LANDMARK STUDY

BENEDICT: primary prevention of

microalbuminuria in hypertensive type 2
diabetes
Bergamo NEphrologic Diabetes Complication Trial (BENEDICT).

N Engl J Med 2004;351:1941-51. Location: Italy

Key words: type 2 diabetes, microalbuminuria, nephropathy, hypertension, trandolapril.

JITEN VORA,1 CLIVE WESTON2

O ED S
Trial conclusions ally to microalbuminuria (incipient nephropathy) and thereafter

PR IT EW
B
ENEDICT is the first large scale trial to demonstrate that 2.8% proceed to proteinuria (overt nephropathy).5 Although a
development of microalbuminuria can be reduced in significant proportion develop end-stage renal disease, almost all

D
hypertensive patients with type 2 diabetes and normal uri- proteinuric patients die prematurely of CV disease.3,5 Indeed,

N IM IN

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nary albumin excretion.1 The renoprotective effect of the ACE albuminuria is independently associated with elevated CV mor-
IO ) L ED
inhibitor trandolapril observed in this trial was not enhanced by tality risk across the continuum from normal to overt proteinuria

BI
the addition of the non-dihydropyridine calcium channel blocker levels, with the level of CV risk rising as albuminuria increases.6 In

HI
CT TES M

verapamil. Moreover, reduction in the onset of microalbuminuria
exceeded expectations based upon reduction of BP alone. Given
the alarming CV mortality and nephropathy associated with
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the UKPDS, the annual death rates due to CV disease for subjects
with microalbuminuria, macroalbuminuria and elevated plasma
creatinine/renal replacement therapy were 2.0%, 3.5% and

microalbuminuria, BENEDICT adds to an already compelling case 12.1% respectively.3 Sadly, 32% of type 2 diabetic patients with
for ACE inhibition as a first-line antihypertensive therapy in type microalbuminuria perish within a period of only five years.4
2 diabetes. As witnessed in large scale, randomised, controlled trials such
PR (DI RI

as IRMA-2 and MICRO-HOPE (with respect to existing microalbu-

PY

Aims/purpose minuria) as well as IDNT and RENAAL (with respect to proteinuria),

The World Health Organisation estimates that if the current epi- inhibitors of the RAS that both lower BP and significantly reduce
CO

demic continues, by the year 2030, 370 million people will be
affected by type 2 diabetes worldwide.2 Over a lifetime of type 2
diabetes, approximately 50% of patients develop microalbumin-
uria.3 The cross-sectional prevalence of microalbuminuria is 25%
in Caucasian populations but is much higher in ethnic groups.4
Depending on the geographical location, 20–40% of patients
with type 2 diabetics develop nephropathy, as defined by persis-
RE
albuminuria can delay the progression of renal dysfunction to
nephropathy and thereafter towards end-stage renal disease in
type 2 diabetics.7-10 Similar, if somewhat less conclusive data for
albuminuria reduction are also available for non-dihydropyridine
calcium channel blockers, most notably in combination with an
ACE inhibitor.11 Although there are as yet no data from prospec-
tive trials examining whether urinary albumin reduction directly

tent proteinuria, hypertension and an inexorable decline in renal
function (glomerular filtration rate). Abnormal renal function and
urinary protein excretion carry ominous health risks.3 An elo-
quent evaluation of UAE in the UKPDS demonstrated that fol-
lowing diagnosis, 2% of type 2 diabetic patients progress annu-
1
Royal Liverpool University Hospitals, Link 7C, Prescot Street, Liverpool,
L7 8XP, UK.
2
Singleton Hospital, Sketty, Swansea, SA2 8QA, UK.
Correspondence to: Dr Jiten Vora
Royal Liverpool University Hospitals, Link 7C, Prescot Street, Liverpool,
L7 8XP, UK.
Tel: +44 (0)151 706 3470; Fax: +44 (0)151 706 5870
E-mail: jiten.vora@rlbuht.nhs.uk
Br J Diabetes Vasc Dis 2006;6:84–8
reduces CV risk, a recent post-hoc analysis of RENAAL has indi-
cated that albuminuria reduction appears to provide long-term CV
protection, and cardiovascular protection was observed only in
those patients with reduced proteinuria.12 The weight of indirect
evidence is such that some authors suggest albuminuria is not
only a CV risk factor but may also be an important target for ther-
apy.6,12
BENEDICT is the first large scale-trial designed to examine
whether ACE inhibitors and non-dihydropyridine calcium chan-
nel blockers, alone or in combination, can prevent the develop-
ment of microalbuminuria in hypertensive type 2 diabetic
patients with normal urinary albumin excretion at baseline.1
Design
Following a six-week wash out of any existing antihypertensive

