dtb.bmj.com Dare we think the unthinkable?

Transcription

CME/CPD section inside ▶
Vol 54 | No 7 | July 2016 74 DTB Select: 7 - July 2016
78 Empagliflozin, diabetes
81 Vitamin supplementation in pregnancy
and outcomes
Dare we think the unthinkable?
The effects of higher service costs, increased demand for healthcare and
tighter budgets continue to take their toll on all parts of the health service
and are thought to be impacting on patient care. Expenditure on medicines
(one of the drivers of higher service costs) is growing in primary and
secondary care,1 and has long been targeted as an area for rationalisation.
Prescribing-related financial savings plans have been part of the NHS
landscape for over 20 years and it is appropriate that the costs associated
with the most common therapeutic intervention in the NHS should come
under close scrutiny. However, it should be remembered that the UK spends
less on pharmaceuticals than many other countries.2 Nevertheless, it will
come as no surprise that the scale of the financial crisis facing the NHS has
led to medicines optimisation teams in Clinical Commissioning Groups
(CCGs) and pharmacy departments in hospitals daring to think unthinkable
thoughts: what other areas of prescribing expenditure can be targeted to
generate savings to help safeguard healthcare services?
Radical ideas are being asked for, and consideration is being given to
removing some items from NHS prescription and supply. A number of CCGs
are withdrawing access to gluten-free foods, much to the concern of Coeliac
UK. 3 Along similar lines, the ‘decommissioning’ of bath and shower
emollients is being considered. Some CCGs have their own blacklists of
products (e.g. branded medicines where a cheaper generic is available,
combination products, cosmetic products) that should only be prescribed in
exceptional circumstances that require prior approval.4 Other initiatives
include no longer routinely prescribing a range of over-the-counter
medicines, such as those for minor short-term health problems. 5 Although
promoting self-care and supporting people to take control of managing
their own symptoms is an important and valuable long-term NHS strategy
to help manage GP workload, it may be jeopardised by a short-term need
to save money on low-cost medicines.
Within hospitals, a national review has identified areas of efficiency that
target the use of certain medicines (e.g. soluble prednisolone tablets,
biosimilars and inhaler devices).6 However, more extreme responses are
being considered, such as changing the supply of what has traditionally
been provided to patients (e.g. buy your own analgesia if attending for day
case surgery) as well as reducing the amount of medicines given
on discharge.
In the past, the term ‘postcode prescribing’ typically referred to specialised
high-cost medicines. It would seem that we are at risk of even greater
regional variation for many more types of medicine. Although the NHS has
developed robust assessment and consultation processes for adopting new
medicines, the same cannot be said of the decommissioning agenda. The
cost-effectiveness and long-term impact of many of the proposed
cost-saving initiatives will be unknown. In the past, the NHS has been slow
to recognise that some cost-saving programmes simply led to cost-shifting.
It is unrealistic to think that individual commissioning organisations are of
sufficient scale or have enough resource to model the full impact of such
plans. Dare we think that national departments of health will place greater
emphasis on a coordinated nationwide response to decommissioning
medicines? What is really needed is an honest conversation about NHS
funding and a national vision of what our health services, especially as
regards access to medicines, will and won’t provide.
1. Health and Social Care Information Centre, 2015. Prescribing costs in hospitals and the community England 2014–15 [online]. Available: http://www.hscic.gov.uk/catalogue/
PUB18973/hosp-pres-eng-201415-report.pdf [Accessed 22 June 2016].
2. The Health Foundation, 2015. Funding overview [online]. Available: http://www.health.org.uk/sites/default/files/FundingOverview_InternationalComparisons.pdf
[Accessed 22 June 2016].
3. Coeliac UK, 2015. Taking the prescriptions campaign to the House of Commons [online]. Available: https://www.coeliac.org.uk/about-us/news/taking-the-prescriptions-campaign-tothe-house-of-commons/ [Accessed 22 June 2016].
4. NHS Stockport Clinical Commissioning Group, 2016. Black & grey list [online]. Available: http://stockportccg.org/gp-members-area/medicines-management/black-grey-list/
5. Warrington Clinical Commissioning Group, 2016. Self care [online]. Available: http://www.warringtonccg.nhs.uk/your-health/self-care.htm [Accessed 22 June 2016].
6. Department of Health, 2016. Productivity in NHS hospitals [online]. Available: https://www.gov.uk/government/publications/productivity-in-nhs-hospitals [Accessed 22 June 2016].
DOI: 10.1136/dtb.2016.7.0409
To comment on material published in DTB, please email [email protected]
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DTB Select: 7 | July 2016
MHRA: avoid live vaccines in immunosuppressed patients l Topical NSAIDs for musculoskeletal pain in adults l Adherence
to pregnancy prevention measures during isotretinoin treatment l Impact of the NHS Health Check programme l Ibuprofen:
first choice for migraine in young people? l Neuropsychiatric safety of varenicline and bupropion l Effects of
anticholinergic medication in cognitively normal older adults l New NICE guidance for controlled drugs
MHRA: avoid live vaccines in
immunosuppressed patients
The Medicines and Healthcare products Regulatory Agency (MHRA)
has reminded healthcare professionals to identify clinically
significant immunosuppression in patients before administering
live attenuated vaccines.1
The reminder follows recent Yellow Card reports in which
immunosuppressed patients have received live attenuated vaccines,
resulting in severe infection and death in some cases.1 Notably, there have
been four reports regarding neonates exposed to a TNF-alpha antagonist
in utero who died from disseminated BCG or tuberculosis infection after
being given a live attenuated vaccine. Particular care is warranted for any
infant exposed to immunosuppressive treatment from the mother either in
utero or via breastfeeding. Live attenuated vaccination should be deferred
for as long as a postnatal influence on the infant’s immune status remains
possible. For example, it is suggested that for in utero exposure to
TNF-alpha antagonists and other biological medicines, live attenuated
vaccination should be considered once the infant is aged 6 months.
There have also been reports of elderly patients who received the
shingles vaccine (Zostavax) when they were possibly
immunosuppressed. The suspected adverse reactions noted on these
Yellow Card reports may have been the result of a disseminated viral
infection caused by the vaccine strain.
The MHRA reminds healthcare professionals that:
• live attenuated vaccines should not routinely be given to people who
are clinically immunosuppressed (caused by either drug treatment or
underlying illness);
• healthcare professionals who are administering a particular vaccine
must be familiar with the contraindications and special precautions
before proceeding with immunisation;
• specialists with responsibility for an immunosuppressed patient who
may be eligible for a live attenuated vaccine should include in their
correspondence with primary care a statement of their opinion on the
patient’s suitability for the vaccine;
• if primary care professionals are in any doubt as to whether a person
due to receive a live attenuated vaccine may be immunosuppressed,
immunisation should be deferred until advice from a secondary care
specialist has been sought, including advice from an immunologist if
required; and
• close contacts of immunosuppressed individuals should be fully
immunised to minimise the risk of infection of vaccine-preventable
diseases in immunosuppressed individuals.
The MHRA notes that a minor immunodeficiency may not necessarily
contraindicate vaccination, and healthcare professionals should refer to
the Summary of Product Characteristics for a particular vaccine for
specific contraindications and warnings. Healthcare professionals should
also consult Immunisation against infectious disease (the ‘Green Book’).1,2
Comment: The MHRA alert provides an important reminder of the risks
involved in administering live attenuated vaccines to those who are
clinically immunosuppressed. Healthcare professionals involved in
giving such vaccines should ensure that they have robust systems in
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place to identify all patients who are clinically immunosuppressed.
This should also include assessing the risk in infants who may have
been exposed to immunosuppressive treatment during pregnancy
or breastfeeding. Advice on managing these risks needs to form
part of routine training programmes for all those involved in
administering vaccines.
1. Medicines and Healthcare products Regulatory Agency. Live attenuated
vaccines: avoid use in those who are clinically immunosuppressed. Drug Safety
Update 2016; 9 (9): 7 [online]. Available: https://www.gov.uk/drug-safetyupdate/live-attenuated-vaccines-avoid-use-in-those-who-are-clinicallyimmunosuppressed [Accessed 22 June 2016].
2. Public Health England, 2014. Immunisation against infectious disease [online].
Available: https://www.gov.uk/government/collections/immunisation-againstinfectious-disease-the-green-book#the-green-book [Accessed 22 June 2016].
Topical NSAIDs for
musculoskeletal pain in adults
The place of topical NSAIDs in the management of musculoskeletal pain has
been subject to a long-running debate.1 Of concern has been the lack of
published evidence on topical NSAIDs either in comparison to, or in
combination with, standard treatments. An updated Cochrane review has
assessed the evidence of efficacy of topical NSAIDs for chronic
musculoskeletal pain in adults.2
This updated review included five new studies covering a total of 10,631
participants in 39 studies. All studies examined topical NSAIDs for the
treatment of pain of moderate or severe intensity in adults with osteoarthritis
(mainly of the knee), mostly against a topical placebo. For pooled analyses
the studies were generally rated as of moderate or high quality. The primary
outcome of clinical success was defined as at least a 50% reduction in pain, or
an equivalent measure, by 6–12 weeks after starting treatment. Of note, the
review specifically refers to the supposedly inert control comparator not as
‘placebo’ but as ‘carrier’. This is because the authors acknowledge the
possibility that the carrier medium in which topical NSAIDs are delivered may
itself have some analgesic properties, suggested by its consistently outperforming oral placebos in trials.
For the primary outcome, in studies lasting 6–12 weeks, topical diclofenac and
topical ketoprofen were significantly more effective than carrier for reducing
pain (around 60% of patients experienced reduced pain). With topical
diclofenac (six trials, 2,343 participants), the number-needed-to-treat (NNT)
for clinical success was 10 (95% CI 7 to 16), and with topical ketoprofen (four
trials, 2,573 participants), the NNT was 7 (5 to 9). There was insufficient
information for analysis of other topical NSAIDs compared with carrier. The
few trials that compared topical NSAIDs with oral NSAIDs found similar
efficacy (low quality-evidence).
The main adverse effect was an increase in the number of mild skin
reactions with topical diclofenac compared with carrier or oral NSAIDs,
but there was no increase with topical ketoprofen.
Clinical success with carrier occurred in about half of participants in these
studies. Both direct and indirect comparison of clinical success with oral
placebo indicates that response rates with carrier are about twice those seen
with oral placebo.
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The authors conclude that topical diclofenac and topical ketoprofen can
provide good pain relief for osteoarthritis but only for about 10% more
people than with placebo. There is no evidence for other chronic
painful conditions.
