Insulin-Pump Therapy Benefits Some With

Type 2 Diabetes
Insulin-pump treatment can be effective for patients with type 2 diabetes in whom multiple daily
injections do not provide adequate glycemic control, a new study finds.
Results from the Medtronic-funded randomied, open-label, controlled !"#2MI$% trial were
published online &uly ' in the Lancet by (ves Reni), M*, head of the endocrinology and
diabetology department at the +niversity of ,aen ,-te de .acre Regional /ospital ,enter,
0rance, and colleagues.
In the study, ''1 type 2 diabetes patients who had /b21c levels of 34 to 124 despite a 2-month
run-in period of optimied multiple daily injections with insulin analogs were randomied to
either stay with the many daily injections or to insulin-pump therapy. 2t 5 months, /b21c levels
had decreased by 1.1 percentage points with the pump, vs just 6.7 with daily injections.
8!"#2MI$% demonstrated that pump therapy is beneficial for a group of patients who fail to
respond to all other therapeutics options. #his 9offers:;new hope for patients at high ris) of
complication.;<e thin) that !"#2MI$% is a landmar) study that has the potential to change
the way of thin)ing 9about: insulin therapy for type 2 diabetes patients,8 *r. Reni) told
Medscape Medical News.
2s)ed to comment, =achary #. >loomgarden, M*, clinical professor of medicine at Mount $inai
$chool of Medicine, .ew (or), told Medscape Medical News, 8It is an interesting study of a
very specific and clinically very important subset of patients with diabetes, those who are not
able to achieve good glycemic control despite treatment including multiple doses of insulin.
80ascinatingly, and quite different from earlier studies comparing multiple daily injections with
9insulin-pump therapy: in type 2, there was a pronounced difference in outcome with the 2
approaches.8
2nd in an accompanying editorial, "rati) ,houdhary, M>>$, MR,", M*, senior lecturer and
consultant in diabetes at ?ing@s ,ollege Aondon, +nited ?ingdom, writes, 8!"#2MI$% provides
a compelling case for the clinical effectiveness of insulin-pump treatment in type 2 diabetes,
suggesting that it can help improve glycemic control in this difficult-to-treat group of patients
who are unable to achieve glucose control despite increasing doses of insulin.8
What about Cost-effectiveness?
>ut *r. ,houdhary also points out that the cost-effectiveness of pumps 8in different healthcare
systems will need to be evaluated.8
*r. Reni) said that while the cost of pump therapy may be a concern, it needs to be viewed in
the conteBt of potential savings for national health services if the treatment helps prevent
complications. 8<ith a 1.14 reduction in /b21c, up to a 764 microvascular ris) reduction could
be eBpected, without ris) of severe hypoglycemia. Roughly, those uncontrolled patients with the
higher insulin needs will probably be those for whom pump 9therapy: will be cost-effective.8
0rancine R. ?aufman, chief medical officer and vice president of global, medical, and clinical
affairs for Medtronic *iabetes, agreedC 8Managing glucose effectively helps prevent short-term
and long-term diabetes complications.8 $he told Medscape Medical News that the company plans
to use the !"#2MI$% clinical data 8to inform physicians, patients, and health plans as to the
benefit of insulin-pump therapy in insulin-ta)ing type 2 patients who are not at goal.8
In fact, 8the majority of private payers in the +$ provide coverage for insulin pumps for both
type 1 and type 2 patients,8 she observed, but added that 8for those public and private health
plans that do not yet provide coverage for insulin pumps, this evidence is critical to close the
coverage gap.8
Better Control Without Increased ypo!lycemia
In !"#2MI$%, subjects were recruited from '5 centers in ,anada, %urope, Israel, $outh 2frica,
and the +nited $tates. 2ll were already using insulin. 2 total of 7DE entered the 2-month multiple
daily injections of insulin run-in. !f the ''1 whose /b21c levels remained high, 153 were
randomied to pump treatment and 15' to continuing multiple daily injections. .early 764 of
both groups had abnormal scores on a cognitive assessment test, indicating mild impairment.
/b21c was D.64 in both groups at baseline, decreasing at 5 months to F.D4 with the pump vs
3.54 in the multiple-daily-injection group, with a 6.F-percentage-point between-group difference
GP H .6661I. Results were similar after adjustment for baseline /b21c, the authors note.
#he proportion of patients with /b21c levels of 34 or less was nearly twice as high with the
pump, EE4 vs 234 with the multiple daily injections Godds ratio 1.D, P H .6661I.
!verall, the decrease in /b21c was independent of diabetes duration, body mass indeB, education
level, cognitive-assessment score, and number of blood glucose tests the patient performed per
day. #he decrease in /b21c also did not differ significantly between the patients ta)ing and not
ta)ing metformin, *r. Reni) and colleagues note.
2t the end of the study, the mean total daily dose of insulin was significantly lower with the
pump, DF vs 122 units GP H .6661I with no significant difference in body-weight change between
the 2 groups G1.E )g vs1.1 )gJ P K .'22I.
#he mean number of daily blood glucose tests performed was about '.F for both groups after the
2-month run-in but dropped to '.1 per day in the multiple-daily-injection group during the last '
months of the study while staying the same in the pump group.
#wo diabetes-related serious adverse events Ghyperglycemia or )etosis without acidosisI
resulting in hospital admission occurred in the pump-treatment group compared with 1 in the
multiple-daily-injection group. .o )etoacidosis occurred in either group, and 1 episode of severe
hypoglycemia occurred in the multiple-daily-injection group.
*r. Reni) told Medscape Medical News that one nice surprise was the fact that 8even patients
with mild cognitive impairment eBperienced the same pump benefit as the general population.
