Section 1: Meet Dipa

Dipa, a 54-year-old woman of Indian ethnicity, has recently had a diagnosis of type 2 diabetes. She has received lifestyle advice and been commenced on metformin.

Cardiovascular risk assessment is considered an essential component in assessing the newly diagnosed individual with diabetes. Why is this?

Section 2

It is well established that type 2 diabetes is associated with an increased risk of acute coronary syndrome, ischaemic stroke and heart failure (Kirby, 2014). Cardiovascular disease (CVD) is the major cause of premature mortality in people with type 2 diabetes; this term covers atherosclerotic disease, including angina and myocardial infarction (MI), stroke and transient ischaemic attack, and peripheral vascular disease. A telling observation is that people with diabetes have the same risk of MI as those without diabetes who have already suffered from a previous MI (Haffner et al, 1998).

What factors need to be considered when assessing cardiovascular risk?

Section 3

The following are all factors associated with cardiovascular risk (Hippisley-Cox et al, 2017) and are used in the QRISK3 algorithm recommended by NICE (2022).

• Age
• Sex
• Ethnicity*
• BMI
• Family history of CVD (notably a cardiovascular event before the age of 60 years)
• Smoking status
• Alcohol consumption
• Diabetes status
• Hypertension
• Dyslipidaemia
• Chronic kidney disease
• Atrial fibrillation
• Inflammatory conditions (e.g. rheumatoid arthritis)
• Severe mental health problems (e.g. schizophrenia)

 
*Compared to Europeans, people of South Asian ethnicity are at increased risk of MI and stroke, but reduced risk of peripheral vascular disease (Chaturvedi, 2003). People of African–Caribbean ethnicity are at increased risk of stroke and reduced risk of MI and peripheral vascular disease.
 

 
Dipa is known to have hypertension and her blood pressure is currently at 142/83 mmHg on amlodipine 5 mg once daily. Her HbA_1c is 65 mmol/mol, total cholesterol 5.7 mmol/L, triglycerides 1.8 mmol/L, HDL cholesterol 0.9 mmol/L, non-HDL cholesterol 4.8 mmol/L. Her renal, liver and thyroid function tests are normal and her urinary ACR is <3 mg/mmol. She neither smokes nor drinks alcohol. Her BMI is 28.3 kg/m². Enquiry into Dipa’s family history reveals that her father also has type 2 diabetes and suffered an MI at around 50 years of age.

So what are Dipa’s significant cardiovascular risk factors?

Section 4

Certainly, Dipa has significant cardiovascular risk factors. In addition to her type 2 diabetes, she is over 50, has excess weight and is of Asian ethnicity, with a family history of early CVD. She suffers from hypertension and an adverse lipid profile.

What component of dyslipidaemia principally contributes to increased cardiovascular risk?

Section 5

There is a positive relationship between low-density-lipoprotein (LDL) cholesterol concentration and CVD, and there is strong evidence that addressing this risk factor improves cardiovascular outcomes in people with diabetes (Naeem et al, 2018). In addition, non-high-density-lipoprotein (non-HDL) cholesterol – the difference between total and high-density-lipoprotein (HDL) cholesterol – turns out to be a better predictor of atherosclerotic risk than LDL cholesterol alone, and has become the preferred lipid parameter on which to make therapeutic decisions (Boekholt et al, 2012; NICE, 2023a).

In type 2 diabetes, the profile of dyslipidaemia typically comprises high levels of total cholesterol and triglycerides (also an adverse risk factor for CVD independent of total cholesterol), low levels of HDL cholesterol – a protective lipid fraction – and increased levels of small atherogenic LDL cholesterol particles (Boekholt et al, 2012; NICE, 2023a).

Before considering medication for dyslipidaemia, what lifestyle advice should we offer to help Dipa lower her cardiovascular risk?

Section 6

The NICE NG28 and CG181 guidelines emphasise the following lifestyle modifications, where appropriate (NICE, 2022; NICE, 2023b):

● Dietary adjustment to a cardioprotective diet:

• • Reduced fat intake (<30% of energy intake).
  • Replace saturated fats with monounsaturated fats (e.g. olive oil, rapeseed oil) or polyunsaturated fats.
  • Reduce sugar intake.
  • Choose high-fibre, low-glycaemic-index carbohydrates.
  • Reduce salt intake.
  • Increase intake of fruit, vegetables, whole grains, pulses and oily fish.

● Increased physical activity.
● Weight loss.
● Smoking cessation.
● Avoid excess alcohol consumption.
 
