Unit 2 – Comorbidities and complications: Managing dyslipidaemia in the context of diabetes

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People with diabetes have an increased risk of cardiovascular complications, including acute coronary syndrome, stroke, heart failure and arrhythmias. Data suggest that people with diabetes, without prior cardiovascular disease (CVD), have the same rate of myocardial infarction as people without diabetes who have had previous events (Haffner et al, 1998; Malmberg et al, 2000; Donahoe et al, 2007).  Type 2 diabetes more than doubles the risk of heart failure hospitalisation and death (Davis and Davis, 2015). Women with diabetes are more likely to develop coronary heart disease (CHD; Peters et al, 2014) and are at greater relative risk of dying from CVD than their male counterparts (Juutilainen et al, 2004).

The background to this risk for the development of cardiovascular complications is multifactorial and our understanding of the nature of atherosclerotic disease has progressed considerably. The concept that atherosclerosis is a gradual process, leading to narrowing of the arteries until such a point that a thrombus forms and occludes a vessel, is naive. The concept was originally questioned by pathologists who showed that most myocardial infarctions are caused by low-grade stenosis (Falk et al, 1995). The current approach is to define atherosclerotic plaques as either stable, which can lead to high-grade obstruction, or unstable, which are vulnerable to rupture and show a high incidence of thrombiosis (Davies, 1996).

The initial phase of the development of atherosclerosis is endothelial dysfunction caused by hyperglycaemia, with or without hypertension, and dyslipidaemia and the adverse effect of adipose tissue-derived inflammatory cytokines. These include tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). The effect of this is to produce adhesion molecules, inflammatory mediators and cytokines that stimulate the involvement of inflammatory cells such as monocytes, which then enter the vessel wall and further stimulate the inflammatory response by interacting with oxidised low-density lipoproteins (LDLs). In addition to this, there is a reduction in the release of nitric oxide (NO), leading to vessel constriction (Xu and Zou, 2009). Subsequently, the monocytes differentiate into macrophages and foam cells, which further stimulate the release of inflammatory mediators (Hansson, 2005). What can be seen at this stage is a fatty streak. The platelet hyperactivity that is present in diabetes probably contributes to the further development of lesions at this stage (Ross, 1999). Eventually, more complicated lesions occur and the core of the plaque becomes necrotic. This necrotic core is protected by a fibrous cap, and it is those lesions that have a thin and vulnerable fibrous cap that are likely to become unstable plaques (Hansson et al, 1988).

Plaques in people with diabetes are more likely to rupture, with consequent thromboembolic events, because of the inflammatory process within (Moreno et al, 2000). Techniques using intra-vascular ultrasound with virtual histology (IVUS-VH) have advanced our knowledge of plaque morphology (Lindsey et al, 2009).

In addition to the effect on the wall, there is a subset of people with diabetes who acquire diabetic cardiomyopathy during the course of this disease. The nature of this process in not clearly defined, but there are functional and structural changes in the cardiac muscle that cause cardiac enlargement, increased stiffness and impaired diastolic function, which eventually leads to heart failure (Devereux et al, 2000). Heart failure is more common in the presence of poor glucose control, suggesting that hyperglycaemia may be an important contributor (Lind et al, 2011).

Clearly, good blood glucose control (i.e. reducing hyperglycaemia and avoiding hypoglycaemia in the process), particularly in the early stages of the disease, good blood pressure control throughout, and attention to dyslipidaemia is critically important in people with diabetes to prevent this atherosclerotic process (Colhoun et al, 2004; Holman et al, 2008).

Lipid levels and cardiovascular risk
In diabetes, LDL cholesterol may not be significantly elevated compared with matched individuals without the disease, but it is a smaller, denser, more atherosclerotic particle (Mazzone et al, 2008).

The well-established treatment approach is to focus on the use of LDL cholesterol-lowering drugs such as statins. Statin therapy reduces cardiovascular events by 22–48% (Collins et al, 2003; Colhoun et al, 2004); however, there still appears to be an excess residual cardiovascular risk among statin-treated people with diabetes compared with those without the disease (Costa et al, 2006). This residual risk may result from lipoprotein abnormalities that occur in diabetes, which are not adequately addressed by statin therapy (Mazzone et al, 2008).

