Effect of The Treatment of Type II Diabetes Mellitus On The Development of Cognitive Impairment and Dementia (Review)

Effect of the treatment of Type II diabetes mellitus on the
development of cognitive impairment and dementia (Review)

Grimley Evans J, Areosa Sastre A
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2003, Issue 1
http://www.thecochranelibrary.com
Effect of the treatment of Type II diabetes mellitus on the development of cognitive impairment and dementia (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . .
ABSTRACT . . . . . . . . .
PLAIN LANGUAGE SUMMARY .
BACKGROUND . . . . . . .
OBJECTIVES . . . . . . . .
METHODS . . . . . . . . .
RESULTS . . . . . . . . . .
DISCUSSION . . . . . . . .
AUTHORS CONCLUSIONS . .
ACKNOWLEDGEMENTS
. . .
REFERENCES . . . . . . . .
CHARACTERISTICS OF STUDIES
DATA AND ANALYSES . . . . .
WHATS NEW . . . . . . . .
HISTORY . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS
DECLARATIONS OF INTEREST .
INDEX TERMS
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[Intervention Review]
Effect of the treatment of Type II diabetes mellitus on the

development of cognitive impairment and dementia
John Grimley Evans2 , Almudena Areosa Sastre1
1 Madrid,
Spain. 2 Division of Clinical Geratology, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Contact address: Almudena Areosa Sastre, Madrid, Spain.

Editorial group: Cochrane Dementia and Cognitive Improvement Group.
Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.
Review content assessed as up-to-date: 3 August 2005.
Citation: Grimley Evans J, Areosa Sastre A. Effect of the treatment of Type II diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD003804. DOI: 10.1002/14651858.CD003804.
ABSTRACT
Background
There is increasing interest in preventing cognitive impairment and dementia in later life. Epidemiological evidence shows a relationship
between cognitive impairment and Type II diabetes. This association is stronger in patients who have been diagnosed for longer periods
of time and in those who are on insulin therapy. There is little information on the short- and long-term influence of type of treatment
and level of metabolic control on cognitive function of people with diabetes.
Objectives
To assess the effects of different types and intensities of treatments for Type II diabetes on cognitive function.
Search methods
The CENTRAL Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, SIGLE LILACS and CINAHL as well as a number
of ongoing trials databases were last searched on 4 August 2005 using appropriate strategies.
Selection criteria
Randomized controlled trials in which different treatments for Type II diabetes have been compared and in which measures of cognitive
function were made at entry and after the treatment.
Data collection and analysis
Two reviewers independently assessed trial quality. Five trials were identified for possible inclusion but none of them could be included.
In one, cognitive function was assessed before and after intensive or conventional diabetic treatment, but the comparison was not
double-blind. The three other studies explored the effect of different treatments on QOL but did not include appropriate evaluation
of cognitive function. The fifth did not report baseline data on cognitive function in the trial groups.
Main results
No studies were found to be appropriate for inclusion in meta-analysis.
Authors conclusions
There is no convincing evidence relating type or intensity of diabetic treatment to the prevention or management of cognitive impairment
in Type II diabetes. Future research on treatments for diabetes should include standardized assessments of cognitive function as outcome
measures.
PLAIN LANGUAGE SUMMARY

No evidence that treatment or level of control of Type II diabetes influences cognitive function
Type II diabetes is a chronic disease characterized by high blood glucose levels. It needs to be treated with diet, oral drugs and sometimes
insulin to control symptoms and avoid organ damage. Patients may develop features of cognitive decline (e.g. memory problems) earlier
than healthy people. This review tries to clarify whether the type of treatment or control of the glycemia influences cognitive function.
None of the studies identified had sufficient high quality data to justify any conclusion. Future trials of treatment for Type II diabetes
should include measures of cognitive function as an outcome.
BACKGROUND
People with diabetes mellitus have abnormally high blood levels
of glucose. This may be associated with the symptoms and signs of
excessive thirst, increased urine production, and weight loss. Over
time, particular types of damage to body organs and tissues may
ensue, including arterial disease - such as heart attack, stroke and
gangrene of the legs - renal failure, and impairment of vision due
to damage to blood vessels in the eyes. Type I diabetes typically has
onset in childhood or early adult life and is characterized by a need
for treatment with insulin. Type II diabetes has a different cause;
it appears in adult life, and can often be treated by drugs other
than insulin, particularly the so-called oral hypoglycaemic drugs.
Impaired glucose tolerance is a condition in which blood glucose
rises abnormally high after a meal but later returns to normal. This
condition may be an early stage in the development of diabetes.
Cognition is a collective term for a range of higher brain functions,
including memory, perception, language, and reasoning. Some degree of impairment of one or more cognitive functions (particularly memory) is common, though not universal, in later life. For a
minority of older people impairment becomes severe, progressive,
and disabling and is described as dementia. The commonest diseases leading to dementia are Alzheimers disease, a degenerative
condition of brain cells of unknown cause, and cerebrovascular
disease in which brain cells are starved of blood and oxygen due
to narrowing of the blood vessels serving the brain. Dementia is a
tragedy for affected individuals and their families, and challenging
and costly to health and social services. Measurement of cognitive
function requires validated and reliable tests covering the range
of different domains of interest including memory, reasoning and
language. Tests for acquired impairment need to take into account

previous intelligence and education. This may be assessed by a
patients educational and occupational history, but can also be estimated by verbal skills such as vocabulary since these are more resistant than some other aspects of cognitive function to the effects
of brain damage.
Some forms of cognitive impairment, associated for example with

temporary metabolic derangement, are reversible, but there is as
yet no curative treatment for established dementia. There is therefore interest in possibilities for prevention by identifying and modifying risk factors (Fillit 2002). Although it has been suspected
from the early 1970s that there is a risk of impairment of cognitive
function associated with Type II diabetes mellitus (Bale 1973),
it is only more recently that interest has increased in research on
possible mechanisms of this association. It is not easy to study the
relationship because diabetes is frequently associated with other
vascular risks factors such as hypertension and dyslipidemia, and
with comorbidity such as cerebrovascular or cardiovascular disease (Khanel 1979) that can contribute to cognitive impairment
(Prince 1996; Stewart 1998; Kilander 1998; Rockwood 2002).
The relationship may be spurious; in particular depression can

be mistaken for dementia. It has been reported that depression
occurs more frequently in people with diabetes, particularly in
those with complications (Anderson 2001), and depression can
be one of the most difficult disorders to differentiate clinically
from dementia (Swainson 2001) . Depression is often associated
with deficits in episodic memory and learning, similar to those

