The pharmacodynamic and clinical trial evidence for statin dose

Abstract

Statin doses around estimated effective dose 50 (ED50) can reduce myocardial infarction by over 25% and mortality by around 10%. Being a competitive enzyme inhibitor, statin efficacy plateaus at doses that are multiples above the ED50, whilst on‐ and off‐target adverse events increase in number and severity with increasing dose. For example, myopathy has been shown to increase by up to 29‐fold and liver dysfunction by up to nine‐fold as statin dose is increased. Doses of up to 40‐fold ED50 have been promoted, but above five‐fold ED50, for example 10 mg of atorvastatin, there is no randomized controlled clinical trial evidence that coronary mortality is lowered, or that survival is increased.

Introduction

It is widely accepted that the lower the cholesterol the better. However, treatment to ever lower targets of low density lipoprotein (LDL) concentration with statins based on the epidemiology is not supported by evidence from the randomized controlled trials 1.

It was hoped in the 1970s that the http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=593 the first class of lipid modifying drugs to gain widespread use, would reduce cardiovascular events and confirm that lipids were more than surrogate biomarkers. The strongest evidence would be prolonged survival because cardiovascular disease is the commonest cause of death in most populations. However, in the largest studies, of patients at high risk of cardiovascular death, fibrates tend to increase mortality 2.

It had been argued that the failure of fibrates to improve survival could be overlooked because the trials were not individually powered for mortality as an endpoint and that their benefit is revealed by composite efficacy endpoints. Specifically, fibrates achieve a significant reduction in composite endpoints of cardiovascular mortality, acute myocardial infarction (AMI) and stroke 3. This one‐sided use of a composite, with no comparable composite of safety, can lead to an imbalanced risk assessment 3.

The early disappointments with lipid lowering treatments were turned around by the impressive reduction in mortality with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2955, a http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=639 inhibitor, in the 4S trial, reported in 1994 4. As more trials confirmed statin benefits, a graphic of a regression line plotted through statin trial data was adopted and promoted. Both placebo and active drug data were included, with the lipid concentration on the horizontal axis and the reduction in cardiovascular events on the vertical 5. This regression line conflates epidemiology with the benefits and harms of cholesterol‐lowering pharmacotherapy and is misleading 6. The placebo data in these trials confirm known coronary disease epidemiology, showing the lower the cholesterol the better. However, the effects of the statin intervention can only be measured by comparing the active and control data in each trial individually. When this is done, the greatest benefit is seen in high‐risk populations, for example in the 4S trial (mean baseline cholesterol 6.7 mmol l⁻¹) 4 and the benefit is smaller in trials in lower risk populations such as CARE 7 or ALLIANCE 8 (mean baseline cholesterol 5.4 and 5.8 mmol l⁻¹, respectively). Plotting a line through all the data points 5 exaggerates pharmacologic benefits of cholesterol lowering as it is dominated by the epidemiology mapped by the placebo data 6. This statin trials regression line has increasingly driven clinical guidance and led to the false logic that the greater the reduction in cholesterol with ever higher doses of statins, the greater the clinical benefits. To make a case for higher dose statins requires favourable outcome data from trials which randomized participants to high and low dose statin. Benefits above three‐ to five‐fold ED50 (effective dose 50, the estimated mean population dose necessary to achieve half the maximum possible drug effect, E_max) of any drug are offset by increased unintended dose‐related adverse events and are not supported by pharmacodynamic considerations 9.

Limitations of statin pharmacotherapy

The ED50 centres the dose–response curve. Most drugs are useful across a dose range from about one‐quarter to four‐fold their ED50 (Table 1). It is widely accepted that LDL strongly predicts coronary disease 1 and it is inferred that reduction of coronary events by statins is best predicted by the reduction in LDL concentration. The maximum possible reduction of LDL, on the highest studied statin doses, has been by a mean of 58% (2.8 mmol l⁻¹) with 80 mg of rosuvastatin 10. The mean dose which reduces LDL by half of this (29%), the ED50, becomes clear in systematic review of published dose–response data (Table 2, Law et al. 10) and is only about 1 mg for rosuvastatin. Although symptomatic coronary disease can be reduced with many lifestyle measures and cardiovascular pharmacotherapies 11, the newer statins are currently prescribed at doses as high as 40‐fold their ED50. Such high intensity dosing is unprecedented in other areas of therapeutics (Table 1) and has not been shown to improve coronary or total mortality.

Table 1.