Dyslipidaemia in type 2 diabetes is characterised by increased concentrations of triglyceride-rich lipoproteins, decreased concentrations of high-density lipoprotein (HDL) cholesterol and abnormalities in the composition of triglyceride-rich HDL and LDL particles (Garvey et al, 2003; Deeg et al, 2007). HDL is a very complex lipoprotein particle and changes in its composition may affect its atherosclerotic properties (Mazzone, 2007). The failure of cholesterol ester transfer protein (CETP) inhibition with torcetrapib to protect against cardiovascular events suggests that HDL particle composition may be a more important consideration than HDL cholesterol level in the reduction of cardiovascular risk (Barter et al, 2007). Box 1 examines the relevance of HDL cholesterol functionality to athero- and vasculo-protection.

The case for non-HDL cholesterol
It is likely that combined dyslipidaemia may confer a higher magnitude of risk than elevated LDL cholesterol alone (Assman and Schulte, 1992). Triglycerides appear to be an independent risk factor (Austin et al, 1998), although they may be a marker of low HDL cholesterol. Non-HDL cholesterol may be defined as the difference between total and HDL cholesterol and thus represents cholesterol carried on all the potentially pro-atherogenic particles (Hsai, 2003; see Figure 1). By measuring total cholesterol and HDL cholesterol, and calculating non-HDL cholesterol, we can avoid the potential limitations of triglycerides as a marker of CHD risk and instead measure something that directly reflects the cholesterol content of all the particles that may be pro-atherogenic. NICE (2014), however, recommend we continue to include triglycerides in the baseline blood tests prior to starting treatment for dyslipidaemia. Another advantage of non-HDL cholesterol measurement is that it does not need to be done in the fasting state. Non-HDL cholesterol may be, therefore, a readily obtainable, inexpensive and convenient measure of CHD risk that may be superior to LDL cholesterol in many respects (Hsai, 2003).

A meta-analysis of individual patient data from eight randomised trials, in which nearly 40000 patients received statins, evaluated the relative strength of the association between conventional lipids and apolipoproteins (determined at baseline at 1 year follow-up) with cardiovascular risk.  One standard deviation increases from baseline levels of LDL, apolipoprotein B (apoB) and non-HDL at 1 year were all associated with increased risks of cardiovascular events, but the differences between LDL and non-HDL were significant. Patients reaching the non-HDL target of under 3.4 mmol/L (130 mg/dL) but not the LDL target of under 2.6 mmol/L (100 mg/dL) were – assessed relative to patients achieving both targets – at lower excess risk than those reaching the LDL target but not the non-HDL target (Boekholdt et al, 2012; see Table 1). In other words, non-HDL cholesterol is a better predictor of risk than LDL cholesterol.

Virani (2011) reviewed non-HDL cholesterol as a metric of good quality of care. Non-HDL cholesterol has been shown to be a better marker of risk in both primary and secondary prevention studies. In an analysis of data combined from 68 studies, non-HDL cholesterol was the best predictor among all cholesterol measures both for coronary artery events and for strokes (Emerging Risk Factors Collaboration, 2009). In the IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering) trial, elevated non-HDL cholesterol and apoB levels were the best predictors after acute coronary syndrome of adverse cardiovascular outcomes in patients on lipid-lowering therapy (Kastelein et al, 2008).

Elevated levels of non-HDL cholesterol, in combination with normal levels of LDL cholesterol, identify a subset of patients with elevated levels of LDL particle number, elevated apoB concentrations and LDL of small, dense morphology (Ballantyne et al, 2001). The increase in the incidence of metabolic syndrome probably reduces the accuracy of risk prediction for vascular events when LDL cholesterol is used for that purpose, whereas non-HDL cholesterol has been shown to retain predictive capability in this patient population (Sattar et al, 2004).

The use of non-HDL cholesterol to provide a better prediction of risk and treatment response than LDL cholesterol may be particularly relevant in the growing number of people with type 2 diabetes in whom an increase in atherogenic lipoproteins is not reflected by LDL cholesterol levels (JBS3 Board, 2014). The latest NICE guideline (2014) on CVD risk assessment and reduction, including lipid modification, recommends the use of non-HDL cholesterol instead of LDL cholesterol.

Identifying and assessing CVD risk
NICE (2014) recommends using the QRISK2 risk assessment tool to assess risk for the primary prevention of CVD in people aged up to 84 years, including those with type 2 diabetes. Such tools are not recommended for people aged 85 years and over and those with type 1 diabetes, an estimated glomerular filtration rate <60 mL/min/1.73 m² and/or albuminuria, pre-existing CVD or familial hypercholesterolaemia, as they are known to be at increased risk of CVD. Remember that CVD risk will be underestimated in people taking antihypertensives or lipid-lowering drugs, those who have recently stopped smoking and those who have additional risk due to certain medical conditions or treatments (e.g. people taking medications that can cause dyslipidaemia, such as corticosteroids, antipsychotics and immunosuppressants). CVD risk is also increased by severe obesity (BMI >40 kg/m²). Patients should be prioritised for a full formal risk assessment if their estimated 10-year risk of CVD is ≥10%.