Comment: For some people with osteoarthritis, topical ketoprofen or
diclofenac may be a reasonable first-line option, particularly if it avoids or
delays the need for the use of potentially more harmful oral NSAIDs.
1. Topical NSAIDs for joint disease. DTB 1999; 37: 88-9.
2. Derry S et al. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane
Database Syst Rev 2016; 4: CD007400. DOI:10.1002/14651858.CD007400.pub3
[Last assessed as up-to-date 3 February 2016].
Adherence to pregnancy
prevention measures during
isotretinoin treatment
Oral retinoids (e.g. isotretinoin) are contraindicated in women of childbearing
potential unless the conditions of the Pregnancy Prevention Programme are
met.1 Key elements of the programme include the following:2
• All women should be made aware of the teratogenic risks before
starting treatment;
• Pregnancy must be excluded before treatment with oral retinoids;
• Pregnancy test results must be documented 3 days or less before the
prescription is issued;
• Women of childbearing potential should be on at least one, or
preferably two, complementary forms of effective contraception
(e.g. barrier and hormonal);
• Contraception should start 1 month before treatment, and should
continue throughout oral retinoid treatment and afterwards until the
retinoids have left the patient’s system; and
• Females should undergo a pregnancy assessment every 4 weeks at
follow-up appointments.
A Canadian retrospective cohort study has found adherence to pregnancy
prevention measures in female users of isotretinoin to be poor. 3 The
study assessed the effectiveness of the Canadian pregnancy prevention
programme from 1996 to 2011 in four provinces (British Columbia,
Saskatchewan, Manitoba, and Ontario) in females aged 12–48 years
taking isotretinoin for the treatment of cystic acne. The Canadian
programme stipulates that female patients taking isotretinoin fulfil
certain requirements: specifically, informed written consent, two
pregnancy tests with negative results before starting treatment and two
reliable forms of contraception during treatment.
The study focused on new courses of isotretinoin and on detected
pregnancies during isotretinoin treatment only, and up to 42 weeks after
treatment. During the study period 59,271 female patients received
102,308 courses of isotretinoin. In the 12 months before isotretinoin
treatment was started, use of oral contraceptives across the four provinces
ranged from 28.3% to 35.9%, compared with 24.3% to 32.9% during
isotretinoin treatment. Using the high specificity definition of pregnancy
(only cases with documented pregnancy outcomes), there were 186
pregnancies during isotretinoin treatment (3.1/1,000 isotretinoin users),
and using the high sensitivity definition (also including those recorded as
receiving prenatal care) there were 367 pregnancies (6.2/1,000 users).
By 42 weeks after treatment there were 1,473 pregnancies (24.9/1,000
users; high specificity definition). Of these, 1,331 (90.4%) terminated
spontaneously or were terminated by medical intervention. Among the
118 live births there were 11 (9.3%) cases of congenital malformation.
From the rates of pregnancy documented during isotretinoin use, the
study’s authors estimated that contraceptive measures during isotretinoin
treatment in Canada achieve an effectiveness of about 50% to 70%.
[The study was supported by the Institute for Clinical Evaluative Sciences,
which is funded by an annual grant from the Ontario Ministry of Health
and Long-Term Care.]
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Comment: The authors noted that other studies have reported
difficulties in modifying contraceptive use in women taking oral
retinoids and acknowledged the need to have regular reminders for
prescribers and patients. The Medicines and Healthcare products
Regulatory Agency has reminded healthcare professionals of the need
to be aware of the various measures to help avoid unnecessary
exposure to these potent teratogens during pregnancy.2 Each oral
retinoid has a specific Pregnancy Prevention Programme and details
can be found in each product’s summary of product characteristics.
1. Roaccutane 10mg Soft Capsules. Summary of product characteristics, UK. Roche
Products Limited, July 2015.
2. Medicines and Healthcare products Regulatory Agency, 2013. Oral retinoids:
pregnancy prevention—reminder of measures to minimise teratogenic risk.
Drug Safety Update 2013; 6 (11): H1 [online]. Available: https://www.gov.uk/
drug-safety-update/oral-retinoids-pregnancy-prevention-reminder-of-measuresto-minimise-teratogenic-risk [Accessed 22 June 2016].
3. Henry D et al. Occurrence of pregnancy and pregnancy outcome during isotretinoin
therapy. CMAJ [Epub ahead of print] 25 April 2016; DOI:10.1503/cmaj.151243.
Impact of the NHS Health
Check programme
New research suggests that although the NHS Health Check programme in
England has increased diagnosis of vascular disease, it is having only a
clinically modest effect upon modelled risk for cardiovascular disease (CVD)
and individual risk factors.1
Launched in 2009 by NHS England, the programme offers a check of vascular
and circulatory health every 5 years to individuals aged 40–74 years without
CVD.2 It has not been without critics, who have questioned many aspects of
the programme, including projections that it would prevent 1,600 heart
attacks, 650 deaths and 4,000 new cases of diabetes annually. 3
To assess the impact of the programme, the study analysed retrospective
electronic medical records from a randomly selected sample of 138,788 patients
eligible for the Health Check programme who were registered with 462 GP
practices from 2009 to 2013.1 Patients were grouped into Health Check
attendees and non-attendees (29,672 in each group) and matched by propensity
score to reduce observed heterogeneity. The study’s main outcomes were
modelled CVD risk score (QRISK2 algorithm, 10-year risk), individual CVD risk
factors, prescribing of relevant medicines and diagnosis of vascular diseases.
Only 21.4% of the eligible population attended for a health check.1 After a
median follow-up of 2 years, attendees had a small, but statistically
significant, absolute reduction in modelled risk for CVD compared with
propensity-matched non-attendees (–0.21%, 95% CI –0.24 to –0.19; numberneeded-to-treat=4,762 to prevent one additional cardiovascular event each
year). The reduction in modelled CVD risk was similar for all health check
attendees, regardless of pre-intervention CVD risk.
There were significant reductions in some risk factors in health check
attendees compared with matched non-attendees: systolic blood pressure
(–2.5mmHg, 95% CI –2.8 to –2.3), diastolic blood pressure (–1.5mmHg,
95% CI –1.6 to –1.3), body mass index (–0.27, 95% CI –0.34 to –0.20) and total
cholesterol (–0.15mmol/L, 95% CI –0.18 to –0.13). Statin prescribing increased
significantly after the health check (15.2%, 95% CI 12.2 to 18.1) to 39.9%
among those with baseline cardiovascular risk of 20% or greater. However,
this fell short of the World Health Organization target of 50% of individuals
with high risk for CVD receiving drug therapy.
[The study was funded by the Department of Health.]
Comment: Previously, the Department of Health calculated that the NHS
Health Check programme would require 75% coverage of the eligible
population, with statins being prescribed to 85% of high-risk attendees, to
be cost-effective.4 Limited participation rates and modest clinical benefits
among attendees, suggest that the programme has yet to achieve the
original target for cost-effectiveness and needs to be reappraised.
1. Chang KC et al. Impact of the National Health Service Health Check on cardiovascular
disease risk: a difference-in-differences matching analysis. CMAJ [Epub ahead of
print] 2 May 2016; DOI:10.1503/cmaj.151201.
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2. Public Health England, 2013. NHS Health Check implementation, review and action
plan [online]. Available: https://www.gov.uk/government/uploads/system/uploads/
attachment_data/file/224536/NHS_Health_Check_implementation_review_and_
action_plan_summary_web.pdf [Accessed 22 June 2016].
3. NHS Health Checks: time for a reality check? DTB 2016; 54: 1.
4. Department of Health, 2008. Economic modelling for vascular checks [online].
Available: http://www.healthcheck.nhs.uk/commissioners_and_providers/delivery/
making_the_case/ [Accessed 22 June 2016].
Ibuprofen: first choice for
migraine in young people?
The prevalence of migraine in children and adolescents is thought to be
between 3% and 10%.1,2 Current guidance suggests using a triptan and
an NSAID or a triptan and paracetemol for acute treatment of migraine in
those aged over 12 years. 3 A recently published Cochrane review has
assessed the effects of pharmacological treatments for adolescents
(aged 12–17 years) and children (aged <12 years).2
The review included 27 randomised controlled trials of symptomrelieving migraine medicines in children and adolescents. The trials
enrolled 9,158 participants, of whom 7,630 received medication (range of
mean age between 8.2 and 14.7 years). The primary efficacy outcome
was the percentage of participants who were pain free at 2 hours.
Twenty-four of the trials evaluated triptan drugs, with more than half
investigating sumatriptan. As a class, triptans were more effective than
placebo in three studies with 273 children (risk ratio [RR] 1.67, 95% CI 1.06
to 2.62; moderate-quality evidence) and 21 studies involving 7,026
adolescents (RR 1.32, 1.19 to 1.47; moderate-quality evidence).
Additionally, the combination of sumatriptan plus naproxen sodium was
superior to placebo in one study with 490 adolescents (RR 3.25, 1.78 to
5.94; moderate-quality evidence).
Paracetamol and oral dihydroergotamine (not licensed in the UK) were
not superior to placebo in one small study each, with 80 and 13 children
respectively. Ibuprofen, however, was more effective than placebo in
two small studies with 162 children (RR 1.87, 1.15 to 3.04; low-quality
evidence owing to imprecision).
The trials did not report any serious adverse events. However, triptans
were associated with an increased risk of minor adverse events, which
was significant in adolescents (risk difference [RD] 0.13, 95% CI 0.08 to
0.18) but not in children (RD 0.06, −0.04 to 0.17). The most commonly
reported adverse events included fatigue, dizziness, asthenia, dry mouth
and nausea or vomiting with oral preparations; and taste disturbance,
nasal symptoms and nausea with intranasal preparations.
In contrast, ibuprofen (the only other medicine showing a benefit) was
not associated with an increased risk of minor adverse events, although
the authors caution that the research was limited.
Based on these findings, the authors recommend that ibuprofen should
be the initial choice for children and adolescents with migraine.
Comment: On first reading, the conclusions of the review seem
slightly at odds with the volume and strength of the evidence
presented. Although treatment with ibuprofen was beneficial, the
combination of a triptan and naproxen appeared to produce a better
response than monotherapy. However, this was based on a study that
only included adolescents. Nevertheless, ibuprofen is a logical
first choice given that it is available over-the-counter and is licensed
for use in children. Sumatriptan nasal spray is the only triptan currently
licensed in the UK for use in children (aged 12–17 years).4 Use of a
triptan in young people should only be initiated by a clinician who has
significant experience in treating migraine.