#his suggests that pump treatment can be used effectively by almost all patients regardless of
age.8
"dherence is the #ey
#he powerful effect of pump therapy over multiple daily injections is li)ely attributable in large
part to differences in adherence, *r. >loomgarden told Medscape Medical News.
8#he 366-pound gorilla here is adherence L with it li)ely that those patients failing with
multiple daily injections were not following recommendations for insulin self-administration in
the first place and continued not to do so when randomied to continue the same approach, while
the seeming technologic wonder of the pump encouraged them to ta)e insulin more regularly,
eBplaining the outcome. #he seemingly higher insulin dose in the multiple-daily-injection group
is, I thin), a reflection of this,8 he said.
*r. Reni) and colleagues say there might be several reasons that pump treatment provides better
glycemic control with less insulin than does multiple-daily-injection treatmentC first, the basal
component of insulin infusion, its better and less variable absorption from the subcutaneous
tissue, and optimal flatness of insulin concentrations over 27 hours compared with slow-acting
insulin analogs li)ely play a role, as do the more favorable pharmaco)inetics and
pharmacodynamics of the delivered dose.
"ump treatment is also probably more convenient for patients, 8lessening the burden associated
with dose trac)ing and scheduling and improving adherence to insulin injections,8 they conclude.
The OPT2MISE study was funded by Medtronic. Dr. e!ni" has done clinical trials as a
coin#esti$ator for Medtronic% Eli Lilly% and No#o Nordis". &e has also pro#ided ad#isory
ser#ices to Medtronic% 'bbott% and Eli Lilly and attended conferences or$ani!ed by Eli Lilly and
Medtronic as a contributor. &e has also recei#ed in#esti$ator(s fees in relation to OPT2MISE.
Dr. )houdhary has ser#ed on ad#isory boards and recei#ed spea"er(s fees and tra#el support
fro* Medtronic% oche% and +ohnson , +ohnson. Dr. -loo*$arden $a#e tal"s sponsored by
Medtronic in )hina o#er 2 years a$o but has no rele#ant current disclosures.
Lancet. "ublished online &uly ', 2617. 2bstract, %ditorial
The $ffects of Diabetes on the Brain
#his is the Medscape .eurology Minute. I am *r. 2lan &acobs. #he 2merican *iabetes
2ssociation estimates that as many as 1 in ' 2merican adults will have diabetes in the year 26E6.
.ow, researchers from the "erelman $chool of Medicine
91:
at the +niversity of "ennsylvania
have used MRI to investigate the association between severity and duration of type 2 diabetes
mellitus and brain structure in 517 patients at 7 participating medical centers. #he mean age of
the participants was 52 years, and the mean duration of disease in the study group was D.D years.
#he results showed that a longer duration of diabetes was associated with brain volume loss,
particularly in the gray matter. 0or every 16 years of diabetes duration, the brain of a patient with
diabetes loo)ed 2 years older than that of a nondiabetic person. !f interest, the study found no
association of diabetes characteristics with small-vessel disease in the brain. #he study authors
concluded that diabetes duration correlates primarily with brain gray matter atrophy, and that this
has implications for the future decline in cognitive functions in patients with diabetes, raising the
li)elihood that neurodegenerative changes, such as 2lheimer@s disease, will correlate more
strongly than vascular dementia. #his has been the Medscape .eurology Minute. I@m *r. 2lan
&acobs.
%e& Insi!ht Into 'in( Bet&een Depression)
Dementia
/aving depressive symptoms speeds cognitive decline, but the relationship is not due to the
presence of M-amyloid, tau tangles, or other brain pathology, results of a new postmortem study
suggest.
Researchers have )nown for some time that depression is related to elevated ris) for mild
cognitive impairment GM,II and dementia, but they haven@t agreed on why this is the case. Many
in the field were convinced that the relationship is driven by underlying cognitive issues and that
people become depressed as a result of getting more demented, researchers say.
#his new study, however, puts that theory to rest, concludes lead author Robert $. <ilson, "h*,
professor, neuropsychology, *epartments of .eurological $ciences and >ehavioral $ciences,
Rush +niversity Medical ,enter, ,hicago, Illinois.
8#he most reasonable conclusion from this study is that depression is a ris) factor for cognitive
decline, but that it does not wor) through the common pathologies that we associate with
cognitive decline and dementia in old age, including amyloid plaques, tangles, Aewy bodies,
stro)es, and so on,8 *r. <ilson told Medscape Medical News. 8It@s something else in the brain
contributing to cognitive decline.8
2lthough some past research has associated late-life depression with abnormalities in frontal-
subcortical and limbic networ)s involved in emotional control, *r. <ilson said that pinpointing
the cause of the relationship between depression and dementia is still speculative.
*r. Robert $.
<ilson
8#hat search will continueJ figuring that relationship out will li)ely help us greatly in translating
findings such as this into some sort of effective intervention,8 said *r. <ilson. 8In the meantime,
we thin) that reducing depressive symptoms in older people might have a beneficial effect on
cognition and this ought to be investigated.8
#he study was published online &uly '6 in Neurolo$y.
Depressive Symptoms
Researchers used data from 2 cohort studies begun in the 1DD6sC the Religious !rders $tudy,
which involved older ,atholic clergy, and the Rush Memory and 2ging "roject, which recruited
older lay individuals from the ,hicago area. "articipants completed yearly clinical assessments
and agreed to a postmortem eBamination of their brain.
2nnual eBaminations included a 16-item short form of the ,enter for %pidemiological $tudies
*epression $cale, which is similar to the original version of the scale, including the ability to
capture change in symptoms over time, but doesn@t incorporate cognitive symptoms. "articipants
also completed 13 cognitive tests at the annual visits.
#he 1F57 study participants included in the analysis had an average age of F5.5 years at the start
of the study and an average of 15.2 years of schooling.
