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Diabetes and frailty: an emerging issue. Part 1: Sarcopaenia and factors affecting lower limb function
Pilar Atinzar, Pedro Abizanda, Andrew Guppy and Alan J Sinclair
British Journal of Diabetes & Vascular Disease 2012 12: 110
DOI: 10.1177/1474651412445619
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DVD0010.1177/1474651412445619Atinzar et al.The British Journal of Diabetes & Vascular Disease

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Diabetes and frailty: an emerging issue.

Part 1: Sarcopaenia and factors affecting
lower limb function
PILAR ATINZAR1, PEDRO ABIZANDA1, ANDREW GUPPY2 AND ALAN J SINCLAIR3
Abstract

railty and sarcopaenia are commonly used terms in

the medical management of older people but their
relationship to those with diabetes has not been
explored in great detail. In this review, we hypothesise that
diabetes and frailty are related conditions, and we attempt
to explain the nature of this relationship, and consider the
possibility that sarcopaenia is an intermediate step.
Br J Diabetes Vasc Dis 2012;12:110-116
Key words: diabetes, disability, elderly, frailty, sarcopaenia

Introduction
Diabetes is a disabling chronic cardiovascular and medical disease with a tremendous health, social and economic burden
within our ageing communities. Diabetes has a prevalence of
1030% in subjects above 65 years of age. Diabetic men and
women diagnosed at age 60 have an estimated reduction in life
expectancy of 7.39.5 years, and a good quality of life of
11.113.8 years.1,2
Frailty is described as a state of increased vulnerability to stressors that results from decreased physiological reserve in multiple
systems that cause limited capacity to maintain homeostasis.3
The prevalence of frailty in the elderly has been described to be
between 7 and 30% in different population studies.4 It has been
reported that frailty is a state associated with major health and
social adverse events, including mortality, disability, institutionalisation and the second most common cause of dependency.5
Sarcopaenia is the loss of muscle mass associated with ageing. The prevalence of clinically significant sarcopaenia is estimated to range from 8 to 50% in older people.6 Low strength

1Department

of Geriatrics, Albacete University Hospital, Albacete, Spain.

of Psychology, University of Bedfordshire, Luton, UK.
3Institute of Diabetes for Older People (IDOP), Bedfordshire and
Hertfordshire Postgraduate Medical School, Putteridge Bury Campus,
Luton, UK.
2Department

Corresponding author: Professor AJ Sinclair

Institute of Diabetes for Older People (IDOP),
Beds and Herts Postgraduate Medical School, Putteridge Bury Campus,
Hitchin Road, Luton, LU2 8LE, UK.
Tel: +44 (0)1582 743285; Fax: +44 (0)1582 743286
E-mail: Sinclair.5@btinternet.com

Abbreviations and acronyms

AGE
advanced glycation end product
ATP
adenosine triphosphate
CES-D
Center for Epidemiologic Studies Depression Scale
CML carboxymethyl-lysine
HbA1C
glycated haemoglobin A1C
IGF-1
insulin-like growth factor 1
IL interleukin
IR
insulin resistance
Na+/K+-ATPase
sodiumpotassium adenosine triphosphatase
PGC-1 peroxisome proliferator-activated (PPAR)- g
coactivator-1
TNF
tumour necrosis factor

is one of Frieds frailty criteria, and it has been stated that agerelated loss of muscle mass and strength results in decreased
functional limitation and disability among the elderly.7
It has been hypothesised that diabetes, frailty and sarcopaenia might be inter-related,1 although this was not explored in
detail. We review the significant literature in the field to explain
further the nature of these relationships.

Diabetes
Diabetes is a premature ageing syndrome, a cause of unsuccessful ageing, and a disabling syndrome.8 It is associated with
disability, morbidity, mortality and institutionalisation.9
Diabetes is associated with illnesses such as hypertension,
heart disease, cerebrovascular disease and stroke, and patients
are also at greater risk for several common geriatric syndromes
such as polypharmacy, depression, cognitive impairment, urinary incontinence, infections, pressure ulcers, falls, hip fractures
in the elderly and persistent pain.10 The disease is also associated with a decrease in leisure activities, a decline in quality of
life and an increase in the requirement of healthcare.8 Current
standards of diabetes care do not specify a different approach
to frailty in a setting of diabetes.11 It has been proposed that
diabetes in ageing patients may be associated with frailty at an
earlier stage than in non-diabetic counterparts.3,12

Sarcopaenia
Sarcopaenia is a progressive decline of muscle mass during ageing, leading to low impaired strength and functioning although

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DOI: 10.1177/1474651412445619110