occurring in the mild stages of dementia due to Alzheimers disease
(Austin 1997; Reding 1985; Visser 2000). A further complication
is that depressive features may be among the early manifestations
of dementia (Ganguli 1999; Berger 1999).
In addition to reversible impairment of cognitive function due to
short-term metabolic disturbance, there are several possible mechanisms that might underlie an association between diabetes and
irreversible cognitive impairment. In Type I (insulin-dependent)
diabetes there has been concern about possible deleterious effects
on cognitive function of repeated hypoglycaemic episodes that
may occur when tight control of blood sugar levels is attempted
(Diabetes 1998; Hung 1984; Prescott 1990; Langan 1991; Lincoln
1996; Reichard 1996). This possibility has not been studied in
people with Type II diabetes, although hypoglycaemia can occur
with some types of oral antidiabetic drugs, and some people with
Type II diabetes are treated with insulin. The frequency of hypoglycaemia may be underestimated in older people because the
symptoms may be less distinctive in later life (Thomson 1991).
The effect of acute hyperglycemia on cognitive function has also
been studied. During acute hyperglycemia, cognitive function was
impaired and mood state deteriorated in a group of people with
Type II diabetes (Sommerfield 2004).
A gene that produces a particular lipid-carrying protein the blood
(apoliprotein e4 - APOE-e4) is known to increase the risk of brain
damage from a range of causes and may be relevant to the effect
of diabetes on cognitive function (Haan 1999).
Another possible link between diabetes and cognitive impairment
would be through brain ischaemia due to cerebrovascular disease,
a well-established complication of diabetes (Folsom 1999). Cerebrovascular disease is the commonest cause of the clinical syndromes of vascular and mixed dementia, but might also, it has been
postulated, trigger a cascade of events that leads to Alzheimers
disease (De la Torre 2000; Kalaria 2000; Shi 2000). This raises
another possible aetiopathogenic mechanism to link diabetes and
dementia (Katzman 1989; Mortel 1993; Brayne 1998). Consideration of this possibility was delayed perhaps by the diagnostic criteria used for research in Alzheimers disease that exclude
risk of cerebrovascular disease (McKhann 1994). It is now recognised that mixed forms involving both pathologies are common
(Kalaria 1999). The relationship between diabetes and dementia
after stroke is well recognised (Lindsay 1997; Pohjasvaara 1998;
Ross 1999; Tatemichi 1993), but the suggestion that diabetes
might have a pathogenic role in nonvascular dementia (Launer
1999; Shalat 1987; Van Duijn 1992) has received less attention.
Other mechanisms have been suggested in which insulin might
play an important role (Freychet 2000; Park 2001). Insulin receptors are widely distributed in the brain, especially in neurons of
areas related to memory and learning such as the hippocampus
and parts of the cerebral cortex (Wickelgren 1998) . It is possible
that insulin may play a part in glucose utilization in these areas.

It has been found that an intraventricular injection of streptozotocin, which damages insulin receptors, impairs the ability of an
experimental animal to remember an electric shock (Launer 1999).
The giving of glucose produced a temporary improvement in the
memory of people with Alzheimers disease, and this effect was
later demonstrated to be attributable to an increase in the release
of insulin (Craft 1996; Fujisawa 1991). People with Alzheimers
disease have significantly increased blood insulin levels (Carantoni
2000; Kuusisto 1993; Razay 1994; Stolk 1997) and there is an
inverse relationship between the ratio of blood to cerebrospinal
fluid insulin levels and the severity of the dementia (Craft 1998).
One possible interpretation is that insulin function is impaired
and there is a compensatory increase in secretion. It has even been
proposed that desensitization of the neuronal insulin receptor is a
fundamental factor in the aetiopathogenesis of Alzheimers disease
(Henneberg 1995). Insulin resistance represents the earliest biochemical characteristic of Type II diabetes (Meneilly 1999) and
may therefore be a predisposing factor for cognitive impairment.
Insulin has also been controversially implicated in other beneficial
roles in cognitive function, but it is not the purpose of this work to
explore them (Boyt 2000; Gasparini 2001; Hong 1997; Lovestone
1999).
EPIDEMIOLOGICAL EVIDENCE
Cross-sectional studies
The epidemiology of the relationship of diabetes or impaired glucose tolerance with cognitive impairment has for many years been
restricted to cross-sectional (prevalence) studies, which examine
the associations between diseases and risk factors in a population
at a single point in time (Assisi 1996; Bent 2000; Cerizza 1990;
Cosway 2001; Croxon 1995; Dey 1997; Grodstein 2001; Helkala
1995; Hiltunen 2001; Jagusch 1992; Kalmijn 1995; Lindeman
2001; Mattlar 1985; Mooradian 1988; Motta 1996; Ott 1996;
Perlmuter 1987; Reaven 1990; Ryan 2000a; Scott 1998; Soininen
1992; Stewart 1998; Tun 1987; URen 1990; Vanhanen 1998;
Worral 1993; Zalavsky 1995). These have suggested a link between the disorders, but with some discrepancies because of variable methodology and heterogeneity of the populations studied.
Many studies depended on recruiting small samples of volunteer
patients from clinics (Drinka 1988; Drinka 1989), with inadequate controls, and using variable inclusion criteria that limited
generalization of the results. Many of the reports failed to explore
and control for potential confounding factors (Grimes 2002), especially those related to poor cognitive performance that are highly
prevalent in later life and also common among people with diabetes. Not all of the studies controlled plasma glucose during testing in order to prevent any effect of hypoglycaemia on cognitive
function (Holmes 1983).
The studies cited have focused on cognitive test performance,

rarely with the assessors blind to the participants diabetic status,
at a single time point. The issue of greater importance is change
in cognitive function over time. Test performance at a single point
can be influenced by many factors including education (Farmer
1995; Ott 1995; Kittner 1986; Stern 1999) but there will also
be other factors. The majority of authors have controlled for the
level of education in their analyses. Others have argued that low
education can reflect more a lack of social opportunity than deficient aptitude and have preferred to estimate pre-morbid abilities
(Atiea 1995). (In the process of cognitive impairment verbal skills
are preserved better than other mental skills, so that tests of verbal
ability - such as ability to pronounce and define unusual words are an indication of original mental abilities even when reasoning
abilities or memory have been damaged by disease). More than
sixty tests have been used to explore various domains of cognitive
function in different settings, and this makes it difficult to compare the results of studies. In broad terms, cross-sectional studies
have shown a tendency for lower scores by people with diabetes
than by control subjects, mainly in learning and verbal memory.
Some studies, however, have not found significant differences between people with diabetes and controls. It is not clear how far
variations in findings reflect differences in methods.
Longitudinal studies
Some longitudinal studies, particularly those designed for the
study of cardiovascular risk factors (Elias 1997), have taken the
opportunity of a subsequent long period of follow-up to evaluate the cognitive performance of participants at the time of entry.
This provides valuable and reliable information of function at the
time of the diagnosis and sometimes of the severity of relevant
risk factors. This information is useful because cardiovascular risk
factors predominantly manifest in middle life (Harris 1998) but it
is reasonable to suspect that their effect on cognitive function has
begun earlier. Another virtue of longitudinal studies is that they
can provide evidence on the quality of risk factor control over the
years. People with established dementia have worse diabetic control (Sinclair 2000) partly because of their difficulties in self-care
and partly because of having their treatment suspended (Farmer
1990).
A report from the Baltimore Longitudinal Study of Aging
(Robertson 1986) found no evidence of accelerated cognitive decline in 52 diabetic men compared with 610 controls matched
for age and education. The sample was, however, composed of
volunteers and not representative of a definable population .The
studies of particular relevance are those that are population-based
studies avoiding selection bias, and that have longitudinal designs
measuring cognitive performance in several assessments over time
(Morris 1999). A problem with these studies is determining what
constitutes a clinically or functionally important change in cognitive function (Colsher 1991). It could also be useful to address
the impact of cognitive impairment on basic, instrumental and

