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The following combinations should generally be avoided:

Evidence-based recommendations Grade

Blood pressure-lowering therapy

therefore treatment for lipid lowering should aim towards these targets rather than consider them definitive.

Order of lipid-lowering treatment

Lipid-lowering pharmacotherapy includes statins, fibrates, bile acid binding resins, niacin (nicotinic acid) and selective cholesterol absorption inhibitors (e.g. ezetimibe). The effectiveness of each of these agents is covered in section 2.2.2 Lipid-lowering therapy. Of all the methods to modify lipids, the weight of evidence suggests that statins are the most effective and should be the first-line agent.216-219 The lipid-lowering efficacy provided by the different statins appears to be fairly similar.211, 217, 236 For the reduction of cardiovascular events, meta-analyses suggest that although the point estimates of their effect sizes vary, the confidence intervals overlap in each case except for non-fatal MI where simvastatin can just be differentiated from pravastatin (RR 0.62, 95% CI 0.56–0.69 and 0.78, 95% CI 0.70–0.87, respectively).211 Another meta-analysis of 164 short-term primary and secondary trials found rosuvastatin 5 mg/day, atorvastatin 10 mg/day and lovastatin or simvastatin 40 mg/day reduced LDL-C by about 35%, but fluvastatin and pravastatin produced smaller reductions.217 Rosuvastatin 10 mg/day, atorvastatin 20 mg/day and lovastatin or simvastatin 80 mg/day reduced LDL-C by about 45% and rosuvastatin 80 mg/day by about 60%. In clinical practice, the choice of statin is more likely to be related to the dosage required for lowering TC and LDL-C. Combination therapies (e.g., statins and ezetimibe) may also be considered when target LDL-C levels are not achievable with statins alone.

Systematic reviews have confirmed that statins, as first-line therapy, are safe and easy to use.208, 287, 288 Liver dysfunction is occasional and reversible. Rhabdomyolysis is very rare and severe muscle pain may require immediate cessation of therapy. Because statins are prescribed on a long-term basis, possible interactions with drugs that are metabolised by the cytochrome P450 pathway (e.g. cyclosporin,

macrolides, azole antifungals, calcium antagonists, protease inhibitors, sildenafil, warfarin, digoxin, nicotinic acid, fibrates, etc.) also deserves particular attention. In cases where there is potential for interaction via this pathway, pravastatin is an acceptable alternative to atorvastatin or simvastatin.

All patients started on a statin should be advised to report unexplained muscle pains or other adverse effects promptly, especially if associated with fever or malaise. If such effects are mild, a different statin may be tried and/or the statin dose reduced after discussing the risks involved with the patient. If severe side effects are experienced, statin therapy should be discontinued.

2.3.2 Lipid-lowering therapy

Lipid-lowering therapy should be determined by individual needs and should aim towards optimal lipid levels

Evidence from several systematic reviews and meta-analyses suggests that more intensive lipid modification produces greater reductions in cardiovascular events.209,

213, 216 In a meta-analysis of 26 randomised trials (mixed populations) of statins, each 1.0 mmol/L decrease in LDL-C equated to a 25% reduction in major vascular events in people without previous CVD (RR 0.75, 95% CI 0.69–0.82) and a 0.4% lower risk difference per year.209 However, there are no clinical trials that have evaluated the relative and absolute benefits of cholesterol lowering to different TC and LDL-C targets in relation to clinical events. Establishing a cholesterol target for therapy is therefore an extrapolation from the apparent benefits indicated by major trials of lipid lowering, while maintaining appropriate margins for safety, given that there are still no long-term follow up studies of statin therapy.

The recommendations in these guidelines also refer to levels of non-HDL-C and triglycerides. Non-HDL-C refers to the cholesterol in LDL, intermediate density lipoprotein and very low-density lipoproteins and is calculated by subtracting HDL-C from TC. Unlike LDL-C, the calculation of non-HDL-C does not require triglycerides to be less than 4.5 mmol/L. This makes it particularly useful for people with high triglycerides. Triglyceride levels are also important.