1. Wöber-Bingöl C. Epidemiology of migraine and headache in children and
adolescents. Curr Pain Headache Rep 2013; 17: 341.
2. Richer L et al. Drugs for the acute treatment of migraine in children and
adolescents. Cochrane Database Syst Rev 2016; 4: CD005220. DOI:10.1002/14651858.
CD005220.pub2 [Last assessed as up-to-date 3 February 2016].
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3. National Institute for Health and Care Excellence, 2012. Headaches in over 12s:
diagnosis and management [online]. Available: https://www.nice.org.uk/
guidance/cg150 [Accessed 22 June 2016].
4. Imigran 10mg and 20mg Nasal Spray. Summary of product characteristics, UK.
Glaxo Wellcome UK Ltd., November 2014.
Neuropsychiatric safety of
varenicline and bupropion
Neither varenicline nor bupropion was associated with an increased risk of
neuropsychiatric adverse events in smokers with or without a psychiatric
diagnosis, the authors of a randomised controlled study have suggested.1
The trial was requested by the US Food and Drug Administration (FDA) and the
European Medicines Agency because of concerns regarding the
neuropsychiatric safety of these agents.
The double-blind, triple-dummy, placebo- and active-controlled trial stratified
8,144 smokers (aged 18–75 years, ≥10 cigarettes/day) from 16 countries into
psychiatric (clinically stable with a DSM-IV-TR diagnostic criteria for any of a
variety of mood disorders) and non-psychiatric cohorts. Participants were then
randomised to varenicline (1mg twice a day), bupropion (150mg twice a day)
or a reducing dose of nicotine replacement patch (initially 21mg/day) for
12 weeks, with a 12-week non-treatment follow-up. The primary endpoint was
the incidence of a composite measure of volunteered or observed moderate
and severe neuropsychiatric adverse events; smoking abstinence was
biochemically determined for weeks 9–12.
Among smokers who did not have a psychiatric disorder, neuropsychiatric
adverse events were reported for 1.3% of participants receiving varenicline,
2.2% with bupropion, 2.5% with nicotine replacement therapy (NRT) and 2.4%
with placebo. In the psychiatric cohort, the incidence of neuropsychiatric
events was 6.5% among participants randomised to varenicline, 6.7% for
bupropion, 5.2% with NRT and 4.9% with placebo. The increased incidence of
neuropsychiatric events reported in the psychiatric cohort was statistically
significant compared with the non-psychiatric cohort (5.8% vs. 2.1%, p<0.0001).
In the non-psychiatric cohort, the lower risk of the primary safety endpoint
among participants randomised to varenicline than to placebo was statistically
signficant (risk difference [RD] –1.28, 95% CI –2.40 to 0.15). Differences
between varenicline and NRT, and bupropion and NRT, were not significant.
The risk of the primary safety endpoint did not differ significantly in any of the
pairwise treatment analyses in the psychiatric cohort.
Participants randomised to varenicline were more likely to be abstinent than
those receiving bupropion (odds ratio [OR] 1.75, 95% CI 1.52 to 2.01), NRT (OR
1.68, 95% CI 1.46 to 1.93) or placebo (OR 3.61, 95% CI 3.07 to 4.24). Bupropion
efficacy was comparable to that of NRT (OR 0.96, 95% CI 0.83 to 1.11). Both
bupropion (OR 2.17, 95% CI 1.75 to 2.45) and NRT (OR 2.15, 95% CI 1.82 to 2.54)
were superior to placebo. Abstinence rates were numerically lower in smokers
with a psychiatric disorder than non-psychiatric smokers.
The authors note that the findings may not be generalisable to those with
untreated or symptomatically unstable psychiatric illness. In addition, they
limited the scope of the psychiatric cohort to people with mood, anxiety,
psychotic and borderline personality disorders.
[The study was funded by Pfizer and GlaxoSmithKline.]
Comment: The results of the study suggested that varenicline and
bupropion were not associated with a significant increase in
neuropsychiatric adverse events compared with NRT or placebo. Among
people using a pharmacotherapeutic intervention to try to stop smoking,
the incidence of neuropsychiatric adverse events was greater in those with
a psychiatric diagnosis (but who are clinically stable) than those without.
The findings on adverse neuropsychiatric events are generally in line with
those reported from previously published systematic reviews.2,3
Nevertheless, clinicians should be aware of the increased incidence of
neuropsychiatric events reported in the psychiatric cohort.
1. Anthenellli RM et al. Neuropsychiatric safety and efficacy of varenicline, bupropion,
and nicotine patch in smokers with and without psychiatric disorders (EAGLES):
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a double-blind, randomised, placebo-controlled clinical trial. Lancet [Epub ahead of
print] 22 April 2016; DOI:10.1016/S0140-6736(16)30272-0.
2. Cahill K et al. Nicotine receptor partial agonists for smoking cessation. Cochrane
Database Syst Rev 2016; 5: CD006103. DOI:10.1002/14651858.CD006103.pub7 [Last
assessed as up-to-date 12 May 2015].
3. Cahill K et al. Pharmacological interventions for smoking cessation: an overview
and network meta-analysis. Cochrane Database Syst Rev 2013; 5: CD009329.
DOI:10.1002/14651858.CD009329.pub2 [Last assessed as up-to-date 16 November 2012].
Effects of anticholinergic
medication in cognitively
normal older adults
The impact of drugs with anticholinergic activity on cognitive function in
older people has been widely investigated.1-3 A systematic review reported
significant decline in cognitive ability with increasing anticholinergic load.2
A new study has used various markers of brain function to assess the
effects of drugs with anticholinergic activity on cognition, brain atrophy
and brain metabolism in cognitively normal older adults (mean age 73
years), using neuroimaging biomarkers and cognitive function measures.4
The study looked at whether cognitive performance, brain glucose
hypometabolism, structural brain atrophy and clinical progression to mild
cognitive impairment and/or Alzheimer’s disease were associated with the
use of drugs with medium or high anticholinergic activity compared with a
control group who were not taking anticholinergic drugs. The study used
data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the
Indiana Memory and Aging Study (IMAS).
The use of medication with medium or high anticholinergic effects in this
population was associated with:
• poorer cognition (particularly in immediate memory recall and
executive function), as shown by lower mean scores on several
measures of cognitive function in the anticholinergic group (n=52)
compared with control group (n=350). Assessment tools included the
the Weschler Memory Scale–Revised Logical Memory Immediate Recall
score and the Trail Making Test Part B;
• reduced brain glucose metabolism in the hippocampus;
• whole-brain and temporal lobe atrophy (reduced total cortical volume
and temporal lobe cortical thickness and greater lateral ventricle and
inferior lateral ventricle volumes); and
• clinical decline (increased risk of clinical conversion to
cognitive impairment).
According to the authors, the effect appeared additive as increased
burden of anticholinergic drugs was associated with poorer executive
function and increased brain atrophy.
The authors note that theirs is one of the first studies to examine
structural and functional differences between cognitively normal
participants taking medication with medium or high anticholinergic
activity and cognitively normal participants not taking them. They
conclude that use of such medication among older adults should be
discouraged when other treatments are available.
[Funding support came from the ADNI and Department of Defense ADNI.
ADNI receives funding from a variety of sources including pharmaceutical
companies and patient support organisations].
Comment: This study adds to the growing body of research that has
highlighted the potential cognitive and functional adverse effects of
drugs with anticholinergic activity in older people. It is important that
the use of medicines with anticholinergic activity in older people and
those at risk of cognitive impairment is regularly reviewed. However,
there is a paucity of high-quality outcome evidence on the effect of
stopping such treatments.
1. Fox C et al. Anticholinergic medication use and cognitive impairment in the
older population: the Medical Research Council Cognitive Function and Ageing
Study. J Am Geriatr Soc 2011; 59: 1477-83.
2. Fox C et al. Effect of medications with anti-cholinergic properties on cognitive
function, delirium, physical function and mortality: a systematic review. Age
Ageing 2014; 43: 604-15.
3. Salahudeen MS et al. Anticholinergic burden quantified by anticholinergic risk
scales and adverse outcomes in older people: a systematic review. BMC Geriatr
2015; 15: 31.
4. Risacher SL et al. Association between anticholinergic medication use and
cognition, brain metabolism, and brain atrophy in cognitively normal
older adults. JAMA Neurol [Epub ahead of print] 18 April 2016; DOI:10.1001/
jamaneurol.2016.0580.
New NICE guidance for
controlled drugs
The National Institute for Health and Care Excellence (NICE) has published new
guidance to ensure safe and effective use of controlled drugs (CDs) in all NHS
settings except care homes.1 The aims of the guidance are to improve working
practices in line with legislation, ensure robust governance arrangements and
reduce the safety risks associated with CDs. The use of the term CD refers to
drugs in Schedule 2, 3, 4 and 5 of the 2001 Misuse of Drugs Regulations.2
The guidance includes advice on record keeping and risk assessment, as well as
on prescribing, obtaining, supplying, administering, handling and monitoring
use of CDs.1 It is intended for use by those with responsibilities relating to CDs,
including healthcare professionals, social care practitioners, commissioners of
services using CDs, providers of services where CDs are used as well as by
people being treated with CDs, their families or carers and the public.
Some key areas covered by the guidance include:
• governance arrangements and accountability—for example, the
establishment within organisations of agreed governance arrangements with
clear lines of responsibility and accountability for CDs in their contracts;
• processes and procedures that comply with relevant laws—for example,
arrangements for storage, stock checks, and audits, transportation and
destruction and disposal of CDs;
• policies and processes for prescribing—for example, ensuring that
prescribing policies support prescribers and do not create barriers that
prevent health professionals who are competent to prescribe CDs
from prescribing;
• making and recording prescribing decisions—for example, decisions about
prescribing CDs should take into account both the benefits of CD treatment
and the risks of prescribing, including dependency, overdose and
diversion;
• providing information and advice to people taking or carers administering
CDs—such as information on how long the person is expected to use the
drug, how long it will take to work and why it has been prescribed;
• reviewing repeat prescriptions and anticipatory prescribing;
• records of handling CDs;
• systems for reporting concerns and incidents;
• identifying and reporting trends and barriers; and
• reviewing concerns and incidents and sharing information.
Comment: The guideline has used NICE’s rigorous development process and
helpfully brings together many sources of information and evidence relating
to the use of CDs. However, there is a need for some practical tools to help
support its implementation.
1. National Institute for Health and Care Excellence, 2016. Controlled drugs: safe use and
management (NG46) [online]. Available: https://www.nice.org.uk/guidance/ng46
2. HM Government, 2015. The misuse of drugs regulation 2001 [online]. Available:
http://www.legislation.gov.uk/uksi/2001/3998/contents/made [Accessed 22
June 2016].