advanced daily living activities.
In an observational study of 77 patients with diabetes, no significant association was found between cognitive function and HbA1c
(Worrall 1996). HbA1C is a compound of the blood red pigment
haemoglobin and glucose. Its level reflects the average blood sugar
level over a period of time and is therefore a widely used index of
the quality of diabetes control
In an historical study of medical records of people resident in
Rochester, Minnesota, USA from 1970 to 1985 (Leibson 1997),
it was found that people with a diagnosis of adult onset diabetes
experienced a significantly higher risk of developing dementia than
did the rest of the population (RR=1.66, 95% CI 1.55-3.31 for
men and 1.37, CI 0.94-2.01 for women).
Elias 1997 administered a neuropsychological test battery to the
Framingham cohort who had been followed for 28-39 years. They
concluded that Type II diabetes and higher blood pressure were
associated independently with increased risk of poor cognitive performance in neuropsychological tests measuring immediate and
delayed memory for prose. The duration of diabetes was predictive
of poor performance in complex verbal memory tasks, abstract
reasoning and concept formation. Insulin treated patients were
at higher risk of poor performance compared with a nondiabetic
referent group for three of the neuropsychological test involving
verbal and visual memory. However the number of people with
diabetes on insulin was low.
The Rotterdam Study (Ott 1999) is a community-based prospective study in which 7,046 participants at risk for dementia were
followed up for a period of up to 6 years (average 2.2 years) and
changes in their cognitive function were monitored. Although
18% of the participants were not re-screened in person, information about their cognitive status was obtained from general practitioners and medical records. The conclusion of the study was that
Type II diabetes doubled the risk of dementia (RR: 1.9 95% CI:
1.3-2.8). Unfortunately the duration of the diabetes was not examined. They detected that the risk of dementia was modified by
baseline treatment with the lowest risk in untreated patients (RR:
1,3, 95% CI 0,7 to 2,3) and the highest among patients treated
with insulin (RR 4,3, 95% CI 1,7 to 10,5). This higher risk for
the insulin treated patients might be interpreted like a mark of
the length or severity of the disease. Patients on insulin may have
more severe diabetes or a longer history and thus, have been exposed to the risk factor for a greater time. In addition patients on
oral medication have an intermediate risk between those receiving
insulin and those patients controlled by diet alone. However we
cannot exclude other possible explanations as the higher rate of
hypoglycaemic events with this treatment.
The Epidemiology of Vascular Aging Study (Fontbonne 2001),
involved a community-dwelling volunteer cohort of 926 people
aged between 59-71 years at baseline. Cardiovascular risk factors
were measured and changes in cognitive function assessed over
four years. A broad battery of tests was employed under blinded
conditions to explore various areas of cognitive function at three

time points. The results indicated a more than twofold enhanced
probability of serious worsening in people with diabetes in tests
assessing immediate verbal memory, attention and psychomotor
speed.
The Study of Osteoporotic Fractures (Gregg 2000) assessed the
cognitive function of 9,679 community-dwelling women aged 6590 years. This study employed used the Mini-Mental State Evaluation (MMSE) (Folstein 1972), a general cognitive function test
widely employed as a screening test, at baseline and over the subsequent 3 and 6 years. In the last two visits, other tests were used to
explore attention, psychomotor performance and visual scanning.
It was found that women with self-reported diabetes had a twofold
increase in risk of major cognitive decline, as defined by the greatest
10th percentile reduction in performance from initial to followup. As in the Framingham study, an association was found between
the length of the time since diabetes had been diagnosed and the
probability of developing cognitive impairment, this relationship
being particularly strong in participants who had had diabetes for
15 years or longer. This study observed that women reporting insulin use had an appreciably higher risk of major cognitive decline
as well. The results of the study have the limitation that they are
based on self-reported diagnosis of diabetes. This is relevant in that
approximately one-third of all older people with diabetes remains
undiagnosed (Franse 2001) and untreated, and are at least at the
same risk from the morbidity and mortality associated with the
disease (Harris 1993). Another consideration is that the tests used
in the study did not adequately explore memory tasks, which show
the earliest changes detectable in the majority of people with mild
cognitive decline (Small 1999; Hogan 2001; Petersen 2001). The
nurses health study (Logroscino 2004) examined the association
of type II diabetes with baseline cognitive function and cognitive
decline over two years of follow up. After multivariate adjustment,
women with self-reported diabetes mellitus performed worse on
all cognitive tests than women without diabetes at baseline. Odds
of poor cognition were particularly high for women who had had
diabetes for a long time as well (1.52, 1.15 to 1.99, and 1.49, 1.11
to 2.00, respectively, for diabetes for 15 years or longer)
In the Atherosclerosis Risk in Communities (ARIC) Study
(Knopman 2001) cognitive assessments were administered to
10,963 middle-aged individuals on two occasions separated by 6
years. This study observed small performance decrements associated with hypertension and diabetes in tests measuring sustained
attention, psychomotor speed and logical reasoning in a young age
group. These results suggest that alterations in cognitive function
begin earlier than is generally recognised, although the expression
of their effects is more marked in later life (Ryan 2000a).
The Honolulu Asia Heart Study investigated the relationship
of being diabetic (Curb 1999), or having a group of clustered
metabolic cardiovascular risk factors (Kalmijn 2000) measured at
middle age, with the development of dementia in old age. In both
studies an increase of vascular dementia was found, but no connection with AD. However the study was cross-sectional in design. At the time of neurological diagnosis the patients were old
and the lower rate of survival in diabetics could have biased the
findings. The Fremantle Study (Bruce 2001) determined whether
vascular or diabetes-related risk factors predicted the development
of dementia three years later in a small sample of people with type
II diabetes. The results suggested that the association between diabetes and dementia might be better explained by the increased
incidence of hypertension in this population.
The Hisayama Study (Yohitake 1995) followed up 887 subjects
for seven years with the objective of determining the incidence of
dementia risk factors for the condition. The authors concluded
that diabetes may have a role only in the development of vascular
dementia. However, the lack of specific data about the evolution of
the 70 diabetic patients makes interpretation of the results difficult.
Luchsinger et al (Luchsinger 2001) published another longitudinal study in which a random sample of 1,799 multiethnic participants was followed up annually for 4 years. Diabetes was found
to be related to stroke-associated dementia (hazard ratio 1.6, 95%
CI: 1.7-6.9) and to a composite outcome of Alzheimers disease
and cognitive deficit without dementia (hazard ratio=1.6, 95% CI:
1.21-2.1). They detected a higher risk of stroke-associated dementia (Hazard Ratio 3,9, 95%: 1,29-11,56) and a slightly greater risk
of Alzheimers disease (Hazard Ratio: 1,4, 95% CI: 0,61, 3,24)
among patients using insulin than hypoglycaemic agents. Again
there is the limitation of self-reported risk factor status leading to
possible under-diagnosis, and a high proportion (30%) of participants lost to follow-up.
The Canadian Study of Health and Aging (MacKnight 2002) included 5574 participants at risk of cognitive impairment after a
5-year period (62% of the 9131 who were initially selected for
following-up). Only 27.6% of the participants underwent diabetes assessment at baseline. This consisted of self-report diagnosis
that was confirmed by laboratory testing in 45%. Of the diabetics, 1,5% were on insulin treatment suggesting that the duration
or severity of the diabetes was low in this group although these
factors were not specifically assessed. The authors concluded that
diabetes mellitus was associated with incident vascular cognitive
impairment (RR: 1,62; 95% CI: 1,12-2,33) but not with mixed
Alzheimers/vascular dementia (RR: 0,87; 95% CI: 0,34-2,21) or
incident Alzheimers disease (RR: 1,30; 95% CI: 0,0,83-2,03).
This study observed that insulin users were more likely to develop
vascular cognitive impairment but not Alzheimers disease.
Results from the Religious Orders Study have been recently published (Arvanitakis 2004). For up to 9 years, 824 older Catholic
nuns, priests, and brothers underwent annual clinical evaluations.
In a proportional hazards model adjusted for age, sex, and educational level, those with self reported Diabetes Mellitus had a 65%
increase in the risk of developing AD compared to those without
diabetes mellitus (Hazard ratio 1.65; 95% CI 1.10-2.47). In random effects models, diabetes mellitus was associated with lower
levels of global cognition, episodic memory, semantic memory,