84 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

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 LANDMARK STUDY

Abbreviations Acronyms

ACE angiotensin-converting enzyme BENEDICT Bergamo NEphrologic Diabetes Complication Trial

ARBs angiotensin receptor blockers EUCLID EURODIAB Controlled Trial of Lisinopril in Insulin Dependent
BMI body mass index Diabetes
BP blood pressure IDNT Irbesartan Diabetic Nephropathy Trial
CV cardiovascular IRMA-2 Irbesartan in Reduction of Microalbuminuria in Type II study
HbA1C haemoglobin A1C MICRO-HOPE The Microalbuminuria, Cardiovascular, and Renal Outcomes
RAS renin-angiotensin system – Heart Outcomes Prevention Evaluation substudy
SR sustained release NICE National Institute for Clinical Excellence
UAE urinary albumin excretion RENAAL Reduction of Endpoints in NIDDM with the Angiotensin II
Antagonist Losartan
UKPDS United Kingdom Prospective Diabetes Study

inhibitors of the RAS system and a three-week wash out of any

non-dihydropyridine calcium channel blockers, this multicentre,
prospective, double-blind, parallel group study randomised both trandolapril treatment groups clearly separated from place-
1,209 eligible subjects to one of four treatments: the non-dihy- bo after three months and continued to diverge through the
dropyridine calcium channel blocker verapamil (in a SR formula- study (figure 1A). In contrast, the effect of verapamil alone, was

O ED S
tion) 240 mg/day; the ACE inhibitor trandolapril 2 mg/day; the similar to that of placebo and not statistically significant (figure

PR IT EW
combination of verapamil SR 180 mg/day plus trandolapril 2 1B). Although, there were consistent reductions in average
mg/day; or placebo. The target BP was 120/80 mmHg, with trough systolic and diastolic BPs in all four arms of the study

D
additional antihypertensive drugs permitted as needed in the (average trough systolic/diastolic BPs throughout the study in the

N IM IN

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sequence: diuretics, alpha- or beta-blockers, minoxidil or long- verapamil, trandolapril, trandolapril plus verapamil and placebo
IO ) L ED
acting dihydropyridine calcium channel blockers. All patients arms were 141/82, 139/81, 139/80 and 142/83 mmHg respec-

BI
continued to receive usual care for diabetes. BP was evaluated at tively, compared to an average of 151/87.5 mmHg at baseline),

HI
CT TES M

randomisation, after one week, one month and every three
months, whilst UAE and other laboratory values were measured
at randomisation and every six months thereafter.
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with small significant differences between the trandolapril (with
or without verapamil) and placebo groups (p≤0.002), the reno-
protective effect of trandolapril exceeded expectations based on

reduction in BP alone. Indeed, the delay in onset of microalbu-

Patients and criteria minuria in both trandolapril groups remained significant, even
Eligible patients were aged ≥ 40 years (mean age at baseline: 62 after separate adjustment for systolic and diastolic BP at follow
PR (DI RI

years), with a history of hypertension (mean BP at baseline: up visits (p<0.04).

PY

151/88 mmHg) and type 2 diabetes (mean known duration at

baseline 7.9 years). All subjects had normal UAE < 20 µg/min in Commentary
CO

at least two of three consecutive overnight urine samples), nor-
mal renal function (mean serum creatinine at baseline 0.9 mg/dL)
and their mean BMI and HbA1C values were 29 kg/m2 and 5.8%
respectively, at baseline.
End points
The primary end point was the development of persistent
RE
The conclusion of the BENEDICT study is that ACE inhibitor ther-
apy with trandolapril, alone or in combination with verapamil,
can prevent the onset of microalbuminuria in hypertensive type
2 diabetic patients with normal UAE. This represents the first
large-scale, adequately powered study to report of the primary
prevention of microalbuminuria with any antihypertensive agent
in this patient group. Slowed onset of microalbuminuria has