REVIEW

there remains a lack of consensus on the definition and how to

screen for sarcopaenia.6,13 After 50 years of age, muscle mass
is reported to decline at an annual rate of approximately 12%;
it accelerates to as much as 1.53% per year after age 60, and
becomes ever faster after age 75.14 This is also associated with
a decline in the quality of type I and type II muscle fibres due to
a reduction in muscle quality from the infiltration of fat and
other non-contractile material such as connective tissue.15
There is also a metabolic deregulation, which includes a
reduction in insulin sensitivity, impaired oxidative defence, and
decreased mitochondrial function.16
Sarcopaenia results in decreased functional limitation, disability (like falls and fractures), morbidity and mortality among
the elderly, and also it has been suggested that sarcopaenia is
an integral component of frailty, and increasing demands on
public healthcare.17,18

Frailty
Frailty can be defined as a multisystemic condition, whose
essential feature is the risk to instability. It is a complex clinical
entity characterised by the imbalance of homeostatic capacity,
which becomes particularly evident as an inability to regain a
stable homeostasis after a stressful destabilising event.12,19
Although agreement between a standardised definition
and an empirical basis is lacking, Linda Fried and colleagues
defined a clinical phenotype of frailty identified by the presence
of three or more of the following components20:
weight loss: unintentional loss of 4.5 kg in the past year;
weakness: hand-grip strength in the lowest 20% quintile at
baseline, adjusted for sex and body mass index;
exhaustion: poor endurance and energy, self reported from
the CES-D;
slowness: walking speed under the lowest quintile adjusted
for sex and height;
low physical activity level: lowest quintile of kilocalories of
physical activity during the last week, measured with the
Minnesota Leisure Activity Scale.
A biological model, the cycle of frailty, that includes sarcopaenia and neuroendocrine and inmune dysfunction as potential
causes, has been proposed. The downward spiral leading to
this syndrome could be precipitated by trigger events.21
Frailty predicts adverse outcomes incrementally and independently from coexisting medical conditions: it increases the
risks of falls, hospitalisation, physical disability, institutionalisation, poor quality of life and mortality.3,5

Is sarcopaenia an intermediate step between

diabetes and frailty?
Different studies have shown a close relationship between diabetes and sarcopaenia and these are reviewed and summarised
in table 1.18,2231 It was recently described that newly diagnosed
older men with diabetes have significant weaker muscle
strength and higher odds of impaired physical function than
women.31

This relationship cannot be standardised because of major

methodological factors. Firstly, some authors have measured
muscle strength, while others have measured muscle mass or
muscle quality, in different body segments such as legs, arms
or hands. Sarcopaenia has been measured with different
instruments: dual energy x-ray absorptiometry, bioimpedance,
dynamometry, computerised tomography or muscle biopsies.22-31
The maintenance of skeletal mass is a function of multiple
factors including hormonal, inflammatory, neurological, nutritional and activity components13,32 and these are briefly discussed below.

Nutritional factors
Community dwelling elderly subjects with diabetes may be at
risk of malnutrition when compared with non-diabetic citizens.
Studies in older subjects with diabetes found that weight loss
was related to an increased risk of muscle atrophy and wasting,
when they have concomitant disease.33,34
Anorexia due to comorbidity (infectious disease, end-stage
renal failure or malignance), drug adverse effects (like metformin) and excessive dietary restriction may be responsible for
some malnutrition in older diabetic people. Malnutrition is
widely prevalent in patients with diabetic nephropathy, because
of severe dietary protein restriction and the independent association with vitamin D deficiency.34,35
Also, sub-clinical deficiencies in vitamin B groups have been
described in the elderly and, recently, B12 deficiency has been
found in the type 2 diabetic population, especially those taking
metformin.12,36

Hormone imbalance
Hormones are key regulators of human muscle metabolism,
and age-related hormonal changes are important biological
contributors to skeletal muscle decline, with an accelerated loss
of muscle mass and frailty.37
IGF-1 is decreased in diabetes, and it plays a role in the protein synthesis of the muscle because of increase proteolysis.1,2
It has been shown that testosterone levels are low both in
diabetic patients and those with metabolic syndrome. In addition, it has been described that low testosterone levels are associated with IR, and that testosterone treatment may reduce IR.12,38
Vitamin D levels are lower in patients with diabetes than in
non-diabetic individuals and, recently, it has been suggested
that vitamin D deficiency may contribute to B cell dysfunction,
IR and inflammation and that this may result in type 2 diabetes;
small intervention studies show that vitamin D supplementation
reduces systematic inflammation and improves glucose tolerance.12,39 Some, but not all studies, suggest that vitamin D
levels correlate with muscle mass and strength, low levels of
vitamin D are associated with falls, functional decline and the
frailty syndrome.40
Increased cortisol levels are also associated with sarcopaenia, although the presence of enhanced cortisol secretion in
patients with type 2 diabetes is debated. It had been described
that serum cortisol levels are a predictor of IR followed by IL6,
TNF, leptin and adiponectin.41,42