working memory and visuospatial ability at baseline.
There are two complete reviews about this topic. Strachan
(Strachan 1997) published in 1997 a critical analysis of the literature, before the majority of the longitudinal studies were finished.
Stewart (Stewart 1999) later on in 1999, added more evidence to
this link explaining all the possible mechanisms of this association.
Cognitive function has not been included as an outcome variable
in large scale RCTs (Stratton 2000; UKPDS 33 1998; UKPDS
34 1998). Nor has the effect of diabetes been taken into account
in interventional studies exploring the effect of other vascular risk
factors such as hypertension (Forette 1998) on cognitive function.
In summary, there is now sufficient evidence to support the view
that there is an up to twofold increase in risk of cognitive impairment or dementia in people with diabetes in comparison with
the general population, and especially in patients who have been
diagnosed for longer periods. There is little information about the
influence of the severity or level of control of the disease in this
relationship. The negative effect of diabetes on cognitive function
probably begins in middle life.
The issue is whether treatment for diabetes can affect the risk for
cognitive impairment. From a public health point of view, if there
is a connection between diabetes and dementia, Type II diabetes
will present a greater problem than Type I, both numerically and
because of the greater range of possible treatments. Observational
studies are subject to possible confounding and the issue can only
be settled by appropriate intervention studies comparing different
forms of treatment in terms of their impact on the incidence and
severity of cognitive impairment and dementia. The primary need
therefore is for a review of RCT evidence on the relationship of
cognitive impairment and Type II diabetes mellitus with particular
regard to:
-Type of treatment
-Effects of improvement of metabolic control
-Effects of treatments improving insulin resistance
-Differentiation of vascular dementia and Alzheimers disease.
-Impact of the impairment on daily life activities
-Significance of predisposing factors and comorbidity
OBJECTIVES
Primary objective: Determine the influence of diabetes management on cognitive function.
Secondary objective: Determine the quality and quantity of available evidence from clinical trials about this topic.
METHODS
Criteria for considering studies for this review
Types of studies
Randomized controlled trials in which different treatments for
Type II diabetes mellitus have been compared and in which measures of cognitive function of participants have been made at entry
and after treatment.
Types of participants
All patients diagnosed by accepted criteria as having Type II diabetes mellitus.
Types of interventions
Any form of treatment for Type II diabetes mellitus.
Types of outcome measures
-Cognitive function measured by neuropsychological tests
-Diagnosis of dementia by explicit criteria
-Severity and significance of cognitive impairment as reflected in
impact on social and behavioural functions
-Relevant indices of rigour of diabetic metabolic control including
fasting and random blood glucose, HbAic, insulin levels
-Where appropriate, indices of effectiveness of prevention of complications of diabetes including diabetic retinopathy and renal disease, incidence of vascular disease (all forms) and total mortality,
and mortality form diabetes-related causes.
Search methods for identification of studies

On 4 August 2005 the following databases were searched:
CCTR (Cochrane Library): issue 3/2005
Search strategy:
1 DIABETES-MELLITUS-NON-INSULIN-DEPENDENT*:
ME
2 OBESITY-IN-DIABETES*:ME
3 ((NIDDM or II DM) or DM2)
4 ((#1 or #2 or #3)
5 (COGN* or DEMENT* or MEMOR*)
6 (#4 and #5)
MEDLINE: 1966-2005/08 week 1
Search strategy:
1 explode Diabetes-Mellitus-Type-2/ all subheadings
2 diabet* near (2 or type II)
3 DM2 or NIDDM or IIDM
4 #1 or #2 or #3
5 cognit* or memor* or QOL or quality of life
6 #4 and #5
7 (randomized-controlled-trial in PT) or (controlled-trial in PT)
8 Randomized-Controlled-Trials/ all subheadings