microalbuminuria, defined as UAE 20–200 µg/min in at least two
of three overnight urine collections, confirmed at clinic visits two
months apart.
Results
One thousand, two hundred and four patients were followed up
for a median of 3.6 years. Persistent microalbuminuria developed
in 5.7% of patients who received trandolapril plus verapamil,
6% who received trandolapril alone, 11.9% who received vera-
pamil alone and 10% who received placebo. After adjustment
for predefined baseline variables, trandolapril slowed the onset
of persistent microalbuminuria by 53% alone (a factor of 2.1),
and by 61% (a factor of 2.6) in combination with verapamil,
respectively compared to placebo (both p=0.01). Kaplan-Meier
curves for the percentage of subjects with microalbuminuria in
been observed in a couple of earlier, smaller scale studies with
ACE inhibitors in similar diabetic patient groups. In a six-year
study of 156 type 2 diabetic patients who were normalbuminuric
(defined as albumin excretion < 30 mg/24 hours) with mean BP
of 97 mmHg (inclusion required < 140/90 mmHg or < 107 mmHg)
at baseline, enalapril treatment resulted in an absolute risk reduc-
tion of 12.5% (p=0.042) for the development of microalbumin-
uria compared to placebo.13 Whilst, in the EUCLID study of 530
type 1 diabetic patients, more than 80% of whom were nor-
moalbuminuric with a mean BP of 121.5/79.5 mmHg at baseline,
lisinopril provided a 12.7% reduction in albumin excretion rate at
two years compare to placebo (p=0.1).14 The marked reduction in
new onset microalbuminuria in BENEDICT, assumes particular
significance, as by current BP level definitions, most patients with
type 2 diabetes are hypertensive. Additionally the size of the

VOLUME 6 ISSUE 2 . MARCH/APRIL 2006 85

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LANDMARK STUDY

Figure 1. Kaplan-Meier curves for the percentages of subjects with

microalbuminuria during treatment with trandolapril or
placebo (panel A) and during treatment with verapamil or Key messages
placebo (panel B). The difference between the trandolapril
group, and the placebo group, adjusted for prespecified
baseline covariates, was significant (p=0.01) according to the
● Albuminuria is an important CV and renal risk factor,
accelerated failure-time model. The difference between the
verapamil group and the placebo group was not significant and a potential target for therapy
(p=0.54) ● BENEDICT has shown that ACE inhibitor therapy with
trandolapril can prevent the onset of microalbuminuria
A
in hypertensive type 2 diabetic patients with normal
urinary albumin excretion
Subjects with microalbuminuria (%)

15
Placebo ● BENEDICT is the first large-scale study to demonstrate
the primary prevention of microalbuminuria in
10
hypertensive type 2 diabetes
● To address the CV/renal risks associated with progressive
5 nephropathy, BENEDICT supports early ACE inhibition in
Trandolapril
normoalbuminuric hypertensive type 2 diabetes

O ED S
PR IT EW
0
0 6 12 18 24 30 36 42 48

D
Follow-up (months)

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No. at risk study of 3,773 Chinese type 2 diabetic patients with varying
IO ) L ED
Trandolapril 301 254 237 224 207 198 188 149 104 degrees of albuminuria (from normo- through to macroalbumin-

BI
Placebo 300 229 214 203 187 176 164 136 89
uria) found that ACE inhibition was associated with a significant

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B 59% reduction in mortality for the entire study group.17 Current

NICE guidelines already recommend ACE inhibitors as the anti-
Subjects with microalbuminuria (%)

15
hypertensive class of first choice in type 2 diabetic patients with
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Verapamil existing microalbuminuria or proteinuria.18 BENEDICT suggests

10 that this recommendation may usefully be extended to encour-
age early ACE inhibition in normoalbuminuric hypertensive type
PR (DI RI

2 diabetes, with the aim of preventing the onset of microalbu-

Placebo
PY

5
minuria, and reducing CV mortality and end-stage renal disease.
CO

0 References
0 6 12 18 24 30 36 42 48 1. Ruggenenti P, Fassi A, Ilieva AP et al. Preventing microalbuminuria in type
2 diabetes. N Engl J Med 2004;351:1941-51.
Follow-up (months)
2. Wild S, Roglic G, Green A et al. Global prevalence of diabetes. Estimates
No. at risk for the year 2000 and projections for 2030. Diabetes Care 2004;27:
Verapamil 303 234 210 202 189 181 174 134 98 1047-53.
Placebo 300 229 214 203 187 176 164 136 89
3. Adler AI, Stevens RJ, Manley SE et al. Development and progression of
nephropathy in type 2 diabetes: The United Kingdom Prospective
Adapted from reference 1
RE

Diabetes Study (UKPDS 64). Kidney International 2003;63:225-32.

