Lipid-modifying agents
| Type | Recommendation |
|---|---|
| When to deprescribe | |
| CBR |
Following a shared decision-making discussion in which potential benefits and harms are clearly communicated along with considerations of other individual factors, we suggest deprescribing be offered to older people taking lipid-modifying agents:
|
| GPS |
Healthcare providers should use the Australian CVD Risk Calculator* to assess cardiovascular risk over the next five years, as it accounts for the specific contexts of the Australian population and healthcare system (https://www.cvdcheck.org.au/calculator) (ungraded good practice statement). * Note that the Australian cardiovascular disease risk calculator is validated for use in people without known CVD aged 30 to 79 years who do not already meet high risk criteria. |
| GPS |
The 'Surprise Question' should be used as a prognostic tool to estimate life expectancy in individuals with advanced disease or progressive life-limiting conditions (“Would you be surprised if this person were to die in the next 12 months?”) in conjunction with clinical judgement (ungraded good practice statement). |
| Ongoing treatment | |
| CBR |
We suggest ongoing treatment with statins be considered in people without limited life expectancy:
provided this aligns with the individual's goals and preferences, following informed consent. |
| How to deprescribe | |
| CBR |
We suggest discontinuing lipid-lowering agents without the need for tapering provided it aligns with the individual's wishes and goals. |
| Monitoring | |
| CBR |
We suggest monitoring lipid concentrations annually. |
CBR, consensus-based recommendation
HMG-CoA reductase inhibitors (i.e. statins) are the first-line lipid-modifying therapy for hypercholesterolemia or for CVD prevention in people at a high risk of coronary heart disease, regardless of their cholesterol levels [177]. Other lipid-lowering agents such as ezetimibe and fenofibrate, are also commonly prescribed. Irrespective of the lipid-lowering effects, fenofibrate also plays a role in delaying the progression of diabetic retinopathy and improving glycaemic control in people with diabetes [388].
Refer to the narrative evidence summary, the GRADE Summary of Findings table in the guidelines, and the Technical Report for a complete presentation of the deprescribing evidence based on the GRADE framework (including other factors considered in developing the recommendations).
Primary prevention
While statins are widely used for primary prevention, evidence supporting their efficacy in individuals aged 80 and older remains limited. However, their use in this age group has increased in recent years [389].
At the time of writing, the follow-up or reporting for both STAREE and PREVENTABLE trials are still ongoing.
The Statins in Reducing Events in the Elderly (STAREE) trial is a double-blind, placebo-controlled RCT evaluating the benefits of statins versus placebo in people aged 70 and older (mean age = 75) for primary prevention [390].
The Pragmatic Evaluation of Events and Benefits of Lipid Lowering in Older Adults (PREVENTABLE) is another double-blind placebo-controlled trial that targeted community-dwelling adults aged > 75 years. The study compares the impact of high-intensity atorvastatin 40mg and placebo on cardiovascular death, hospitalisations for unstable angina, myocardial infarction, heart failure, stroke, or coronary revascularisation [391].
Below is a summary of key clinical trials that have contributed to current guidelines on lipid-lowering therapy in older people.
One of the few RCTs specifically targeting older people is the PROSPER trial, which enrolled 5,804 participants aged 70 to 82 years (mean age 75) with either risk factors for vascular disease (primary prevention) or a history of vascular disease (secondary prevention) [392]. Over a mean follow-up of three years, pravastatin significantly reduced the risk of coronary heart disease in the secondary prevention group. However, no significant benefit was observed for primary prevention.
Complementing this evidence, a 2018 retrospective cohort study using the SIDIAP database included 46,864 individuals aged 75 years and older without clinically established cardiovascular disease [393]. Participants were followed for a mean of six years, with analyses stratified into two age groups: 75-84 years and ≥85 years. Statin use was not associated with a significant reduction in cardiovascular events, stroke, or all-cause mortality among individuals aged ≥ 85, nor among those aged 75-84 without type 2 diabetes. In contrast, a significant reduction in cardiovascular events and all-cause mortality was observed among participants under 85 years of age with type 2 diabetes.
The HOPE-3 trial, which included participants with a mean age of 65.7 years, demonstrated a significant reduction in cardiovascular events and mortality among individuals at intermediate cardiovascular risk, with a reported number needed to treat (NNT) of 378 per year [35]. Conversely, a post hoc secondary analysis of the ALLHAT-LLT trial, which recruited older people with moderate hyperlipidaemia and hypertension but no baseline atherosclerotic cardiovascular disease, found no significant benefit of statin therapy for primary prevention when initiated after the age of 65 [394].