9 random* and (allocat* or assign*)
10 (doubl* or singl* or trebl* or tripl*) near (blind* or mask*)
11 placebo*
12 Double-Blind-Method in MIME,MJME
13 cross-over or crossover
14 #7 or #8 or #9 or #10 or #11 or #12 or #13
* 15 #6 and #14
EMBASE: 1985-2005/06
Searchstrategy:
1 non-insulin-dependent-diabetes-mellitus/ all subheadings
2 diabetic-obesity/ all subheadings
3 diabetes mellitus and (type 2 or type II)
5 (typ* 2 or typ* II) near (diabet* or DM)
6 diabetes type 2 or diabetes type II
7 #1 or #2 or #3 or #4 or #5 or #6
8 cogn* or dement* or alzheimer* or memor* or QOL or quality
of life
9 #7 and #8
10 explode clinical-trial/ all subheadings
11 double-blind-procedure/ all subheadings
12 single-blind-procedure/ all subheadings
13 alloc*
14 random* and (assign* or alloc*)
15 (singl* or double* or trebl* or tripl*) and (blind* or mask*)
16 #10 or #11 or #12 or #13 or #14 or #15
17 #9 and #16
PsycINFO: 1872-2005/07 week 4
searchstrategy:
1 Diabetes-Mellitus in DE
2 #1 and (type 2 or type II)
3 DM2 or NIDDM ir IIDM
4 diabetes mellitus type 2
5 diabetes mellitus type II
6 (type 2 or type II) near (diab* or DM)
8 #2 or #3 or #4 or #5 or #6 or #7
9 cogn* or dement* or alzheimer* or QOL or quality of life
10 #8 and #9
11 random* and (alloc* or assign*)
12 (doubl* or singl* or trebl* or tripl*) near (blind* or mask*)
13 randomi?ed
14 controlled trial*
15 placebo*
16 #11 or #12 or #13 or #14 or #15
17 #10 and #16
Cinahl: 1982-2002/07
Searchstrategy:
1 Diabetes-Mellitus-Non-Insulin-Dependent/ all topical subheadings / all age subheadings

3 diabetes mellitus type 2 or diabetes mellitus type II
5 (type 2 or type II) near (diab* or DM)
6 #1 or #2 or #3 or #4 or #5
7 cogn* or dement* or alzheimer* or memor* or QOL or quality
of life
8 #6 and #7
9 random* near (assign* or alloc*)
10 randomi?ed
11(singl* or doubl* or trebl* or tripl*) near (blind* or mask*)
12 placebo*
13 controlled trial
14 #9 or #10 or #11 or #12 or #13
15 #8 and #14
SIGLE:1980-2004/12: no results
ClinicalTrials.gov : USA based databases of ongoing trials: last
search 4 August 2005: no results
CurrentControlledTrials: UK based databases of ongoing trials:
last search 4 August 2005: no results
Data collection and analysis
SELECTION OF STUDIES
Abstracts of the references retrieved by the search were read by one
reviewer to discard those that were clearly not eligible for inclusion.
The two reviewers studied the full text of the remaining references
and independently selected studies for inclusion. Any disparity in
the final lists (there was none) were to be resolved by discussion
in order to arrive at the final list of included studies.
QUALITY ASSESSMENT
The reviewers assessed the methodological quality of each trial using the Cochrane Collaboration guidelines (Mulrow 1997). Category A (adequate) is where the report describes allocation of treatment by: (i) some form of centralized randomized scheme, such as
having to provide details of an enrolled participant to an office by
phone to receive the treatment group allocation; (ii) some form of
randomization scheme controlled by a pharmacy; (iii) numbered
or coded containers, such as in a pharmaceutical trial in which capsules from identical-looking numbered bottles are administrated
sequentially to enrolled participants; (iv) an on-site or coded computer system, given that the allocations were in a locked, unreadable file that could be accessed only after inputting the characteristics of an enrolled participant; or (v) if assignment envelopes
were used, the report should at least specify that they were sequentially numbered, sealed, and opaque; (vi) other combinations of
described elements of the process that provide assurance of adequate concealment. Category B (intermediate) is where the report
describes allocation of treatment by: (i) use of a list of table to

allocate assignments; (ii) use of envelopes or sealed envelopes;
(iii) stating the study as randomized without further detail. Category C (inadequate) is where the report describes allocation of
treatment by: (i) alternation; (ii) reference to case record numbers,
dates of birth, day of week, or any other such approach; (iii) any allocation procedure that is entirely transparent before assignment,
such as an open list of random numbers or assignments. Empirical
research has shown that lack of adequate allocation concealment
is associated with bias. Trials with unclear concealment measures
have been shown liable to yield more pronounced estimates of
treatment effects than trials that have taken adequate measures to
conceal allocation schedules, but the effect is less pronounced than
in inadequately concealed trials (Chalmers 1983; Schulz 1995).
Trials were to be considered if they conformed to categories A or
B, but those falling into category C were excluded. Other aspects
of trial quality were not assessed by a scoring system although details were noted of blinding, appropriateness of methods and the
number of patients lost to follow-up.
The second approach, which may not exclude the first, is to concatenate the data into two categories which best represent the contrasting states of interest, and to treat the outcome measure as binary. For binary outcomes, the endpoint itself is of interest and
the Peto method of the typical odds ratio is used.
A test for heterogeneity of treatment effect between the trials is
made using a chi-square statistic. If no heterogeneity is indicated
then a fixed effect parametric approach can be taken.
A separate meta-analysis is performed for each single comparison
of two treatments. The age range of patients in the selected studies
may differ, in which case meta-analyses have to be considered
for different age bands. The duration of disease before entering
the study may also be a factor that varies considerably and again
separate meta-analyses may have to be undertaken to take this into
account.
Subgroup and sensitivity analyses will be performed relevant to
linking changes in cognitive function to other outcomes of diabetes treatment (including vascular disease) and to pre-existing
characteristics including lifestyle (e.g. smoking and exercise) and
the presence of comorbidity (such as hypertension).
DATA COLLECTION
Data for any meta-analyses were to be based on reported summary
statistics for each study. For the intention-to-treat analyses data
would be sought for each outcome measure that included every
patient randomized, irrespective of compliance. For the analyses
of completer data would include every patient who completed the
study on treatment.
For continuous variables, or ordinal variables which can be approximated to continuous variables, the main outcomes of interest
would be the final assessment and the change from baseline at final
assessment. For some ordinal and binary outcomes, the endpoint
category relative to baseline category would be the outcome of
interest. For others, such as the global impression of change, the
endpoint itself is of clinical relevance as all patients will, by definition, have been at the same baseline score. The baseline assessment
is defined as the latest available assessment prior to randomization,
but no longer than two months before.
DATA ANALYSIS
The analysis strategy implemented for each outcome depends on
the type of data (ordinal, continuous, dichotomous) and whether
the analysis is based on intention-to-treat or completer. Ordinal
scales with many categories, such as psychometric test scores, are
treated as continuous data, and ordinal scales with few categories
as ordinal data. A vast number of rating scales and tests have been
devised to assess cognition in clinical trials. Meta-analyses are fairly
straightforward in the situation where the included studies use
the same outcome measures and the method of weighted mean
difference is used. When different scales are used in the studies
the method of standardized mean difference is used where it is
considered appropriate to combine the scales.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Five studies that met the inclusion criteria for the review were
identified.
Ginseng is a plant extract claimed to elevate mood and reduce
fatigue. It has been reported to improve glucose homoeostasis and
increase insulin sensitivity. Sotaniemi 1995 reported a doubleblind randomized parallel-group comparison of ginseng, 100 mg
or 200 mg daily, with placebo as additional therapy for 36 newly
diagnosed patients with Type II diabetes treated by diet alone.
Memory was tested by digit span (maximum number of random
digits accurate in immediate recall) and a timed diagram completion test. After 8 weeks the two ginseng groups had better scores in
the diagram test but there was no differences in digit span scores
between the three groups. The scores at entry were not reported.
The two ginseng groups reported better mood. Fasting blood glucose was lower in the ginseng groups and HbA1c was lower in
the group taking 200 mg daily of ginseng. Again, entry data were
not reported. The authors suggest that the improvement in diabetic control was secondary to elevation of mood and motivation
due to ginseng. The improvement in scores in the timed diagram
completion test with no change in digit-span is also compatible
with a change in mood and motivation rather than in cognitive