2t baseline, each of these participants reported a mean of 1.6 symptom on the depression scale.
In an analysis that assessed change in depressive symptoms during a mean of F.3 years of
follow-up, depressive symptoms increased over time, mainly because of a slight decline in the
li)elihood of having no symptoms.
!ver the course of follow-up, E2.24 of the participants developed mild cognitive impairment
GM,II. Incident M,I was associated with a higher level of depressive symptoms before M,I
onset but not with rate of change in symptoms after M,I onset.
&ust less than 134 of participants developed dementia during follow-up. Incident dementia was
associated with a higher level of depressive symptoms before dementia onset and a slight
decrease in symptoms thereafter.
!f the 536 participants who died during follow-up, a neuropathologic eBamination was
completed on the first E32. 2t baseline, these participants reported a mean of 1.2 depressive
symptoms. 2fter adjustment for age at death, seB, and education, depressive symptoms slightly
increased during a mean of 3.7 years of observation.
In these participants, the composite measure of M-amyloid plaque burden ranged from 6 to 22.D
and the composite measure of tau tangle density ranged from 6 to '2.2. 2lso, '2.14 had at least
1 chronic gross infarct, 2F.D4 at least 1 chronic microinfarct, 12.14 had neocortical Aewy
bodies, and E.D4 had hippocampal sclerosis.
#he study found that severity of depressive symptoms, or change in symptoms over time, was
not associated with any of these neuropathologic mar)ers, all of which are )nown to be
associated with dementia.
Continuous *utcomes
$ince dementia develops by minute degrees, researchers loo)ed at continuous outcomes. In a
model loo)ing at the interaction of neuropathologic mar)ers with time, the mar)ers together
accounted for '1.34 of the variability in rates of cognitive decline.
<hen depressive symptoms and mar)ers were included in the analysis, a higher level of
depressive symptoms continued to be associated with a faster rate of cognitive decline. #his
higher level accounted for 7.74 of the residual variability in cognitive decline not attributed to
neuropathologic burden.
*r. <ilson noted that it@s not just depression in older people but also depression in middle age
that predicts later cognitive problems.
2long with his research colleagues, *r. <ilson is reviewing some of the neuroimaging results
from tests carried out during the annual visits and after death to see whether these shed any new
light.
8!ne thing we can loo) at is the connectivity between brain regions,8 he said. 8<e can loo) for
functional and structural changes that are associated with depression and its association with
cognitive decline, so it helps us narrow down a little bit the areas and the )inds of abnormalities
that might be present in the brain that might be driving this association.8
2 limitation of the research was that because participants were self-selected, the generaliability
of the results is unclear. 2s well, measures of some disease processes, such as cerebrovascular
disease, were incomplete, or, in the case of, for eBample, transactive response *.2-binding
protein, weren@t measured. In addition, some mar)ers, such as hippocampal sclerosis, were
infrequently observed.
To+ic Processes
0or a comment on this study, Medscape Medical News approached Richard >. Aipton, M*,
professor and vice chair, neurology, professor, epidemiology and population health, professor,
psychiatry and behavioral science, and director, *ivision of ,ognitive 2ging and *ementia,
2lbert %instein ,ollege of Medicine, >ronB, .ew (or).
*r. Aipton called the study 8unique8 in that its findings are inconsistent with the theory that
depression is a manifestation of dementia-related brain pathology or that depression causes
cognitive decline.
Instead, said *r. Aipton, the findings support the hypothesis that late-life depressive
symptoms, or factors accompanying depressive symptoms, independently contribute to cognitive
decline.
8#reatment of depression may therefore represent a remediable ris) factor for cognitive decline
in older adults that is independent of the pathology of dementia,8 he said.
2lso approached for comment, Meryl 2. >utters, "h*, associate professor, psychiatry,
+niversity of "ittsburgh $chool of Medicine, "ennsylvania, agreed that the study suggests some
still un)nown changes related to depressive symptoms probably enhance or accelerate cognitive
decline.
8#o me, this suggests not only that depressive symptoms are associated with toBic processes in
the brain causing more rapid cognitive decline, but that as a research field, we should begin to
investigate whether depressive symptoms L or major depression L in younger people have the
same negative effect both in the brain and on cognitive decline once they reach older adulthood.8
#he implication of this, said *r. >utters 8is that not only may intervening quic)ly when older
adults develop depression be important for cognitive health, but that ultimately this may apply to
younger people as well.8
>ut *r. >utters said caution is in order when interpreting the results of the study because it didn@t
include information about participants@ psychiatric history. It@s 8highly li)ely8 that some
participants had a history of major depression or generalied anBiety disorder as these are the
most common mental disorders, she said.
8#hese could be influencing either the levels of pathologic changes in the brain andNor rate of
cognitive decline, far more than the depressive symptoms in old age measured in the study.8
In addition, said *r. >utters, in the overall sample, the level of depressive symptoms was quite
low, with most having no symptoms. 8!nly a tiny percent had high enough depressive burden or
symptoms that a mental health professional would consider substantial.8
*r. >utters added that at 7.74, the amount of cognitive decline accounted for by depressive
symptoms was 8rather modest.8
The study was funded by the National Institute on '$in$ and the Illinois Depart*ent of Public
&ealth. Dr. .ilson ser#es as a consultin$ editor for '$in$% Neuropsycholo$y and )o$nition%
Psycholo$y and '$in$% and Neuropsycholo$y% has ser#ed as a consultant for Pain Therapeutics
Inc% and recei#es research support fro* NI& and 'l!hei*er(s 'ssociation.
Neurolo$y. "ublished online &uly '6, 2617. 2bstract
Depression a ,-ed .la!, for Dementia -is( in
$lderly Women
%levated depressive symptoms may predict later development of mild cognitive impairment
GM,II and even dementia in the patient population classified as the 8oldest old,8 new research
suggests.