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Table 1. Studies showing a close relationship between diabetes and sarcopaenia

Study

Author

Study design

Main Outcomes

Conclusion

Decreased muscle
and quality in
older adults with
type 2 diabetes

Park SW.
et al.
200622

3,075 adults in the Health

ABC study
Age 7079 years
Follow-up March 1997
July 98
Diabetes: HbA1C > 7%
Muscle strength with
dynamometer

Men with diabetes showed significantly

lower muscle strength in both upper
and lower extremities (p<0.05, each)
Arm and leg regional muscle masses were
significantly greater in non-diabetic male
subjects compared with diabetes (p<0.001)
Muscle quality was consistently lower in
both upper and lower extremities in both
men and women with diabetes (p<0.001)
Muscle quality was associated with diabetes
duration

Muscle
strength and
quality was
lower in men
with diabetes
Longer
duration of
diabetes and
poorer
glycaemic
control, were
associated with
poorer muscle
quality

Accelerated loss
of skeletal musclestrength in older
adults with type 2
diabetes

Park SW
et al.
200723

1,840 adults in the Health

ABC Study
Age 7079 years
Follow-up 3 years
Muscle:
mass by DXA
strength by dynamometer
quality by maximal
strength per unit of muscle

Older adults with type 2 diabetes showed

greater declines in the leg muscle mass
(p<0.05), and strength (p=0.001)
Leg muscle quality also declined more in
older subjects with diabetes (p<0.005)

In older adults,

type 2 diabetes
is associated
with
accelerated loss
of leg muscle
strength and
quality

Frailty syndrome
and skeletal
muscle: results
from the INChianti
study

Cesari M
et al.
200618

923 participants in the

INCHIANTI study
Aged > 65 years.
Follow-up 3 years
Frieds criteria of frailty
Measure muscle area and
fat: pQCT (tomography)

Participants with no frailty criteria had

significantly higher muscle density (71.1
mg/cm3, SE=2) and muscle area (71.2%,
SE=0.4) than did frail participants (69.8 mg/
cm3, SE=0,4; 68.7%, SE=0.9)
Fat area was significantly higher in frail
(22%, SE=0.9) than no frail (20.3%,
SE=0.4)
Physical inactivity and low walking speed
were the frailty criteria that showed the
strongest associations with pQCT measures.

Frail subjects,
identified by an
easy and
inexpensive
frailty score
have less
muscle mass
and higher fat
mass than nonfrail subjects

Frailty in Mexican
American older
adults

Ottenbacher
K et al.
200530

Prospective population
based survey
621 noninstitutionalised
Mexican American men
and women aged 70 and
older Part of the Hispanic
Established Population
Epidemiological Study of
the Elderly (EPESE)

Combination of statistically significant

independent variables explained 37% of
the variance in the summary frailty score for
males
Lower extremity strength approached
statistical significance (p=0.08) for males
The logistic regression model for females
included three statistically significant
variables, disability (ADL/IADL), lower
extremity strength, and BMI

Sex was
associated with
frailty at
baseline
Predictors of
frailty in men
included upper
extremity
strength, ADL
score,
comorbidites
and mental
status scores
(Continued)

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Table 1.(Continued)

Study

Author

Study design

Main Outcomes

Conclusion

Relationship
between grip
strength and the
metabolic
syndrome

Sayer AA
et al.
200728

Hertfordshire Cohort
Study cross-sectional study
2,677 men and women.
59 73 years
Grip strength by
dynamometer

A standard deviation (SD) decrease in grip

strength was significantly associated with
higher: fasting triglycerides (p=0.006),
blood pressure (p=0.004), waist
circumference (p<0.001), 2 h glucose
(p=0.001) and HOMA resistance (p=0.008),
after adjustment for sex, weight, age,
walking speed, social class, smoking habit
and alcohol intake
Lower grip strength was also significantly
associated with increased odds of having
the metabolic syndrome according to both
the ATPIII (p<0.001) and IDF definitions
(p=0.03).

Impaired grip
strength is
associated with
the individual
features as well
as with the
overall
summary
definitions of
metabolic
syndrome

Is grip strength a
useful single
marker of frailty?