capabilities.
Naor 1997 compared the effect of intensive inpatient diabetic therapy with unchanged regular diabetic therapy on cognitive function. In this RCT the investigators assessing outcomes were blind
to the treatment group to which each patient had been assigned. At
the time of randomization there were 20 patients in each group, all
of them treated by diet and oral antidiabetic drugs. The mean age
was 64 years and there was a predominance of females. The investigators recorded the years of education of participants, and noted
that the duration and severity of diabetes was similar in the two
groups. Patients with a history of cerebrovascular events, uncontrolled hypertension, depression or use of drugs affecting central
nervous system function were excluded. The intensive treatment
regimen comprised an individually adapted diet, daily monitoring
of blood glucose, a standardized educational programme, and such
changes in the treatment as were needed to achieve fasting blood
glucose levels below 130 mg/dl and postprandial blood glucose
levels below 180 mg/dl during a two-week period in hospital. The
patients were encouraged to follow the same diet and treatment
at home for six weeks after discharge. No change in established
treatments was made for patients assigned to the regular therapy
group. Cognitive function was assessed on three occasions in each
group: on admission, at discharge, and six weeks after leaving the
hospital. Measurements included reaction time to visual and auditory stimuli, cognitive flexibility, psychomotor speed and concentration using a range of validated tests. These comprised a simple
reaction time test, the Zahlen-Verbidungs test (a German version
of the Trail Making Test-A), and two letter-cancelling tests - Test
d2 and the Bourdon-Freyberg-concentration test. Blood glucose
concentrations were measured before testing to exclude possible
effects of hypoglycaemia. Test results at baseline were similar in
the two groups. At six weeks the mean scores of the intensive treatment group in the letter-cancelling tests were significantly better
statistically than those of the regular therapy group. Performance
in the Zahlen-Verbidungs test, but not in the reaction time tests,
was significantly and inversely related to HbA1c levels.
Three trials studied the effect of different diabetic treatment on
Quality of Life (QOL) using questionnaires that included the
respondents subjective impressions of cognitive function. Testa
1998 compared the QOL of a heterogeneous group of people with
Type II diabetes assigned to glipizide or placebo in a randomized,
double-blind parallel trial. Five hundred and ninety-four patients
of a wide range of age (mean: 58 years) and variable diabetes duration were randomized; 202 were assigned to diet and placebo,
and 393 patients to diet and glipizide. The investigators explored
possible confounding factors such as education, occupation, other
vascular risks like hypertension or dyslipidemia, and perceived
mental and emotional health were included in the questionnaires.
Self-reported cognitive function was assessed with a Visual Analogue Scale at screening, randomization, and at 4,8,12 weeks after randomization. At 15 weeks there was a statistically significant
improvement in self-assessed cognitive function in the glipizide

group but a non-significant decline in mean score in the placebo
group.
Tovi 1998 compared quality of life assessments by Type II diabetic
patients with suspected secondary failure on oral antidiabetic drug
therapy. In parallel group open trial, 40 participants were randomly
divided into two groups, 22 to receive insulin and 18 to continue
on the previous treatment. Cognitive function at entry to the study
was assessed with the Mini-Mental State Examination (MMSE) to
ensure comparability of the groups. Quality of life was evaluated at
baseline, and again at 6 and 12 months using the Goteborg Quality
of Life instrument that includes an item of perceived memory on
a self-report scale graded from 1 to 7. No data are reported on the
effect of different treatments in this specific area.
UKPDS 37 1999 compared the effects on QOL of two regimens
for improving blood glucose and blood pressure control in with
a randomized, parallel and open trial. Randomization was performed by centrally produced, computer-generated therapy allocations. A total of 374 patients were included; 105 were assigned
to conventional treatment and 269 to an intensive treatment regimen (UKPDS 33 1998). Patients were 52 years old on average at
entry and predominantly male. The effect of education was not
taken into account in the assessment of memory changes. Blood
pressure and BMI were measured. Questionnaires, administered
at 6 months, and 1,2,3,4,5, and 6 years after randomization included self-report of cognitive mistakes using the Cognitive Failures Questionnaire (Broadbent 1982). No significant differences
in responses to the Questionnaire emerged over a 6-year period
between patients allocated to conventional or to intensive diabetes
therapy.
Grandman (Gradman 1993) in a non-randomized control trial
studied cognitive function changes after one month of treatment
for improving glycemic control in type II diabetes. They recruited
healthy people as controls. We cannot include this study for these
reasons. Meneilly (Meneilly 1993) designed a similar study. Sixteen
type II diabetes patients were tested with a neuropsychological
battery before and after improving diabetes control. This study
could not be included because of the lack of a control group.
Update 2005: No new studies were found which were suitable for
inclusion in this review.
Risk of bias in included studies

