Family Practice

Oxford University Press 2002

Vol. 19, No. 1

Printed in Great Britain

Do lipid-lowering drugs cause erectile dysfunction?

A systematic review
Kash Rizvi, John P Hampson and John N Harvey
Rizvi K, Hampson JP and Harvey JN. Do lipid-lowering drugs cause erectile dysfunction?
A systematic review. Family Practice 2002; 19: 9598.
Background. Erectile dysfunction (ED) is common although under-reported by patients. Along
with the better known causes of ED, drug-induced impotence needs to be considered as a cause
of this symptom. Lipid-lowering drugs have been prescribed increasingly. Their relationship to
ED is controversial.
Objectives. Our aim was to clarify the relationship between lipid-lowering therapy and ED. A
secondary aim was to assess the value of the sytematic review procedure in the area of adverse
drug reactions.
Methods. A systematic review was carried out using computerized biomedical databases and
Internet sources. Terms denoting ED were linked with terms referring to lipid-lowering drugs.
Information was also sought from regulatory agencies.
Results. A significant literature was identified, much from obscure sources, which included
case reports, review articles, and information from clinical trials and from regulatory agencies.
Information from all of these sources identified fibrates as a source of ED. A substantial number
of cases of ED associated with statin usage have been reported to regulatory agencies. Case
reports and clinical trial evidence supported the suggestion that statins can also cause ED. Some
information on possible mechanisms was obtained, but the mechanism remains uncertain.
Conclusions. The systematic review procedure was applied successfully to collect evidence
suggesting that both statins and fibrates may cause ED. More numerous reports to regulatory
agencies complemented more detailed information from case reports to provide a new perspective on a common area of prescribing.
Keywords. Adverse drug reactions, erectile dysfunction, fibrates, statins.

Thiazides and -blockers are well known causes, but the

situation with lipid-lowering drugs is less clear. Statins in
particular have become widely used but are not generally accepted as a cause of ED. As part of a programme
looking at the usefulness of the sytematic review procedure in the area of adverse drug reactions, we undertook
a literature search linking lipid-lowering therapy with
ED. This technique has been little used in the area of
adverse drug reactions.

Introduction
Erectile dysfunction (erectile impotence, ED) is
under-reported by patients. It may have a neuropathic,
vascular, psychogenic or endocrine aetiology. Before
initiating treatment, reversible causes needed to be
considered, including drug-induced ED. One study
surveyed 1180 men attending medical out-patients and
found that 34% reported ED.1 Of those investigated,
25% were thought to be drug induced. Many of the drugs
listed in textbooks as causing this adverse effect (e.g.
reserpine, methyl-dopa, guanethidine) are little used now,
but modern cardiovascular drugs are also candidates.

Methods
The online literature search using Datastar (Dialog
Corporation) was performed during March 1999. The
term impotence was used initially in the CROS database to detect the most relevant biomedical databases.
As a result, the complete databases of Medline, Pharmline, Embase, Toxline, Pharmline, Iowa, International
Pharmaceutical Abstracts and Biosis were examined.
The two main themes of lipid-lowering drugs and impotence

Received 5 January 2001; Revised 29 June 2001; Accepted

3 September 2001.
University of Wales College of Medicine, Wrexham Academic
Unit, Wrexham, UK. Correspondence to Dr JN Harvey,
Diabetes Unit, Gladstone Centre, Maelor Hospital, Wrexham
LL13 7TD, UK.

95

96

Family Practicean international journal

were linked together by entering the drug names (as used

in the UK) and a mixture of MESH and Emtree
thesauri terms together with free text. The same strategy
was run in each of the above databases. Results from
each were combined and duplicate entries removed. A
total of 107 references were identified in this way, the
majority (.70%) coming from Embase. Further details
of the strategy are available from the authors. All
available information (i.e. title, journal and abstract if
available) was downloaded for each reference. Using
these data, it was decided whether or not to obtain the
full article from the local library. If there was the slightest
suggestion of reference to a drug-induced reaction, the
full reference was obtained. In addition, an Internet
search was performed and regulatory agencies contacted
for further information. All articles received were scanned for relevance. Other reports were identified using
the references given by these authors.