4. The Royal College of General Practitioners Effective Clinical Practice Unit.
Guideline entitled ‘Diabetic renal disease: prevention and early manage-
ment.’ 2002 Accessed at: http://www.nice.org.uk/page.aspx?o=39385
5. Marshall SM. Review. Recent advances in diabetic nephropathy. Postgrad
hypertensive, diabetic population looks set to increase with the Med J 2004;80:624-33.
rising prevalence of type 2 diabetes and obesity. In addition, 6. de Zeeuw D. Albuminuria, not only a cardiovascular/renal risk marker,
recent data indicate that a dose-response association also exists but also a target for treatment? Kidney Int Suppl 2004;92:S2-S6.
7. Parving H-H, Lehnert H, Brochner-Mortensen J et al. The effect of irbe-
between albuminuria and risk of atherosclerosis in the general
sartan on the development of diabetic nephropathy in patients with type
population, and that it extends to levels well below that current- 2 diabetes. N Engl J Med 2001;345:870-8.
ly classified as microalbuminuria.15 8. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators.
Although there is strong evidence that both ARBs and ACE Effects of ramipril on cardiovascular and microvascular outcomes in peo-
ple with diabetes mellitus: Results of the HOPE study and MICRO-HOPE
inhibitors reduce the progression of existing micro- and macroal-
substudy. Lancet 2000;355:53-9.
buminuria, a recent systematic review indicates that, to date, 9. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect of the
there is evidence for ACE inhibitors but not ARBs of significant angiotensin-receptor antagonist irbesartan in patients with nephropathy
reduction in the burden of early CV mortality in patients with dia- due to type 2 diabetes. N Engl J Med 2001;345:851-60.
betic nephropathy.16 In addition, a recent three-year prospective Continued on page 88