DOI: 10.1136/dtb.2016.7.0410
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DTB | Empagliflozin, diabetes and outcomes
DTB CME/CPD*
Empagliflozin, diabetes and outcomes
The prevalence of type 2 diabetes is rising, and in 2015 more than 5% of adults in the UK were affected by this
condition.1,2 Management of type 2 diabetes includes encouraging lifestyle changes (increased exercise, modification of
diet and smoking cessation) alongside the provision of medication to minimise long-term complications and manage
blood sugar control while avoiding unwanted effects of drug treatment.3 Of particular importance, people with type 2
diabetes are at increased risk of cardiovascular disease, and therefore the aims of treatment also include modification
of associated risk factors.2-5
Empagliflozin (Jardiance-Boehringer Ingelheim) is the third sodium-glucose co-transporter-2 (SGLT2) inhibitor licensed
for use in the UK. It was launched in August 2014, and acts in a similar way to the other SGLT2 inhibitors, dapagliflozin
and canagliflozin, by inhibiting renal glucose resorption and promoting glycosuria.6 It is indicated for the treatment
of type 2 diabetes in adults to improve glycaemic control, as monotherapy when metformin cannot be used, and in
combination with other glucose-lowering drugs including insulin. Here we review the evidence for empagliflozin and
discuss the results of a recent study that assessed cardiovascular outcomes.
Background
Although a range of drugs are licensed to manage glycaemic control in
type 2 diabetes, evidence of improved cardiovascular outcomes for these
treatments is limited.7 Metformin has been shown to reduce
macrovascular and microvascular complications compared to diet control
alone in a trial that included 753 overweight patients with newly
diagnosed type 2 diabetes.8 In comparison, the UK Prospective Diabetes
Study (UKPDS) 33 trial demonstrated that sulfonylureas reduced microbut not macrovascular complications.9,10
The European Medicines Agency (EMA) requires evidence that any new
drug for glycaemic control does not increase the risk of cardiovascular
complications.11 Placebo-controlled randomised trials of newer agents
(e.g. dipeptidyl peptidase 4 [DPP-4] inhibitors and glucagon-like peptide
1 receptor agonists) have not shown that they improve
cardiovascular outcomes.12-14
SGLT2 inhibitors
In healthy adults, the kidney filters approximately 180g of glucose per
day,15 almost all of which is resorbed via sodium-glucose co-transporter
(SGLT) proteins.16 SGLT2, found in the initial segment of the proximal
convoluted tubule, is responsible for 90% of this resorption, with SGLT1,
found in the distal aspect of the proximal tubule, accounting for the
remaining 10%. Inhibitors of SGLT2 reduce renal glucose resorption by
competitive inhibition of SGLT2, thereby increasing urinary glucose
excretion.17 In addition to reducing plasma glucose levels, this increase in
urinary glucose excretion results in a loss of 200–300kcal per day, which
may contribute to modest weight reduction. A moderate fall in systolic
blood pressure, attributable to mild osmotic diuresis, may also occur.17
The mechanism of action of SGLT2 inhibitors is independent of insulin and
* DTB CME/CPD A CME/CPD module based on this article is available for completion online via BMJ
Learning (learning.bmj.com) by subscribers to the online version of DTB. If prompted,
subscribers must sign on to DTB with their username and password. All users must also
complete a one-time registration on BMJ Learning and subsequently log in (with a BMJ
Learning username and password) at every visit. The answers to the multiple choice
questions will be freely available on dtb.bmj.com on publication of the next issue of DTB.
78
therefore may result in a lower risk of hypoglycaemia.18 The efficacy of
SGLT2 inhibitors is dependent on the functional status of the kidney,19
with treatment effects diminishing with decreasing renal function.18
Empagliflozin
The starting dose for empagliflozin is 10mg daily and it can be taken
with or without food (maximum dose 25mg daily).6 After administration,
empagliflozin is rapidly absorbed with maximal concentration achieved
after 1.5 hours. It has an elimination half-life of 12.4 hours and is
eliminated in the faeces (41%) and urine (54%). Empagliflozin does not
inhibit or induce any cytochrome p450 isozymes and pharmacokinetic
interaction studies did not demonstrate any drug-drug interactions of
clinical significance.6,18
Clinical trial evidence
Four phase III double-blind placebo-controlled studies were included in
the clinical trial programme.20-23 The main inclusion and exclusion criteria
were similar for all four trials. Adults with type 2 diabetes with glycated
haemoglobin (HbA1ci) ≥7.0% and <10.0%, and a body mass index (BMI)
≤45kg/m2 were included. Exclusion criteria included history of acute
coronary syndrome, stroke or transient ischaemic attack within 3 months
prior to study entry and estimated glomerular filtration rate (eGFR)
<30mL/min/1.73m2 (<50mL/min/1.73m2 for the monotherapy trial).20
At 24 weeks, empagliflozin produced statistically significant reductions
in HbA1c compared with placebo (primary outcome). Across the studies,
the difference from placebo in the absolute reduction of HbA1c from
baseline ranged from –0.48% to –0.74% for empagliflozin 10mg and
–0.59% to –0.85% for empagliflozin 25mg. In addition, patients treated
with empagliflozin had statistically significant reductions in weight
(secondary outcome) compared with placebo (1.8–2.2kg).20-23
Similarly designed placebo-controlled trials compared empagliflozin 25mg
as add-on to basal daily insulin, with or without metformin and/or a
sulfonylurea,24 and add-on to multiple daily insulin with or without
metformin.25 The difference from placebo in change from baseline HbA1c
was –0.7% and –0.5% at 18 weeks, for empagliflozin for the basal daily
i The HbA units are reported from the original studies. To convert from the DCCT unit
1c
(%) to the IFCC unit (mmol/mol) please see DTB 2010; 48:23-4.
▶
DTB_54-7.indd 78
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DTB CME/CPD | Produced in association with BMJ Learning
DTB CME/CPD
Activity
Target audience: primary and secondary care healthcare professionals
Goal of the activity: updating knowledge; helping clinical decision-making
Authors/disclosures: DTB editorial team/no conflict of interest
Specific learning objectives: to improve knowledge and understanding
regarding the use of empagliflozin for type 2 diabetes
Question 1
Empagliflozin is the third sodium-glucose co-transporter-2 (SGLT2)
inhibitor licensed for use in the UK for adults with type 2 diabetes to
improve glycaemic control. Which one of the following statements
regarding empagliflozin is correct?
DOI: 10.1136/dtb.2016.7.0412
Question 3
a. Empagliflozin should be initiated at 25mg daily in patients requiring
tight glycaemic control
The effect of empagliflozin on cardiovascular outcomes in patients with
type 2 diabetes and a history of cardiovascular disease was investigated
in the EMPA-REG OUTCOME non-inferiority double-blind placebo-controlled
trial. What was the number-needed-to-treat (NNT) to prevent the
primary outcome (a composite of death from cardiovascular causes,
non-fatal myocardial infarction or non-fatal stroke)?
b. Empagliflozin inhibits CYP3A4 activity
a.107
c. Empagliflozin should be discontinued if eGFR persistently falls below
60mL/min/1.73m2
b.93
d. Diabetic ketoacidosis (DKA) has been reported with empagliflozin
d.27
e. Empagliflozin should be initiated with caution in patients aged ≥85
years due to risk of volume depletion
e.17
c.63
Question 2
Question 4
The primary endpoint of four phase III double-blind placebo-controlled
trials of empagliflozin was the change from baseline HbA1ci at 24 weeks.
Compared with placebo, what was the range of HbA1c reductions
associated with empagliflozin 10mg in the phase III studies?
In pooled data from the pivotal trials of empagliflozin, what percentage
of patients receiving empagliflozin 25mg had genital infections?
a. –0.79% to –0.85%
a.0.9%
b. –0.48% to –0.74%
b.1.5%
c. –0.38% to –0.65%
c.2.7%
d. –0.29% to –0.54%
d.4.7%
e. –0.19% to –0.37%
e.11.5%
Question 5
According to National Institute for Health and Care Excellence (NICE)
recommendations for treating type 2 diabetes, empagliflozin is an
option as part of triple therapy with metformin and which one of the
following drugs?
a.sitagliptin
b.pioglitazone
c.exenatide
d.vildagliptin
The HbA1c units are reported from the original studies. To convert from the DCCT unit (%) to the
IFCC unit (mmol/mol) please see DTB 2010; 48:23-4.
i
dtb.bmj.com
DTB_54-7.indd 1
e.liraglutide
DTB CME/CPD accompanying Vol 54 | No 7 | July 2016 |
i
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DTB CME/CPD | Produced in association with BMJ Learning
DTB CME/CPD: Summary
As evidence of continuing medical education, this form may be used to record the key learning points and actions resulting from reading a DTB article.
Name:
Date of completion:
This article helped by: (please tick all that apply)
Introducing new ideas
Challenging existing knowledge
Reinforcing existing knowledge
Identifying further gaps in my knowledge
This article helped me: (please mark on the scale)
Not at all
A lot
The article would have been even better if: (what would you change?)
What have I learnt from this article? (What were the key learning points for you?)
As a result of reading this article, what will I do?
(What will you do next? E.g. change or maintain current practice, do further reading, discuss with colleagues)
How long did it take me to read and reflect?
ii
| DTB CME/CPD accompanying Vol 54 | No 7 | July 2016dtb.bmj.com
DTB_54-7.indd 2
29-06-2016 13:48:51
DTB CPD/CME | Produced in association with BMJ Learning
DTB CPD/CME
Activity
Target audience: healthcare professionals
Goal of the activity: updating knowledge; helping clinical decision-making
Authors/disclosures: BMJ Learning
Specific learning objectives: to improve knowledge and understanding
regarding blood glucose control in type 2 diabetes
Type
2 diabeteswith spironolactone
Hyperkalaemia
DOI: 10.1136/dtb.2016.5.0254
10.1136/dtb.2016.7.0413
DOI:
This month we are including a link to a BMJ Learning module on type 2 diabetes
http://learning.bmj.com/learning/home.html
BMJ Learning module - Clinical pointers: Blood glucose control in type 2 diabetes
http://learning.bmj.com/learning/module-intro/clinical-pointers-blood-glucose-control-diabetes.html?moduleId=10056517&searchTerm=%E2
%80%9Cdiabetes%E2%80%9D&page=1&locale=en_GB
The module covers the 2015 National Institute for Health and Care Excellence type 2 diabetes guideline, how to set appropriate HbA1c targets,
and a stepwise approach to medication, including the role of newer drugs.