Syddall H
et al.
200329

Prospective, crosssectional
study
717 men and women
6474 years
Grip strength by
dynamometer

Grip strength was substantially higher in

men than in women (p<0.0001, for
difference)
Grip strength decreased with increasing age
(p=0.002, men, p=0.001, women) and
lower height (p<0.0001, men and
p=0.0007, women)
The all cause mortality rate was higher for
men than women (hazard ratio 1.88, 95%
CI 1.033.43, p=0.04)
In men (but not women), grip strength was
significantly correlated with all cause
mortality

Grip strength
was associated
with markers of
frailty

Muscle strength in
type 2 diabetes

Andersen H
et al.
200425

36 type 2 diabetic patients

and 36 control subjects
Age < 70 years.
Measure strength of flexors
and extensors at elbow,
wrist, knee and ankle by
dynamometry
Use of neuropathy rank
sum score (NRSS)

Maximal isokinetic muscle strength in

patients with diabetes was reduced by 14%
for ankle extensors and by 17% for the
ankle flexors
Knee flexor strength was reduced by 14%
(p<0.05).
Degree of retinopathy was related to the
combined strength at the ankle (p<0.05)
and knee (p<0.02).

The NRSS was

related to the
strength at the
ankle but not
to the degree
of nephropathy
or retinopathy
Type 2 diabetic
patients may
have muscle
weakness at
the ankle and
knee related to
presence and
severity of
peripheral
neuropathy
(Continued)

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Table 1.(Continued)

Study

Author

Study design

Main Outcomes

Conclusion

Excessive loss of
skeletal muscle
mass in older
adults with type 2
diabetes

Park SW
et al.
200924

2,675 older adults

Follow-up six years
Measurement of mid-thigh
muscle cross-sectional area
(CSA): computed
tomography

Older adults with either diagnosed or

undiagnosed type 2 diabetes showed
excessive loss of appendicular lean mass
and trunk fat mass compared with nondiabetic subjects
Thigh muscle CSA declined twice as fast in
older women with diabetes than their nondiabetic counterparts
Findings remained significant after adjusting
for age, sex, race, clinic site, baseline BMI,
weight change intention, and actual weight
changes over time

Type 2 diabetes
is associated
with excessive
loss of skeletal
muscle and
trunk fat mass
in communitydwelling older
adults
Older women
with type 2
diabetes are at
especially high
risk for loss of
skeletal muscle
mass

Strength training
improves muscle
quality and insulin
sensitivity in
Hispanic older
adults with type 2
diabetes

Brooks N.
et al 200627

62 community-dwelling
Hispanics with type 2
diabetes
16 weeks of strength
training plus standard care
(ST group) or standard care
(CON) alone
Skeletal muscle biopsies

ST group show improved muscle quality

(mean SE: 283) vs CON (-42, p<0.001)
and increased type I (860252 m(2)) and
type II fibre cross-sectional area (720285
m(2)) compared to CON (type I: -164290
m(2), p=0.04; and type II: -130336
m(2), p=0.04)
This was accompanied by reduced insulin
resistance (ST: median (interquartile range)
-0.7(3.6) vs CON: 0.8(3.8), p=0.05); FFA (ST:
-8430 mol/L vs CON: 14948 mol/L,
p=0.02); and CRP (ST: -1.3(2.9) mg/L vs
CON: 0.4(2.3) mg/L, p=0.05).
Serum adiponectin increased with ST
(1.0(1.8) g/mL) compared to CON
(-1.2(2.2) g/mL, p<0.001).

Strength
training
improved
muscle quality
and wholebody insulin
sensitivity
Decreased
inflammation
and increased
adiponectin
levels were
related with
improved
metabolic
control

Muscle strength is
a marker of insulin
resistance in
patients with type
2 diabetes: a pilot
study

Nomura
Takuo et al.
200726

20 men and 20 women

(mean age 53 years)
Knee extension force
normalised for body weight
(KEF) dynamometer
Insulin resistance (IR) by
HOMA

The knee extension force normalised for

body weight was found to be significantly
correlated with HOMA-IR in both male
(r=8.260, p<0.05), in female (r=-0.462,
p<0.05)
KEF % was an independent determinant of
HOMA-IR (B -0.331, F 5.400, 0<0.005)

Lower extremity
muscle strength
is independently
associated
with IR

Key: ADL = activities of daily living; ATP111 = Adult Treatment Panel 111; BMI = body mass index; HbA1C = glycated haemoglobin A1C; HOMA = Homeostatic
Model Assessment; IADL = instrumental ADL; IDF = International Diabetes Federation; pQCT = peripheral quantitative computed tomography.