Lifestyle change should be agreed on an individual basis and be both achievable and sustainable.

Control of hypertension and hyperglycaemia should be tackled in accordance with advice from guidelines and in parallel with lipid-modification strategies (NICE, 2019; NICE 2022).

What group of medications would you choose first-line for managing dyslipidaemia in diabetes and why? When would you seek alternative therapies?

Section 7

Statins have the best evidence base for improving cardiovascular outcomes in people with diabetes (whether secondary or primary prevention), and so they are the first-line pharmacological therapy for dyslipidaemia.

The two situations where additional/alternative treatments to a statin may be sought are:

• When the highest tolerated dose of statin does not provide sufficient reduction in non-HDL (or LDL) cholesterol.
• When statins are not tolerated or are contraindicated.

 
Statins should, however, only be commenced after discussion of lifestyle interventions (see Section 6 previously), formal cardiovascular risk assessment (see Section 8), review of the risks and benefits of treatment in the individual concerned (see Sections 11 and 14) and, ultimately, patient preference.

Alternative treatments to statins will be dealt with in a subsequent case study on dyslipidaemia; however, for a brief guide, see Davies (2023).

How would you formally assess Dipa’s cardiovascular risk?

Section 8

NICE CG181 now recommends QRISK3 as a cardiovascular risk assessment tool to be used in people without existing CVD, including in people with type 2 diabetes, from the ages of 25 to 85 years, to calculate their 10-year risk of CVD (NICE, 2023b). If IT systems have not yet engaged QRISK3 then QRISK2 should be used, but bear in mind that this does not incorporate factors such as systemic lupus erythematosus, migraine, erectile dysfunction, severe mental health, or the use of antipsychotic or corticosteroid therapy, and it so may underestimate risk in these situations.

The Joint British Societies for the Prevention of CVD have published an alternative online calculator to assess cardiovascular risk (available at: http://www.jbs3risk.com).

At what level of cardiovascular risk does NICE recommend considering statin therapy?

Section 9

The threshold recommended by NICE CG181 for considering initiating a statin for primary prevention of CVD is a 10% or greater risk of a cardiovascular event over 10 years. If QRISK is <10% over the next 10 years then offer lifestyle advice and ensure regular review of CVD risk (NICE, 2023b).
 

 
Dipa’s QRISK3 score is 21.3%; thus, in line with NICE guidance, use of a statin should be considered to reduce cardiovascular risk.

Under what circumstances should QRISK not be used to assess cardiovascular risk?

Section 10

For those people with type 2 diabetes and established CVD (angina, MI, transient ischaemic attack, stroke, or peripheral vascular disease), statin therapy is recommended without formal risk assessment because this population is at increased risk of recurrence of CVD. Secondary prevention of CVD will be dealt with in a future interactive case study.

Because of the amplified risk of CVD in people with chronic kidney disease, NICE advises against using QRISK in people with an eGFR <60 mL/min/1.73 m² and/or albuminuria; rather, this group should routinely be offered atorvastatin 20 mg daily for cardiovascular protection (NICE, 2023b). Lower doses of statins may be necessary for certain stages of chronic kidney disease (see details in the BNF).

NICE also advises that QRISK should not be used in people with type 1 diabetes. In this group, atorvastatin 20 mg daily is recommended for primary prevention if the person is more than 40 years old or has had diabetes for more than 10 years.

Finally, QRISK is not appropriate to use in people with inherited disorders of lipid metabolism (NICE, 2023b). Familial hypercholesterolaemia should be suspected if the total cholesterol concentration exceeds 7.5 mmol/L and there is a family history of premature coronary heart disease (or, in the absence of the latter, if total cholesterol is >9 mmol/L or non-HDL cholesterol is >7.5 mmol/L, or if triglyceride levels are >20 mmol/L). Where lipid profile is grossly abnormal referral to a specialist lipid clinic is appropriate.

The mechanism of action of statins and some of the key evidence supporting use of statins for primary prevention of CVD in type 2 diabetes are included in Sections 19 and 20.

What useful baseline blood tests are useful for Dipa before commencing statin therapy?

Section 11

In addition to a non-fasting lipid profile and HbA_1c test, it is important to have recent renal and liver function tests (looking for causes of secondary hyperlipidaemia). A fasting sample would be required to assess triglycerides. Further causes of hyperlipidaemia would be hypothyroidism (consider checking thyroid function tests if clinically indicated) and nephrotic syndrome (dipstick urine for protein) (NICE, 2023a).

