Section 1 – Prashant

Prashant, 47 years old, was diagnosed with type 2 diabetes three months ago and has had a QRISK3 assessment placing him at 18% risk of cardiovascular disease (CVD) over the next 10 years. After discussion, Prashant agrees to try atorvastatin 20 mg daily.

Prashant’s lipid profile significantly improved on atorvastatin and his liver function tests are undisturbed, but unfortunately he quickly developed symptoms of muscle pain and stiffness in his upper arms and thighs, symmetrically distributed and worse on exercise, after commencing atorvastatin.

How would you manage Prashant’s situation?

Section 2

It is worth considering whether Prashant might have any modifiable risk factors for statin-related myopathy and statin intolerance such as:

• Drug interactions (including herbal medicines).
• Excessive alcohol intake.
• Vitamin D deficiency.
• Excessive high-intensity exercise.

 
Also be aware of any inherent risk factors such as:

• Hypothyroidism.
• Impaired renal or hepatic function.
• Personal history of muscle disorders or high creatine kinase levels.
• Family history of statin intolerance.

 
Prashant’s symptoms and presentation bear the hallmarks of statin-induced myalgia. You should therefore consider stopping the statin treatment and checking his creatine kinase (CK) level (NHS England, 2023a). If symptoms and timing did not appear consistent with statin-related muscle toxicity, think about other possible diagnoses such as polymyalgia rheumatica and vitamin D deficiency (check erythrocyte sedimentation rate, C-reactive protein levels, vitamin D levels and bone profile).

The NHS statin intolerance pathway (NHS England, 2023a), based on NICE guidelines, suggests:

• If symptoms are mild, there is no clinical concern and CK levels are less than 4-times the upper limit of normal (ULN), statin treatment could reasonably be continued to see if symptoms resolve.
• If symptoms are intolerable, there is clinical concern or CK is in the range of 4–10-times the ULN (defining a myopathy), then stop statin therapy for 4–6 weeks.
  • If symptoms resolve and CK normalises on re-testing, consider restarting the statin (after at least 2 weeks symptom-free) at a lower dose to see if symptoms recur. Alternatively, consider switching to a different statin.

 
Prashant’s symptoms are causing him significant distress and thus his atorvastatin is stopped. His CK level comes back at around 3-times the ULN. Subsequently, Prashant’s symptoms resolve and he is re-challenged on a lower-intensity regimen (atorvastatin 10 mg) after 2 months. Unfortunately, his symptoms of myalgia quickly return.

What might you try next?

Section 3

You could consider switching to a different statin, such as rosuvastatin 5 mg once daily, and if this is well tolerated then future uptitration may be an option. It is worth trying a statin with different physical properties (for example, if a lipophilic statin such as simvastatin or atorvastatin has been used, consider a hydrophilic statin such as pravastatin or rosuvastatin). This latter approach may be particularly useful if neurocognitive symptoms are problematic (NHS England, 2023a).

If necessary, consider reduced-frequency statin therapy; for example, rosuvastatin 5 mg per day three times weekly (NHS England, 2023a). NICE suggests trying three different statins for people with diabetes before moving to an alternative treatment for dyslipidaemia (NICE, 2023a).

Despite further variations in statin type and dose, Prashant’s muscle pains continue to be problematic. He appears to be genuinely intolerant of statins.

If Prashant had returned CK levels >10-times the ULN, how would you have responded?

Section 4

A marked elevation of CK more than 10-times the ULN, although rare, is much more concerning. If the statin is still being taken, it should be stopped immediately. Where CK levels are particularly high (NICE advises when >50-times the ULN), rhabdomyolysis – muscle breakdown – is a real concern and urgent hospital admission should be arranged (NHS England, 2023a). Rhabdomyolysis is signalled by severe muscle pain and weakness, and darkening of the urine due to myoglobinuria. The accumulation of myoglobin – a muscle protein released into the circulation from muscle breakdown – causes acute deterioration in renal function.

In situations of lesser elevation of CK (10–50-times the ULN), check renal function (and possible deterioration secondary to rhabdomyolysis) and ascertain whether CK levels subsequently normalise with statin discontinuation. If they do not, specialist referral is indicated for further investigation (NHS England, 2023a).

Given his statin intolerance, what alternative treatment for dyslipidaemia could you offer Prashant?

Section 5

Ezetimibe 10 mg once daily can be offered to those with significant adverse side effects (or contraindications) preventing statin therapy (NICE, 2016a; NICE, 2023a). Beyond this, if targets are not met, consider referral to a specialist lipid clinic.

The mechanism of action of ezetimibe relies on inhibition of intestinal absorption of cholesterol by interference with the cholesterol transport protein, and thus it functions in a complementary fashion to statins. Early trials showed that ezetimibe monotherapy reduced LDL cholesterol concentrations by around 10–19% (Vavlukis and Vavlukis, 2018). However, in comparison with statins, there is much less evidence supporting ezetimibe for primary prevention of CVD.