In a prospective study of more than '66 women who were at least 3E years of age, those who had
higher depression scores at baseline had more than a '-fold increase in ris) of developing M,I or
dementia within E years compared with the women who had lower depression scores.
In addition, the investigators found that only 1D4 of the participants who had scores of 5 or
higher on the Oeriatric *epression $cale GO*$I showed normal cognitive functioning E years
later.
*r. 2dam $pira
8In general, our results were consistent with what we@ve seen in younger samples, and it eBtends
what we )now about the potential negative effects of depression to an older and very relative
population,8 lead author 2dam ". $pira, "h*, assistant professor in the *epartment of Mental
/ealth at the &ohns /op)ins >loomberg $chool of "ublic /ealth in >altimore, Maryland, told
Medscape Medical News.
In addition, 8the magnitude of the effect we found was substantial,8 said *r. $pira.
2lthough he noted that the observed results did not demonstrate a causal association between
depression and cognitive decline, they are still important.
8In the future, if we find that a causal lin) is there, that could be one means of preventing
cognitive decline. !r it could be that increased depressive symptoms and cognitive decline arise
from a third variable, such as a neurodegenerative disease,8 he said.
8$till, it could be of prognostic value and serve as some sort of mar)er of abnormal process that
should be addressed. It could serve as a warning or raise a red flag that a person is at elevated
ris) for cognitive decline, even if it@s not the depression that is driving that decline.8
#he study is published in the *ecember issue of the '*erican +ournal of /eriatric Psychiatry.
*ldest *ld
2ccording to past population studies, between '4 and 254 of older adults have significant
levels of depressive symptoms, whereas 24 to 74 of adults older than 57 years and
approBimately 114 of those older than F6 years have major depression.
In addition, 174 of those older than F6 years and 'F4 of those older than D6 years have
dementia.
8Increasing evidence suggests that depression is a ris) factor for cognitive impairment, but it is
unclear if this is true among the oldest old,8 write the researchers.
#hey note that this classification, which denotes adults who are older than 37 years, is one of the
fastest-growing segments of the +$ population.
#he investigators assessed '62 women aged 3E years or older Gmean age, 35.D yearsJ all but 1
whiteI who participated in the <omen, ,ognitive Impairment $tudy of %Bceptional 2ging
G<I$%I, an offshoot of the prospective $tudy of !steoporotic 0ractures G$!0I. $!0 has enrolled
DF67 women from "ennsylvania, !regon, Maryland, and Minnesota.
%ovel "ntidepressant Sho&s Promise in
Depressed $lderly
PI%..2, 2ustria L #he eBperimental multimodal antidepressant Au 2221667 GvortioBetineI is
effective and well tolerated in the treatment of elderly patients with recurrent major depressive
disorder GM**I, new research suggests.
2 double-blind, randomied controlled trial GR,#I of more than 7E6 elderly adults with M**
from F countries showed that those treated with Au 2221667 showed significantly greater
improvement on several depression rating scales and cognitive tests compared with those who
received placebo.
In addition, the only adverse event that occurred at a higher incidence with the eBperimental
medication than with placebo was nausea.
8<e found that this is an effective antidepressant in older people, with clear separation between
the vortioBetine group and the placebo group on standard depression measures,8 lead author
,ornelius ?atona, M*, 0R,"sych, from the *epartment of Mental /ealth $ciences at the
+niversity ,ollege Aondon in the +nited ?ingdom, told Medscape Medical News.
8$everal similarly designed studies of antidepressants in old age have proved negative. #his is 1
of relatively few recent studies where it shows a new antidepressant to be effective. 2nd we
found that it was eBtremely well tolerated and had a very nice effect on cognition,8 said *r.
?atona.
*r. ,ornelius
?atona
#a)eda "harmaceutical and Aundbec) recently jointly announced that they had submitted a .ew
*rug 2pplication to the +$ 0ood and *rug 2dministration and a mar)eting authoriation
application to the %uropean Medicines 2gency for this medication in the treatment of M** in
adult patients.
82s, and when, this drug becomes available, I thin) it will be a very interesting drug to consider
L especially because it has a novel mode of action,8 said *r. ?atona.
#he study was presented here at the 2Eth %uropean ,ollege of .europsychopharmacology
G%,."I ,ongress.
/ulticountry Study
Au 2221667 is a bis-arylsulfanyl amine compound that is 8thought to wor) through a
combination of 2 pharmacological modes of actionC E-/# reupta)e inhibition and receptor
activity,8 write the investigators.
8In vitro studies indicate that 9it: is a E-/#' and E-/#F receptor antagonist, E-/#1> receptor
partial agonist, E-/#12 receptor agonist, and inhibitor of the E-/# transporter,8 they add
2t the 2merican "sychiatric 2ssociation 2611 2nnual Meeting, and reported at the time by
Medscape Medical News, an R,# of more than E66 adult patients of all ages with M** from 7
continents showed that those who received 1-, E-, or 16-mg doses of Au 2221667 had
significantly reduced symptoms over 3 wee)s compared with those who received placebo.
Dementia 'in(ed With Increased -is( for
ospitali0ation in $lderly
Clinical Context
*ementia is one of the most common chronic illnesses among older adults, and an editorial by
,onstantine Ay)etsos, M*, M/$, which accompanies the current study, describes the disease
course. !verall, the rate of progression of dementia can vary substantially from patient to patient,
with one third of cases demonstrating little progression after E years. Means to reduce the ris) for
progression to severe dementia include mental eBercises, good relationships between caregiver
and patient, and management of neuropsychiatric symptoms. *ementia care can prevent
institutionaliation, and is thus cost-effective.