Deficiency of the adipocyte hormone leptin results in hyperphagia, obesity and IR. Ghrelin could produce glucose intolerance, decreased glucose stimulated insulin secretion and reduced
leptin sensitivity. This provides partial evidence that ghrelin may
play an important role in regulating beta-cell function.43

Insulin and insulin resistance

In patients with type 2 diabetes, IR may lead to impairment of
muscle strength and performance16 or executive function.44
During ageing, IR seems to be involved in muscle protein loss, and
the distinctive lower effect of insulin on skeletal muscle protein

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synthesis may involve a defect in the insulin signal transduction

pathway. Moreover, development of IR during ageing may induce
mitochondrial alterations leading to a reduction in energy production required for muscle contraction. Some of the protein involved
are phosphatidylinositol 3-kinase, S6K1, GLUT4 and 4E-BP1.45-6

Inflammation and anti-inflammatory responses

Some inflammatory markers have been associated with chronic
medical conditions. Increased IL-1/6 or decreased IGF-1 are
related with induction anorexia, sarcopaenia and diabetes, as
well as the development of frailty, functional decline and functional disability in elderly populations.12,47-9

Obesity

In one study, those with diabetes who had HbA1C > 6.3% had
on average a significantly higher body weight, higher waist
circumference and higher body mass index, than those with
mean HbA1C 6.3% or those without diabetes.50
Obesity is a precipitating factor for the development of
type 2 diabetes, and IR, and the development of obesity-related
disease. A progressive increase in body and intramyocellular fat
mass is associated with an increased risk of IR, and the rise in
IR with ageing is associated with increased visceral adiposity.32
Sarcopaenia is strongly connected with parallel increase in
fat mass. Recently, several authors have described a state of
sarcopenic obesity. With higher fat mass and lower muscle
mass, physical activity becomes progressively more difficult, and
its habitual level declines, promoting more muscle mass loss
and physical disability.51

Mitochondrial dysfunction
Diabetes is associated with a decrease in DNA unwinding rate,
increase collagen cross-linking, and oxidative damage and
decreased Na+/K+-ATPase activity in cells.1 The sequence of
events between sarcopaenia and diabetes may start with mitochondrial dysfunction, and these abnormalities could lead to a
vicious cycle in which mitochondrial dysfunction, elevation of
intramyocellular lipids, impaired lipid oxidation and IR amplify
each other leading to sarcopaenia. In these patients, increased
free fatty acid availability results in accumulation of intramyocellular fatty acyl-coA, inducing a series of alterations52,53:
impaired insulin-stimulated oxidative phosphorylation (ATP
synthesis)
reduced expression of PGC-1 and PGC-1 controlled genes
involved in mitochondrial biogenesis and oxidative
phosphorylation
initiation of inflammatory process by activation of protein
kinase C and nuclear factor and decreased expression of
matrix metalloproteinases.

Advanced glycation end products

AGEs have been hypothesised to play a role in the pathogenesis
of sarcopaenia, through AGE-mediated increases in inflammation and endothelial dysfunction in the microcirculation of
skeletal muscle and through cross-linking of collagen in skeletal

Key messages
By virtue of also being a state associated with major

health and social adverse events, including mortality,

disability, institutionalisation and dependency,
diabetes shares some of the key characteristics of
frailty and can be regarded as a frailty-prone state
The maintenance of skeletal muscle mass is
influenced by multiple factors including hormonal,
inflammatory, neurological, nutritional and limb
activity components
Sarcopaenia by way of its profound effects on lower
limb function is a potentially important contributor to
the disabling condition associated with diabetes and
may be a precursor to frailty

muscle. Also it has been described that high AGE levels, such
as of plasma CML, are related with low gait speed. Those with
the highest quartile of plasma CML levels were at higher risk of
slow walking speed compared with those in the lower three
quartiles of plasma CML adjusting for age, education, cognitive
function, smoking and chronic diseases.54-55

Conclusions
In this first paper we have explored sarcopaenia and frailty as
potential mediators of disability and lower limb muscle dysfunction in those with diabetes. We have also reviewed the factors
that are important in the maintenance of skeletal muscle mass.
In Part 2, we examine further the potential influence of diabetes in the development of one or more frailty characteristics and
attempt to schematically summarise their relationship.

Funding
This research received no specific grant from any funding
agency in the public, commercial, or not for-profit sectors.

Conflict of interest statement

There is no conflict of interest.