Use of ezetimibe may lead to gastrointestinal side-effects but it is generally a well-tolerated treatment. When used in combination with statins, there may be an increased risk of myopathy and rhabdomyolysis.

In general, fibrates, nicotinic acid and bile acid sequestrants and omega-3 fatty acids are not recommended for the prevention of CVD (NICE, 2023b).

Section 6 – Maureen

Maureen has type 2 diabetes with a 10-year QRISK3 score of well over 10%. Her lipid profile remains above target despite treatment with atorvastatin 20 mg once daily. She is unable to tolerate higher-intensity statin treatment.

How would you manage Maureen’s dyslipidaemia given this situation?

Section 7

The first-line option in this situation, where the maximally tolerated statin dose has been reached and lipid profile is above target, would be ezetimibe (NICE, 2023a). Beyond this, if targets are not met, consider referral to a specialist lipid clinic.

When ezetimibe is added to statin therapy, up to an additional 24% reduction in LDL cholesterol levels can be achieved (Morrone et al, 2012). Note that this is significantly greater than that expected from doubling the statin dose.

Ezetimibe 10 mg once daily is added to Maureen’s atorvastatin 20 mg. The combination therapy is well tolerated and, after 3 months, her non-HDL cholesterol target is achieved.

Section 8

Subsequently, Maureen develops a productive cough, mild shortness of breath and a fever. Examination reveals inspiratory crackles in the right lung field. She is not tachypnoeic, however, and her oxygen saturation is 96%. She is diagnosed with bronchitis and it is decided to institute antibiotic therapy.

What would be your antibiotic choice and, specifically, what class of antibiotics would you aim to avoid given Maureen’s treatment with atorvastatin?

Section 9

Macrolide antibiotics are CYP3A4 inhibitors. The cytochrome P450 enzyme system is responsible for metabolising statins. Thus, co-administration of antibiotics such as clarithromycin and erythromycin with statins can lead to increased statin levels and myotoxicity. Myopathy risk is greatest with simvastatin, followed by atorvastatin, while rosuvastatin and pravastatin are less affected (Abu Mellal et al, 2019).

So to avoid this problem with Maureen, you should choose an alternative antibiotic to a macrolide, such as amoxicillin or doxycycline, or if these alternatives are contraindicated or poorly tolerated, temporarily withdraw the statin for the duration of the macrolide treatment.

Can statins increase the risk of diabetes?

Section 10

A meta-analysis in 2014 indicated that statin therapy was associated with a 9% increased risk of new-onset diabetes after 4 years of treatment (Sattar et al, 2010), and it has been estimated that use of statins leads to a slight deterioration of glycaemic control in people with pre-existing diabetes – around a 1.3 mmol/mol (0.12%) increase in HbA_1c (Erqou et al, 2014). However, it is generally accepted that the overall benefits of statins in preventing CVD clearly outweigh potential risks in those with or without pre-existing diabetes (NICE, 2023a).

Section 11 – Geoff

Geoff is 49 years old and was diagnosed with type 2 diabetes a year ago. He is admitted to hospital suffering from chest pain and is diagnosed as having an ST-elevated myocardial infarction. Prior to admission he had not been taking a statin.

What should Geoff be offered in terms of statin therapy for secondary prevention of CVD?

Section 12

Geoff should be offered atorvastatin 80 mg once daily. NICE, SIGN, JBS3 and other guidelines recommend this treatment for people with or without diabetes who have established CVD (myocardial infarction, angina, transient ischaemic attack, stroke, peripheral vascular disease) without formal risk assessment (i.e. without using QRISK), because they are a population at high risk of a further cardiovascular event (JBS3 Board, 2014; SIGN, 2017; NICE, 2023b). If people are already maintained on a lower dose of atorvastatin, this should be increased to 80 mg daily.

A lower dose of atorvastatin for secondary prevention is advised if there is concern about side effects, if drug interactions are anticipated or, indeed, if this is the preference of the individual (NICE, 2023b). In the case of chronic kidney disease, atorvastatin 20 mg daily is advised for secondary prevention of CVD, although if targets are not met, upward dose titration is suggested provided that eGFR is >30 mL/min/1.73 m².

Geoff’s repeat prescription is altered to atorvastatin 80 mg once daily, with arrangements made to re-check his lipid profile and liver function tests after 2 months. Lifestyle measures (covered in our previous interactive case study) are reinforced.

How would you assess the effectiveness of Geoff’s high-intensity statin treatment?

Section 13

It is probably easiest to use the JBS3 target of non-HDL cholesterol <2.5 mmol/L to assess the effectiveness of atorvastatin 80 mg (or of the maximum tolerated dose of statin). As with primary prevention of CVD, ezetimibe 10 mg once daily can be added if lipid targets are not met on the statin alone.

