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The British Journal of Diabetes & Vascular

http://dvd.sagepub.com/content/12/3/110The online version of this article can be found at:

 DOI: 10.1177/1474651412445619

2012 12: 110British Journal of Diabetes & Vascular DiseasePilar Atiénzar, Pedro Abizanda, Andrew Guppy and Alan J Sinclair

Diabetes and frailty: an emerging issue. Part 1: Sarcopaenia and factors affecting lower limb function  

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Abstract

Frailty 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

IntroductionDiabetes is a disabling chronic cardiovascular and medical dis-ease with a tremendous health, social and economic burden within our ageing communities. Diabetes has a prevalence of 10–30% in subjects above 65 years of age. Diabetic men and women diagnosed at age 60 have an estimated reduction in life expectancy of 7.3–9.5 years, and a good quality of life of 11.1–13.8 years.1,2

Frailty is described as a state of increased vulnerability to stress-ors 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, institutionalisa-tion and the second most common cause of dependency.5

Sarcopaenia is the loss of muscle mass associated with age-ing. The prevalence of clinically significant sarcopaenia is esti-mated to range from 8 to 50% in older people.6 Low strength

is one of Fried’s frailty criteria, and it has been stated that age- related 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 sarcopae-nia 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.

DiabetesDiabetes is a premature ageing syndrome, a cause of unsuc-cessful 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, uri-nary incontinence, infections, pressure ulcers, falls, hip fractures in the elderly and persistent pain.10 The disease is also associ-ated 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

SarcopaeniaSarcopaenia is a progressive decline of muscle mass during age-ing, leading to low impaired strength and functioning although

Diabetes and frailty: an emerging issue. Part 1: Sarcopaenia and factors affecting lower limb functionPILAR ATIÉNZAR1, PEDRO ABIZANDA1, ANDREW GUPPY2 AND ALAN J SINCLAIR3

1Department of Geriatrics, Albacete University Hospital, Albacete, Spain.2Department of Psychology, University of Bedfordshire, Luton, UK.3 Institute of Diabetes for Older People (IDOP), Bedfordshire and Hertfordshire Postgraduate Medical School, Putteridge Bury Campus, Luton, UK.

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 743286E-mail: Sinclair.5@btinternet.com

445619 DVD0010.1177/1474651412445619Atiénzar et al.The British Journal of Diabetes & Vascular Disease2012

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 sodium–potassium adenosine triphosphatase

PGC-1 peroxisome proliferator-activated (PPAR)- g coactivator-1

TNF tumour necrosis factor

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THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 111

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 1–2%; it accelerates to as much as 1.5–3% 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, dis-ability (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

FrailtyFrailty 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 sarcopae-nia 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 inde-pendently from coexisting medical conditions: it increases the risks of falls, hospitalisation, physical disability, institutionalisa-tion, 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 dia-betes and sarcopaenia and these are reviewed and summarised in table 1.18,22–31 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, nutri-tional and activity components13,32 and these are briefly dis-cussed below.

Nutritional factorsCommunity 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 met-formin) 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 asso-ciation 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 imbalanceHormones 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 pro-tein 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 addi-tion, it has been described that low testosterone levels are associ-ated 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 toler-ance.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 sarcopae-nia, 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, TNFα, leptin and adiponectin.41,42

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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 studyAge 70–79 yearsFollow-up March 1997– July 98Diabetes: 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 muscle-strength in older adults with type 2 diabetes

Park SW et al. 200723

1,840 adults in the Health ABC StudyAge 70–79 yearsFollow-up 3 yearsMuscle:mass by DXAstrength by dynamometerquality 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 studyAged > 65 years.Follow-up 3 yearsFried’s criteria of frailtyMeasure 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 non-frail subjects

Frailty in Mexican American older adults

Ottenbacher K et al. 200530

Prospective population–based survey621 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)

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

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Study Author Study design Main Outcomes Conclusion