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25. Andersen H, Nielsen S, Mogensen CE, Jakobsen J. Muscle strength in
type 2 diabetes. Diabetes 2004;53:1543-8.
26. Nomura T, Ikeda Y, Nakao S et al. Muscle strength is a marker of insulin resistance in patients with type 2 diabetes: a pilot study. Endocrine
2007;54:791-6.
27. Brooks N, Layne JE, Gordon PL et al. Strength training improves muscle
quality and insulin sensitivity in Hispanic older adults with type 2 diabetes. Int J Med Sci 2006;4:19-27.
28. Sayer AA, Syddall HE, Dennison EM et al. Hertfordshire Cohort. Grip
strength and the metabolic syndrome: findings from the Hertfordshire
Cohort Study. QJM 2007;100:707-13.
29. Syddall H, Cooper C, Martin F et al. Is grip strength a useful single
marker of frailty? Age Ageing 2003;32:650-6.
30. Ottenbacher KJ, Ostir GV, Peek MK et al. Frailty in older Mexican
Americans. J Am Geriatr Soc 2005;53:1524-31.
31. Sayer AA, Dennison EM, Syddall HE et al. Type 2 diabetes, muscle
strength, and impaired physical function: the tip of the iceberg?
Diabetes Care 2005;28:2541-2.

32. Baumgartner RN, Walters DL. Sarcopenia and sarcopenic-obesity.

Principles and Practice of Geriatric Medicine. Pathy MSJ ed. United
Kingdom. 2006.
33. MacIntosh C, Morley JE, Chapman IM. The anorexia of aging. Nutrition
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34. Morley JE, Silver AJ. Anorexia in the elderly. Neurobiol Aging 1988;9:
9-16.
35. Khan MS, Chandanpreet S, Kewal K et al. Malnutrition, anthropometric, and biochemical abnormalities in patients with diabetic
nephrophaty. J Ren Nutr 2009;19:275-82.
36. Matthew C, Robert C, Aaron S et al. The prevalence of vitamin B12
Deficiency in patients with type 2 diabetes: a cross sectional study.
J Am Board Fam Med 2009;22:528-34.
37. Capola AR, Xue QL, Fried LP. Multiple hormonal deficiencies in anabolic hormones are found in frail older women: the womens health
and aging studies. J Gerontol A Biol Sci Med Sci 2009;64:243-8.
38. Spark RF. Testosterone, diabetes mellitus, and the metabolic syndrome. Curr Urol Rep 2007;8:467-71.
39. Ozfirat Z, Tahseen AC. Vitamin D deficiency and type 2 diabetes.
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40. Moreira-Pfrimer LD, Pedrosa MA, Teixeira L et al. Treatment of vitamin
D deficienciy increases lower limb muscle strenth in institutionalized
older people independently of regular physical activity: a randomized
double-blind controlled trial. Ann Nutr Metab 2009;54:291-300.
41. Lehrke M, Broedl UC, Biller-Friedmann IM et al. Serum concentrations of cortisol, interleukin 6, leptin and adiponectin predict stress
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42. Shaap LA, Pluijm SMF, Deeg DJ, Visser M. Inflammatory markers and loss of muscle mass (sarcopenia) and strength. Am J Med
2006;119:526.e9-17.
43. Sun Y, Asnicar M, Smith RG. Central and peripheral roles of ghrelin on
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44. Abbatecola AM, PaolisSo G, Lamponi M et al. Insulin resistance and
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45. Roubenoff R, Parise H, Payette HA et al. Cytokine, insulin-like
growth factor 1, sarcopenia, and mortality in very old communitydwelling men and women: the Framingham Heart Study. Am J Med
2003;115:429-35.
46. Halvatsiotis P, Short KR, Bigelow M et al. Synthesis rate of muscle
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Diabetes 2002;51:2395-404.
47. Figaro MK, Kritchevsky SB, Resnick HE et al. Diabetes, inflammation
and functional decline in older adults. Diabetes Care 2006;29:2039-45.
48. Puts MT, Visser M, Twisk JWR et al. Endocrine and inflamatory markers
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49. Barzilay JI, Blaum C, Moore T et al. Insulin resistance and inflammation
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50. Bates CJ, Lean ME, Mansoor MA et al. Nutrient intakes: biochemical
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51. Waters DL, Baumgartner RN. Sarcopenia and obesity. Clin Geriatr Med
2011;27:401-21.
52. Roden M. Muscle triglycerides and mitochondrial function: possible
mechanisms for the development of type 2 diabetes. Intern J Obes
2005;29:S111-15.
53. Yokota T, Kinuga S, Hirabayashi K et al. Oxidative stress in skeletal mucle
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diabetic mice. Am J Physiol Heart Circ Physiol 2009;297:h1069-77.
54. Haidi AR, Jassim AI. Endothelial dysfunction in diabetes mellitus. Vasc
Health Risk Manag 2007;3:853-76.
55. Semba RD, Bandinelli S, Sun K et al. Relationship of an advanced glycation end product, plasma carboxymethyl-lysine, with slow walking
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BYDUREON is indicated for treatment of type 2 diabetes mellitus in combination with

metformin, sulphonylureas, thiazolidinediones, or combinations of metformin and a
sulphonylurea or metformin and a thiazolidinedione, in adults who have not achieved
adequate glycaemic control on maximally tolerated doses of these oral therapies.