Hypertriglyceridaemia is associated with the development of early onset CVD and significantly increases the risk of acute pancreatitis.285

The evidence for fixed-dose or individual titration of statin therapy is limited. One large meta-analysis performed a pre-determined assessment on the effects of statin dose on outcomes based on secondary prevention studies.286 Intuitively, one would expect that as the dose of a drug is increased, a greater amount of benefit is attained. However, with statin therapy, this was not the case above a certain dose. Over the range of doses reported, all statins, with the exception of pravastatin, showed some evidence of a dose response for reduction in TC and/or LDL-C with fixed dosing, but not with dose titration. Overall, there appeared to be no major difference between dose titration regimens or use of a fixed dose in studies of longer duration.

In summary, lipid lowering reduces cardiovascular events irrespective of initial lipid levels. Targets for lipid-lowering therapy have been developed by extrapolation from the apparent benefits indicated by major trials of lipid lowering,

Due to the weight of evidence in favour of statins, fibrate monotherapy cannot be recommended as first-line treatment for raised lipid levels, but may be considered in those whose triglyceride levels remain elevated despite treatment with the maximally tolerated dose of statins and who have persistently low HDL-C levels. Triglyceride levels greater than 10mmol/L pose a risk of pancreatitis and should be treated with fenofibrate, nicotinic acid or fish oil as first-line therapy.

Nicotinic acids and ezetimibe may be considered in addition to statin therapy where insufficient lipid control has been achieved. Bile acid sequestrants using cholestyramine may be considered as monotherapy where statins are not tolerated or are contraindicated. They may also be considered in addition to statin therapy. Overall, there is limited evidence for various lipid lowering agents either in combination with statins or alone.

People with diabetes

Several systematic reviews have looked exclusively at responses to lipid modification of people with type 2 diabetes. The results from these reviews are consistent and suggest that people with diabetes gain similar benefits from statin therapy as people without.206, 208, 209, 211, 289 Perhaps the best evidence for people with diabetes comes from the Collaborative Atorvastatin Diabetes Study (CARDS), a large study conducted entirely in people with diabetes who did not have either raised cholesterol levels or a clinical history of CVD, even though many were hypertensive.290 In that study, the AR reduction attributable to statin therapy was 1.70%

(95% CI, 0.11–3.29) for all-cause mortality and 1.35% (95%

CI 0.30–2.40) for total stroke. The NNT for four years to prevent one death was 59 (95% CI 30.4–88.5).

The evidence for fibrates in people with type 2 diabetes is less clear. One systematic review of 11 trials (78% of population were deemed primary prevention) reported a significant reduction in non-fatal coronary events (RR 0.84, 95% CI 0.74–0.96) but no effect on stroke or mortality outcomes.222 In the largest study included in the review, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate therapy did not significantly reduce the risk of coronary events.291 However, it did reduce total cardiovascular events, mainly due to fewer non-fatal MIs and revascularisations. Furthermore, in people with dyslipidaemia (defined as low HDL-C with high triglycerides), the benefit of fenofibrate appeared to be more pronounced. In that group, CVD events occurred in 16.3% of people randomised to placebo and 14.0% in people receiving fenofibrate (p=0.06).

A more recent trial (ACCORD) found that the combination of fenofibrate and simvastatin did not reduce the rate of fatal

CVD events, non-fatal MI or non-fatal stroke, compared with simvastatin alone.292 Of interest, however, was a possible benefit according to lipid subgroups. People with dyslipidaemia displayed a more pronounced benefit (p=0.057 for interaction), similar to the result reported in the FIELD study.291 However, in contrast to the FIELD study, a gender difference was observed, with the primary outcome rate increasing by 38% for women and decreasing by 18% for men.292

Collectively, these findings do not support the routine use of combination therapy with fenofibrate and statins to reduce CVD risk in people with type 2 diabetes, except in those with dyslipidaemia. Clinicians should note that in primary prevention, the treatment threshold is determined by the level of AR while the treatment target for triglycerides is

<2.0mmol/L. In contrast, in secondary prevention of CVD for people with type 2 diabetes, the treatment threshold is a triglyceride level above 2.3 mmol/L in combination with HDL levels below 1.0 mmol/L (refer to the National Evidence-based Guideline on Secondary Prevention of Vascular Disease in type 2 diabetes currently being drafted).