Estimated ED50 and approved doses of preventive cardiovascular drugs

	ED50 a (mg)	Approved doses (mg) (tablet strengths)	Approved doses as a ratio of ED50
Original statins
Simvastatin	15	5–80	0.3–5.3
Lovastatin	20	10–40	0.5–2
Pravastatin	40	10–80	0.25–2
Cerivastatin	0.1	0.05–3	0.5–3
Newer statins
Atorvastatin	2	10–80	5–40
Rosuvastatin	1	5–40	5–40
Ezetimibe	0.3	5–10	17–33
Triglyceride lowering Rx
Fenofibrate	150	67–267	0.4–1.8
Niacin	500	500–3000	1–6
Antiplatet Rx
Aspirin	40	50–100	1.2–2.5
Clopidogrel	30	75	2.5
Antihypertensive Rx
Hydrochlorothiazide	10	12.5–25	1.2–2.5
Spironolactone	10	25–50	2.5–5
Metoprolol	30	50–100	1.6–3.3
Amlodipine	2	5–10	2.5–5
Irbesartan	50	75–300	1.5–6
Moxonidine	300	200–400	0.7–1.3

^a

ED50 = the mean population dose necessary for half the maximum possible drug effect, estimated from published dose response data and based on:

• – LDL reduction for statins (Table 2, Law et al 10) and ezetimibe 47
• – triglyceride reduction for fenofibrate and niacin
• – platelet aggregation for antiplatelet agents
• – blood pressure reduction for antihypertensive drugs.

Table 2.

Statin dose–response. RCTs of statin vs. placebo which recruited >2000 participants

Rosuvastatin equivalent dose (mg)			% reductions in:
					Mortality
	Study (year completed)	Statin a	LDL	AMI	Coronary	Total
1b	12 MEGA 2004	P	−15	−48	−46	−28
	13 LIPID 1997c	P	−25	−28	−24	−22***
	14 AFCAPS 1996	L	−25	−40	−27	+4
	15 WOSCOPS 1996	P	−26	−31	−28	−22
	16 ALLHAT 2002	P	−28	−15	−1	−1
	6 CARE 1996c	P	−32	−25	−20	−9
	17 PROSPER 2002	P	−34	−13	−24	−3
	Mean (weighted)		−26	−28	−23	−12
	Median		−26	−28	−24	−9
	Range		−15 to −34	−13 to −48	−1 to −46	+4 to −28
2.5	34 HPS 2001c	S	−30	−38	−17	−13***
2	5 4S 1994c	S	−35	−30	−42	−30***
5	54 ASCOT 2002	A	−35	−36	−10	−13
10	55 HOPE‐3 '16	R	−27	−35	−11	−7
20	8 ALLIANCE 2002c	A	−34	−48	−31	−8
20	18 JUPITER 2008	R	−50	−54	−24	−20*

Listed in order of Dose and LDL reduction

^* P < 0.05,

^*** P < 0.001, for total mortality/survival

^a pravastatin P, lovastatin L, simvastatin S, atorvastatin A, rosuvastatin R

^b 20 mg lovastatin and 40 mg pravastatin (and rosuvastatin 1 mg) are all close to ED50 and reduce LDL‐cholesterol by about 1.4 mmol l⁻¹. Studies listed in order from least to greatest lowering of LDL.

^c ‘Secondary’ prevention trials

Cardiovascular event reduction with cholesterol‐lowering in the published statin clinical trials is less than that predicted by the epidemiology 3, possibly because of unintended on‐ and off‐target adverse events. The absolute increase in survival (reduction in total mortality) was a modest 0.5% in primary prevention and 1.8% in secondary prevention studies 2. The older statin products, simvastatin and pravastatin, at doses near ED50 (Tables 1 and 2) have been the most studied. Compared to placebo, there is a relative risk reduction (RRR) of AMI of over 25% and total mortality of about 10% (Table 2) 6, 12, 13, 14, 15, 16, 17. The reduction in LDL plateaus with increasing dose 8, 18 and above about five‐fold ED50, there is no further reduction in coronary or total mortality (Tables 2 and 3) 19, 20, 21, 22, 23, despite reported increases in angiographic coronary lumen diameter 24.

Table 3.