!ne of the challenges of caring for patients with dementia is the ris) for hospitaliation for other
illnesses. /owever, this ris) is not well-quantified. #he current study addresses this issue.
Study Synopsis and Perspective
%lderly people with dementia have a significantly higher rate of hospital admissions for all
causes, including admissions for conditions that could have been managed on an outpatient basis
had those conditions been recognied in a timely manner, according to a new study published in
+'M'.
Aed by %liabeth 2. "helan, M*, from the +niversity of <ashington, $eattle, the study found
that people with dementia had a 714 higher rate of hospital admissions for all causes and a F34
higher rate of admissions for ambulatory care-sensitive conditions, such as urinary tract
infection, than their peers who did not have dementia.
8#his is an awareness-raising message for providers of care to older patients,8 *r. "helan told
Medscape Medical News.
8*ementia is increasing with the ageing of the population, and more and more providers are
going to be managing these patients, whether in primary care or in specialty care for other
conditions,8 *r. "helan said. 8If a person with dementia gets admitted to hospital, there can be
adverse consequences, so it is desirable to )eep them out of the hospital as much as possible.8
"dverse Conse1uences
#hese adverse consequences include increased ris) for delirium and worsening of cognition,
functional decline, use of restraints, and iatrogenic complications.
In partnership with the Oroup /ealth Research Institute in $eattle, <ashington, *r. "helan and
her team did a retrospective analysis of hospitaliations among ',61D volunteers aged 5E years
and older in 2dult ,hanges in #hought G2,#I, a longitudinal cohort study of aging and
dementia.
#he analysis spanned a period of almost 1' years, from 0ebruary 1, 1DD7, to *ecember '1, 266F.
"articipants were enrollees of the Oroup /ealth ,ooperative, an integrated health delivery
system in the $eattle area. #he ,ooperative trac)ed all healthcare use, which enabled the
researchers to lin) hospitaliation data and dementia data for the cohort.
In addition, 2,# provided rigorous dementia diagnostic evaluations every 2 years for each
participant.
!ver the study period, 7D7 individuals developed dementia. !f these, 72F G354I were admitted
to hospital at least once. !f the remaining 2E2E individuals who did not develop dementia, 17F3
GED4I were admitted to hospital at least once.
#he analysis showed significantly higher rates of hospitaliations for those individuals who
developed dementia compared with those who remained dementia free.
%eed for Better *utpatient Care
2fter adjusting for age, seB, and other potential confounders, the ratio of admission rates for all-
cause admissions was 1.71 GDE4 confidence interval 9,I:, 1.2' - 1.51J P H .661IJ for potentially
preventable admissions Gambulatory careQsensitive conditions 92,$,s:I, it was 1.F3 GDE4 ,I,
1.'3 - 2.'1J P H .661I.
"otentially preventable conditions included bacterial pneumonia, congestive heart failure,
dehydration, duodenal ulcer, and urinary tract infectionJ admission rates for these 2,$,s were
significantly higher in the individuals with dementia, the study found.
8<e need to improve care in the outpatient setting. Right now we donRt have good models of
chronic illness that incorporate the special needs of persons with dementia,8 *r. "helan said.
8*esigning new models of care that specifically target this subgroup of patients and focus on
their ongoing outpatient longitudinal primary care would be in order,8 she added.
*r. "helan would also li)e to see more funding to support additional research on ways to
improve care for these patients.
8#here have been interventions, but these havenRt really touched on primary care. 0or eBample,
studies of eBercise showing benefits in delaying cognitive decline in persons with dementia or
studies that loo) at reducing psychotropic medications in the elderly have not been conducted in
the primary care setting, nor have they involved primary care providers, and I thin) thatRs an
important group in the future to wor) to discover how we can improve outpatient primary care.8
2ulnerable Population
#he study provides strong evidence that dementia ma)es people vulnerable to developing
medical illnesses that require hospitaliation, ,onstantine O. Ay)etsos, M*, M/$, from &ohns
/op)ins +niversity, >altimore, Maryland, told Medscape Medical News.
8#hese patients also become vulnerable to not being adherent to primary or ambulatory care,8 he
said. 8#his is reflected in almost twice the rate of hospitaliations after the onset of dementia for
ambulatory careQsensitive conditions, or the things that usually get treated in ambulatory care.8
*r. Ay)etsos, who wrote an accompanying editorial on this study, agrees that outpatient care for
patients with dementia needs to be improved.
8<e need to do a better job at diagnosing dementia early, in part so that we can better manage
medical illnesses and prevent hospitaliations. #he unfortunate thing is that primary or
ambulatory care still misses dementia, so the first thing clinicians need to do is ma)e sure they
detect dementia when it is there,8 he said.
!nce they do detect dementia, the neBt step is to involve family members or others who may be
close to the affected patient. 8#hey need to put into place assistants, or supervisory activities to
ma)e sure that the patient is following medical recommendations for conditions li)e
hypertension, diabetes, which pretty much everybody with dementia has,8 *r. Ay)etsos said.
It is also important to ma)e sure that patients with dementia, if at all possible, as well as family
members are educated to recognie early signs and symptoms of medical illness. #hese may be
different in patients with dementia, he said.
8$ometimes patients will develop a bladder infection, and instead of manifesting the usual
symptoms, li)e burning on urination or frequent urination, the patient might develop different
sleep patterns, or become more confused, or become agitated. !r, they may )now they are
having burning on urination while they are urinating and then forget to tell anyone or to act on
it,8 he said.
8*eveloping a partnership between the family members and the family doctor, to ma)e sure
these conditions are properly managed and that when they occur they get treated early, will go a
long way to preventing unnecessary hospitaliations for patients with dementia,8 he said.