The JBS3 risk calculator is based on the QRISK2 risk assessment tool but has some additional features that are very helpful in explaining risk, such as life expectancy and life years gained by modifying risk factors. This can be accessed online at http://www.jbs3risk.com

Both total and HDL cholesterol should be measured to give the best estimation of CVD risk. Before lipid modification therapy is offered for the primary prevention of CVD, patients should have a full lipid profile, including total cholesterol, HDL cholesterol, non-HDL cholesterol and triglycerides. A fasting sample is not required (NICE, 2014).

Lipid management
People at high risk of, or with, CVD should be encouraged to play a part in reducing their personal risk through lifestyle changes, including achieving and maintaining a healthy weight, eating a cardioprotective diet, taking more physical activity, stopping smoking and moderating alcohol consumption. The management of modifiable risk factors should also be optimised (NICE, 2014).

For primary prevention, NICE (2014) recommends offering high-intensity statin treatment (defined as atorvastatin 20–80 mg/day, simvastatin 80 mg/day or rosuvastatin 10–40 mg/day) when lifestyle modification is not appropriate or not effective, following risk assessment. Atorvastatin 20 mg is the preferred option in patients with a ≥10% 10-year risk of CVD estimated using the QRISK2 assessment tool, including those with type 2 diabetes. This treatment should also be considered for primary prevention in all adults with type 1 diabetes and offered to the following people with type 1 diabetes:

• Those who are aged over 40 years.
• Those who have had the condition for more than 10 years.
• Those who have established nephropathy.
• Those who have other risk factors for CVD.

For the secondary prevention of CVD, NICE (2014) recommends that the statin treatment is not delayed by the management of modifiable risk factors, and this should be started with atorvastatin 80 mg. A lower dose is recommended if there is a high risk of adverse effects or the potential for drug interactions, or if the patient prefers this option. The decision to start statin treatment should follow discussion with the patient regarding the risks and benefits, and consideration of additional factors, such as potential benefits from lifestyle modification, informed patient preference, comorbidities, polypharmacy, frailty and life expectancy (NICE, 2014).

Patients started on high-intensity statin treatment should have their total cholesterol, HDL cholesterol and non-HDL cholesterol checked after 3 months, with a target >40% reduction in non-HDL cholesterol. If a >40% reduction in non-HDL is not achieved, look at adherence and timing of dose and/or consider increasing the dose if the patient was started on less than 80 mg atorvastatin and is thought to be higher risk due to risk score, comorbidities or clinical judgement (NICE, 2014).

The JBS3 Board (2014) also recommends a more intensive treatment strategy for the prevention of CVD, with a target non-HDL cholesterol level of <2.5 mmol/L, which is broadly equivalent to an LDL cholesterol of <1.8 mmol/L. Patients taking statins should be offered annual medication reviews. They should also be advised to seek medical advice if they develop muscle symptoms. JBS3 provides a step-wise therapeutic approach for patients who require statin therapy but appear to be intolerant. NICE (2014) advises practitioners to seek specialist advice about the options for treating people at high-risk of CVD, including those with type 1 or type 2 diabetes, who are intolerant to three different statins.

Ezetimibe monotherapy should be considered for people with primary hypercholesterolaemia in whom initial statin therapy is contraindicated or not tolerated. It is recommended as add-on therapy for people with primary hypercholesterolaemia who have started statin therapy if the total or LDL cholesterol is not appropriately controlled after appropriate dose titration of statin therapy, if appropriate dose titration is limited by intolerance or if a change from the initial statin therapy is required (NICE, 2016a).

Draft guidance on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors recommends the use of alirocumab and evolocumab for patients with primary hypercholesterolaemia or mixed dyslipidaemia if their cholesterol remains uncontrolled despite making lifestyle changes and taking other cholesterol-lowering drugs, as long as they are provided at the discounted price agreed with the companies. This is based on evidence that alirocumab reduces LDL cholesterol levels by up to 62% versus placebo and up to 40% versus ezetimibe. Similar reductions were seen with evolucumab (NICE, 2016b).