Trials comparing established and high statin dose

TRIAL Statin (mg)	Study duration (years)	AMI a (%) (% reduction)	Coronary mortality (%)	Survival (%)	ALT b (%)	Myopathy (%)	Rosuvastatin equivalent daily dose b (mg)
19 SEARCH (n = 12 064)	6.7
Simvastatin 20		7.7	7.3	83.9	2.9	0.03	1.3
Simvastatin 80		6.6	7.4	84.0	4.3	0.88	5
(4‐fold)		(14%) P < 0.05	NS	NS	NS	P < 0.0001
20 A to Z (n = 4497)	2.0
Simvastatin 20		7.4	(5.4)c	93.3	0.4	0.04	1.3
Simvastatin 80		7.1	(4.1)	94.5	0.9	0.44	5
(4‐fold)		(4%) NS	NS	NS	P = 0.05	P = 0.02
21 TNT (n = 10 001)	4.9
Atorvastatin 10		6.2	2.5	94.4	0.2	4.8	5
Atorvastatin 80		4.9	2.0	94.3	1.2	4.7	40
(8‐fold)		(21%) P = 0.004	NS	NS	P < 0.001	NS
22 IDEAL (n = 8888)	4.8
Simvastatin 20		7.2	4.0	91.6	0.11	1.1	1.3
Atorvastatin 80		6.0	3.9	91.8	0.97	2.2	40
(30‐fold)		(17%) P = 0.02	NS	NS	P < 0.001	P < 0.001
25 PROVE‐IT TIMI (n = 4162)	2.0
Pravastatin 40		7.4	1.4	96.8	1.1	2.7	1
Atorvastatin 80		6.6	1.1	97.8	3.3	3.3	40
(40‐fold)		(11%) NS	NS	NS	P < 0.001	NS

All patients had symptomatic coronary disease.

NS = not significant

^aConfirmed acute myocardial infarction

^bALT = alanine transferase > three‐fold upper limit of reference range

^ccardiovascular mortality as coronary mortality not specified

Total mortality, or survival, summarizes risk and benefit and is the most uncontentious and robust outcomes endpoint 1. Cerebral haemorrhage doubled and total mortality increased in the Multiple Risk Factor Intervention Trial (MRFIT) at total cholesterols below 4.5 mmol l⁻¹ (LDL‐cholesterol just under 3 mmol l⁻¹), despite lower coronary mortality 25.

For comparison, there are many more antihypertensive clinical drug trials, and blood pressure lowering appears to have greater benefits 26. Doses of up to about four‐fold ED50 of each of the main antihypertensive drug classes (Table 1) reduced coronary events and cardiac failure by over 20%, stroke by over 30% and total mortality by a mean of 13% 26. Statins effectively reduce atheroma‐related ischaemic events, in particular coronary disease 10, whilst antihypertensive drugs in addition also reduce cardiac failure, all stroke 26, progression of renal failure and retinopathy.

High multiples of ED50 have no precedent in preventive cardiovascular pharmacotherapy

Cholesterol is one contributing factor in cardiovascular disease which is most effectively reduced when a sufficient dose of statin is used in combination with other preventive measures, such as smoking cessation, weight loss and exercise. However, statins are prescribed across a 160‐fold dose range (0.25‐ to 40‐fold ED50), as illustrated by the use of 10 mg of pravastatin compared to 40 mg of rosuvastatin (Table 1). In contrast, clopidogrel is used in coronary disease at just one dose. It is unclear how much the wide range of statin dose is explained by lipid levels, clinician uncertainty about the importance of cholesterol, statin toxicities or marketing.

Four statins dominate the market. Simvastatin (10–40 mg) and pravastatin (20–80 mg) were approved in 1991. Atorvastatin (10–80 mg doses approved in 1996) and rosuvastatin (5–40 mg doses approved in 2003), have half‐lives at least ten‐fold longer than earlier statins. Despite their consequent ten‐fold greater potency, the newer statins were licensed across a similar dose range and were marketed at doses of up to 40‐fold ED50 (Table 1). The incremental benefits on lipoprotein profile and coronary events with high intensity pharmacotherapy assisted manufacturer promotion in an increasingly crowded statin market. However, being a competitive enzyme inhibitor, the efficacy of statins plateaus at doses around four‐fold their ED50, whilst a range of adverse events emerge and continue to increase at higher doses. Acknowledgement of the efficacy and safety of statin doses near ED50 was behind the approval of simvastatin 10 mg as an over‐the‐counter pharmacy medicine in the UK in 2004. The use of atorvastatin and rosuvastatin at maximum licensed doses could alter the risk–benefit ratio and should be supported by favourable comparative dosing trials.