Results
The articles obtained could be divided into four
categories:
Case reports
Cases of ED were first reported after clofibrate.2,3 Those
described by Schneider showed recovery after drug
withdrawal and recurrence on rechallenge.2 Five reports
identified seven cases of ED following gemfibrozil.48
Rechallenge confirmed the effect in two.5,6 Therapy with
bezafibrate was without adverse effect in three of these
patients, but clofibrate had a similar effect in one.4,5,8
ED in association with statins was first reported by
Halkin et al. where both lovastatin and pravastatin separately caused ED in a 57-year-old man.9 Jackson reported
five cases of ED with simvastatin at doses of 10 and
20 mg.10 Sexual function was restored within 1 week of
stopping the drug. Two patients were rechallenged and
impotence recurred. Alternative lipid-lowering therapies
(fluvastatin or fenofibrate) did not cause this effect in
these patients.
Review articles of lipid-lowering drugs and
drug-induced impotence
Several reviews of the management of ED listed
clofibrate as a cause1114 and another listed gemfibrozil.15
The adverse drug reaction bulletin listed clofibrate and
bezafibrate.16 In a substantial review of bezafibrate,
impaired libido was noted to have been seen in a number
of studies, but was rarely significant enough to require
cessation of therapy.17 A review of clinical trial experience with fenofibrate reported that erectile impotence
had been identified in ~1.3% of clinical trial patients
with use of this drug.18 No reviews listed statins as a cause
of ED. No systematic reviews have been reported
previously.

Data from clinical trials

In the 4S study, a prospective randomized trial, 37 patients
of 1814 on simvastatin developed ED, as did 28 of 1803
on placebo, a difference which was not significant. Thus
the suggestion that statins cause ED has been challenged.19 ED was not reported in other major RCTs: the
Helsinki Heart study (gemfibrozil), CARE or LIPID
(both pravastatin).2022
In a casecontrol study, Bruckert et al. investigated the
prevalence of ED in 339 patients attending a lipid clinic
compared with matched controls. Treatments with both
fibrates [odds ratio (OR) 1.46] and statins (OR 1.51)
were independent predictors of ED.23
Sexual dysfunction is prevalent in male patients
with cardiovascular disease. Measurement of nocturnal
penile tumescence (NPT) has been used to investigate
drug effects. -blockers and diuretics have been associated
with decreased NPT in some studies whereas pravastatin
and lovastatin appeared to have a beneficial effect. The
authors of these studies admit methodological difficulties.24
Information from regulatory agencies
The Australian Adverse Drug Reaction Advisory
Committee (ADRAC) reports 11 cases of ED due to
clofibrate, six due to gemfibrozil and 42 cases of ED
in association with simvastatin.25 The men affected by
simvastatin ranged in age from 43 to 72 years (median
57) and the onset occurred from 48 hours to 27 months
(median 6 weeks) after the drug was started. Simvastatin
was the only drug implicated in 35 of the reports and,
in four rechallenged, the symptom recurred. Of the
29 reports in which recovery was mentioned, 14 had
recovered after discontinuing the drug whereas in the
other 15 there had been no recovery at the time the
report was submitted. ADRAC also lists 11 reports of
gynaecomastia in association with simvastatin.26
In addition to the above letters and papers, we requested details of cases of ED on lipid-lowering therapy
reported to the UK Committee on Safety of Medicines
(Yellow Card Scheme). This identified a further 170
cases. Cases reported as ejaculatory disorder have been
included, but abnormalities of seminal fluid or sperm
production have not. Loss of libido or gynaecomastia
was reported in a few cases. Two patients experienced
ED with two hypolipidaemic drugs (separately). Data
from these reports to the CSM are given in Table 1.

Discussion
Although the numbers of cases of ED associated with
lipid-lowering therapy reported to regulatory agencies is
substantial, the information provided is sparse. Other
factors that can cause ED are likely to be present in some
patients, for example psychological influences in the postmyocardial infarction situation. Recovery after drug withdrawal is the best available confirmation of drug-induced

Erectile dysfunction and hypolipidaemic drugs

TABLE 1

Drug

Reports to the Committee on Safety of Medicines (Yellow Card Scheme) of cases of erectile dysfunction thought to be caused by
lipid-lowering drugs
No. of cases
reported

Age (years)
median (range)

Outcome

Recovered

No. of not recovered patients using another drug

known to cause ED or with other factors

Unknown

Gemfibrozil

16

56 (3869)

Bezafibrate

39

56 (3571)

24

15

Fenofibrate

56 (3765)

Ciprofibrate

18

51.5 (1864)

3: nicardipine, atenolol, cimetidine

Simvastatin

49

56 (2576)

27

22

Pravastatin

10

59 (5267)

Fluvastatin

97

58 (4466)

Atorvastatin

26

51 (4169)

16

10

Cerivastatin

55

Cholestyramine

43

Colestipol

38

2: CABG surgery, nifedipine, spirolactone

3: nifedipine, atenolol, LVF, diabetes

4: lisinopril, atenolol, diabetes

1: bendrofluazide, gemfibrozil, methyl-dopa

6: atenolol, lofepramine, ranitidine, azathioprine,

bezafibrate

The table describes total number of reports for each drug, whether erectile dysfunction had resolved at the time of reporting and, in those where it
had not, the number in whom other possible explanations are given.