NICE (2014) does not recommend the use of fibrates (routinely), nicotinic acid, bile-acid sequestrants (anion exchange resins), omega-3 fatty acid compounds or plant stanols or sterols in people being treated for the primary or secondary prevention of CVD, including those with type 1 or type 2 diabetes (NICE, 2014). Aspirin is not recommended for the primary prevention of CVD in people with diabetes (JBS3 Board, 2014). Coenzyme Q10 and vitamin D are not recommended for increasing adherence to statin therapy (NICE, 2014).

Quality and Outcomes Framework
The total cholesterol Quality and Outcomes Framework indicator for people with diabetes in England, Northern Ireland and Wales is as follows (NHS Employers, 2016):

DM004: The percentage of patients with diabetes, on the register, whose last measured total cholesterol (measured within the preceding 12 months) is 5 mmol/L or less.

This is based on advice that statin therapy to reduce cholesterol is initiated and titrated as appropriate to reduce total cholesterol to <5 mmol/L (NHS Employers, 2016).

The latest evidence on lipid-lowering approaches
There have been concerns that halving the risk threshold for primary prevention will result in a large majority of men and women above the recommended age for cholesterol testing being indicated for statin therapy. However, a recently published study using mathematical modelling estimated that only a small number of patients indicated for treatment would be due to false positive tests, and these are mainly in those close to the threshold, be it 20% or 10%. The researchers believe the implications depend on the benefits of statin therapy, in those at low to medium risk, and the harms (McFadden et al, 2015). Two of the best-known harms associated with statin therapy are muscle problems and a small or moderate increased risk of new-onset diabetes (JBS3 Board, 2014), but there may be other harms associated with monitoring (McFadden et al, 2015), as a harm associated with “labelling” has been found for hypertension (Hamer et al, 2010). The Cholesterol Treatment Trialists’ Collaboration concluded that statins provide a net benefit in those at low risk (Mihaylova et al, 2012). Therefore, a move to a lower threshold should extend a treatment from which almost all middle-aged men and women stand to benefit, to an increasing proportion of the population (McFadden et al, 2015).

Rosuvastatin
Because many of the statin studies have involved mainly Caucasian populations and a majority of men, there has been a lack of information regarding the efficacy of these drugs for primary prevention in people of other ethnicities and women. The HOPE 3 trial randomly assigned 12705 participants from 21 countries who did not have CVD and were at intermediate risk to receive either rosuvastatin 10 mg/day or placebo. Only 20% of participants were Caucasian (29% Chinese and 27% Hispanic), and 46% were women (Yusuf et al, 2016).

Two possible outcomes were investigated; the first was a composite of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke, while the second also included revascularisation, heart failure and resuscitated cardiac arrest. Patients were followed up for a median of 5.6 years (Yusuf et al, 2016).

The overall mean LDL cholesterol level was 26.5% lower in people taking rosuvastatin than those taking placebo. The first and second outcomes occurred in 3.7% and 4.4% of people taking rosuvastatin versus 4.8% and 5.7% of those taking placebo respectively. There was no evidence of heterogeneity of effect in the subgroups defined according to ethnic group or gender. There was no excess of diabetes or cancers in the participants taking rosuvastatin versus those taking placebo. While more people taking rosuvastatin had muscle pain or weakness than those taking placebo (5.8% vs 4.7%), there was no significant difference between the groups in the number of people permanently discontinuing treatment because of muscle symptoms (1.3% on rosuvastatin vs 1.2% on placebo; Yusuf et al, 2016). This study showed that for primary prevention, rosuvastatin 10 mg/day is associated with a significantly lower risk of cardiovascular events than placebo in an intermediate-risk ethnically diverse population, well represented by women (Yusuf et al, 2016).

Muscle-related side effects
Although statins are highly effective at reducing cardiovascular morbidity and mortality in high-risk patients, poor adherence can be an issue. One of the commonest causes of non-adherence to statin therapy is statin intolerance, mainly due to muscle-related symptoms (Bitzur et al, 2013). Nissen et al (2016) set out to identify patients with muscle symptoms confirmed by statin rechallenge and compare the lipid-lowering efficacy of ezetimibe and evolocumab in a 2-stage randomised clinical trial. The trial included 511 adults with uncontrolled LDL cholesterol levels and a history of intolerance to two or more statins. The trial started with a 24-week crossover procedure using atorvastatin 20 mg or placebo to identify the patients having symptoms with the statin only (phase A). Following a 2-week washout period, patients were randomised to ezetimibe (10 mg/day) or evolocumab (420 mg/month) for 24 weeks (phase B). The co-primary endpoints were the mean percentage change in LDL cholesterol from baseline to the mean of weeks 22 and 24, and from baseline to week 24 levels.