Systematic reviews and meta-analyses examining statin use in older people (mean age ≥ 70 years) in the context of primary prevention have generally demonstrated a significant reduction in cardiovascular events, although they have not shown a consistent benefit in reducing all-cause mortality [395-397]. Furthermore, a systematic review and meta-analysis that combined both primary and secondary prevention populations reported that the relative reduction in cardiovascular events with lipid-lowering therapy (including statins, PCSK9 inhibitors, and ezetimibe) was consistent between individuals aged ≥75 years and those younger than 75 years [398].
While mortality benefits are often not observed in trials, this may be due to inadequate statistical power, small sample sizes, or low event rates. Individual risk factor assessment is again important. In order to determine which people above the age of 65 would benefit from lipid-lowering agents for primary prevention, the Heart Foundation recommends calculation of cardiovascular risk [399]. In Australia, the Australian Cardiovascular Disease Risk Calculator (Aus CVD Risk Calculator) is a validated tool to estimate five-year cardiovascular risk in people aged 30 to 79 years who do not already meet the high-risk criteria [399]. The guideline provides a conditional recommendation for people with a risk of 10% or more (high risk) to initiate pharmacotherapy including a lipid-lowering agent [399].
In people at intermediate cardiovascular risk (AusCVDrisk 5 to < 10%), determining who will benefit from lipid-lowering therapy can be challenging. As discussed in the 'anti-thrombotic agents' section, CAC scoring in addition to clinical risk assessment may provide guidance in pharmacological treatment decisions [257, 258]. While CAC score is not recommended for routine cardiovascular risk screening in the general population, CAC score can be useful in reclassifying individuals at intermediate risk to a lower or higher cardiovascular risk category when treatment decisions are uncertain [399]. CAC is a highly specific marker of atherosclerosis and has strong predictive value for future cardiovascular events [400]. The association between arterial calcification and cardiovascular disease risk is well-established [401]. One study reported a five-year number needed to treat (NNT) with statins of 549 for individuals with a CAC score of zero, compared to 24 for those with a CAC score greater than 100 [400]. In individuals at intermediate cardiovascular risk with a CAC score of zero - or with no evidence of coronary artery disease on CT or invasive coronary angiography - lipid-lowering therapy is generally not required following the reclassification of risk level to low [400]. In contrast, those with a CAC score above 100, or with prior imaging evidence of arterial calcification or atheromatous plaques, are more likely to benefit from lipid-modifying therapy.
In people with familial hypercholesterolaemia and very high cholesterol (i.e. total cholesterol levels > 7.5mmol/L), initiation of lipid-modifying agents is often required, rather than according to calculated absolute AusCVD risk [399]. Refer to disease-specific guidelines for the management guidance.
Secondary prevention
For secondary prevention of cardiovascular and ischemic cerebrovascular disease, strong evidence supports a significant benefit of statins, even in individuals over 75 years of age [402]. The PROSPER study [392] reported an NNT of 23.2 over 3.2 years for secondary prevention [35].
For the secondary prevention of haemorrhagic stroke, a recent systematic review and meta‐analysis of RCTs found limited benefits of LDL-C-lowering therapy (statins, ezetimibe, and PCSK9 inhibitors) [403].
For individuals undergoing percutaneous coronary intervention (PCI), long-term statin therapy improves epicardial perfusion post-PCI [404]. A meta-analysis of six RCTs (mean age 58-65 years) showed that post-PCI statin therapy significantly reduced myocardial infarction but had no significant effect on all-cause mortality or revascularisation compared to placebo [405].
In terms of the intensity of statin therapy, high-intensity therapy is recommended for people aged ≤ 75 years with chronic coronary syndrome [303]. Emerging data suggests that people aged over 75 years may also benefit from high-intensity statins [406]. For those unable to tolerate high-intensity statins, moderate-intensity therapy remains beneficial and should be considered [303].
Other considerations
The benefits of statins typically manifest within two to five years [407]. Therefore, individuals with advanced life-limiting illnesses and a prognosis of fewer than 12 months are unlikely to benefit from initiating statins solely for mortality reduction. However, continuation may be warranted if there are other compelling indications. In addition to life expectancy, polypharmacy, treatment burden, functional status, and quality of life are all important considerations for the continuation or discontinuation of statins in older people.