Actions to be taken: (what am I going to do?)
Reflection: (what have I learnt?)
Follow up: (what will I do next?)
dtb.bmj.com
DTB_54-7.indd 3
DTB CPD/CME accompanying Vol 54 | No 7 | July 2016 |
iii
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DTB CPD/CME | Produced in association with BMJ Learning
DTB CPD/CME: Summary
Type 2 diabetes
As evidence of continuing medical education, this form may be used to record the key learning points and actions resulting from reading a DTB article.
Name:
Date of completion:
This article helped by: (please tick all that apply)
Introducing new ideas
Challenging existing knowledge
Reinforcing existing knowledge
Identifying further gaps in my knowledge
This article helped me: (please mark on the scale)
Not at all
A lot
The article would have been even better if: (what would you change?)
What have I learnt from this article? (What were the key learning points for you?)
As a result of reading this article, what will I do?
(What will you do next? E.g. change or maintain current practice, do further reading, discuss with colleagues)
How long did it take me to read and reflect?
iv
| DTB CPD/CME accompanying Vol 54 | No 7 | July 2016dtb.bmj.com
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insulin and multiple daily insulin trials, respectively (p<0.001 for both).24,25
Empagliflozin (25mg daily) was compared to glimepiride (maximum
4mg daily) in a randomised double-blind non-inferiority trial as add-on
therapy for patients inadequately controlled on metformin.26 At 2 years,
empagliflozin resulted in a statistically significant reduction in HbA1C
(–0.66% vs. –0.55%; absolute difference –0.11%, 95% CI –0.19 to –0.02). Body
weight was also reduced with empagliflozin (–3.1kg vs. +1.3kg; absolute
difference 4.5kg). In addition, there were fewer hypoglycaemic events
(plasma glucose ≤3.9mmol/L) with empagliflozin (2% vs. 24%; p<0.0001).
Limitations of the study
Other data
The improvements in cardiovascular outcomes appear to be partly
related to a reduction in heart failure-related risk and are thought
to have occurred too rapidly to be as a result of a reduction in
atherosclerotic disease. 31 Empagliflozin was associated with a slight
reduction in blood pressure, which may explain some of the
cardiovascular outcome benefit. More patients in the placebo group
received additional antihypertensive medication compared with the
empagliflozin group (47.4% vs. 40.6%). 29
The reductions in HbA1c demonstrated with empagliflozin are broadly
similar to those seen with the other SGLT2 agents, canagliflozin and
dapagliflozin.17,19 A systematic review of published randomised controlled
trials of SGLT2 inhibitors compared HbA1c reduction via a network
meta-analysis and found minimal difference between agents.27
Cardiovascular outcomes and
mortality trial
The effect of empagliflozin on cardiovascular outcomes was investigated
in the EMPA-REG OUTCOME study.28 In this double-blind trial, 7,028 people
with type 2 diabetes and a history of cardiovascular disease (myocardial
infarction, stroke or unstable angina, or evidence of significant coronary
artery or occlusive peripheral artery disease)29 were randomised to take
empagliflozin 10mg, 25mg or placebo daily.28 Other inclusion criteria
included BMI ≤45kg/m2, eGFR ≥30mL/min/1.73m2,ii and HbA1c of ≥7.0%
and ≤10.0% on stable doses of glucose-lowering therapy, or HbA1c of
≥7.0% but ≤9.0% if not on glucose-lowering therapy. The primary
outcome was a composite of death from cardiovascular causes, non-fatal
myocardial infarction or non-fatal stroke. The key secondary outcome was
the composite of the primary outcome plus hospitalisation for unstable
angina. The study was designed as a non-inferiority trial, with the
non-inferiority margin for the hazard ratio (HR) for the pooled
empagliflozin groups versus placebo set at 1.3. (This is the margin
stipulated in the USA Food and Drug Administration guidance for studies
investigating cardiovascular risk in new treatments for type 2 diabetes). 30
Background glucose lowering therapy was unchanged for the first
12 weeks after trial entry, though rescue therapy was permitted if the
patient had a fasting plasma glucose >13.3mmol/L. After week 12,
glucose-lowering therapy was adjusted to achieve glycaemic control.
Cardiovascular risk factors were also treated throughout the trial
according to the best available local standard of care.
The median duration of treatment and observation time was 2.6 and
3.1 years, respectively. The primary outcome occurred in 10.5% of patients
in the empagliflozin group compared with 12.1% in the placebo group
(HR 0.86, 95.02% CI 0.74 to 0.99, p<0.001 for non-inferiority; p=0.04 for
superiority) with the benefits appearing during the first few months of
treatment. The key secondary outcome occurred in 12.8% with
empagliflozin and 14.3% with placebo (HR 0.89, 95% CI 0.78 to 1.01,
p<0.001 for non-inferiority; not significant for superiority). Several other
prespecified outcomes were also statistically significant, including
cardiovascular death (3.7% vs. 5.9%; HR 0.62, 95% CI 0.49 to 0.77),
hospitalisation for heart failure (2.7% vs. 4.1%; HR 0.65, 95% CI 0.50 to
0.85) and death from any cause (5.7% vs. 8.3%; HR 0.68, 95% CI 0.57 to
0.82). The differences in the occurrence of myocardial infarction (4.8% vs.
5.4%) or stroke (3.5% vs. 3.0%) were not statistically significant.
The reduction in the primary composite outcome corresponds to a
number-needed-to-treat (NNT) of 63 patients for 2.6 years to prevent one
event. The NNT for death from any cause was 39.
Empagliflozin should not be initiated in patients with an eGFR below 60mL/min/1.73m2
or CrCl <60mL/min.6
ii dtb.bmj.com
DTB_54-7.indd 79
Patients had established cardiovascular disease and a very high baseline
risk of an event. Small relative differences would therefore be easier to
detect in such a high-risk population. Nevertheless, the primary outcome
only just reached statistical significance. Secondary analysis of the
outcomes from the individual doses of empagliflozin compared with
placebo were not statistically significant. In a prespecified subgroup of
patients with higher baseline HbA1c (≥8.5%), the difference in the primary
outcome was not statistically significant.
Cardiovascular outcome trials are also underway for the other SGLT2
inhibitors, the results of which might help establish whether the
improved outcomes reported in the empagliflozin study are a class effect.
Safety
Pooled data from the pivotal trials showed similar rates of adverse
effects with empagliflozin 10mg, 25mg and placebo (71.8%, 70.1% and
74.1% respectively).18 There was an increased risk of genital infections
(e.g. vulvovaginitis, balanitis) with empagliflozin 10mg and 25mg (4.4%
and 4.7%) compared with placebo (1.1%); more common in women than
in men. The frequency of urinary tract infections with empagliflozin was
similar to placebo. Although there was no significant increase in
hypoglycaemic events in most trials, there was an increased incidence
compared to placebo when empagliflozin was used in combination with a
sulfonylurea.18 The incidence of adverse effects caused by volume
depletion (e.g. hypotension, syncope) was higher in patients receiving
diuretics (2.5%, 2.7% and 2.2% for empagliflozin 10mg, 25mg and
placebo, respectively).18
Recent safety alerts from the Medicines and Healthcare products
Regulatory Agency (MHRA) and the EMA have highlighted that rare but
serious and sometimes fatal cases of diabetic ketoacidosis (DKA) have
been reported with SGLT2 inhibitors. 32,33 Patients taking these drugs
should be warned about the symptoms of DKA. Many reports were of
atypical DKA with only moderately increased blood glucose levels. DKA
should be considered in patients presenting with non-specific symptoms
(e.g. vomiting, anorexia, excessive thirst) and where suspected, SGLT2
inhibitors should be discontinued and only restarted after resolution of
symptoms if another clear precipitating factor is resolved. 33 Patients
admitted for severe acute illness and for major surgery should have
SGLT2 inhibitors withheld until their condition has stabilised.
Cautions and contraindications
As the mechanism of action of empagliflozin is dependent on renal
function, the drug should not be started in patients with eGFR
<60mL/min/1.73m2.6 For patients who are taking empagliflozin, in
whom eGFR is persistently below 60mL/min/1.73m2, the dose should be
reduced or maintained at 10mg daily. If eGFR falls persistently below
45mL/min/1.73m2 empagliflozin should be discontinued. Although dose
adjustment in hepatic impairment is not required, empagliflozin should
not be used in severe hepatic impairment due to limited experience.
As SGLT2 inhibition can cause volume depletion, caution should be used
if initiating in patients 75 years and over, those with a history of
hypotension and those on diuretics. In conditions that may lead to fluid
loss (e.g. gastrointestinal illness), careful monitoring of volume status and
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29-06-2016 13:48:51
electrolytes is recommended and temporary interruption of treatment
should be considered until the fluid loss is corrected.6 Initiation in
patients over 85 years is not recommended.
Cost
The cost of treatment with empagliflozin (10–25mg/day) is £36.59 for
28 days.
National guidance
The National Institute for Health and Care Excellence (NICE) recommended
empagliflozin as an option for type 2 diabetes:34
• as add-on to metformin if a sulfonylurea is contraindicated,
not tolerated or there is a significant risk of hypoglycaemia or
its consequences
• as part of triple therapy with metformin and a sulfonylurea or
metformin and a thiazolidinedione (pioglitazone)
• in combination with insulin with or without other antidiabetic drugs.
A separate NICE appraisal reviewed SGLT2 inhibitors as monotherapy. 35
NICE recommended canagliflozin, dapagliflozin or empagliflozin as an
option for monotherapy for type 2 diabetes when metformin is
contraindicated or not tolerated only if:
• a DPP-4 inhibitor would otherwise be prescribed, and
• a sulfonylurea or pioglitazone is not appropriate.
The Scottish Medicines Consortium (SMC) recommended empagliflozin for
type 2 diabetes as dual therapy with metformin, as triple therapy with
metformin plus standard of care, or added to insulin therapy plus
standard of care. 36 SMC advice on the use of empagliflozin as
monotherapy has been superseded by NICE’s appraisal guidance on the
use of SGLT2 inhibitors as monotherapy. 36
Conclusion
Empagliflozin is the third sodium-glucose co-transporter-2 (SGLT2) inhibitor licensed in the UK for the management of people with type 2
diabetes. SGLT2 inhibition in the proximal tubules of the nephron leads to increased urinary glucose excretion and reduced plasma glucose levels.