Establish whether Dipa suffers from persistent generalised muscle pain or if there is a personal or family history of muscular disease; if this is the case, check creatine kinase (CK) levels before statin initiation (NICE, 2023). Renal and hepatic impairment and hypothyroidism are all risk factors for development of muscle problems, and in these situations a baseline CK test is prudent.

NICE CG181 advises that patients with a CK more than five-times the upper limit of normal (ULN) should be investigated and statin treatment withheld (NICE, 2023b). With lower elevations of CK, a statin may be started but at reduced dose. The NHS statin intolerance pathway suggests a CK threshold of more than four-times the ULN for avoiding statin therapy (NHS Accelerated Access Collaborative, 2022).

Who should avoid statin therapy?

Section 12

Avoid statins in the following cases (NICE, 2023a):

• Pregnancy (or planning pregnancy) and breastfeeding.
• Women of child-bearing age without adequate contraception.
• Active liver disease; serum transaminases more than three-times the ULN.
• Creatine kinase more than five-times the ULN.

 
Use statins with caution in:

• Frail elderly with limited life expectancy.
• Predisposing factors for rhabdomyolysis: renal impairment, hypothyroidism, personal or family history of unexplained muscle pain.
• History of liver disease or excessive alcohol consumption.
• Taking medications that may increase plasma levels of statin (e.g. macrolide antibiotics, azole antifungals, HIV protease inhibitors).

 
In Dipa’s case, renal, liver and thyroid function tests and a urinary ACR have all been within the normal range.

What would be your choice of statin for Dipa, and why?

Section 13

NICE CG181 and SIGN 149 recommend atorvastatin 20 mg once daily for people with type 2 diabetes who do not have established CVD (i.e. for primary prevention) (SIGN, 2017; NICE, 2023b).

Atorvastatin is favoured because it has a strong evidence base for primary prevention of CVD (both for those with and without type 2 diabetes). It is a potent statin and, at the dose of 20 mg, would be classified as a high-intensity statin expected to reduce LDL cholesterol by 40%.

Atorvastatin is generally well tolerated and it has a relatively low risk of adverse reactions. Its long half-life means it does not have to be taken at night – in contrast to simvastatin, pravastatin and fluvastatin, which have a half-lives and should ideally be taken in the evening to maximally impact on cholesterol synthesis, the bulk of which happens during the night (NICE, 2023a).

What side effects should you warn Dipa about before commencing atorvastatin?

Section 14

You should advise Dipa to seek help if she develops muscle pain, tenderness or weakness. Note that the muscle ache associated with statins typically is symmetrically distributed, primarily affecting the large proximal muscles, in contrast to the localised pain frequently associated with a muscle sprain. Typically, symptoms are aggravated by exercise. Myalgia is more likely to arise within the first 3 months of statin therapy and particularly if a high-intensity statin regimen is employed.

Warn Dipa that gastrointestinal disturbance and headaches may occur with statins, but rarely does this lead to discontinuation. In general, the side effects of statins are mild and reversible.

Dipa should be aware that there may be situations where the statin would have to be temporarily stopped; for example, when using macrolide antibiotics such as clarithromycin (NICE, 2023a). She needs to be aware that over-the-counter treatments (such as St John’s wort) may interact with statins, and she should inform her GP or pharmacist before using any).
 

 
After discussion of benefits and risks of taking a statin, Dipa agrees to try atorvastatin 20 mg once daily.

How would you follow up Dipa’s statin therapy?

Section 15

Repeat Dipa’s lipid profile, along with liver function tests, within 3 months. Has the atorvastatin been effective in modifying lipid levels? Is it well tolerated? Review possible side effects from statin therapy (see Section 14 previously).

If serum transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) are raised to three-times the ULN, statin therapy should be discontinued and liver function tests subsequently repeated (NICE, 2023b). Given the cardiovascular benefits of statins in people with diabetes, re-challenge could reasonably be considered at some point in the future.

It should be noted that statin therapy is viewed as beneficial in fatty liver disease, a common accompanying condition in type 2 diabetes.

What lipid profile targets would you aim for in Dipa’s case?

Section 16

NICE CG181 suggests aiming for a reduction of 40% or more in non-HDL cholesterol. If this has not been achieved then adherence to medication should be checked, and diet and lifestyle measures should re-emphasised. If necessary, the dose of atorvastatin can be increased – this can be repeated every 3 months up to a maximum of 80 mg atorvastatin. Each doubling of statin dose further reduces LDL cholesterol by (only) around 6% on average. If the maximum tolerated dose of atorvastatin does not achieve the target non-HDL cholesterol then further lipid-lowering agents, such as ezetimibe, can be considered (NICE, 2023b).