Sotaniemi 1995 did not describe the method of randomization,
and reported mean results after 8 weeks rather than mean changes
in cognitive function scores. The comparability of the three groups
with regard to cognitive function at entry is unattested.
Naor 1997 did not specify the method of randomization. The follow up was complete in eighteen (90%) of the intensive therapy
group and fifteen (75%) of the regular therapy group. The investigator assessing outcomes was blind to the assignment of the patients but all the patients recruited gave informed consent so were
necessarily aware of their assignment status and of the alternative

form of care being assessed. This may have introduced bias.
The three studies that explored the effect of different types of
treatment on quality of life have some characteristics in common.
All were randomized controlled trials with low drop-out rates. In
the UKPDS Testa 1998 and Sotaniemi 1995 were the only doubleblind trials. Testa 1998 used a visual analogue scale, and Tovi 1998
a graded scale from 1 very bad to 7 excellent to quantify how
patients perceived their memory. None of these tests is validated as
an adequate measure of cognitive function. Self-reported memory
may not be related, or is only weakly related, to cognitive function
(Schmidt 2001). Metamemory, knowledge about the limitations
and characteristics of ones own memory, was traditionally thought
to be unaffected by age, but is now known to be affected by ageassociated decrements (Rabbitt 1991) and may reflect changes
in confidence or attitude rather than in cognitive ability. Some
patients with Alzheimers disease report normal memory (Feher
1994). Reliable screening for dementia requires objective cognitive
tests (Ganguli 1997) accompanied by informant questionnaires
(Jorm 1997).
A similar problem affects the interpretation of UKPDS 37 1999.
This study compared long-term effects on quality of life of therapies for improving blood glucose and blood pressure, diabetic complications and hypoglycaemic episodes. The tests used included
the Cognitive Failures Questionnaire (CFQ) (Broadbent 1982),
for which the patient and a relative have to report the frequency
in which minor cognitive mistakes occur. The CFQ was devised
initially for measuring perceptual memory and action failure; later,
the authors suggested that it could be a promising measure for
showing individual vulnerability to stress (Broadbent 1982). The
ability of the CFQ to detect memory difficulties has been controversial, at least in studies of students (Matthews 1990; Pollina
1992), and it has been demonstrated to have limitations in the
study of cognitive ageing (Matthews 1990). At present the CFQ
is not considered a reliable test for measuring cognitive function
(Wagle 1999).
Effects of interventions
No studies were found to be appropriate for inclusion in metaanalysis.
DISCUSSION
The epidemiological evidence, both cross-sectional and longitudinal provides compelling evidence that diabetes mellitus is associated with an increased risk of cognitive impairment and dementia.
A number of factors could contribute to this relationship. These
include disturbance to the metabolism of neurons consequent on
hyperglycaemia or non-optimal insulin levels, and impaired blood
supply to the central nervous system. The latter might be due to

the atherosclerosis of arteries associated with diabetes causing regional hypoperfusion or stroke, or more diffuse brain ischaemia
due to obstruction of blood supply at the arteriolar level, sometimes referred to as small vessel disease. There is also the possibility that cognitive impairment might be in part an adverse effect
of one or more forms of treatment, perhaps some direct metabolic
effect of a drug of the cumulative impact of recurrent episodes
of hypoglycaemia. But depression can impair cognitive function
and people with diabetes may be more likely than coevals to he
depressed. This may arise partly by the knowledge of having the
condition, by the some of its symptoms, the cost of drug treatment
and the impact on lifestyle of dietary and exercise prescriptions,
both for the diabetes and significant exacerbating factors such as
smoking and high blood pressure. Moreover, as pointed out by
Sotaniemi 1995, the onset of Type II disease is often in middle age
when a range of other psychosocial factors may increase a persons
predisposition to depression. It may be that the primary effect of
ginseng was to heighten mood; this would be compatible with the
observation that it was associated with an improvement in scores
on the timed diagram test but not in memory as assessed by digit
span.
It is not clear whether the risk of cognitive impairment and dementia is globally associated with diabetes or is linked to particular
subgroups characterised by severity or comorbidity. If the mechanism were predominantly vascular it would not be surprising if
the main impact were on those people with diabetes who are also
hypertensive or who smoke.
These issues could be most reliably resolved by appropriately designed and analysed clinical trials linking measures of cognitive
function with individual characteristics of participants, mode of
treatment and metabolic and clinical outcomes. It is therefore disappointing to find that so few clinical trial of treatment for Type II
diabetes have included measures of cognitive function as outcome
variables. While it might well take years of follow-up to identify an
impact on the prevention of dementia, direct metabolic effects of
disease and treatment on neurons, or the influence of depression,
are likely to be detectable in short-term trials.
As detailed above, there was some suggestion in the studies reviewed that more rigorous control of diabetes was associated with
improvement in various indices of cognitive function. None of
the studies as reported was without methodological failings. At
present , therefore, it is impossible to draw useful conclusions. No
large-scale randomized controlled trial in Type II diabetes has included validated tests of cognitive function among the outcome
measures. However, there is compelling evidence that, whether as
a consequence of the disease and its associated conditions, or its
treatment, diabetes is associated with an increased risk of cognitive
impairment. Appropriate indices of cognitive function should be
included among the outcome measures of future short- and longterm interventional studies of treatment of diabetes.
10
AUTHORS CONCLUSIONS
Implications for practice
There is no evidence on which to recommend any type of diabetic
treatment to prevent cognitive impairment in people with Type II
diabetes.
effects of treatment, in particular insulin and glucose levels, and

indices of glucose homoeostasis. Relationships of cognitive function with mood and other aspects of functional status and quality
of life also need further elucidation.
Implications for research
ACKNOWLEDGEMENTS
Interventional studies of treatment for Type II diabetes should

include reliable and validated measures of cognitive function. A
battery of tests covering a range of domains of cognitive function
is desirable, to detect differential changes and to assist in avoiding
confounding from factors such as education and premorbid abilities. Studies should be designed to permit analysis of changes in
cognitive function in relation to the mechanisms and metabolic
The contributions of the consumer editor, Corinne Cavender, the

support of the Cochrane Dementia and Cognitive Improvement
Group and particularly the advice of Helen Lee, Research Assistant, are gratefully acknowledged. We are grateful for helpful comments on an early draft from peer reviewers, in particular from
colleagues in the Cochrane Endocrine, Metabolic and Diabetes
Group
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Indicates the major publication for the study
17
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Naor 1997
Methods
Randomized
Controlled
Parallel group
Single blind
Duration: 6 Weeks
Participants
Country: Germany
Number: 40 participants (15 M; 25 F)
Inclusion criteria: Type II diabetic patients referred to the outpatient clinic at the Diabetes Research Institute Dusseldorf in poor metabolic control. All treated by diet and oral antidiabetic of sulfonylurea type.
Exclusion criteria: descompensate cardiac failure, renal failure, cerebrovascular events, uncontrolled hypertension,
liver cirrhosis, alcoholism, use neuroleptics, depression
Interventions
1- Intensive inpatient treatment: individually adapted diet, daily monitoring of blood glucose, standardized educational programme for NIDDM. Fasting blood glucose levels below 130 mg/dL and postprandial blood glucose levels
below 180 mg/dL.
2- Regular treatment: Continued with unchanged previous therapy
Outcomes
Cognitive and metabolic parameters were assessed on three occasions in each group. They measured:
Reaction time test
Zahlen-Verbindungs test
Test d2
Bourdon-Freyberg concentration test
Notes
Sotaniemi 1995
Methods
Randomized placebo-controlled doble-blind parallel-group design