All three SGLT2 inhibitors have been shown to reduce HbA1c by a similar amount. In addition, they produce a modest reduction in body weight and
blood pressure. Adverse effects of SGLT2 inhibitors include an increased risk of genital infection, hypoglycaemia when used in combination with
sulfonylureas and volume depletion when used in combination with diuretics. In addition, there have been safety warnings with respect to a risk
of diabetic ketoacidosis with SGLT2 inhibitors and this has occurred with relatively low levels of blood glucose.
The results of one study have shown that in people with type 2 diabetes and a history of a previous cardiovascular event, empagliflozin reduced
total and cardiovascular mortality compared with placebo. Hospitalisation due to heart failure was reduced with empagliflozin but outcomes
relating to myocardial infarction and stroke did not reach statistical significance. It is not clear if the mortality benefits resulted from an effect on
weight, blood pressure or cardiovascular load. However, the reduction in mortality does not appear to be due to an effect on atherosclerotic
disease. The primary outcome for the pooled empagliflozin doses only just reached statistical significance for superiority and was not statistically
significant for individual doses.
This is only the second randomised controlled study of an antidiabetic drug to demonstrate a reduction in cardiovascular events. Overall, the
results are encouraging, particularly for people with type 2 diabetes and cardiovascular disease who are at high risk of heart failure. Nevertheless,
a lack of evidence of longer-term outcomes in people at lower risk of cardiovascular disease and concerns over the safety profile of SGLT2
inhibitors suggest that clinicians should take a cautious approach until the benefits have been more clearly established.
Available: http://www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2012/06/WC500129256.pdf [Accessed 22 June 2016].
[R=randomised controlled trial; M=meta-analysis]
1. Diabetes UK, 2015. Key facts and stats [online]. Available: https://www.
diabetes.org.uk/About_us/What-we-say/Statistics/ [Accessed 22 June 2016].
2. National Institute for Health and Care Excellence, 2015. Type 2 diabetes in
adults: management (NG28) [online]. Available: https://www.nice.org.uk/
guidance/ng28 [Accessed 22 June 2016].
3. HbA1c targets in type 2 diabetes: guidelines and evidence. DTB 2013; 51: 42-5.
4. Fox C et al. Lifetime risk of cardiovascular disease among individuals with and
without diabetes stratified by obesity status in the Framingham heart study.
Diabetes Care 2008; 31: 1582-84.
R 12. White WB et al. Alogliptin after acute coronary syndrome in patients with type
2 diabetes. New Eng J Med 2013; 369: 1327-35.
R 13. Green J et al. Effect of sitagliptin on cardiovascular outcomes in type 2
diabetes. N Engl J Med 2015; 373: 232-42.
R 14. Pfeffer M et al. Lixisenatide in patients with type 2 diabetes and acute coronary
syndrome. N Engl J Med 2015; 373: 2247-57.
15. Gerich J. Role of the kidneys in glucose homeostasis and hyperglycaemia of
diabetes mellitus: therapeutic implications. Diabet Med 2010; 27: 136-42.
16. Shubrook J et al. Empagliflozin in the treatment of type 2 diabetes: evidence to
date. Drug Des Devel Ther 2015; 9: 5793-803.
6.
Jardiance 10 mg and 25 mg film-coated tablets. Summary of product
characteristics, EU. Boehringer Ingelheim International GmbH, April 2016.
17. Whalen K et al. The role of sodium-glucose co-transporter 2 inhibitors in the
treatment of type 2 diabetes. Clin Ther 2015; 37: 1150-66.
18. European Medicines Agency, 2014. Jardiance (Emapgliflozin) public assessment
report [online]. Available: http://www.ema.europa.eu/docs/en_GB/document_
library/EPAR_-_Public_assessment_report/human/002677/WC500168594.pdf
19. Vivian E. Sodium-glucose cotransporter 2 inhibitors in the treatment of type 2
diabetes mellitus. Diabetes Educ 2015; 41 (suppl 1): 5S-18S.
5. American Diabetes Association. Standards of medical care in diabetes – 2012.
Diabetes Care 2012; 35 (suppl 1): S11-S63.
7. Holman R et al. Cardiovascular outcome trials of glucose lowering drugs or
strategies in type 2 diabetes. Lancet 2014; 383: 2008-17.
R 8. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control
with metformin on complications in overweight patients with type 2 diabetes
(UKPDS 34). Lancet 1998; 352: 854-65.
R 9. UK Prospective Diabetes Study Group. Intensive blood-glucose control with
sulfonylureas or insulin compared with conventional treatment and risk of
complications in type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-53.
10. Holman R et al. 10-year follow-up of intensive glucose control in type 2
diabetes. N Eng J Med 2008; 359: 1577-89.
11. European Medicines Agency, 2012. Guideline on clinical investigation of
medicinal products in the treatment or prevention of diabetes mellitus [online].
80
R 20. Roden M et al. Empagliflozin monotherapy with sitagliptin as active comparator
in patients with type 2 diabetes: a randomised, double blind, placebo
controlled, phase III trial. Lancet Diabetes Endocrinol 2013; 1: 208-19.
R 21. Häring H-U et al. Empagliflozin as add-on to metformin in patients with type 2
diabetes: a 24-week, randomised, double-blind, placebo-controlled trial.
Diabetes Care 2014; 37: 1650-9.
DTB_54-7.indd 80
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R 22. Häring H-U et al. Empagliflozin as add on to metformin plus sulfonylurea in
patients with type 2 diabetes: a 24-week, randomised, double-blind,
placebo-controlled trial. Diabetes Care 2013; 36: 3396-404.
30. Food and Drug Administration, 2008. Guidance for industry diabetes mellitus
- evaluating cardiovascular risk in new antidiabetic therapies to treat type 2
diabetes [online]. Available: http://www.fda.gov/downloads/drugs/
guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf
31. Wilding J. SGLT2 inhibitors: providing cardiovascular protection in type 2
diabetes? Lancet Diabetes Endocrinol 2016; 4: 379-81.
32. Medicines and Healthcare products Regulatory Agency. SGLT2 inhibitors:
updated advice on the risk of diabetic ketoacidosis. Drug Safety Update
2016; 9 (9): 1 [online]. Available: https://www.gov.uk/drug-safety-update/
sglt2-inhibitors-updated-advice-on-the-risk-of-diabetic-ketoacidosis
33. European Medicines Agency, 2016. EMA confirms recommendations to minimise
ketoacidosis risk with SGLT2 inhibitors for diabetes [online]. Available: http://
www.ema.europa.eu/docs/en_GB/document_library/Press_release/2016/02/
WC500202388.pdf [Accessed 22 June 2016].
34. National Institute for Health and Care Excellence, 2015. Empagliflozin in
combination therapy for treating type 2 diabetes (TA336) [online]. Available:
https://www.nice.org.uk/guidance/ta336 [Accessed 22 June 2016].
M 27. Shyangdan D et al. SGLT-2 receptor inhibitors for treating patients with type 2
diabetes mellitus: a systematic review and network meta-analysis. BMJ
Open 2016; 6: e009417.
35. National Institute for Health and Care Excellence, 2016. Canagliflozin, dapagliflozin
and empagliflozin as monotherapies for treating type 2 diabetes (TA390) [online].
Available: https://www.nice.org.uk/guidance/ta390 [Accessed 22 June 2016].
R 28. Zinman B et al. Empagliflozin, cardiovascular outcomes and mortality in type 2
diabetes. N Engl J Med 2015; 373: 2117-27.
36. Scottish Medicines Consortium, 2014. Empagliflozin ( Jarndice) [online].
Available: https://www.scottishmedicines.org.uk/SMC_Advice/Advice/993_14_
empagliflozin_Jardiance [Accessed 22 June 2016].
R 23. Kovacs C et al. Empagliflozin improves glycaemic and weight control as add-on
therapy to pioglitazone or pioglitazone plus metformin in patients with type 2
diabetes: a 24-week, randomised, placebo-controlled trial. Diabetes Obes
Metab 2014; 16: 147-58.
R 24. Rosenstock J et al. Impact of empagliflozin added on to basal insulin in
type 2 diabetes inadequately controlled on basal insulin: a 78-week
randomised, double-blind, placebo-controlled trial. Diabetes Obes
Metab 2015; 17: 936-48.
R 25. Rosenstock J et al. Improved glucose control with weight loss, lower insulin
doses and no increased hypoglycaemia with empagliflozin added to titrated
multiple daily injections of insulin in obese inadequately controlled type 2
diabetes. Diabetes Care 2014; 37: 1815-23.
R 26. Ridderstraele M et al. Comparison of empagliflozin and glimepiride as add-on to
metformin in patients with type 2 diabetes: a 104-week, randomised,
active-controlled, double-blind, phase 3 trial. Lancet Diabetes
Endocrinol 2014; 2: 691-700.
R 29. Zinman B et al. Empagliflozin, cardiovascular outcomes and mortality in type 2
diabetes – supplementary appendix. N Engl J Med 2015; DOI: 10.1056/
NEJMoa1504720.
DOI: 10.1136/dtb.2016.6.0411
Vitamin supplementation in pregnancy
Ensuring that a woman is well-nourished, both before and during pregnancy, is crucial for the health of the woman and
that of the unborn child.1 Maternal deficiency in key nutrients has been linked to pre-eclampsia, restricted fetal growth,
neural tube defects, skeletal deformity and low birth weight.1,2 Many nutritional supplements containing vitamins,
minerals and other micronutrients are heavily marketed to women for all stages of pregnancy. However, much of the
evidence for vitamin supplementation in pregnancy comes from studies carried out in low-income countries,3 where
women are more likely to be undernourished or malnourished than within the UK population. The challenges lie in
knowing which supplements are beneficial and in improving uptake among those at most need. Here we summarise
current UK guidance for vitamin supplementation in pregnancy and review the evidence behind it.
Background
The National Institute for Health and Care Excellence (NICE) recommends
that women should take 400µg of folic acid each day, from before
pregnancy until the end of the first trimester, and 10µg (400 units) of
vitamin D daily throughout pregnancy and breastfeeding.1,4 No other
supplements are recommended for routine use. The Royal College of
Obstetricians and Gynaecologists states that supplements of vitamins
other than vitamin D and folic acid are not usually advised since they
may actually be harmful in pregnancy. 5
A wide range of over-the-counter vitamin products are promoted to
pregnant women for use at various stages of pregnancy. Typically, such
products contain 20 or more vitamins and minerals (e.g. vitamins B1, B2,
B3, B6, B12, C, D, E and K, folic acid, iodine, magnesium, iron, copper, zinc
and selenium) and may cost as much as £15/month.