BYDUREON: the first and only therapy to provide

continuous glycaemic control with a once-weekly injection.
Mean HbA 1c reduction, between 1.3%2 and 1.9%.3 Sustained weight loss in a once-weekly regimen.3

Prescribing information can be found overleaf

UKBDR00135b 2011 AMYLIN PHARMACEUTICALS, INC. AND LILLY, LLC.

March 2012
ALL RIGHTS RESERVED.
BYDUREON is a registered trade mark and BYDUREON By Your Side is a trade mark of Amylin Pharmaceuticals, Inc.
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Friday

Thursday

Wednesday

Tuesday

Monday

Saturday

Sunday

Introducing BYDUREON.
Continuous glycaemic control
with a once-weekly injection.

BYDUREON (exenatide)
ABBREVIATED PRESCRIBING INFORMATION
Presentation Exenatide 2mg powder and solvent for prolonged-release
suspension for injection. Each single-dose kit contains one vial of 2mg
exenatide and one pre-filled syringe of 0.65ml solvent. Uses Bydureon is
indicated for treatment of Type 2 diabetes mellitus in combination with
metformin, sulphonylureas, thiazolidinediones, or combinations of
metformin and a sulphonylurea or metformin and a thiazolidinedione, in
adults who have not achieved adequate glycaemic control on maximally
tolerated doses of these oral therapies. Dosage and Administration The
recommended dose is 2mg once weekly, on the same day each week.
Each dose should be administered in the abdomen, thigh, or the back of
the upper arm as a subcutaneous injection immediately after suspension
of the powder in the solvent. Instructions on the suspension and
administration of Bydureon can be found in the Instructions for the User
provided in the carton and must be followed carefully by the patient.
Appropriate training is recommended for non-healthcare professionals
administering the product. Patients switching from exenatide twice daily
(Byetta) to Bydureon may experience transient elevations in blood glucose
concentrations, which generally improve within the first two weeks after
initiation of therapy. When Bydureon is added to existing metformin and/
or thiazolidinedione therapy, the current dose of metformin and/or
thiazolidinedione can be continued. When Bydureon is added to
sulphonylurea therapy, a reduction in the dose of sulphonylurea should be
considered to reduce the risk of hypoglycaemia. Blood glucose selfmonitoring may be necessary to adjust the dose of sulphonylurea. If a
different antidiabetic treatment is started after the discontinuation of
Bydureon, consideration should be given to the prolonged release of
Bydureon. Elderly: No dose adjustment is required based on age.
Consideration should be given to the patients renal function. Renal or
hepatic impairment: No dosage adjustment is necessary in patients with
mild renal impairment (creatinine clearance 50-80ml/min) or hepatic
impairment. Not recommended in patients with moderate renal
impairment (creatinine clearance 30-50ml/min), severe renal impairment
(creatinine clearance <30ml/min), or end-stage renal disease. Paediatric
population: The safety and efficacy in children and adolescents aged
under 18 years have not yet been established. No data are available.
Contra-indications Hypersensitivity to the active substance or to any of
the excipients. Warnings and Special Precautions Should not be used
in patients with Type 1 diabetes mellitus or for the treatment of diabetic
ketoacidosis. Must not be administered by intravenous or intramuscular
injection. Not recommended for use in patients with moderate or severe
renal impairment or end-stage renal disease. There have been rare,
spontaneously reported events of altered renal function with exenatide,
including increased serum creatinine, renal impairment, worsened chronic
renal failure, and acute renal failure, sometimes requiring haemodialysis.
Some of these occurred in patients experiencing events that may affect