Dr. Phelan reports no rele#ant financial relationships. Dr. Ly"etsos reports financial
relationships with Lilly% Pfi!er% Elan% '#anir% N0LP'% N0L -enefits.
+'M'. 2612J'6FC15E-1F2, 1DF-1D3. 2bstract, %ditorial
Study Highlights
Study data were drawn from the ACT cohort. This was a prospective study of
incident dementia among adults at age 65 years or older who belonged to a
health cooperative. Beginning in 1!" participants were followed#up every $
years with an in#person e%amination for incident dementia.
The current study e%amines inpatient admissions in the study cohort"
comparing hospitali&ation rates among participants both with and without
incident dementia. 'esearchers also followed the type of hospitali&ation" as
determined by discharge billing codes. Speci(cally" researchers were
interested in ACSCs" which are conditions in which hospitali&ations may be
avoided with timely" evidence#driven outpatient care.
The main study outcomes were ad)usted to account for sociodemographic"
disease" health behaviors" and self#rated health variables.
*+1 participants were included in the analysis. The mean age of participants
at baseline was ,5 years. -ost participants were woman.
The median follow#up period was .6 years among participants who
developed dementia" and ,.. years among participants who did not.
!! participants developed dementia" and 5./ of these participants had
Al&heimer0s disease alone as a cause of their dementia.
1articipants who developed dementia were older at study entry and had
lower educational attainment.
There were a total of 5*$. hospital admissions. Circulatory" respiratory" and
digestive disorders were the principal maladies on most admissions.
The unad)usted all#cause admission rate in the dementia group was an
average of !1 admissions per 1+++ person#years compared with an average
of $++ admissions per 1+++ person#years in the dementia#free group.
After ad)ustment for confounders" the rate ratio for admissions associated
with the diagnosis of dementia was 1.!1 25/ C3" 1.$* # 1.614.
5%amining ACSCs admissions separately" the rate ratio for admissions
associated with the diagnosis of dementia was 1.,. 25/ C3" 1.*. # $.*14.
6ementia signi(cantly increased the ris7 for admissions for disease in
multiple organ systems" including most ACSCs 2bacterial pneumonia"
congestive heart failure" dehydration" duodenal ulcer" and urinary tract
infection4.
8owever" rates of digestive and endocrine admissions were similar in
participants both with and without dementia" and dementia did not confer
higher ris7s for admissions resulting from cellulitis" gastric ulcer" and chronic
obstructive pulmonary disease.
5%cluding participants who died during follow#up failed to signi(cantly alter
the main study results.
Clinical Implications
9verall" the rate of progression of dementia can vary substantially from
patient to patient" with one third of cases demonstrating little progression
after 5 years. -eans to reduce the ris7 for progression to severe dementia
include mental e%ercises" good relationships between caregiver and patient"
and management of neuropsychiatric symptoms.
3n the current study" the presence of dementia signi(cantly increased the ris7
for admissions for disease in multiple organ systems" including most ACSCs
2bacterial pneumonia" congestive heart failure" dehydration" duodenal ulcer"
and urinary tract infection4.
"ntidepressants in *lder Patients /ay ave
"dverse *utcomes
Clinical Context
2ccording to the &anuary 2E, 2665, issue of the )ochrane Database Syste*atic e#iew by
Mottram and colleagues of elderly people with depression, tricyclic antidepressants G#,2sI and
selective serotonin reupta)e inhibitors G$$RIsI have similar efficacy, but #,2s appear to have a
higher discontinuation rate because of adverse effects. In 266D, the .ational Institute for /ealth
and ,linical %Bcellence National )linical Practice /uideline 12 recommended $$RI use for
treatment of depression, but adverse effects and patient preference should also be considered.
#his cohort study by ,oupland and colleagues assesses whether antidepressant class or
individual antidepressants are associated with certain adverse outcomes in elderly persons with
depression.
Study Synopsis and Perspective
+se of antidepressant medication in those over age 5E is ris)y, new research suggests.
2 population-based cohort study in the +nited ?ingdom published online 2ugust 2 in the -ritish
Medical +ournal showed significant associations between the use of antidepressants and adverse
outcomes, including falls, stro)e, seiures, and all-cause mortality in elderly people with
depression.
"atients prescribed $$RIs, which were the most commonly prescribed antidepressants, fared
worse than those receiving the older tricyclic antidepressants, according to the researchers.
8!ur findings are new and uneBpected, and need to be confirmed in other studies,8 lead author
,arol ,oupland, "h*, +niversity of .ottingham, +nited ?ingdom, told Medscape Medical
News.
8#he benefits of the different classes of antidepressant drugs also need to be considered
alongside the adverse effects,8 *r. ,oupland added. 8If our findings are confirmed, then low-
dose #,2s should be considered when assessing antidepressant treatment for older people with
depression.8
3nder--epresented 4roup
#he study was commissioned and funded by the +nited ?ingdom@s .ational Institute of
Research /ealth #echnology 2ssessment program in 2665 to investigate the potential ris)s of
antidepressant use in the elderly.
8Aittle is )nown about the adverse effects associated with antidepressants in the elderly, who
may be at increased ris) because of their higher levels of comorbidity, age-related physiological
changes, and polypharmacy,8 *r. ,oupland said.
8!lder people are also under-represented in clinical trials of antidepressants, and most of these
trials are short-term, which ma)es it difficult to derive reliable estimates of the incidence of
adverse events in this group,8 she said.
*r. ,oupland and her team identified 56,F75 patients aged 5E to 166 years with a newly
diagnosed episode of depression between 1DD5 and 266F. #he mean age of the patients was FE
yearsJ ''.'4 of patients were men and 55.F4 were women. Many patients had other conditions,
such as heart disease and diabetes, and were ta)ing several medications.