People with CKD

The benefits provided by statin therapy for people with CKD are similar to those observed in the general population. Statin therapy decreased all-cause mortality (RR 0.81, 95% CI 0.74–0.89) and cardiovascular mortality (RR 0.80, 95% CI 0.70–0.90) among people with non-dialysis dependent CKD to an extent similar to that found in the general population.235,

293 The same authors reported that statins reduced fatal cardiovascular events (RR 0.81, 95% CI 0.73–0.90) and non-fatal cardiovascular events (RR 0.78, 95% CI 0.73–0.84), for all stages of CKD but had no significant effect on all-cause mortality (RR 0.92, 95% CI 0.82–1.03).293 Importantly there were no significant differences in adverse events reported (including rhabdomyolysis and elevated liver enzymes).

However, trials usually included people with pre-existing CVD.

Meta-regression analysis found that treatment effects did not vary significantly with stage of CKD. This is consistent with a subgroup analysis in another meta-analysis, which found no difference in the effect of statins with varying levels of GFR.209 The Study of Heart and Renal Protection (SHARP) represents the largest trial of lipid modification in people with CKD performed to date.294 In that study, 9,438 participants with advanced CKD and no known history of CHD were randomised to one of three treatment arms: ezetimibe 10 mg plus simvastatin 20 mg daily, matching placebo or simvastatin 20 mg daily. In the latter arm, participants were re-randomised at one year to either ezetimibe 10 mg plus simvastatin 20 mg daily, or to placebo. The primary

endpoint was a composite of MI, coronary death, ischaemic stroke or any revascularisation procedure. Compared with placebo, randomisation to ezetimibe 10 mg plus simvastatin 20 mg daily yielded average LDL-C differences of 1.10 mmol/L at one year and 0.85 mmol/L at 2.5 years.

Recent evidence from the SHARP trial, published during the finalisation of these guidelines, showed similar reductions in LDL-C (0.85 mmol/L) at a median follow up of 4.9 years.

This data reported a 17% proportional reduction in major atherosclerotic events compared with placebo (RR 0.83, 95%

CI 0.74-0.94) with no evidence of adverse effects.226 While this evidence did not result in a regrading of recommendation EBR14, the outcome data further support the use of

ezetimibe in combination with a statin if LDL-C levels are not sufficiently reduced on a statin alone.

A secondary analysis from the Justification for the Use of Statins in Prevention – an Intervention Trial Evaluating

Rosuvastatin (JUPITER) trial reported positive effects from statin therapy on cardiovascular and mortality outcomes among people with moderate CKD (eGFR <60 ml/min/1.73 m2) at study entry (n=3,267), compared with those with baseline eGFR ≥60 ml/min/1.73 m2 (n=14,528).295 Over a median follow-up period of 1.9 years, a higher rate of vascular events was observed in the group with moderate CKD (HR 1.54, 95% CI 1.23–1.92, p=0.0002). In the same group, rosuvastatin was associated with a 45% reduction in risk of the combined primary endpoint – MI, stroke, hospital stay for unstable angina, arterial revascularisation or confirmed cardiovascular death (HR 0.55, 95% CI 0.38–0.82, p=0.002) and a 44% reduction in all-cause mortality (HR 0.56, 95% CI 0.37–0.85, p=0.005). An almost identical effect of rosuvastatin on the primary endpoint was observed among those with more preserved renal function (HR 0.57, 95% CI 0.45–0.72, p<0.001).

Evidence-based recommendations Grade

Lipid-lowering therapy

EBR 13: Statins should be used as first-line therapy A206, 208, 209

EBR 14: If LDL-C levels are not sufficiently reduced on maximally tolerated doses of statin, one