hydration and/or receiving medicinal products known to affect renal

function/hydration status, including angiotensin converting enzymes
inhibitors, angiotensin-II antagonists, non-steroidal anti-inflammatory
medicinal products, and diuretics. Not recommended in patients with
severe gastro-intestinal disease. There have been rare, spontaneously
reported events of acute pancreatitis. Patients should be informed of the
characteristic symptom of acute pancreatitis: persistent, severe abdominal
pain. Resolution of pancreatitis has been observed with supportive
treatment, but very rare cases of necrotizing or haemorrhagic pancreatitis
and/or death have been reported. If pancreatitis is suspected, Bydureon
and other potentially suspect medicinal products should be discontinued.
Treatment with Bydureon should not be resumed after pancreatitis
has been diagnosed. The concurrent use of Bydureon with insulin,
D-phenylalanine derivatives (meglitinides), alpha-glucosidase inhibitors,
dipeptidyl peptidase-4 inhibitors, or other GLP-1 receptor agonists has not
been studied. The concurrent use of Bydureon and exenatide twice daily
(Byetta) has not been studied and is not recommended. The risk of
hypoglycaemia was increased when Bydureon was used in combination
with a sulphonylurea in clinical trials. Furthermore, patients on a
sulphonylurea combination, with mild renal impairment, had an increased
incidence of hypoglycaemia compared to patients with normal renal
function. To reduce the risk of hypoglycaemia associated with the use of
a sulphonylurea, reduction in the dose of sulphonylurea should be
considered. Rapid weight loss (>1.5 kg per week) has been reported in
patients treated with exenatide. Weight loss of this rate may have harmful
consequences. There have been some reported cases of increased INR,
sometimes associated with bleeding, with concomitant use of warfarin
and exenatide. After discontinuation, the effect of Bydureon may continue
as plasma levels of exenatide decline over 10 weeks. Choice of other
medicinal products and dose selection should be considered accordingly
until exenatide levels decline. Interactions The following interaction
studies were conducted using 10 micrograms exenatide twice daily, but
not exenatide once weekly: HMG CoA reductase inhibitors: Lovastatin AUC
and Cmax were decreased and Tmax was delayed when exenatide (10g BD)
was administered concomitantly with a single dose of lovastatin (40mg).
Concomitant use of exenatide twice daily and HMG CoA reductase
inhibitors was not associated with consistent changes in lipid profiles.
Lipid profiles should be monitored as appropriate. Warfarin: Tmax was
delayed when warfarin was administered 35 min after exenatide twice
daily. No clinically relevant effects on Cmax or AUC were observed. Increased
INR has been reported during concomitant use of warfarin and exenatide
twice daily. INR should be monitored during initiation of Bydureon therapy
in patients on warfarin and/or cumarol derivatives. Digoxin and lisinopril:
A delay in Tmax was observed in interaction studies between digoxin or
lisinopril and exenatide twice daily. No clinically relevant effects on Cmax or
AUC were observed. Fertility, Pregnancy, and Lactation Women of
childbearing potential should use contraception during treatment with

Bydureon. Bydureon should be discontinued at least 3 months before a

planned pregnancy. Bydureon should not be used during pregnancy and
the use of insulin is recommended. Bydureon should not be used during
breast-feeding. Driving, etc No studies on the effects on the ability to
drive and use machines have been performed. When Bydureon is used in
combination with a sulphonylurea, avoid hypoglycaemia while driving
and using machines. Undesirable Effects Adverse Reactions Reported
From Clinical Studies Very common: Hypoglycaemia (with a sulphonylurea),
constipation, diarrhoea, nausea, vomiting, injection site pruritus, injection
site nodules. Common: Decreased appetite, dizziness, headache,
abdominal distention, abdominal pain, dyspepsia, eructation, flatulence,
gastro-oesophageal reflux, fatigue, injection site erythema, injection site
rash, somnolence. Rapid weight loss has been reported with Bydureon.
Patients may develop anti-exenatide antibodies following treatment with
Bydureon. These patients tend to have more injection site reactions (eg,
skin redness, itching). Acute pancreatitis and acute renal failure have been
reported rarely and anaphylactic reaction has been reported very rarely in
spontaneous post-marketing reports with exenatide twice daily. For full
details of these and other side-effects, please see the Summary of Product
Characteristics, which is available at http://emc.medicines.org.uk/. Legal
Category POM Marketing Authorisation Number EU/1/11/696/001
Basic NHS Cost 73.36 per 4 weekly pack Date of Preparation or Last
Review June 2011
Full Prescribing Information is Available From
Eli Lilly and Company Limited
Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL
Telephone: Basingstoke (01256) 315 000
E-mail: ukmedinfo@lilly.com Website: www.lillypro.co.uk
BYDUREON (exenatide) is a registered trademark of Amylin
Pharmaceuticals, Inc.

Adverse events should be reported. Reporting

forms and further information can be found at:
www.mhra.gov.uk/yellowcard. Adverse events and
product complaints should also be reported to Lilly:
please call Lilly UK on 01256 315 000.
References 1. National Institute for Health and Clinical Excellence.
Exenatide prolonged-release suspension for injection in combination
with oral antidiabetic therapy for the treatment of type 2 diabetes.
Technology Appraisal Guidance No. 248. London: NICE; 2012 (www.nice.
org.uk). 2. Buse JB, Nauck MA, Forst T et al. Efficacy and safety of exenatide
once weekly versus liraglutide in subjects with type 2 diabetes
(DURATION-6): a randomised, open-label study. Diabetologia 2011;
54(Suppl 1): S38 4. 3. BYDUREON (Summary of Product Characteristics).

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