There is a paucity of evidence from high-quality randomised controlled
trials (RCTs), and a tendency for systematic reviews to draw conclusions
from heterogeneous populations that included resource-rich and
dtb.bmj.com
DTB_54-7.indd 81
resource-poor countries, which may not be generalisable to a UK
population. In addition, the evidence for some supplements relies on
observational studies of diet and supplementation that are associated
with confounding and bias.
Folic acid
Folic acid is a synthetic form of folate, which is used in supplements and
in fortified foods such as flour and bread, with the aim of reducing
neural tube defects (NTDs). The most common NTDs are anencephaly
and spina bifida. The Europe-wide prevalence of NTD is around 9 per
10,000 births.6
The protective effect of folic acid was identified during the 1980s, when
studies suggested that supplementation reduced recurrence of NTD
pregnancy.7 The use of folic acid to prevent recurrent NTDs was
established in a RCT published in 1991 of 1,817 women with a previous
NTD pregnancy, which showed a reduced risk of NTD recurrence (relative
risk 0.28, 95% CI 0.12 to 0.71).8
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DTB | Vitamin supplementation in pregnancy
In the 1990s, research showed evidence of a protective effect to prevent
a first NTD.9,10 Since then, most countries around the world have
recommended supplementation and some have introduced mandatory
fortification of staple foods with folic acid.11
from a mixture of high- and low-income countries) measured the effect
of vitamin D supplementation during pregnancy on levels of 25(OH)D in
the cord blood of newborns.14 A meta-analysis found a summary mean
difference of 22.5nmol/L between groups (95% CI 15.9 to 29.1).
A recent systematic review of RCTs or quasi-randomised controlled trials (five
studies, 6,708 births from nine high income countries and one low-to-middle
income country; 2,033 women with previous NTD pregnancy and 5,358
without NTD history) examined the effect of folic acid in doses ranging from
0.36mg to 4mg/day, with and without other vitamins and minerals. It found
that supplementation with any folate compared with no folate prevented
the occurrence of NTDs (risk ratio [RR] 0.31, 95% CI 0.17 to 0.58).12
A second systematic review measured the effect of supplementation on the
25(OH)D levels of women at term (13 RCTs, 2,299 women from a mixture of
high- and low-income countries).21 Unsurprisingly, women taking
supplements had higher levels of 25(OH)D (mean difference 66.5nmol/L,
95% CI 66.2 to 66.7). This systematic review measured a range of clinical
outcomes including pre-eclampsia, gestational diabetes, small for gestational
age, low birth weight and preterm birth, which did not differ statistically
significantly between groups. Birth weight was slightly greater in women
who had taken supplements (mean difference 108g, 95% CI 60g to 155g).21
UK guidance
Women in the UK are advised to take 400µg folic acid daily from when
they first start trying to conceive, until 12 weeks of pregnancy.13
A higher dose of 5mg/day of folic acid is recommended for pregnant
women at higher risk of having a child with a NTD.1 These include women
(or their partner) who have a NTD; women who have had a previous baby
with a NTD; women (or their partner) who have a family history of a NTD;
and women with diabetes.1
Folic acid needs to be taken before pregnancy and in the first trimester,
but around 50% of pregnancies are unplanned.1
Vitamin D
Vitamin D can be synthesised when the skin is exposed to ultraviolet (UV)
light. It plays a major role in bone health, by increasing calcium absorption
from the gut.14 Concerns have been raised in recent years over the
re-emergence of skeletal problems such as rickets, due to a lack of
vitamin D.1 Figures from 2007 suggest that around one third of women aged
19–24 years are deficient in vitamin D, with levels of the main circulating
form of vitamin D, 25-hydroxyvitamin D [25(OH)D], below the generallyaccepted level of 25nmol/L.15 UV levels in the UK are not thought to be
sufficiently strong during the winter to allow synthesis of vitamin D,
especially in people who have dark skin or whose skin is not often exposed
to sunlight.15 Women in these groups, or who ingest only low levels of
dietary vitamin D, may benefit most from vitamin D supplementation.
Vitamin D deficiency in infancy has been linked to low levels of maternal
vitamin D in pregnancy and may adversely affect infant skeletal growth
and bone formation, tooth enamel formation and calcium absorption.
Infant vitamin D status seems more strongly linked to maternal status
during pregnancy than during lactation.15 A draft report from the UK
Scientific Advisory Committee on Nutrition (SACN) published in 2015,
concluded that evidence was suggestive of a positive association
between maternal 25(OH)D concentration during pregnancy and bone
health indices in the fetus/newborn.16 However, the authors commented
that the physiological significance of this finding is not known. Other
adverse effects that have been linked to low maternal vitamin D in
pregnancy include pre-eclampsia, gestational diabetes, preterm birth,
low birth weight and asthma in children.17-19
The main outcome of concern, osteomalacia or rickets, has not been
assessed in recent RCTs. One RCT (1,134 UK pregnant women randomised
to placebo or 1,000 units/day colecalciferol [400 units=10µg]), measured
bone mineral content in neonates using a dual X-ray absorptiometry scan
at birth.19 The study found no difference in bone mineral content between
babies born to women who had taken supplements and those who had
not. However, the study authors say a secondary analysis found a
possible seasonal interaction, suggesting that babies born in the winter
might benefit from maternal vitamin D supplementation.20
Other trials have investigated the impact of vitamin D supplementation
on 25(OH)D levels. One systematic review (13 RCTs, 1,636 participants
82
Systematic reviews of observational studies found a range of outcomes,
with little consistency and much heterogeneity between studies.17-19 One
systematic review included eight case control studies (1,353 participants)
and two cohort studies (26,373 participants) with pre-eclampsia as an
outcome.17 The cohort studies and three of the case control studies found
that lower vitamin D levels were associated with a higher risk of preeclampsia, while five case control studies found no association. The Royal
College of Obstetricians and Gynaecologists (RCOG) advises women at risk
of pre-eclampsia to take 800 units daily as a preventive measure.22 Also,
the RCOG suggests that ‘high-risk’ women should take at least 1,000 units
daily; this includes women with increased skin pigmentation, reduced
exposure to sunlight or those who are socially excluded or obese.22
Three systematic reviews of observational studies found an association
between low vitamin D levels and gestational or type 2 diabetes.
However, the association could be due to confounding by obesity, which
raises the risk of both vitamin D deficiency and diabetes.17,23,24
Acute and chronic exposure to excess vitamin D intake can result in
hypercalcaemia, demineralisation of bone, soft tissue calcification and
renal damage.15 Toxicity has been reported at excessively high levels of
vitamin D. A SACN report published in 2007 noted that a daily dose of
25µg is not expected to cause adverse effects in the general population,
when consumed regularly over a long period.15 Furthermore, a review of
clinical trials suggested that vitamin D is not toxic at levels considerably
higher than that.25 The draft report produced by SACN concluded that the
tolerable upper limit of 100µg/day (4,000 units) set for adults was
considered appropriate for pregnant and lactating women.16
UK guidance
Women in the UK are advised to take 10µg of vitamin D daily, throughout
pregnancy and lactation.4
Other vitamins and minerals
Iron
Moderate anaemia (haemoglobin [Hb] levels between 70 and 90g/L)
or severe anaemia (Hb <70g/L) are thought to be associated with
increased risk of maternal and child mortality and infectious diseases. 26
A recent systematic review (44 RCTs, 43,274 women), found iron
supplementation reduced maternal anaemia (defined as Hb
concentration <110g/L) at term by 70% (RR 0.30, 95% CI 0.19 to 0.46)
but had less clear effect on other outcomes such as low birth weight or
preterm birth. 26 In 2014, NICE concluded that iron supplementation
should not be offered routinely to all pregnant women, as iron tablets
can cause gastric irritation and constipation or diarrhoea.13 NICE
recommended that pregnant women are offered screening for anaemia
and that Hb levels outside the normal UK range for pregnancy
(11g/100mL at first contact and 10.5g/100mL at 28 weeks) should be
investigated and iron supplementation considered if indicated.
DTB_54-7.indd 82
29-06-2016 13:48:51
Vitamin C
Multiple vitamin supplements
A systematic review (29 trials, 24,300 women in high- and low-income
countries) assessed the role of vitamin C, which is included in many
multivitamin preparations.27 The most common daily dosage was
1,000mg. The review found no clear effect of vitamin C supplementation
on outcomes including stillbirth, birthweight, growth restriction, preterm
birth and pre-eclampsia. A possible positive impact on prevention of
placental abruption and pre-labour rupture of membranes required
further research, the researchers said. Vitamin C may increase the
absorption of iron.
Systematic reviews of trials of multiple vitamin supplements showed
that most trials were carried out in low-income countries. 3,30 Results are
therefore not generalisable to high-income countries like the UK.
One UK-based study of a micronutrient supplement demonstrated
improvement in surrogate markers of micronutrient status using iron,
folate, thiamine and vitamin D status in later pregnancy. However, this
study was carried out in a low-income multi-ethnic population in London
and did not demonstrate a beneficial effect on birth outcomes and
infant development. 31
Vitamin E
A systematic review of vitamin E (21 trials, 22,129 women in high- and
low-income countries) found no support for vitamin E supplementation
in prevention of stillbirth, neonatal death, preterm birth, pre-eclampsia,
preterm or term premature rupture of membranes or poor fetal growth.28
Doses varied but were all above the recommended daily limit of 7mg
alpha-tocopherol.
Vitamin A
Pregnant women should be advised that vitamin A supplementation
might be teratogenic.13 The use of supplements containing vitamin A is
not recommended during pregnancy.
UK guidance
Pregnant women should be informed that vitamin A supplementation (intake
above 700µg) might be teratogenic and should therefore be avoided.29 Healthy Start programme
Healthy Start is a UK-wide scheme to provide free vitamin supplements
to pregnant women who are at least 10 weeks pregnant if they are in
receipt of certain low-income benefits. 32 It is the responsibility of NHS
England, Clinical Commissioning Groups and Local Authorities in England,
trusts and health boards in Scotland and Wales, and the Business Services
Organisation in Northern Ireland to make the vitamins available. 32
Healthy start vitamins contain 400µg folic acid, 10µg vitamin D and 70mg
vitamin C. For those not eligible for free supply, they cost £1.14 for
2 months’ supply (56 tablets).
