Section 1 – John

John is a 56-year-old man with a 5-year history of type 2 diabetes. He attends surgery reporting left calf pain brought on by walking or climbing stairs, which eases with rest. His symptoms have become more prominent over the last 3 months.

Recent results: HbA_1c 55 mmol/mol (7.2%); eGFR 62 mL/min/1.73 m²; total cholesterol 4.2 mmol/L, non-HDL cholesterol 3.1 mmol/L; urinary ACR <3 mg/mmol; blood pressure 138/71 mmHg; BMI 27.6 kg/m².

Current medication: Metformin 1 g twice daily; dapagliflozin 10 mg once daily; atorvastatin 20 mg once daily, ramipril 10 mg once daily.

Comorbidities: Background retinopathy.

What diagnoses might you consider following John’s opening statement?

Section 2

A differential diagnosis might include (Kirby, 2023):

• Peripheral arterial disease leading to intermittent claudication.
• Musculoskeletal pain – muscle sprain, arthritis, Baker’s cyst.
• Deep vein thrombosis.
• Nerve root compression.
• Diabetic peripheral neuropathy.

The location and triggering factors for pain have been established. What further questions would you ask John to clarify the diagnosis?

Section 3

Ask John about the nature of his pain. Establish the walking distance before pain onset and the time taken for the pain to resolve. Has there been any calf or knee swelling or redness?

John describes the pain as aching and burning in nature. The pain appears after walking around 100 metres on the flat and sooner if he is walking up a gradient. The pain reduces gradually over 2–3 minutes. There is no history of pain onset in the calf at rest and nor is the pain related to posture. The pain is not sharp or stabbing in nature and John denies any numbness or weakness of his legs. He has not noticed any calf or knee swelling or redness. He has not been feverish or acutely unwell.

What would you look for when examining John’s leg?

Section 4

Check for calf swelling, tenderness, erythema and warmth, which might indicate deep vein thrombosis or cellulitis. Examine the knee and popliteal fossa for tenderness, warmth and swelling.

Signs of peripheral arterial disease (PAD) include a shiny, hairless leg with foot pallor on elevation of the leg and redness on lowering. Is there any sign of foot ulceration or peripheral cyanosis or gangrene, which could indicate arterial insufficiency?

However, the most reliable sign of peripheral arterial disease is weak or absent peripheral pulses – check femoral, popliteal, dorsalis pedis and posterior tibial pulses in the left leg and compare these to the right leg (Soyoye et al, 2021).

A check for peripheral neuropathy is particularly relevant in the individual with diabetes; its presence alongside peripheral arterial disease confers a high risk of neuroischaemic foot ulcers.

John has no calf or knee swelling, tenderness or erythema. Power and sensation appear intact in the legs. John has weak popliteal and foot pulses in the left leg compared to the right. Abdominal examination does not reveal any evidence of an aortic aneurysm.

What is John’s clinical diagnosis given the history and examination findings?

Section 5

The history of exercise-induced calf pain relieved by rest, together with the peripheral pulse findings, strongly suggests the diagnosis is intermittent claudication.

Can you explain the pathology involved in intermittent claudication?

Section 6

The key pathology in intermittent claudication is atherosclerosis. Atherosclerotic plaques narrow and may occlude the peripheral arteries, limiting the blood supply to leg muscles. Intermittent claudication is the most common arterial manifestation of PAD (Criqui and Aboyans, 2015).

What risk factors for PAD need to be explored to both strengthen the diagnosis and to guide management?

Section 7

Type 2 diabetes is linked to accelerated atherosclerosis and carries a higher risk of PAD than in people without diabetes (ADA Professional Practice Committee, 2025). Other risk factors you should cover include the following (Morley et al, 2018; NICE, 2020):

• Smoking.
• Dyslipidaemia.
• Hypertension.
• The presence of other macrovascular complications of diabetes: ischaemic heart disease (angina, myocardial infarction), cerebrovascular disease (stroke, transient ischaemic attack).

Having multiple cardiovascular risk factors increases the risk of PAD.

John has a 25-year history of moderately heavy smoking, ending when he quit smoking following the diagnosis of type 2 diabetes. Blood pressure and lipid profile have subsequently been addressed.

Can you suggest a simple, non-invasive investigation for John to confirm the diagnosis of arterial insufficiency of his left leg?

Section 8

Measurement of ankle–brachial pressure index (ABPI) is a sensitive and specific test for PAD. It is the ratio of blood pressure at the ankle to that in the arm.

Interpretation of ABPI is as follows (Morley et al, 2018; CKS, 2025a):

• 9–1.4: Normal result.
• 5–0.9: Consistent with diagnosis of PAD.
• <0.5: Severe PAD. Refer urgently to vascular surgeon.
• >1.4: Falsely elevated, suggestive of arterial calcification and vessel incompressibility.

Note that a normal ABPI does not exclude the diagnosis of PAD.

