and triglycerides, however, there are currently no data to suggest treating elevated triglyceride levels and low HDL cholesterol values leads to a reduction in morbidity and mortality in people with PAD. Therefore the treatment of dyslipidaemia remains focused on lowering LDL levels, primarily through the use of HMG-CoA reductase inhibitors (statins).

The ideal target values for LDL cholesterol levels in at-risk patients remains unknown. An inverse correlation has been shown between the level of LDL cholesterol and the ABPI in patients with newly diagnosed PAD. In one large randomised control trial (RCT), lowering LDL reduced the risk of a cardiovascular event in patients with atherosclerosis, even in patients with ‘normal’ starting cholesterol values.

Indeed, the international guidelines for treatment of dyslipidaemias diverge on this point. In the United States, a fixed-dose strategy utilising moderate- to high-dose statins for all adults with a 10-year cardiovascular disease event risk of 7.5% or greater has been recommended instead of a goal-targeted therapy to a particular lipid target level. ^, The UK National Institute for Health and Care Excellence (NICE) has adopted a similar recommendation for statin therapy in at-risk populations without the goal of a particular lipid level target. The European Society of Cardiology guidelines recommend lowering LDL cholesterol levels to <100 mg/dL (<2.58 mmol/L) in high-risk patients and to <70 mg/dL (<1.81 mmol/L), or reduced by ≥50% in those at a very high risk including PAD patients.

Recently, high-intensity statin therapy versus low-intensity statin therapy has been shown to improve graft patency and reduce adverse limb outcomes including amputation. In addition to providing cardiovascular protection, there is some evidence that statins may alter vasomotor tone, stimulate angiogenesis and they have been shown to improve pain-free walking distance in patients with claudication. ^, It appears that the benefits of statins go beyond their lipid-lowering properties and are linked with their ability to decrease oxidative stress and vascular inflammation, as well as their protection against thrombosis through platelet influence.

High-dose statin therapy (e.g., atorvastatin 40–80 mg daily or rosuvastatin 20–40 mg daily) should be considered for all patients with symptomatic vascular disease who are <75 years old and not on haemodialysis. Moderate statin doses should be considered for all other patients with symptomatic PAD or with >7.4% 10-year risk of atherosclerotic vascular disease.

Non-statin agents for lowering low-density lipoprotein cholesterol levels

The most common adverse effect limiting the use of statin therapy is associated with muscle aching. This may be difficult to interpret in people with claudication. If muscle aches occur, the statin dose can be lowered to the maximum tolerated dose, and a second non-statin cholesterol-lowering agent can be added. Similarly, for very high-risk patients who do not achieve adequate reduction in LDL levels while on high-dose statin therapy, the addition of a second agent is reasonable. In either scenario, the addition of the selective cholesterol-absorption inhibitor ezetimibe is recommended. ^,

In addition, monoclonal antibodies against pro-protein convertase subtilisine Kesine 9 (PCSK9), which direct the degradation of LDL receptors in the liver, have recently gained traction in clinical practice. Reduction in PCSK9 activity by two monoclonal antibodies approved for use in the United States, alirocumab and evolocumab, available as injections once every 2 or 4 weeks, have demonstrated substantial reductions in LDL cholesterol levels, when administered as either monotherapy or in addition to statin therapy. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial demonstrated evolocumab also reduced major adverse cardiovascular events (MACE) including MI and stroke, as well as a reduction in the risk of acute limb ischemia and major amputation. The cost of these two agents currently limits their generalizability, however, recent cost-benefit analyses suggest they can be cost-effective in select high-risk patients with symptomatic PAD on maximum tolerated statin therapy, plus ezetimibe, who do not reach a target LDL.

Treatment of diabetes

Type 2 diabetes mellitus is an important risk factor for the development of asymptomatic and symptomatic PAD. The severity and duration of diabetes is related to the extent of PAD. Every 1% increase in haemoglobin A1c (HbA1C) level has been associated with a 28% increased relative risk for the development of PAD and has been shown to increase the risk of adverse outcomes among patients with PAD, including progression to CLTI, amputation and death. ^, Diabetes mellitus is thought to worsen atherosclerosis as a consequence of arterial wall degeneration and inflammation, in addition to increases in platelet aggregation, blood viscosity and fibrinogen levels.