The scheme has been criticised for being difficult to access and
because 10 weeks is too late to begin NTD prevention.1 NICE has
recommended making Healthy Start vitamins easier to access, both for
women entitled to free vitamins and for those who could buy them.4
In Scotland, free Healthy Start vitamin supplements are to be offered
to all pregnant women. 33
Conclusion
Of the supplements routinely offered to pregnant women in the UK, folic acid has the strongest evidence base. A dose of 400µg daily is
recommended for women from when they first start trying to conceive, until 12 weeks of pregnancy with the aim of reducing the risk of neural
tube defects. A higher dose of 5mg daily is recommended for pregnant women at higher risk of having a child with a neural tube defect. The
evidence for vitamin D supplementation for all pregnant women is less clear cut, with little randomised controlled trial evidence supporting an
effect on clinical outcomes. Nevertheless, a dose of 10µg vitamin D daily is recommended throughout pregnancy and breastfeeding (with a higher
dose suggested for some women). For other vitamin supplements, the evidence does not show clear benefit for clinical outcomes for most
women who are well nourished. Women should also be advised to avoid taking vitamin A supplements during pregnancy.
We found no evidence to recommend that all pregnant women should take prenatal multi-nutrient supplements beyond the nationally advised
folic acid and vitamin D supplements, generic versions of which can be purchased relatively inexpensively. The primary focus should be on
promoting a healthy diet and improving the use of folic acid supplements, which have a poor uptake, particularly among those from lower
income families.
For most women who are planning to become pregnant or who are pregnant, complex multivitamin and mineral preparations promoted for use
during pregnancy are unlikely to be needed and are an unnecessary expense. The marketing of such products does not appear to be supported by
evidence of improvement in child or maternal outcomes. Pregnant women may be vulnerable to messages about giving their baby the best start
in life, regardless of cost, and be unaware that the only supplements recommended for all women during pregnancy are folic acid and vitamin D,
which are available at relatively low cost.
We believe that there is a need to promote the availability of simple vitamin preparations. Greater use should be made of the Healthy Start
scheme to ensure that low-cost tablets containing vitamin D, folic acid and vitamin C are made more widely accessible.
[R=randomised controlled trial; M=meta-analysis]
1. National Institute for Health and Care Excellence, 2014. Maternal and child
nutrition (PH11) [online]. Available: https://www.nice.org.uk/guidance/ph11
2. Ramakrishnan U et al. Effect of women’s nutrition before and during early
pregnancy on maternal and infant outcomes: a systematic review. Paediatr
Perinat Epidemiol 2012; 26 (suppl 1): 285-301.
M 3. Ramakrishnan U et al. Effect of multiple micronutrient supplementation on
pregnancy and infant outcomes: a systematic review. Paediatr Perinat
Epidemiol 2012; 26 (suppl 1): 153-67.
dtb.bmj.com
DTB_54-7.indd 83
4. National Institute for Health and Care Excellence, 2014. Vitamin D: increasing
supplement use in at-risk groups (PH56) [online]. Available: http://www.nice.
org.uk/guidance/ph56 [Accessed 22 June 2016].
5. Royal College of Obstetricians and Gynaecologists, 2014. Healthy eating and
vitamin supplements in pregnancy [online]. Available: https://www.rcog.org.
uk/globalassets/documents/patients/patient-information-leaflets/pregnancy/
pi-healthy-eating-and-vitamin-supplements-in-pregnancy.pdf [Accessed 22
June 2016].
6. Khoshnood B et al. Long term trends in prevalence of neural tube defects in
Europe: population based study. BMJ 2015; 351: h5949.
Vol 54 | No 7 | July 2016 | DTB |
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29-06-2016 13:48:51
7. Laurence KM et al. Double-blind randomised controlled trial of folate
treatment before conception to prevent recurrence of neural-tube defects.
BMJ 1981; 282: 1509-12.
R 20. Cooper C et al. Maternal gestational vitamin D supplementation and offspring
bone health (MAVIDOS): a multiple, double-blind, randomised placebocontrolled trial. Lancet Diabetes Endocrinol 2016; 4: 393-402.
R 8. MRC Vitamin Study Research Group. Prevention of neural tube defects:
results of the Medical Research Council Vitamin Study. Lancet 1991;
338: 131-7.
M 21. Pérez-López FR et al. Effect of vitamin D supplementation during pregnancy on
maternal and neonatal outcomes: a systematic review and meta-analysis of
randomized controlled trials. Fertil Steril 2015; 103: 1278-88.
9. Czeizel AE et al. Prevention of the first occurrence of neural-tube
defects by periconceptional vitamin supplementation. N Eng J Med 1992;
327: 1832-5.
10. Berry RJ et al. Prevention of neural-tube defects with folic acid in china.
N Eng J Med 1999; 341: 1485-90.
M 23. Poel YHM et al. Vitamin D and gestational diabetes: a systematic review and
meta-analysis. Eur J Intern Med 2012; 23: 465-9.
11. Barua S et al. Folic acid supplementation in pregnancy and implications in
health and disease. J Biomed Sci 2014; 21: 77.
M 24. Zhang MX et al. Vitamin D deficiency increases the risk of gestational diabetes
mellitus: a meta-analysis of observational studies. Nutrients 2015; 7: 8366-75.
22. Royal College of Obstetricians and Gynaecologists, 2014. Vitamin D in pregnancy
[online]. Available: https://www.rcog.org.uk/globalassets/documents/guidelines/
scientific-impact-papers/vitamin_d_sip43_june14.pdf [Accessed 22 June 2016].
M 12. De-Regil LM et al. Effects and safety of periconceptional oral folate
supplementation for preventing birth defects. Cochrane Database Syst Rev
2015; 12: CD007950. DOI:10.1002/14651858.CD007950.pub3 [Last assessed as
up-to-date 31 August 2015].
M 14. Yang N et al. Effects of vitamin D supplementation during pregnancy on
neonatal vitamin D and calcium concentrations: a systematic review and
meta-analysis. Nutr Res 2015; 35: 547-56.
27. Rumbold A et al. Vitamin C supplementation in pregnancy. Cochrane Database
Syst Rev 2015; 9: CD004072. DOI:10.1002/14651858.CD004072.pub3 [Last
assessed as up-to-date 31 March 2015].
15. Scientific Advisory Committee on Nutrition, 2007. Update on vitamin D [online].
Available: https://www.gov.uk/government/publications/sacn-update-onvitamin-d-2007 [Accessed 20 June 2016].
28. Rumbold A et al. Vitamin E supplementation in pregnancy. Cochrane Database
Syst Rev 2015; 9: CD004069. DOI:10.1002/14651858.CD004069.pub3 [Last
assessed as up-to-date 31 March 2015].
16. Scientific Advisory Committee on Nutrition, 2015. Draft vitamin D and health
report [online]. Available: https://www.gov.uk/government/uploads/system/
uploads/attachment_data/file/447402/Draft_SACN_Vitamin_D_and_Health_
Report.pdf [Accessed 22 June 2016].
29. National Institute for Health and Care Excellence, 2016. Antenatal care for
uncomplicated pregnancies (CG 62)[online]. Available: https://www.nice.org.uk/
30. Haider BA et al. Multiple-micronutrient supplementation for women during
pregnancy. Cochrane Database Syst Rev 2015; 11: CD004905. DOI:10.1002/14651858.
CD004905.pub [Last assessed as up-to-date 11 March 2015].
17. Christesen HT et al. The impact of vitamin D on pregnancy: a systematic review.
Acta Obstet Gynecol Scand 2012; 9: 1357-67.
18. Christesen HT et al. The impact of vitamin D in pregnancy on extraskeletal
health in children: a systematic review. Acta Obstet Gynecol Scand 2012;
91: 1368-80.
31. Brough L. Effect of multiple-micronutrient supplementation on maternal
nutrient status, infant birth weight and gestational age at birth in a lowincome, multi-ethnic population. Br J Nutr 2010; 104: 437-45.
32. Healthy Start, 2014. Vitamins [online]. Available: https://www.healthystart.nhs.
uk/for-health-professionals/vitamins/ [Accessed 22 June 2016].
33. Christie B. Pregnant women in Scotland to be offered free vitamins. BMJ 2016;
353: i3129.
13. National Institute for Health and Care Excellence, 2016. Antenatal care for
uncomplicated pregnancies (CG62) [online]. Available: http://www.nice.org.uk/
M 19. Thorne-Lyman A et al. Vitamin D during pregnancy and maternal, neonatal and
infant health outcomes: a systematic review and meta-analysis. Paediatr
Perinat Epidemiol 2012; 26 (suppl 1): 75-90.
Editor in Chief: James Cave OBE FRCGP
Deputy Editor: David Phizackerley
Publisher: Allison Lang
Associate Publisher: Lindsey Fountain
Marketing: Rebecca Vickerstaff
Project Team: Laura Stephenson, Varsha Mistry, Gemma Spink, Alan Thomas,
Samantha Barton, Olwen Beaven, Alex McNeil, Vanessa Sibbald
Senior Production Editor: Malcolm Smith
Contributing Editors: Sophie Ramsey, Grant Stewart
Scientific Editors: Chei Hung, Sam Love, Adam Mitchell, Martin O’Brien,
Irene Chiwele, Helena Delgado-Cohen, Emma Scott
Clinical Editors: Kathleen Dryburgh, Sheila Feit, Julie Costello, Caroline Blaine
25. Hathcock JN et al. Risk assessment for vitamin D. Am J Clin Nutr 2007; 85: 6-18.
M 26. Peña-Rosas JP et al. Daily oral iron supplementation during pregnancy.
Cochrane Database Syst Rev 2015; 7: CD004736. DOI:10.1002/14651858.
CD004736.pub5 [Last assessed as up-to-date 10 January 2015].
DOI: 10.1136/dtb.2016.7.0414
Editorial Board: Paul Caldwell MB BS, MRCGP, general practitioner; Jo Congleton MA,
MD, MRCP, Brighton and Sussex University Hospitals NHS Trust; Martin Duerden B Med
Sci, DRCOG, MRCGP, Dip Ther, DPH, Bangor University; David Erskine FRPharmS, Guy’s
Hospital, London; Joanna Girling MB BS, MA, MRCP, FRCOG, West Middlesex University
Hospital NHS Trust, London; Sean Kelly MB ChB, MD, FRCP, York Hospital; Teck Khong MB
ChB, St George’s, University of London; Monica Lakhanpaul MB ChB, MD MRCP, FRCPCH,
UCL Institute of Child Health, London; Julian Treadwell MBBS, MRCGP, DCH, DRCOG,
general practitioner; Mike Wilcock MRPharmS, Royal Cornwall Hospitals NHS Trust.
Editorial correspondence: DTB, BMJ Group, BMA House, Tavistock Square,
London WC1H 10JR, UK
Email: [email protected]
Website: www.dtb.bmj.com
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Cover illustration: The chemical formula of folic acid
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dtb.bmj.com Dare we think the unthinkable?

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