John has an ABPI of 0.7 in his left leg compared to 1.0 in his right leg, confirming the presence of PAD in the left leg and clinching the diagnosis of intermittent claudication as the cause of his left calf pain (most likely due to atherosclerotic disease of his superficial femoral artery).

What baseline investigations should John have?

Section 9

It would be advisable that John has recent results available for:

• Urea and electrolytes and eGFR.
• HbA_1c.
• Lipid profile.
• Full blood count.
• Blood pressure.
• BMI
• An ECG should also be considered given the common pathophysiology of PAD and coronary artery disease (Morley et al, 2018).

What are the main complications associated with intermittent claudication?

Section 10

PAD may remain stable but can progress to limb-threatening ischaemia, with attendant risk of amputation. Ischaemia can lead to foot ulceration and, in severe cases, gangrene. Intermittent claudication is likely to impair quality of life and can lead to psychological complications including anxiety and depression (Morley et al, 2018).

The presence of atherosclerosis in leg arteries makes it likely that similar pathology exists in other vascular beds. People with intermittent claudication are at high risk of ischaemic heart disease, cerebrovascular events, vascular dementia and renovascular disease (CKS, 2025a).

Can you summarise the key aims in managing John’s intermittent claudication?

Section 11

There are two key aims (Soyoye et al, 2021):

• Managing cardiovascular risk factors.
• Managing symptoms of intermittent claudication.

Which risk factors need to be addressed to reduce the risk of cardiovascular events, such as myocardial infarction and stroke?

Section 12

The following cardiovascular risk factors should be covered (NICE, 2022; CKS, 2025a):

• Smoking cessation – encourage and refer to appropriate services.
• Lifestyle issues – diet, exercise, weight loss.
• Antiplatelet therapy.
• Managing dyslipidaemia – statin therapy.
• Blood pressure control.
• Glycaemic control.

Would you offer an antiplatelet agent for John? If so, which one?

Section 13

Antiplatelet agents reduce the risk of cardiovascular disease in people with PAD (CKS, 2025b). Clopidogrel is superior to aspirin in this respect (Katsanos et al, 2015), although if it is poorly tolerated or contraindicated then aspirin should be substituted.

Whilst dual antiplatelet therapy appears to be more effective than monotherapy, this benefit is counteracted by an increased risk of bleeding events.

John is prescribed clopidogrel 75 mg once daily.

What would be your blood pressure target for John?

Section 14

John’s blood pressure target should be <140/90 mmHg (NICE, 2023a).

ACE inhibitors and angiotensin receptor blockers are the first-line antihypertensives in people with diabetes. NICE NG136 advises a blood pressure of <130/80 mmHg if urinary ACR is >70 mg /mmol, and a target of <150/90 mmHg for those over 80 years of age (NICE, 2023a).

John’s blood pressure is appropriately controlled with ramipril.

Does John’s statin therapy need adjustment following the diagnosis of intermittent claudication?

Section 15

Statin therapy has been demonstrated to reduce cardiovascular events and all-cause mortality in people with PAD (Antoniou et al, 2014).

John’s non-HDL cholesterol is above target at 3.1 mmol/L, so intensification of treatment for dyslipidaemia is indicated. However, as intermittent claudication is a manifestation of established atherosclerotic cardiovascular disease, a dose of atorvastatin 80 mg once daily is recommended, in line with secondary prevention of cardiovascular events (NICE, 2023b).

John’s 20 mg dose of atorvastatin is increased to 40 mg once daily, with a view to further increasing to 80 mg once daily. A reasonable alternative would be to add ezetimibe 10 mg once daily to his atorvastatin 20 mg, particularly if statin side effects prove problematic.

How would you advise John in managing his symptoms of intermittent claudication?

Section 16

There is good evidence that supervised exercise programmes in people with intermittent claudication improve walking distance irrespective of whether ABPI improves (Lyu et al, 2016; Lane et al, 2017). Exercise also reduces the risk of cardiovascular events and improves quality of life.

NICE recommends offering a supervised exercise programme to all people with intermittent claudication: 2 hours per week for 3 months (CKS, 2025a).

If a supervised exercise programme is available, refer John to this. If not, encourage John to walk for 30 minutes at least three times a week to near-maximal pain (CKS, 2025a), but be mindful that any plan should be agreed and individualised so that it is both achievable and sustainable.

Is it likely that John’s intermittent claudication will respond to conservative measures?

Section 17

The majority of people who manage to achieve lifestyle change, undertake regular exercise and embrace relevant medical treatments will be able to stabilise their condition and avoid surgical intervention (Barraclough and Bradbury, 2018).

If John’s symptoms of intermittent claudication do not improve after 3 months, what further options could you offer him?

Section 18

You could offer referral to the vascular surgeons for further investigation and consideration of angioplasty, stent insertion or bypass surgery (CKS, 2025a).

Alternatively, if John prefers to avoid surgery, you could try a peripheral vasodilator. There is evidence indicating that naftidrofuryl oxalate is more effective than cilostazol and pentoxifylline in treating intermittent claudication, and achieves this with minimal serious adverse events (Stevens et al, 2012). NICE TA223 recommends a 3–6-month trial of naftidrofuryl oxalate 100–200 mg three times daily, discontinuing if no benefit accrues (NICE, 2011).