Increases in statin doses since their introduction are in contrast to the reductions seen in doses of many other drugs in preventive cardiology 27, which are now recommended between about one‐quarter and four‐fold their ED50 (Table 1). Aspirin, with an ED50 of around 40 mg, is recommended in most countries in symptomatic coronary and cerebrovascular disease at 75 mg 28, in contrast to use in the past, for example in transient ischaemic attack, at doses of up to 650 mg. Antihypertensive agents are employed at lower doses, in combination 26. Metformin improves cardiovascular outcomes and mortality in type 2 diabetes mellitus and is used only below its mean population ED50, 2 g 29. Moxonidine 3 g daily increased mortality in Phase II study 30 and is now recommended around its ED50, 300 μg. Fenofibrate was evaluated in clinical trials at up to 600 mg daily but is now recommended at doses around its ED50, 150 mg.

Statins should undoubtedly be introduced after coronary disease becomes symptomatic, but it may not be prudent to begin with high doses. High dose statins are used in acute coronary syndrome on the basis of just two sizeable clinical studies 31, neither of which demonstrated improved survival when compared to doses of around ED50 19, 20, 21, 22, 23. Compared to placebo/usual care, a Cochrane systematic review of all 18 relevant studies, over a range of statin doses in acute coronary syndrome, failed to demonstrate a significant impact by 4 months on AMI, stroke or survival 32. There was a 24% reduction in unstable angina but this is usually managed with vasodilators.

Systematic review has shown that statin benefits increase over time. The RRR in coronary events with a 1 mmol l⁻¹ lowering of LDL achieved with about 5 mg of simvastatin, increased from around 10% by the end of the first year, to up to 30% after 3 years 10. Long‐term statin treatment of familial hypercholesterolaemia can be remarkably effective. A mean dose of around three‐fold ED50 reduced coronary events by 76% in a frequently cited long‐term cohort study 33.

Efficacy plateaus, safety does not

Twelve placebo‐controlled primary and secondary prevention statin trials (Table 2) recruited more than 2000 patients without major comorbidities. Participants were treated for 4.5–6.2 years, probably sufficient to give reliable estimates of efficacy and safety. Survival increased with convincing statistical significance in only three studies, 4S 4, HPS 34 and LIPID 13 (all P < 0.001). Most of these patients had a history of coronary disease and the doses used (pravastatin 40 mg, simvastatin 20 or 40 mg) were between ED50 and three‐fold ED50 (Table 1). This appears to represent the peak in survival benefit, as no other clinical trials, at any dose, have demonstrated greater reductions in total mortality and none with such convincing statistical significance.

Most trials were conducted with statin doses around ED50 (Table 2) but many commentators have attempted to extrapolate coronary and other benefits with higher doses based on meta‐analysis 35. More robust meta‐regression analysis shows that nonlinear modelling of statin dose response provides a better fit and reveals that reduction of LDL by more than 1 mmol l⁻¹ is associated with almost no further reduction in major vascular events 36.

The reported incidence of adverse event in statin trials depend significantly on participant selection and methods of ascertainment. Exclusion criteria and recruitment in clinical trials favours a younger population with fewer comorbidities. Individuals known to be intolerant of statins, or who experienced adverse events during study run‐in, were excluded from participation in statin clinical trials.

Independent audits and earlier randomized clinical trials have reported frequent adverse events 37. It is not clear if some of these events are due to the lower cholesterol concentrations, or off‐target effects. Adverse events can occur early and may persist, for example, myalgia (prevalence of up to 29% 38) and neurocognitive impairment 39. Other adverse events can develop later, for example cerebral haemorrhage 10 (in up to 1% of patients 40) and new diabetes mellitus 41. Some adverse events may be cumulative, for example liver dysfunction (seen in over 2% 23) and cataracts (about 3% 37). Statins worsen pre‐existent renal impairment in up to 33% of patients 42, not acknowledged until relatively recently and perhaps may similarly exacerbate common fatty and other liver disease.

Adverse events may overshadow statin benefits. For example, the 15% RRR of ischaemic stroke incidence with statin pharmacotherapy in meta‐analysis is partially offset by a 19% increase of less common haemorrhagic stroke 10. This may be an on‐target effect as low cholesterol in the population is also associated with increased cerebral haemorrhage 25. Statin myopathy increases with dose 43, by up to 11‐ to 29‐fold as simvastatin dose is increased from around ED50 to up to five‐fold ED50 19, 20 and liver dysfunction by up to three‐ to nine‐fold as atorvastatin is increased to up to 20‐fold ED50 21, 22, 23 (Table 3). Such striking escalations of toxicity with statin doses many multiples of ED50 may have been overlooked related to different methodologies and populations in some clinical trials, all of which were principally designed and powered to demonstrate efficacy.