Duration: 8 weeks
Participants
Country: Finland. Number: 36 newly diagnosed patients with Type II stabilized on diet alone
Interventions
Ginseng at doses of 100mg or 200 mg daily
Outcomes
Indices of glucose homoeostasis, serum lipids, mood, physical activity. Memory assessed by digit-span, psychophysical
performance by a numbered digram completion test
Notes
18
Testa 1998
Methods
Randomized Placebo-controlled
Double blind
Duration: 12 weeks
Participants
Country: USA
Number participants: 569
Inclusion criteria: type 2 diabetics, at least 30 years old, not pregnant, treated with sulfonylurea and diet or diet alone
for a minimum of three months. English or spanish speaking.
Exclusion: Body weight less than 80% or more than 160% of the ideal weight. Had received insulin for longer than
1 week 3 months before the enrollment, had ketoacidosis during the past year, history of confounding illness or
substance abuse
Interventions
1- Diet and placebo

2- Diet and Glipizide
Outcomes
Visual Analog Scales of perceived health:

1- Self-reported cognitive funcion.
2- Mental and emotional health
3- General health perceptions.
4- Symptom distress
Health economic indices.
Notes
Tovi 1998
Methods
Randomized controlled
Open trial
Duration: 12 months
Participants
Country: Sweden
Number: 40 patients.
Inclusion criteria: type 2 diabetes with suspected secundary failure on oral antidiabetic drug therapy.
Exclusion criteria: Stroke or heart failure 6 months before the trial
Interventions
1- Insulin: 0.53 (0.27) units [mean and (SD)]

2- Continue sulphonylurea treatment.
Outcomes
- Goteborg quality of life instrument: Health, fitness, memory, hearing, vision, appetite.
- 30 General symptoms
- Diabetic symptoms
Notes
19
UKPDS 37 1999
Methods
Randomized controlled trial

Open trial
Duration: 6 years
Participants
Country: UK
Number:374 participants.
Inclusion criteria: Newly diagnosed patients with type II diabetes.
Exclusion criteria: Medical complications precluding randomization, severe physical illness, or an inadequate understanding of English
Interventions
1- Intensive blood glucose control

2- conventional blood glucose policy
Outcomes
Cognitive Failures Questionnaire

Profile of mood state
Symptoms
Work satisfaction
Generic Questionnaire (EQ5D)
Notes
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Gradman 1993
Non-randomized and inappropriately controlled trial
Meneilly 1993
No control group
20
DATA AND ANALYSES

This review has no analyses.
WHATS NEW
Last assessed as up-to-date: 3 August 2005.
Date
Event
Description
10 October 2008
Amended
Converted to new review format.
HISTORY
Protocol first published: Issue 3, 2002
Review first published: Issue 4, 2002
Date
Event
Description
16 November 2005
New search has been performed
An update search in August 2005 was run but no new

studies were found for inclusion or exclusion
30 August 2002
New citation required and conclusions have changed
Substantive amendment
CONTRIBUTIONS OF AUTHORS
-Areosa Sastre A: all correspondence, development of protocol, retrieval and selection of studies, data analysis, drafting of final review.
-Grimley Evans J: development of protocol, selection of studies, development of final review.
-Consumer editor on this review was Corinne Cavender
-This review has been peer reviewed
-Members of the Cochrane Metabolic and Endocrine Disorders Group have made substantial contributions to this review.
21
DECLARATIONS OF INTEREST
None known.
INDEX TERMS
Medical Subject Headings (MeSH)
Cognition Disorders [ drug therapy; etiology]; Diabetes Mellitus, Type 2 [complications; drug therapy]; Hypoglycemic Agents
[ therapeutic use]; Memory Disorders [drug therapy; etiology]; Randomized Controlled Trials as Topic
MeSH check words

Humans
22

Effect of The Treatment of Type II Diabetes Mellitus On The Development of Cognitive Impairment and Dementia (Review)

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Effect of The Treatment of Type II Diabetes Mellitus On The Development of Cognitive Impairment and Dementia (Review)

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Effect of the treatment of Type II diabetes mellitus on the

development of cognitive impairment and dementia (Review)

Effect of the treatment of Type II diabetes mellitus on the

Contact address: Almudena Areosa Sastre, Madrid, Spain.

PLAIN LANGUAGE SUMMARY

language. Tests for acquired impairment need to take into account

Some forms of cognitive impairment, associated for example with

The relationship may be spurious; in particular depression can

with deficits in episodic memory and learning, similar to those

that insulin may play a part in glucose utilization in these areas.

The studies cited have focused on cognitive test performance,

the impact of cognitive impairment on basic, instrumental and

conditions to explore various areas of cognitive function at three

levels of global cognition, episodic memory, semantic memory,

Criteria for considering studies for this review

Search methods for identification of studies

8 Randomized-Controlled-Trials/ all subheadings

2 DM2 or NIDDM or IIDM

Data collection and analysis

describes allocation of treatment by: (i) use of a list of table to

with a change in mood and motivation rather than in cognitive

improvement in self-assessed cognitive function in the glipizide

Risk of bias in included studies

necessarily aware of their assignment status and of the alternative

supply to the central nervous system. The latter might be due to

effects of treatment, in particular insulin and glucose levels, and

Implications for research

Interventional studies of treatment for Type II diabetes should

The contributions of the consumer editor, Corinne Cavender, the

References to studies included in this review

References to studies excluded from this review

mellitus. Journal of the American Geriatrics Society 1993;41:

improvement following induced hyperinsulinemia in

community based prospective study. Archives of General

treatment? Results from 54 months of the Medical Research

performance. Perceptual and Motor Skills 2001;93(3):

Caribbean population. Journal of the American Geriatrics

2 diabetes mellitus. Journal of the Ameerican Geriatrics

Van Duijn 1992

Indicates the major publication for the study

Characteristics of included studies [ordered by study ID]

Randomized placebo-controlled doble-blind parallel-group design

Ginseng at doses of 100mg or 200 mg daily

1- Diet and placebo

Visual Analog Scales of perceived health:

1- Insulin: 0.53 (0.27) units [mean and (SD)]

Randomized controlled trial

1- Intensive blood glucose control

Cognitive Failures Questionnaire

Characteristics of excluded studies [ordered by study ID]

Reason for exclusion

Non-randomized and inappropriately controlled trial

DATA AND ANALYSES

Converted to new review format.

New search has been performed

An update search in August 2005 was run but no new

New citation required and conclusions have changed

MeSH check words

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