86 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

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INEGY®
ezetimibe/simvastatin
ABRIDGED PRODUCT INFORMATION
Refer to Summary of Product Characteristics (SPC) before prescribing
Information about adverse event reporting can be found at
www.yellowcard.gov.uk. Adverse events should also be reported to
MSD-SP Ltd (tel: 01992 467272).
PRESENTATION: Tablets containing 10 mg ezetimibe and 20, 40 or
80 mg of simvastatin.
USES:As adjunctive therapy to diet in: Hypercholesterolaemia: in primary
(heterozygous familial and non-familial) hypercholesterolaemia or mixed
hyperlipidaemia where use is appropriate:
• patients not appropriately controlled with a statin alone
• patients already treated with a statin and ezetimibe
INEGY contains ezetimibe and simvastatin. Simvastatin (20-40 mg) has
been shown to reduce the frequency of cardiovascular events. Studies to
demonstrate the efficacy of INEGY or ezetimibe in the prevention of
complications of atherosclerosis have not been completed. Homozygous
Familial Hypercholesterolaemia (HoFH): Patients may also receive
adjunctive treatments (e.g., low-density lipoprotein [LDL] apheresis).
DOSAGE AND ADMINISTRATION: For oral administration, with or
without food. Put patients on an appropriate lipid-lowering diet and
continue during treatment. Hypercholesterolaemia: The dosage range
is 10/10 mg/day* through 10/80 mg/day in the evening. The typical dose
is 10/20 mg/day or 10/40 mg/day given as a single dose in the evening.
The 10/80 mg dose is only recommended in patients with severe
hypercholesterolaemia and high risk for cardiovascular complications.
Consider the patient’s low-density lipoprotein cholesterol (LDL-C) level,
coronary heart disease risk status, and response to current
cholesterol-lowering therapy when starting therapy or adjusting the dose.
Individualise the dose based on the known efficacy of the various
dose strengths of INEGY and the response to the current
cholesterol-lowering therapy. Make any adjustments at intervals of not
less than 4 weeks. Homozygous Familial Hypercholesterolaemia:
and gemfibrozil. If treatment with itraconazole, ketoconazole,
erythromycin, clarithromycin or telithromycin is unavoidable, suspend
therapy with INEGY during the course of treatment. The risk of
myopathy and rhabdomyolysis is also increased by concomitant use of
other fibrates, lipid-lowering doses (≥1 g/day) of niacin or by
concomitant use of amiodarone or verapamil with higher doses of
INEGY. There is also a slight increase in risk when diltiazem is used with
the 10/80 mg dose. Concomitant intake with grapefruit juice should be
avoided. Do not exceed 10/10 mg* daily in patients receiving concomitant
medication with ciclosporin, danazol or lipid-lowering doses (≥ 1 g/day)
of niacin. Weigh the benefits of the combined use with ciclosporin,
danazol or niacin carefully against the potential risks of these
combinations. Monitor ciclosporin concentrations in patients receiving
INEGY and ciclosporin.
The combined use of INEGY at doses higher than 10/20 mg daily with
amiodarone or verapamil should be avoided unless the clinical benefit
outweighs the increased risk of myopathy. Liver enzymes: Perform liver
function tests before treatment and thereafter when clinically indicated.
Patients titrated to the 10/80 mg dose should receive an additional test
prior to titration, 3 months after titration to the 10/80 mg dose, and
periodically thereafter (e.g., semi-annually) for the first year of treatment.
Pay special attention to patients who develop elevated serum transaminase
levels. Use cautiously in patients who consume substantial quantities of
alcohol. Hepatic insufficiency: Not recommended in patients with
moderate or severe hepatic insufficiency. Other interactions:
Cholestyramine: Concomitant cholestyramine administration decreased
the mean AUC of total ezetimibe approximately 55%. The incremental
low-density lipoprotein cholesterol (LDL-C) reduction due to adding
INEGY to cholestyramine may be lessened by this interaction. Warfarin
and other coumarin anticoagulants: Very rare cases of elevated INR have
been reported. Prothrombin time should be determined before starting
Continued from page 86
10. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal
and cardiovascular outcomes in patients with type 2 diabetes and
nephropathy. N Engl J Med 2001;345:861-9.
11. Bakris GL, Weir MR, De Quattro V et al. Effects of ACE inhibitor/calcium
channel antagonist combination on proteinuria in diabetic nephropathy.
Kidney Int 1996;50:1641-50.
12. de Zeeuw D, Remuzzi G, Parving H-H et al. Albuminuria, a therapeutic
target for cardiovascular protection in type 2 diabetic patients with
nephropathy. Circulation 2004;110:921-7.
13. Furtner M, Kiechl S, Mair A et al. Urinary albumin excretion is indepen-
dently associated with carotid and femoral atherosclerosis in the general
population. Euro Heart J 2005;26:279-87.
14. Ravid M, Brosh D, Levi Z et al. Use of enalapril to attenuate decline in
renal function in normotensive, normoalbuminuric patients with type 2
diabetes mellitus. Annals Int Med 1998;128:982-8.
15. The EUCLID study group. Randomised placebo-controlled trial of lisino-
pril in normotensive patients with insulin-dependent diabetes and nor-
moalbuminuria or microalbuminuria. Lancet 1997;349:1787-92.
16. Strippoli GFM, Craig M, Deeks JJ et al. Effects of angiotensin converting
enzyme inhibitors and angiotensin II receptor antagonists on mortality
and renal outcomes in diabetic nephropathy: systematic review. BMJ

O ED S
The recommended dosage is 10/40 mg/day or 10/80 mg/day in the INEGY and frequently enough to ensure that no significant alteration of
evening. May be used as an adjunct to other lipid-lowering treatments prothrombin time occurs. Fibrates: concomitant use not recommended. 2004;329:828-31.

PR IT EW
(e.g., LDL apheresis). Coadministration with other medicines: Bile acid *The 10/10 mg tablet is not marketed in the UK. This dose can be met by
sequestrants: dosing should occur either ≥2 hours before or ≥4 hours after co-administering 10 mg of each of ezetimibe and simvastatin. 17. So WY, Ozaki R, Chan NN et al. Effect of angiotensin-converting enzyme
SIDE EFFECTS: Refer to SPC for complete information on side effects. inhibition on survival in 3,773 Chinese type 2 diabetic patients.