#hey were followed for a mean of E years, and the total number of person-years of follow-up
was '6E,133.
-esults
*uring follow-up, 3D4 of the cohort Gn K E7,6'3I received at least 1 prescription for an
antidepressant drug. $$RIs accounted for E7.F4, #,2s made up '1.54, and the group of other
antidepressants GvenlafaBine hydrochloride, and mirtaapineI made up 1'.E4 of prescriptions.
!nly 6.24 of prescriptions were for monoamine oBidase inhibitors, and patients who were
prescribed these drugs were eBcluded from the analysis.
2fter adjusting for confounding factors, including age, seB, severity of depression, other
illnesses, and use of other medications, the study showed that $$RIs and drugs in the group of
other antidepressants were associated with an increased ris) for several adverse outcomes
compared with #,2s.
0or the $$RIs, the adjusted haard ratios G/RI were as followsC
All#cause mortality: 1.*$ 25/ con(dence interval ;C3<" 1.$6 # 1.*4
Stro7e or transient ischemic attac7: 1.15 25/ C3" 1.+5 # 1.$64
=alls: 1.$, 25/ C3" 1.$+ # 1.*54
=racture: 1.$6 25/ C3" 1.15 # 1.*,4
5pilepsy or sei&ures: 1..+ 25/ C3" 1.*$ # $.!*4
8yponatremia: 1.!! 25/ C3" 1.1 # 1.,54
0or the group of other antidepressants the adjusted /Rs wereC
All#cause mortality: 1.!* 25/ C3" 1.** # 1.5!4
Attempted suicide or self#harm: *.+! 25/ C3" $.$1 # !.1,4
Stro7e or transient ischemic attac7: 1.*5 25/ C3" 1.1. # 1.5!4
=racture: 1.*1 25/ C3" 1.15 # 1.5+4
5pilepsy or sei&ures: $.$+ 25/ C3" 1.!6 # *.*+4
#he analysis also showed $$RIs were associated with the highest adjusted /R for falls G/R,
1.55J DE4 ,I, 1.E3 - 1.F'I and hyponatremia G/R, 1.E2J DE4 ,I, 1.'' - 1.FEI vs no
antidepressant use.
$imilarly, in comparison with no antidepressant use, other classes of antidepressants were
associated with the highest adjusted /Rs for all-cause mortality G1.55J DE4 ,I, 1.E5 - 1.FFI,
attempted suicide or self-harm GE.15J DE4 ,I, '.D6 - 5.3'I, stro)e or transient ischemic attac)
G/R, 1.'FJ DE4 ,I, 1.22 - 1.EEI, fracture G/R, 1.57J DE4 ,I, 1.75 - 1.37I, and epilepsy or
seiures G/R, 2.27J DE4 ,I, 1.56 - '.1EI.
2mong individual drugs, traodone, mirtaapine and venlafaBine were associated with the
highest ris)s for several outcomes.
TC"s 'ess -is(y?
#he absolute ris)s over 1 year for all-cause mortality were F.674 for patients, 3.124 for #,2s,
16.514 for $$RIs, and 11.7'4 for other antidepressants vs no antidepressant use.
#he most dangerous times for adverse events were within the first 23 days of starting an
antidepressant and within the first 23 days after stopping.
8#his is new research and needs confirmation in further studies. It has shown associations but not
necessarily a direct causal lin), so there is no need for patients to change or stop their treatments
at this stage if they are finding them beneficial,8 *r. ,oupland cautioned.
8*octors should also advise patients that adverse effects are most common during the first few
wee)s of treatment, and they should be monitored during this period,8 she added.
2s)ed whether #,2s are safer to use in older individuals, *r. ,oupland repliedC 8!ur study
suggests this might be the case, but our findings could also be due to residual confounding due to
differences between patients prescribed different antidepressant drugs.8
/er hope is that this study will prompt further research leading to clearer guidance on how best
to treat depression effectively but safely in older people.
.indin!s Inform Prescribin!
In an accompanying editorial, Ian >. /ic)ie, M*, from the +niversity of $ydney in 2ustralia,
writes that the study has clear implications for more informed prescribing and enhanced clinical
monitoring.
8Oiven the potential harms, the decision to prescribe for an older person with depression should
not be ta)en lightly,8 he writes.
/e adds that older people require careful monitoring for adverse effects and recommends that
they be seen at least wee)ly during their first month of treatment and again when the drugs are
stopped.
Medscape Medical News as)ed &osepha 2. ,heong, M*, professor of psychiatry at the
+niversity of 0lorida ,ollege of Medicine in Oainesville, to comment on the findings.
*r. ,heong, who specialies in geriatric psychiatry, said the paper was important because it
serves as a general reminder that geriatric patients are more li)ely to have medical comorbid
conditions, medical complications, and increased sensitivity to side effects at lower doses than
younger matched cohorts.
$he also questioned the suggestion that #,2s may be safer in older people.
8&ust because traditional #,2s in low doses were found to have fewer associated mortality and
morbidity outcomes than $$RIs does not necessarily imply that they are safer or better tolerated,
as their inherent side effect profiles tend to decrease efficacy due to patientsR early
discontinuation or intolerance of side effects at therapeutic doses,8 she said.
*r. ,heong agreed it is important to monitor geriatric patients very closely.