What foot care advice would be appropriate for John?

Section 19

John’s left foot is at increased risk of infection and ulceration due to his PAD. In people with diabetes, peripheral neuropathy is common and another major risk factor for foot ulceration.

Advise John to examine his feet daily, to keep his feet clean and avoid walking barefoot. Any new foot ulceration should be immediately reported and referral made to the specialist foot multidisciplinary team (NICE, 2019).

This ends John’s case study.

Section 20 – Mira

Mira is a 49-year-old lady of South Asian ethnicity with a 7-year history of type 2 diabetes. She presents at the GP surgery with right foot pain that has steadily increased over 2–3 months and is now present all the time. She does not report any trauma to her right foot.

What diagnoses might you consider here?

Section 21

Musculoskeletal causes including arthritis, gout and plantar fasciitis are possibilities, and infection needs to be considered. Critical limb ischaemia would also cause rest pain, due to inadequate arterial blood supply.

How would you elaborate the history?

Section 22

Detail the nature of the pain. Is there foot swelling, warmth or coldness, redness, numbness or weakness? Check past medical history for musculoskeletal conditions and atherosclerotic cardiovascular disease: coronary heart disease, cerebrovascular disease or intermittent claudication.

Mira’s pain is an unrelenting, severe ache, worsened by foot elevation. At night-time she has taken to sleeping in a chair to lessen the pain.

Mira is an ex-smoker. Two years ago she suffered from a myocardial infarction and is now maintained on antiplatelet, ACE inhibitor, beta-blocker and statin therapy. Blood pressure is well controlled with antihypertensive medication.

The history is consistent with chronic limb-threatening ischaemia – chronic rather than acute because it has developed over more than 2 weeks.

What examination features might support this diagnosis?

Section 23

Mira’s right foot is cold but not significantly swollen. The foot becomes white on elevation and red (hyperaemic) on lowering (the effect of gravity on arterial pressure). A femoral bruit is heard and pulses below the femoral are absent. A small, non-healing ulcer is seen on the medial aspect of the first metatarsal head. Peripheral neuropathy is confirmed, explaining why the ulcer itself is non-painful.

Note that ABPI is considered an unreliable investigation under these circumstances (Barraclough and Bradbury, 2018).

So what are the key features of chronic limb-threatening ischaemia?

Section 24

The key features of chronic limb-threatening ischaemia (CLTI), also known as critical limb ischaemia, are:

• Ischaemic rest pain, with or without:

• Tissue loss – ulceration or gangrene.

Arterial supply to the leg is inadequate and leg elevation is sufficient to aggravate the ischaemic pain. Intermittent claudication may precede CLTI; however, people might not walk sufficiently to bring on symptoms of this.

What are the immediate risks to Mira with a diagnosis of CLTI?

Section 25

Mira is at high risk of the following (Barraclough and Bradbury, 2018):

• Limb amputation.
• A cardiovascular event.
• Mortality.

What action would you now take, given Mira’s diagnosis of CLTI?

Section 26

An urgent appointment with the vascular surgeons should be arranged (CKS, 2025a). If clinically necessary, admit Mira to hospital.

Offer paracetamol and an opioid such as dihydrocodeine for analgesia. If pain relief is inadequate, stronger opioids should be used. Review cardiovascular risk factors to ensure they are optimally treated; as with intermittent claudication, individuals with CLTI need these to be managed in the context of secondary prevention (CKS, 2025a).

What intervention is likely for Mira?

Section 27

In the situation of CLTI, Mira is likely to need a procedure to revascularise her right leg. Options include:

• An endovascular procedure – angioplasty or stenting.
• A bypass procedure – using a leg vein.

Mira is referred to vascular surgery. This ends her case study.

Section 28 – Jack

Jack is a 67-year-old man with type 2 diabetes. He presents with sudden onset of a persistently painful, cold left leg (within the last 24 hours). The leg is pale and mottled, but not swollen, and leg pulses are absent. Radial pulse is 130 beats per minute and irregular.

What is the likely pathology here?

Section 29

This looks like acute limb ischaemia, in which the arterial supply to the leg has been suddenly interrupted (by definition, symptoms must have arisen in less than 2 weeks). The underlying cause could be thrombosis (typically at the site of a ruptured atherosclerotic plaque), or an embolus lodging in the femoral artery (Barraclough and Bradbury, 2018).

It appears that Jack has atrial fibrillation, and this would be a likely source of an embolus.

What action should you take?

Section 30

Jack requires immediate hospital admission for assessment by the vascular team. Interventions for acute limb ischaemia are as follows: (CKS, 2025a):

• Endovascular treatment – thrombolytic therapy, percutaneous thrombus extraction.
• Surgical treatment – thromboembolectomy, endarterectomy, bypass surgery, amputation (if unsalvageable).

John is admitted to hospital. This ends the series of case studies.