D
administration of a bile acid sequestrant. Amiodarone or verapamil: the
dose should not exceed 10/20 mg/day. Ciclosporin or lipid-lowering doses Clinical Studies: The frequencies of adverse events are ranked according
to the following: Very common (≥ 1/10), Common (≥ 1/100, Hypertension 2004;44:294-9.

N IM IN
(≥1 g/day) of niacin: the dose should not exceed 10/10 mg/day*.

Diltiazem: do not exceed 10/40 mg unless clinical benefit outweighs
increased risk of myopathy and rhabdomyolysis. Use in elderly:no dosage
adjustment required. Use in children and adolescents: not recommended.
TE
< 1/10), Uncommon (≥ 1/1000), < 1/100), Rare (≥ 1/10,000, 18. NICE. Inherited guideline H, 2002. Management of type 2 diabetes –
< 1/1000), Very rare (< 1/10,000) including isolated reports. INEGY:
management of blood pressure and blood lipids. Accessed at: http://
IO ) L ED
Nervous system disorders: Common: headache. Gastro-intestinal

BI
Use in hepatic impairment: no dosage adjustment required in mild hepatic disorders: Common: flatulence. Musculoskeletal, connective tissue, www.nice.org.uk/page.aspx?o=38551
insufficiency (Child Pugh score 5 to 6). Not recommended in patients with and bone disorders: Common: myalgia: Laboratory values:
The incidence of clinically important elevations in serum transaminases

HI
moderate (Child Pugh score 7 to 9) or severe (Child Pugh score >9) liver
CT TES M

dysfunction. Use in renal impairment: no dosage adjustment required in
moderate renal insufficiency. If treatment in patients with severe renal
insufficiency (creatinine clearance ≤30 ml/min) is deemed necessary,
(ALT and/or AST ≥3 X ULN, consecutive) was 1.7% for patients treated
with INEGY. Clinically important elevations of CK (≥10 X ULN) were
seen in 0.2% of the patients treated with INEGY. Post-marketing
experience: Adverse reactions reported for INEGY are consistent with
DU E T

implement dosages above 10/10 mg/day* cautiously.

CONTRA-INDICATIONS: Hypersensitivity to ezetimibe, simvastatin, those previously reported with ezetimibe and/or simvastatin. In addition to
O AB GH

or to any of the excipients. Pregnancy and lactation. Active liver disease or
unexplained persistent elevations in serum transaminases. Concomitant
administration of potent CYP3A4 inhibitors (e.g., itraconazole,
ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease
the above, other side effects reported with one of the individual components
may be potential undesirable effects with INEGY. Ezetimibe: Blood and
lymphatic system disorders: Very rare: thrombocytopaenia.
Gastro-intestinal disorders: Common: abdominal pain, diarrhoea.
Rare: nausea. Very rare: pancreatitis. Hepato-biliary disorders: Rare;
PR (DI RI

inhibitors and nefazodone).

PRECAUTIONS: Myopathy/Rhabdomyolysis: In post-marketing hepatitis. Very rare: cholelelithiasis, cholecystitis. Skin and subcutaneous
experience with ezetimibe, cases of myopathy and rhabdomyolysis have tissue disorders: Rare: hypersensitivity reactions, including rash,
PY

been reported. Most patients who developed rhabdomyolysis were taking
a statin concomitantly with ezetimibe. However, rhabdomyolysis has been
reported very rarely with ezetimibe monotherapy and very rarely with the
urticaria and very rarely, angioedema. Musculoskeletal, connective
tissue disorders: Rare: arthralgia. Very rare: myopathy/rhabdomyolysis.
General disorders and administration site conditions: Common:
fatigue. Laboratory values: Rare: increased transaminases, increased
CO