Beyond this, consider referral to a lipid specialist.

The effectiveness of ezetimibe in combination with statins was demonstrated in the IMPROVE-IT trial, in which the addition of ezetimibe to simvastatin in people with recent acute coronary syndrome significantly reduced the risk of cardiovascular events, in association with a further 22% reduction in LDL cholesterol, compared with statin therapy alone (Cannon et al, 2015).

How would you manage dyslipidaemia in a person with type 2 diabetes who has established CVD (i.e. for secondary prevention) and for whom statin therapy is contraindicated or not tolerated?

Section 14

As for primary prevention, ezetimibe 10 mg once daily would be the first-line choice. If lipid targets are not reached (and this is quite likely), the next option recommended by NICE (2023b) is combination treatment of ezetimibe with bempedoic acid 180 mg once daily. If this dual therapy does not achieve target lipid levels, referral to a lipid clinic is indicated.

Bempedoic acid is metabolised in the liver to produce a metabolite that inhibits an enzyme in the cholesterol synthesis pathway. Because of reduced cholesterol production, there is increased expression of LDL cholesterol receptors in the liver, which leads to greater clearance of plasma LDL cholesterol (Masana Marín and Plana Gil, 2021). Bempedoic acid reduces LDL cholesterol by around 15–25% (NHS England, 2023b).

When bempedoic acid was administered as a fixed-dose combination with ezetimibe to a population established on a maximally tolerated statin dose, LDL cholesterol was reduced by 38% versus placebo, compared to an 18% reduction with bempedoic acid alone and a 23% reduction with ezetimibe alone (Ballantyne et al, 2020). A randomised controlled trial of bempedoic acid versus placebo in statin-intolerant people at high cardiovascular risk showed that bempedoic acid was associated with a significantly lower risk of major cardiovascular events (Nissen et al, 2023).

In light of this evidence, NICE recommends bempedoic acid 180 mg once daily in combination with ezetimibe 10 mg once daily for both primary and secondary prevention of cardiovascular events where statins are contraindicated or not tolerated and ezetimibe alone does not adequately control non-HDL/LDL cholesterol levels (NICE, 2021a; NICE, 2023b).

If the combination of ezetimibe and bempedoic acid does not achieve desired non-HDL/LDL cholesterol targets, referral to a lipid clinic would be the next step.

Bempedoic acid is not associated with an increased risk of myalgia. There can be a small increase in uric acid concentration, however.

Are you aware of further treatments available from secondary care for dyslipidaemia?

Section 15

Inclisiran is an injectable therapy recommended by NICE for secondary prevention of CVD if fasting LDL cholesterol is >2.5 mmol/L despite maximum tolerated lipid-lowering therapy using statins and ezetimibe (NICE, 2021b). Inclisiran induces an LDL reduction of around 50% either when used as monotherapy or when added to statins or ezetimibe (NICE, 2023a; Ray et al, 2020). A cardiovascular outcomes trial is underway.

Inclisiran is a small interfering RNA-based agent that binds to PCSK9 mRNA and destroys it, thereby preventing hepatic synthesis of the PCSK9 protein; this in turn leads to reduced LDL cholesterol levels (Rogula et al, 2012). It is administered as a twice-yearly subcutaneous injection and, thus, is potentially deliverable from primary care – this will depend on local commissioning strategies; if necessary, referral to specialist care can be requested.

An option from secondary care might be a PCSK9 inhibitor – alirocumab or evolocumab. These agents have equivalent efficacy to statins, reducing LDL cholesterol by up to 60%, either as monotherapy or as add-on treatments to statins (Katzmann et al, 2020). There is evidence from randomised controlled trials that evolocumab and alirocumab significantly reduce the risk of cardiovascular events compared to placebo in people at high cardiovascular risk (Sabatine et al, 2017; Schwarz et al, 2018).

PCSK9 inhibitors are administered by subcutaneous injection every 2–4 weeks. They are generally well tolerated but side effects include flu-like symptoms and local injection site reactions and, as a relatively new therapy, long-term side-effects remain uncertain. Their high cost may also restrict use.

NICE recommends considering PCSK9 inhibitors for secondary prevention of CVD, and in cases of severe dyslipidaemia in patients at high cardiovascular risk (e.g. familial hyperlipidaemia), when the highest tolerated statin dose and ezetimibe have not achieved the necessary lowering of LDL/non-HDL cholesterol (NICE, 2016b; NICE, 2016c).

PCSK9 is a protein that binds to LDL cholesterol receptors and triggers their degradation. PCSK9 inhibitors are monoclonal antibodies directed against PCSK9, thereby facilitating increased levels of LDL cholesterol receptors in the liver and, thus, lower levels of plasma LDL (Katzmann et al, 2020).