adverse effect from the data that are available. This was
documented in many cases, including a majority of the
cases of ED due to both fibrates and statins reported to
the CSM. Recurrence on rechallenge was documented in
a few (although blinded rechallenge was not used).
Applying criteria suggested by Sackett and colleagues,
the relationship between this adverse drug effect and
both fibrates and statins would be classed as probably
causal.27
ED has not been reported in the major randomized
double blind trials of lipid-lowering therapy, and on this
basis the causative link has been disputed.19 However,
large trials of both fibrates and statins failed to find this
adverse effect despite the fact that evidence from other
sources for ED, following fibrate therapy at least, is
strong. Although RCTs are generally a good source of
information on adverse drug effects, ED is well known to
be under-reported by patients. It was not asked about
specifically in these trials, and without specific inquiry
we feel it is likely that no reliable picture will emerge in
the case of this particular adverse effect. On the basis
of the large number of reports to the CSM and the other
evidence cited above, we believe that all of the commonly used statins and fibrates may cause ED.
Statins inhibit the rate-limiting step of cholesterol
synthesis (HMG-CoA reductase) and hence potentially
may inhibit the synthesis of steroid hormones derived
from cholesterol, including tetosterone. There is evidence
that simvastatin causes minor changes in circulating
androgen concentrations in asymptomatic men.2830
Pravastatin and bezafibrate do not seem to have this

effect.3133 It is far from clear that this effect accounts

for reported cases of ED in patients on a variety of hypolipidaemic drugs. Gonadal hormone measurements
from men with ED on lipid-lowering therapy do not
seem to have been done except in one patient on simvastatin reported to the CSM where levels of testosterone
and sex hormone-binding globulin were low. Statins as a
class are known to undergo extensive first-pass extraction in the liver where their effect is to inhibit cholesterol
synthesis. The major route of excretion is in the bile. With
simvastatin, only 14% of drug/metabolites circulating in
plasma is active in inhibiting cholesterol synthesis.34
With atorvastatin, the systemic availability of HMG-CoA
reductase inhibitory activity is ~30%.34 Thus the potential
to inhibit steroid hormone synthesis elsewhere is limited,
although it does increase with increasing statin dose.
Although Halkin et al. suggested that ED is a class
effect of statins,9 other reports suggest that switching
to alternative lipid-lowering drugs of the same or a
different class can resolve the problem (CSM data and
reference 10). There are a number of mechanisms likely
to cause ED in treated hypercholesterolaemic patients,
including the direct effects of cardiac disease, the
psychological sequelae of a cardiac diagnosis, peripheral
vascular disease affecting the pudendal vessels, direct
effects on the brain (lipid-soluble drugs in particular),
multiple drugs and drug interactions, and effects on hormone synthesis. We feel there is sufficient evidence from
the above case reports to recommend trying a different
lipid-lowering drug, even of the same class, in such cases
of ED.

98

Family Practicean international journal

The systematic review procedure identified relevant

articles from a variety of sources. Individual case reports
provided the most detail whereas regulatory agencies
produced the largest numbers. Reviews were a measure
of what is accepted wisdom. It has not been accepted
previously that statins might cause ED. The information
compiled in this review challenges that assumption. The
frequency of reports of ED with simvastatin may be due
to its market domination rather than an increased risk
with this particular drug. The frequency with which lipidlowering drugs adversely affect sexual function is not
clear and is an area for further study. The use of statins
in particular in primary care has increased substantially
in recent years such that cases of ED may be seen more
often.35 Given the strong evidence we have of the benefit
from lipid-lowering therapy, this report should not
inhibit the use of these drugs in coronary prevention.
Switching drugs may be beneficial. Such patients should
be advised of the risk from discontinuing lipid-lowering
therapy altogether.

14

15

16

17

18

19

20

21

22

23

Acknowledgements
24

We are grateful to the Drug Alert Unit of the Committee

on Safety of Medicines for providing us with information
on reports to them. Financial support for this study was
provided by the Small Grants Scheme of the NHS Wales
Office for Research and Development.