addition of ezetimibe to other agents known to be associated with

increased risk of rhabdomyolysis. Simvastatin, like other HMG-CoA
reductase inhibitors, occasionally causes myopathy manifested as muscle
pain, tenderness or weakness with creatine kinase (CK) above 10 X the
upper limit of normal (ULN). Myopathy sometimes takes the form of
rhabdomyolysis with or without acute renal failure secondary to
myoglobinuria, and very rare fatalities have occurred. The risk
of myopathy/rhabdomyolysis is dose related for simvastatin.
CK measurement:CK should not be measured following strenuous exercise
or in the presence of any plausible alternative cause of CK increase. If CK
levels are significantly elevated at baseline (>5 X ULN), measure levels
again within 5 to 7 days. Before treatment: Advise all patients starting
CK. Simvastatin: Blood and lymphatic system disorders: Rare:
anaemia. Nervous system disorders: Rare: dizziness, paraesthesia,
peripheral neuropathy. Gastro-intestinal disorders: Rare: constipation,
abdominal pain, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis.
Hepato-biliary disorders: Rare: hepatitis/jaundice. Skin and
subcutaneous tissue disorders: Rare: rash, pruritus, alopecia.
Musculoskeletal, connective tissue and bone disorders: Rare:
myopathy, rhabdomyolysis, muscle cramps. General disorders and
administration site conditions: Rare: aesthenia. A hypersensitivity
syndrome has been reported rarely which included some of the following
features: angioedema, lupus-like syndrome, polymyalgia rheumatica,
dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, red blood
RE

therapy, or in whom the dose is being increased, of the risk of myopathy

and to report promptly any unexplained muscle pain, tenderness or
weakness. Exercise caution in patients with pre-disposing factors for
rhabdomyolysis. Measure CK level before starting treatment in the
following: elderly (age >70 years); renal impairment; uncontrolled
hypothyroidism; personal or familial history of hereditary muscular
disorders; previous history of muscular toxicity with a statin or fibrate;
alcohol abuse. In these situations, clinical monitoring is recommended.
If a patient has previously experienced a muscle disorder on a fibrate or a
statin, initiate treatment with caution. If CK levels are significantly
elevated at baseline (>5 X ULN), treatment should not be started. Whilst
on treatment: If muscle pain, weakness or cramps occur measure CK levels
and stop treatment if found to be significantly elevated (>5 X ULN).
If muscular symptoms are severe even if CK levels are <5 X ULN,
consider discontinuation. Discontinue if myopathy is suspected for any
other reason. If symptoms resolve and CK levels return to normal, then
re-introduction of INEGY or another statin-containing product may be
considered at the lowest dose and with close monitoring. Stop therapy
temporarily a few days prior to elective major surgery and when any major
medical or surgical condition supervenes. Measures to reduce the risk of
myopathy caused by interactions: The risk of myopathy and
rhabdomyolysis is significantly increased by concomitant use with potent
inhibitors of CYP3A4 (such as itraconazole, ketoconazole, erythromycin,
clarithromycin, telithromycin, HIV protease inhibitors, nefazodone,
whose concomitant use is contra-indicated), as well as ciclosporin, danazol
cell sedimentation rate increased, arthritis and arthralgia, urticaria,
photosensitivity reaction, pyrexia, flushing, dyspnoea and malaise.
Laboratory values: Rare: increases in =-glutamyl transpeptidase,
elevated alkaline phosphatase.
PACKAGE QUANTITIES AND BASIC NHS COST: 28 Tablets 10/20 mg:
£33.42; 28 Tablets 10/40 mg: £38.98; 28 Tablets 10/80 mg: £41.21.
Marketing Authorisation number: 10/20 mg: PL 19945/0004;
10/40 mg: PL 19945/0005; 10/80 mg: PL 19945/0006.
Marketing Authorisation holder: MSD-SP Limited, Hertford Road,
Hoddesdon, Hertfordshire EN11 9BU, UK.
Date of review of prescribing information:
POM November 2005
® denotes registered trademark of MSP Singapore Company, LLC
© Merck Sharp & Dohme Limited, 2006. All rights reserved.
References
1. Ballantyne CM, Abate N, Zhong Y, et al. Dose-comparison study of
the combination of ezetimibe and simvastatin (Vytorin*) versus
atorvastatin in patients with hypercholesterolaemia: The Vytorin
Versus Atorvastatin (VYVA) Study. Am Heart J. 2005;149:464-473.
*Vytorin is the trade name of INEGY in the USA.
2. JBS2: Joint British Societies’ Guidelines on prevention of CVD
in clinical practice. Heart 2005;91(Suppl 5):V1-V52.

BETTER TOGETHER
06-06 INY.05.GB.70056.J Date of preparation: January 2006 INE/06-245 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

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