Adverse events increase with dose 44 (Table 3). The dose required for 50% expression of any given adverse event is the toxic dose 50 (TD50), usually above the ED50. The difference between the TD50 and ED50 defines the therapeutic window, or therapeutic index. Efficacy endpoints are commonly amalgamated in publications from cardiovascular trials to best emphasize benefits, for example combining coronary events with stroke and cardiovascular mortality as a common primary endpoint. These publications fail to balance combined benefits against any similar composite estimates of safety, based on the wide range of known statin toxicities, which distorts the analysis in favour of benefit 2. A composite of the full range of adverse events may leave little or no therapeutic window in many patients. Up to two‐thirds of patients discontinue statins 45. Any adverse event may be perceived by patient or clinician as unacceptable with life‐long pharmacotherapy. Although toxicity may resolve after drug cessation, statin benefits are only likely to accrue if therapy is continued. Some adverse events may abate when statin dose is lowered, probably better than taking no statin at all.

Dose comparison trials

The comparative efficacy of higher statin doses has been addressed in five large clinical trials 19, 20, 21, 22, 23 in which participants were randomized to high dose (up to 40‐fold ED50) or usual dose (up to five‐fold ED50) statin and followed for 2–6.7 years, summarized in Table 3. Neither coronary nor total mortality were reduced with high compared to usual statin doses. High doses reduced AMI by only 4–21%, consistent with plateauing of statin efficacy.

The lower lipid levels achieved in some of these high dose statin studies were interpreted by some alongside epidemiology as treatment targets, even though the studies were not designed to define a target LDL. Coronary angiographic improvement correlates best with percentage reduction, rather than achieved concentration of LDL 46. The most recent US Guidelines (2013 and 2016) emphasized percentage reduction of LDL but stated that the Expert Panel was unable to find RCT evidence to support continued use of specific LDL‐C or non‐HDL‐C treatment targets 1, which concurs with the UK National Institute of Health and Care Excellence (NICE) guidelines.

Similarly, further reduction of LDL with the addition of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6816 10 mg daily (a high dose given that its ED50 is around 0.3 mg 47) to statin for 6 years reduced AMI a further 13% but with no improvement in survival or coronary mortality in this well powered study 48, possibly because of unspecified toxicity.

The addition of the PCSK‐9 inhibitor, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7343, to statin in the recent FOURIER study lowered LDL by 59% and AMI by 27% (absolute risk by 1.2%) in the high‐risk cohort studied 49. This benefit appears smaller than the reductions of LDL and AMI seen with the statins over a wide dose range, for example 30% and 38%, respectively, in HPS 34 and 50% and 54% in JUPITER 18 and are consistent with the known plateau of reductions in coronary disease at lower LDL concentrations 25. Total mortality was 12% and 20% lower on statin compared to placebo in HPS and JUPITER, respectively. In contrast, cardiovascular and total mortality increased by 5% and 4%, respectively, with the addition of evolocumab to statin in the larger FOURIER study 49.

Conclusion

After a first AMI, the risk of a second AMI by 1 year is just over 6% and by 7 years, around 15% 50. Statins at around ED50 reduce this by about one‐third and have their place alongside the other available preventive pharmacotherapies, such as antihypertensive and antithrombotic agents, which can each reduce coronary events by around 20%. Statin doses above their ED50 have diminishing impact on cholesterol concentrations and coronary events. Higher doses have not been shown to increase survival. The wide range of dose‐related adverse events is of particular concern given that treatment is intended for decades.

Statin dosing should be governed by the pharmacological principles that would apply to any competitive enzyme inhibitor. The ED50 for an individual will vary with body size and pharmacokinetics around the mean population ED50. However, even in high‐risk patients, efficacy–benefit considerations appear unlikely to favour doses above five‐fold ED50, for example 10 mg of atorvastatin, similar to the other preventive cardiovascular drug therapies. Maximum coronary risk reduction is likely to be achieved when the different pharmacotherapies are combined with smoking cessation, weight reduction and increased exercise. Higher statin doses appear unnecessary and risk safety, tolerability and compliance. There are compelling grounds to lower the doses of the newer, more potent statins, and this has major implications for current teaching, guidelines and practice.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 51, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 52, 53.

Competing Interests

All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare no other support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. The views expressed in this paper are those of the authors and do not reflect the official policy or position of the University of Western Australia.

Dimmitt, S. B. , Stampfer, H. G. , and Warren, J. B. (2018) The pharmacodynamic and clinical trial evidence for statin dose. Br J Clin Pharmacol, 84: 1128–1135. doi: 10.1111/bcp.13539.