Good glucose control, with a HbA1C level between 6.5–7.5% is recommended. ^, In elderly vascular patients, a range of 7–8%, may be used generally to avoid hypoglycaemic events. In addition, intensive glycaemic control has been shown to reduce the development of microvascular complications such as neuropathy.

Biguanides , specifically metformin monotherapy is generally recognised as the best initial oral hypoglycaemic agent for patients with an estimated glomerular filtration rate (eGFR) >30 mL/min. Furthermore, an observational study has shown that the use of metformin was associated with a lower prevalence of below-the-knee arterial calcification. While metformin is associated with improved survival and decreased incidence of major adverse cardiac and limb events in patients with PAD compared with insulin or other hypoglycaemics, it does not appear to improve limb salvage or patency rates after open or endovascular interventions. People with diabetes and abnormal renal function treated with metformin may be at higher risk for contrast-induced nephropathy and lactic acidosis and may benefit from withholding metformin for 24 to 48 hours following delivery of iodinated contrast.

When additional therapy is needed, other classes of oral hypoglycaemic agents can be added without significant differences in all-cause mortality, however, each comes with important considerations:

Glucagon-like peptide 1 (GLP-1) receptor agonists such as dulaglutide, liraglutide and semaglutide have recently been shown to decrease MACE, reduce hospitalisations for heart failure and slow the progression of chronic kidney disease (CKD) in high-risk patients with type 2 diabetes, whether or not they have a prior history of established cardiovascular disease. Furthermore, in the LEADER study, liraglutide was associated with reduced amputation rates. The American Diabetes Association now recommends GLP-1 receptor agonists can also be considered in patients with type 2 diabetes with or without established cardiovascular disease if they have other indicators of high risk, specifically, patients aged 55 years or older with coronary, carotid or lower extremity artery stenosis >50%, left ventricular hypertrophy, an eGFR <60 mL min−1[1.73 m]−2 or albuminuria to reduce risk of MACE, regardless of baseline or target HbA1c level. It should be noted, however, semaglutide should be avoided in patients with diabetic retinopathy, as rates of retinopathy complications were significantly higher even though rates of new or worsening nephropathy were decreased overall.

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a newer class of agents that have been associated with beneficial effects in patients with heart failure and CKD on cardiovascular complications, renal disease and mortality in type 2 diabetics. However, one large trial (>10 000 subjects) demonstrated an almost twofold increased risk of lower limb amputations associated with the use of the SGLT-2 inhibitor, canaglifozin, prompting a warning from the US Food and Drug Administration. We advise against the use of canaglifozin in diabetic patients with foot ulcers, advanced PAD and/or CLTI.

Sulphonylureas including glyburide may elevate the risk of cardiovascular disease among patients with diabetes. Caution is advised in the use of these agents as they have a high risk of hypoglycaemia, weight gain, and may have negative effects in patients with coronary heart disease.

Thiazolidinediones (PPAR γ agonists) such as pioglitazone, cardiovascular survival was improved in patients with diabetes and pre-diabetes in the PROactive and IRIS trials. These studies have also suggested pioglitazone therapy is associated with higher risks of weight gain and fracture. Early analyses within the PROactive trial suggested pioglitazone decreased amputation rates, however, after 10 years, no differences remained in amputation rates compared with the control group.

Dipeptidyl peptidase 4 (DPP4) inhibitors such as saxagliptin and alogliptin may reduce the risks of MI and stroke, however, significantly more hospitalisations for heart failure was observed in patients receiving saxagliptin, so this substance should be used with caution in patients with known heart failure. The impact of DPP4 inhibitors on patients with PAD and CLTI is not yet well defined. ^,

Insulin-providing therapies such as basal insulin, sulfonylureas, repaglinide or nateglinide, are recommended for use in patients with type 2 diabetes only after the initiation of an optimised oral or GLP-1 based therapy. Post-hoc analyses of the BARI-2D trial displayed lower incidence of lower extremity arterial disease among patients assigned to insulin-sensitising therapy (metformin or thiazolidinedione) compared with those assigned to insulin-providing therapy. For basal insulin therapy, no endpoint studies are available for patients with type 2 diabetes and PAD.