25

26

27

References
1

10
11

12

13

Slag MF, Morley JE, Elson MK et al. Impotence in medical clinic

outpatients. J Am Med Assoc 1983; 249: 17361740.
Schneider J, Kaffarnik H. Impotence in patients treated with
clofibrate. Atherosclerosis 1975; 21: 455457.
Vogt HJ. Impotence caused by clofibrate therapy (letter). Med Klin
1976; 71: 257258.
Bain SC, Lemon M, Jones AF. Gemfibrozil-induced impotence
(letter). Lancet 1990; 336: 1389.
Pizzarro S, Bargay J, DAgosto P. Gemfibrozil-induced impotence
(letter). Lancet 1990; 336: 1135.
Bharani A. Sexual dysfunction after gemfibrozil (letter). Br Med J
1992; 305: 693.
Figueras A, Castel JM, Laporte JR, Capella D. Gemfibrozil-induced
impotence (letter). Ann Pharmacother 1993; 27: 982.
Alcala Pedrajas JN, Prada Pardal JL. Impotencia por gemfibrozil
(letter). Ann Med Inter (Madrid) 1998; 15: 175176.
Halkin A, Lossos IS, Mevaorach D. HMG-CoA reductase inhibitorinduced impotence (letter). Ann Pharmacother 1996; 30: 192.
Jackson G. Simvastatin and impotence. Br Med J 1997; 315: 31.
Wein AJ, Van Arsdalen KN. Drug-induced male sexual dysfunction.
Urol Clin North Am 1988; 15: 2331.
Whitehead ED, Klyde BJ, Zussman S, Salkin P. Diagnostic evaluation of impotence. Postgrad Med 1990; 88: 123135.
Wiles PG. Erectile impotence in diabetic men: aetiology, investigation, and management. Diabetic Med 1992; 9: 888891.

28

29

30

31

32

33

34

35

Burns-Cox N, Gingell C. Erectile dysfunction: is medication to

blame? Prescriber 1997; 5 March: 7780.
Koeneman KS, Mulhall JP, Goldstein I. Sexual health for the man at
midlife: in-office workup. Geriatrics 1997; 52: 7686.
Shetty HGM, Routledge PA. Adverse effects of hypolipidaemic
drugs. Adverse Drug Reaction Bull 1990; 142: 532535.
Monk JP, Todd PA. Bezafibrate. A review of its pharmacodynamic
and pharmacokinetic properties, and therapeutic use in hyperlipidaemia. Drugs 1987; 33: 539576.
Blane GF. Review of European clinical experience with fenofibrate.
Cardiology 1989; 76 (Suppl 1): 113.
Pedersen TR, Faergeman O. Simvastatin seems unlikely to cause
impotence (letter). Br Med J 1999; 318: 192.
Frick MH, Elo O, Haapa K et al. Helsinki Heart Study: primaryprevention trial with gemfibrozil in middle-aged men with dyslipemia. Safety of treatment, changes in risk factors, and
incidence in coronary heart disease. N Engl J Med 1987; 317:
12371245.
Sacks FM, Pfeffer MA, Moye LA et al. The effect of pravastatin
on coronary events after myocardial infarction in patients
with average cholesterol levels. N Eng J Med 1996; 335:
10011009.
The long-term intervention with pravastatin in ischaemic disease
(LIPID) study group. Prevention of cardiovascular events and
death with pravastatin in patients with coronary heart disease
and a broad range of initial cholesterol levels. N Engl J Med
1998; 339: 13491357.
Bruckert E, Giral P, Heshmati HM, Turpin G. Men treated with
hypolipidaemic drugs complain more frequently of erectile dysfunction. J Clin Pharm Ther 1996; 21: 8994.
Rosen RC, Weiner DN. Cardiovascular disease and sleep-related
erections. J Psychosom Res 1997; 42: 517530.
Boyd IW. HMG-CoA reductase inhibitor-induced impotence
(letter). Ann Pharmacother 1996; 30: 1199.
Adverse Drug Reactions Advisory Committee. Simvastatin and
adverse endocrine effects in men. Aust Adverse Drug React Bull
1995; 14: 10.
Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical
Epidemiology. A Basic Science for Clinical Medicine, 2nd edn.
Boston: Little, Brown and Company, 1991.
Stein EA, Davidson MH, Dobs AS et al. Efficacy and safety of
simvastatin 80mg/day in hypercholesterolemic patients. Am J
Cardiol 1998; 82: 311316.
Azzarito C, Boiardi L, Vergoni W, Zini M, Portioloi I. Testicular
function in hypercholesterolemic male partients during
prolonged simvastatin treatment. Horm Metab Res 1996; 28:
193198.
Rossato M, Guarneri G, Lavagnini T, Padovan D, Foresta C.
Simvastatin influences testicular steroidogenesis in man. Horm
Metab Res 1993; 25: 503505.
Jay RH, Sturley RH, Stirling C et al. Effects of pravastatin and
cholestyramine on gonadal and adrenal steroid production in
familial hypercholesterolaemia. Br J Clin Pharmacol 1991; 32:
417422.
Dobs AS, Sarma PS, Schteingart D. Long-term endocrine function
in hypercholesterolemic patients treated with pravastatin, a
new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
Metabolism 1993; 42: 11461152.
Papalia D, Maugeri D, Trovato G et al. Study of the interaction of
bezafibrate (BS 490) with some hormones of the hypophyseal
gonadal axis in metabolically healthy subjects. Rass Med Intern
1980; 1: 105116.
ABPI Compendium of Data Sheets and Summaries of Product
Characteristics 199899. London: Datapharm Publications Ltd.
Packham C, Pearson J, Robinson J, Gray D. Use of statins in general
practices, 19968: cross sectional study. Br Med J 2000; 320:
15831584.