An alternative is the treat-to-target strategy, aiming for a non-HDL cholesterol target of <2.5 mmol/L (LDL <1.8 mmol/L), recommended by the Joint British Societies, which may be a simpler method of guiding statin dose (JBS3 Board, 2014).

Dipa tolerates atorvastatin 20 mg once daily without problems. She is taking the medication regularly and is doing her best with diet and lifestyle measures. After 3 months, her lipid profile is improved: total cholesterol is 4.1 mmol/L, HDL cholesterol 1.1 mmol/L and non-HDL cholesterol 3.0 mmol/L. Liver function tests are within normal limits.

Dipa’s lipid profile has improved but is not yet at target. What might you do next to further improve her lipid profile?

Section 17

In accordance with NICE guidance, Dipa’s dose of atorvastatin is increased to 40 mg once daily, and arrangements are made for a repeat non-fasting lipid profile and liver function tests to be performed in 3 months’ time.

The alternative option would be to add in ezetimibe, which offers a significantly greater reduction in LDL cholesterol than doubling the dose of statin (Vavlukis and Vavlukis, 2018). Further details on ezetimibe will follow in a future interactive case study.

At review, Dipa’s non-HDL cholesterol is close to target and she is advised to continue her atorvastatin 40 mg once daily, which she is tolerating well, and a future plan is made for an annual non-fasting lipid profile.

This ends the case study. The next three sections include useful supplemental information on statin efficacy, mechanisms of action and evidence of benefits.

Section 18: Efficacy of various statin regimens

Statins can be grouped into the following intensity categories based on LDL-cholesterol-lowering capacity (NICE, 2023a):

High-intensity statins (>40% reduction in LDL cholesterol):

• Atorvastatin 20 mg, 40 mg, 80 mg daily.
• Simvastatin 80 mg daily.*
• Rosuvastatin 10 mg, 20 mg, 40 mg daily.

 
Medium-intensity statins (31–40% reduction in LDL cholesterol):

• Atorvastatin 10 mg daily.
• Simvastatin 20 mg, 40 mg daily.
• Rosuvastatin 5 mg daily.

 
Low-intensity statins (20–30% reduction in LDL cholesterol):

• Simvastatin 10 mg daily.
• Pravastatin 10 mg, 20 mg, 40 mg daily.

 
*Simvastatin 80 mg is not recommended because it carries a higher risk of muscle toxicity.

Section 19: How do statins work?

The key mechanism by which statins operate appears to be reductions in LDL cholesterol. This is achieved by inhibition of the 3-hydroxy-3 methylglutaryl coenzyme A reductase (HMGCoA) enzyme, which catalyses production of mevalonic acid, an early precursor in the cholesterol synthesis pathway within the liver. The reduced hepatic synthesis of cholesterol leads to upregulation of hepatic LDL receptors and, subsequently, increased clearance of damaging LDL cholesterol from the plasma (Kirby and Betteridge, 2012).

Whether statins provide cardiovascular protection by other mechanisms of action is debateable, but they may also have a more direct beneficial effect on endothelial function and offer stabilisation of atherosclerotic plaques through an anti-inflammatory process.

Section 20: The evidence supporting use of statins for cardiovascular protection in type 2 diabetes

The evidence supporting the use of statins for prevention of cardiovascular events in people with diabetes (both type 1 and type 2) is strong for both those with established CVD (secondary prevention) and those without (primary prevention). Large-scale randomised controlled trials – the Heart Protection, 4S and CARDS studies – have demonstrated unequivocally the  benefits of statin use in type 2 diabetes (Haffner et al, 1999; Collins et al, 2003; Colhoun et al, 2004).

CARDS, for example, was a primary prevention study in patients aged 40–75 years with type 2 diabetes using atorvastatin 10 mg daily. Major coronary events (fatal and non-fatal MI, unstable angina, coronary revascularisation) were reduced by 37%, and stroke by 48%, compared with placebo. This corresponded to an absolute risk reduction of 3.7% over 4 years in cardiovascular events. Benefits were seen independent of age, sex or starting cholesterol level.

A meta-analysis of statin trials in people with diabetes found that for each 1 mmol/L statin-induced reduction in LDL cholesterol, there was a 21% relative risk reduction in major vascular events and a 9% reduction in total mortality over 4 years. These benefits applied to both primary and secondary prevention of cardiovascular events in people with type 2 diabetes (and also held for those with type 1 diabetes) (Cholesterol Treatment Trialists collaborators, 2008).