Of the 491 patients who entered phase A (mean age 60.7 years, 50.1% female, 34.6% with CHD, entry mean LDL cholesterol level 212.3 mg/dL [5.5 mmol/L]), muscle symptoms occurred in 42.6% (n=209) when taking atorvastatin but not when taking placebo. Of these, 199 entered phase B, together with 19 who were fast-tracked to phase B due to elevated creatine kinase (n=218; 73 randomised to ezetimibe, 145 to evolocumab, entry mean LDL cholesterol level 219.9 mg/dL [5.7 mmol/L]; Nissen et al, 2016).

For the mean of weeks 22 and 24, the LDL cholesterol level was 183.0 mg/dL (4.7 mmol/L) with ezetimibe (mean percentage change −16.7%, absolute change −31.0 mg/dL [0.8 mmol/L]) and 103.6 mg/dL (2.7 mmol/L) with evolocumab (mean percentage change −54.5%, absolute change −106.0 mg/dL [2.7 mmol/L]). At week 24, the LDL cholesterol level was 181.5 mg/dL (4.7 mmol/L) with ezetimibe (mean percentage change −16.7%, absolute change −31.2 mg/dL [0.8 mmol/L]) and 104.1 mg/dL (2.7 mmol/L) with evolucumab (mean percentage change −52.8%, absolute change −102.9 mg/dL (2.7 mmol/L; P<0.001). For the mean of weeks 22 and 24, the difference in LDL cholesterol between the groups was −37.8% (absolute difference 171.7 mg/dL [4.7 mmol/L]; Nissen et al, 2016).

Interestingly, in this study, muscle symptoms were reported by 28.8% of patients taking ezetimibe and 20.7% of those taking evolucumab, with the active study drug being withdrawn in 6.8% of patients taking ezetimibe and 0.7% of patients taking evolucumab. The study showed that in patients unable to tolerate statins due to muscle-related adverse effects, evolucumab resulted in a significantly greater reduction in LDL cholesterol levels at 24 weeks than ezetimibe and was also associated with fewer muscle symptoms (Nissen et al, 2016), but it would also be much more expensive.

In practice
Statins are very effective at reducing the risk of serious and life-threatening cardiovascular events and when we take a patient off statin therapy, we may be doing them harm. The European Atherosclerosis Society (EAS) released a consensus statement in 2015 to provide guidance on the diagnosis and management of statin-associated muscle symptoms (Stroes et al, 2015). In their algorithm, they recommend first stopping the drug for either 2–4 weeks (if the patient is symptomatic and has a creatine kinase level less than four times the upper limit of normal) or 6 weeks (if the patient has a creatine kinase level four times the upper limit of normal or greater with or without rhabdomyolysis). If the re-challenged patient is still unable to tolerate a statin, we should aim for a lower dose with an efficacious statin (e.g. atorvastatin or rosuvastatin), or advise the patient to take a statin every other day or twice weekly. If still unsuccessful, then recommend trying again with the highest maximally tolerated dose of statin, then adding additional lipid-lowering agents (specifically ezetimibe) to lower LDL cholesterol levels to goal. If this does not work, we should consider adding a fibrate (not gemfibrozil), bile acid sequestrants, or both, as add-ons to ezetimibe. If the patient is still not at goal, the final options are additional (future) novel therapies (e.g. PCSK9 inhibitors or CETP inhibitors; Stroes et al, 2015). Case examples relating to managing dyslipidaemia in the context of diabetes are presented in Box 2 and Box 3.

Concluding remarks
The 2016 Joint European Cardiovascular Prevention Guidelines point out that reducing the population cardiovascular risk by 1% could prevent 25 000 cases of CVD and save €40 million per year in the UK, and stronger laws on food, physical activity and smoking are required (European Association of Cardiology, 2016; Piepoli et al, 2016).

Rates of obesity and type 2 diabetes are continuing to rise. We know people with diabetes are at increased risk of cardiovascular complications, and non-HDL cholesterol now appears to be a more effective measure of risk in this population than LDL cholesterol. The management of dyslipidaemia in these patients should involve a multifactorial programme to improve lifestyle and adherence to treatment.

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