In older people with advanced life-limiting diseases who have no recent active CVD, discontinuation of statins may be considered with the aim of improving quality of life and reducing medication burden. The 'Surprise Question' may be considered a prognosis tool to estimate life expectancy in people with advanced disease or progressive life-limiting conditions within the last year of life. A recent systematic review reported a modest accuracy for predicting mortality across various populations despite limitations and suggested it may be useful as a starting point to identify people who may benefit from an early integration of palliative care [408]. However, it should not be used alone to base clinical decisions.
We identified four studies (one RCT, one retrospective cohort study, and two before-and-after studies) related to statins deprescribing from the systematic review and meta-analysis [173, 409-411]. We were unable to identify any direct evidence related to the deprescribing of other lipid-modifying agents (e.g. fibrates, bile acid sequestrants, PCSK9 inhibitors).
Overall, the current evidence for deprescribing statins is derived from studies of very low certainty and varied in terms of indication for use and study setting. Deprescribing statins following intracerebral haemorrhage was associated with a significant increase in mortality in a cohort study, but the outcome is of very low certainty due to methodological limitations. In participants nearing the end of life, there was no evidence of significant harms or benefits associated with deprescribing statins. There was also a lack of evidence for deprescribing drugs for dyslipidaemia other than statins. The evidence at this stage is insufficient to inform evidence-based recommendations.
If lipid-modifying agents are considered appropriate to deprescribe, monitoring of cholesterol concentrations at least annually may be appropriate.
Key study characteristics and results
A narrative summary of each study is provided below, highlighting key characteristics and main findings.
Kutner 2015 randomised 381 participants with advanced life-limiting illness (life expectancy less than 12 months) to statins discontinuation (n=189) or continuation (n=192) [411]. Of all participants, 49% had cancer as their primary diagnosis with life expectancy between one month to one year. Participants were included if they had worsening functional status, no recent active cardiovascular diseases, and were taking statin therapy for at least three months, regardless of whether for primary or secondary prevention. Mortality within 60 days did not differ significantly between the two groups (OR 1.23, 95% CI 0.75 to 1.99). Cardiovascular events (OR 1.22, 95% CI 0.53 to 2.79), overall symptoms (MD -2.5, 95% CI -6.0 to 1.1) and statin-specific side effects (muscle-related pain, weakness, headache, and fever) also did not differ significantly between the two groups (MD -0.20, 95% CI -1.4 to 0.9). There was no significant difference in the quality of life between the two groups (MD 0.18, 95% CI -0.28 to 0.64).
Chung 2018 conducted a retrospective cohort study of 2,468 people following intracerebral haemorrhage [409]. Participants were included if they were using statins for dyslipidaemia in the three months prior and were excluded if they had a cerebrovascular accident within three months of intracerebral haemorrhage. At three years, there was a significantly higher all-cause mortality among people who discontinued statins compared to those who continued statins following intracerebral haemorrhage (12.9% vs. 25.3%; OR 2.29, 95% CI 1.74 to 3.03).
Visser 2021 targeted both statins and PPIs by applying a study-specific evidence-based implicit deprescribing algorithm in nursing home residents [173]. The algorithm considered both primary and secondary prevention indications for statins. In this before-and-after study, 34/66 (52%) of the residents had their PPI and/or statin dosage either successfully reduced or discontinued after three months which were maintained at six months. Of the 13 residents who were using a statin, eight (61%) had their statin completely discontinued and five (39%) continued using their statin.
Korsholm 2024 conducted a before-and-after study that included 98 participants who were taking statins for primary prevention treatment on a stable dosage for a minimum of 12 months [410]. This study reported that discontinuation of statins led to a mean increase in total cholesterol concentrations (from 4.8 ± 0.7 to 6.5 ± 0.9 mmol/L) and low-density lipoprotein cholesterol concentrations (from 2.2 ± 0.5 to 3.9 ± 0.8 mmol/L). However, physical function related to muscle performance improved as shown in a chair stand test (number of repetitions per 30 seconds increased from 15.7 ± 4.3 to 16.3 ± 4.9, p< 0.05), 6-minute walking test (distance increased from 544 ± 78 m to 556 ± 80 m, p< 0.05), power (increased from 268 ± 100 to 276 ± 102 W, p< 0.05), and relative power (increased from 3.6 ± 1.1 to 3.7 ± 1.2 W/kg, p not stated).
In one before-and-after study, statins were discontinued abruptly (n=98) [410]; however, this study did not report important or critical outcomes associated with deprescribing. The method of deprescribing was not explicitly described in the other three studies (RCT, n=381; retrospective cohort study, n=2468; before-and-after study, n=67) [173, 409, 411].