8+se caution whenever starting any medication in a geriatric patient,8 she said. 8,arefully
consider concurrent medications and potential for drug-drug interactions, prescribe a medication
only if absolutely indicated and with clear therapeutic goals that can be documented with
assessment, and use the minimum therapeutically effective dose to maBimie therapeutic
response while minimiing potential side effects.8
This study was funded by NI& &ealth Technolo$y 'ssess*ent Pro$ra**e. Dr. )oupland has
disclosed no rele#ant financial relationships. Dr. &ic"ie reports that his research is supported
principally by a National &ealth and Medical esearch )ouncil 'ustralian Medical esearch
0ellowship and that he has also has participated in depression awareness pro3ects for health
professionals supported by $o#ern*ent% co**unity a$ency% and industry sponsors% includin$
.yeth% Eli Lilly% Ser#ier% Pfi!er% and 'stra4eneca. Dr. )heon$ has disclosed no rele#ant financial
relationships.
-M+. "ublished online 2ugust 2, 2611.
-elated 'in(
2 2665 ,ochrane review on use of antidepressants for depressed elderly is available online.
Study Highlights
6+",!6 patients aged between 65 and 1++ years old with a new episode of
depression during a 1$#year period were enrolled.
5,+ general practices in the >nited ?ingdom contributed to a primary care
database.
5%clusion criteria were age 1++ years or older" diagnosis less than 1$ months
after registration with a study practice or practice0s installation of a computer
system" temporary residence" depression diagnosis or antidepressant
prescription in the 1$ months before the diagnosis was recorded" and
psychosis.
-ean age of the patients was ,5.+ years.
$+"$*+ 2**.*/4 were men" and !+"516 266.,/4 were women.
-ean follow#up period was 5.+ years per person.
5!"+*. 2..+/4 received at least 1 prescription for antidepressant during
follow#up.
1"*."*5 antidepressant prescriptions were provided:
o ,6!"65 SS'3s 25!.,/4
o !!$"1$ TCAs 2*1.6/4
o $$+* monoamine o%idase inhibitors 2+.$/4
o 1."*+5 other antidepressants 21*.5/4
The low number of prescriptions for monoamine o%idase inhibitors precluded
use of data.
6ata on adverse outcomes were obtained from computer records and death
certi(cates for a 1*#year study period that included 1 year after the last year
of patient enrollment.
The primary outcome measures were 8's for all#cause mortality" attempted
suicide or self#harm" myocardial infarction" stro7e@transient ischemic attac7"
falls" fractures" upper gastrointestinal tract bleeding" epilepsy@sei&ures" road
traAc crashes" adverse drug reactions" and hyponatremia.
Analysis ad)usted for age at study entry" se%" year of depression diagnosis"
previous depression diagnosis before age 65 years" the severity of inde%
diagnosis of depression" deprivation" smo7ing status" comorbidities" use of
other drugs at baseline" and previous falls before baseline.
SS'3s vs no treatment were lin7ed with the highest ad)usted 8' for falls 28'"
1.664 and hyponatremia 28'" 1.5$4.
9ther antidepressants vs no treatment were lin7ed with the highest ad)usted
8' for all#cause mortality 28'" 1.664" attempted suicide@self#harm 28'" 5.164"
stro7e@transient ischemic attac7 28'" 1.*,4" fracture 28'" 1.6!4" and
epilepsy@sei&ures 28'" $.$!4.
TCAs vs no treatment did not have the highest 8' for any outcome.
SS'3s vs TCAs had a higher ad)usted 8' for all#cause mortality 28'" 1.*$4"
stro7e@transient ischemic attac7 28'" 1.154" falls 28'" 1.$,4" fracture 28'"
1.$64" epilepsy@sei&ures 28'" 1..+4" and hyponatremia 28'" 1.!!4.
9ther antidepressants vs TCAs had a higher ad)usted 8' for all#cause
mortality 28'" 1.!*4" attempted suicide@self harm 28'" *.+!4" stro7e@transient
ischemic attac7 28'" 1.*54" fracture 28'" 1.*14" and epilepsy@sei&ures 28'"
$.$+4.
TCAs vs SS'3s or other antidepressants did not have higher rates of any
adverse outcomes.
The most commonly prescribed individual medications were citalopram"
Buo%etine" paro%etine" and sertraline 2SS'3s4C amitriptyline" dosulepin"
lofepramine" and tra&odone 2TCAs4C and venlafa%ine and mirta&apine 2other4.
3ndividual medications had the highest 8' for certain adverse outcomes:
o Tra&odone 2TCA4: all#cause mortality
o -irta&apine 2other4: attempted suicide@self#harm
o Denlafa%ine 2other4: stro7e@transient ischemic attac7" fracture" and
epilepsy@sei&ures
o Citalopram 2similar to other SS'3s4: falls
o Citalopram" escitalopram" and Buo%etine: hyponatremia
6ose trends were noted for TCAs and SS'3s for all#cause mortality" falls" and
epilepsy@sei&ures and for TCA with fracture.
-ost outcomes had the highest ris7s in the (rst $. days after initiation of
medication and after discontinuation of medication.
Absolute ris7s for all#cause mortality at 1 year were ,.+!/ for no
antidepressant use" ..1$/ for TCA use" 1+.61/ for SS'3 use" and 11.!*/ for
other antidepressants.
Study limitations included observational design and residual confounding.
Clinical Implications
3n elderly patients with depression" SS'3s vs TCAs are lin7ed with higher rates
of all#cause mortality" stro7e@transient ischemic attac7" falls" fracture"
epilepsy@sei&ures" and hyponatremia. 9ther antidepressants vs TCAs are
lin7ed with higher rates of all#cause mortality" attempted suicide@self#harm"
stro7e@transient ischemic attac7" fracture" and epilepsy@sei&ures.
3n elderly patients with depression" individual antidepressant drugs lin7ed
with the highest ris7 for certain adverse outcomes include the TCA tra&odone
for all#cause mortalityC mirta&apine for attempted suicide@self#harmC
venlafa%ine for stro7e@transient ischemic attac7" fracture" and
epilepsy@sei&uresC and citalopram" escitalopram" and Buo%etine for
hyponatremia.