Relationship between grip strength and the metabolic syndrome

Sayer AA et al. 200728

Hertfordshire CohortStudy cross-sectional study2,677 men and women.59 – 73 yearsGrip 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, cross–sectional study717 men and women64–74 yearsGrip 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 1.03–3.43, 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 subjectsAge < 70 years.Measure strength of flexors and extensors at elbow, wrist, knee and ankle by dynamometryUse 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)

Table 1. (Continued)

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Deficiency of the adipocyte hormone leptin results in hyper-phagia, obesity and IR. Ghrelin could produce glucose intoler-ance, 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 resistanceIn 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

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 adultsFollow-up six yearsMeasurement 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 non-diabetic subjects

•• •Thigh muscle CSA declined twice as fast in older women with diabetes than their non-diabetic 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 community-dwelling 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 diabetes16 weeks of strength training plus standard care (ST group) or standard care (CON) aloneSkeletal muscle biopsies

•• •ST group show improved muscle quality (mean ± SE: 28±3) vs CON (-4±2, p<0.001) and increased type I (860±252 µm(2)) and type II fibre cross-sectional area (720±285 µm(2)) compared to CON (type I: -164±290 µm(2), p=0.04; and type II: -130±336 µm(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: -84±30 µmol/L vs CON: 149±48 µmol/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) µg/mL) compared to CON (-1.2(2.2) µg/mL, p<0.001).

•• •Strength training improved muscle quality and whole-body 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) – dynamometerInsulin 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.

Table 1. (Continued)

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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 produc-tion required for muscle contraction. Some of the protein involved are phosphatidylinositol 3-kinase, S6K1, GLUT4 and 4E-BP1.45-6

Inflammation and anti-inflammatory responsesSome 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 func-tional 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 dysfunctionDiabetes 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 mito-chondrial 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 intramyo-cellular 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–κβ and decreased expression of matrix metalloproteinases.

Advanced glycation end productsAGEs have been hypothesised to play a role in the pathogenesis of sarcopaenia, through AGE-mediated increases in inflamma-tion and endothelial dysfunction in the microcirculation of skeletal muscle and through cross-linking of collagen in skeletal

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

ConclusionsIn this first paper we have explored sarcopaenia and frailty as potential mediators of disability and lower limb muscle dysfunc-tion 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 diabe-tes 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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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

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44. Abbatecola AM, PaolisSo G, Lamponi M et al. Insulin resistance and executive dysfunction in older persons. J Am Geriatr Soc 2004;52: 1713-18.

45. Roubenoff R, Parise H, Payette HA et al. Cytokine, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling 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 proteins, muscle functions, and amino acid kinetics in type 2 diabetes. 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 as predictors of frailty. Clin Endocrinol 2005;63:403-11.

49. Barzilay JI, Blaum C, Moore T et al. Insulin resistance and inflammation as precursors of frailty: the Cardiovascular Health Study. Arch Intern Med 2007;167:635-41.

50. Bates CJ, Lean ME, Mansoor MA et al. Nutrient intakes: biochemical and risk indices associated with type 2 diabetes and glycosylated hae-moglobin, in the British National Diet and Nutrition Survey of people aged 65 years and over. Diabet Med 2004;21:677-84.

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 impairs mitochondrial respiration and limits exercise capacity in type 2 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 gly-cation end product, plasma carboxymethyl-lysine, with slow walking speed in older adults. Eur J Appl Physiol 2010;108:191-5.

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

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UKBDR00135b ©2011 AMYLIN PHARMACEUTICALS, INC. AND LILLY, LLC. March 2012ALL RIGHTS RESERVED.BYDUREON is a registered trade mark and BYDUREON By Your Side is a trade mark of Amylin Pharmaceuticals, Inc.

BYDUREON: the first and only therapy to provide continuous glycaemic control with a once-weekly injection.

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.

Mean HbA1c reduction, between 1.3%2 and 1.9%.3 Sustained weight loss in a once-weekly regimen.3

Prescribing information can be found overleaf

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BYDUREON® (exenatide) ABBREVIATED PRESCRIBING INFORMATIONPresentation 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 self-monitoring 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 patient’s 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 (10μg 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 FromEli 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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