Lipoatrophy: re-emerging with analogue insulins. Is there a link with CSII?
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164 PRACTICAL DIABETES VOL. 31 NO. 4 COPYRIGHT © 2014 JOHN WILEY & SONS Case report Introduction Lipoatrophy (LA) was commonly seen with insulin use prior to the 1970s, occurring in 25–55% of patients using conventional bovine or porcine insulin. 1 The incidence of LA fell to less than 10% with the intro- duction of highly purified insulin 1 and it has been largely unreported and hence considered extremely rare since the development of recombi- nant human insulin and insulin ana- logues. In the past decade, however, there has been in an increase in reports of LA among patients using various rapid- and long-acting analogue insulin preparations. Lipo- atrophy is more commonly seen in young people, 1 therefore its inci- dence is particularly relevant in a paediatric setting. The presence of LA is clinically significant because it may lead to impaired insulin absorp- tion and instability of blood glucose control. Furthermore, its adverse cosmetic effects can cause distress to patients and their carers. Case reports We retrospectively collected data on patients identified with LA from our clinic population of 328 patients. Over a two-year period, four patients with type 1 diabetes pre- sented with LA (see Table 1). All four patients were female, and receiving treatment with insulin aspart (NovoRapid) via continuous subcutaneous insulin infusion (CSII). Lipoatrophy was detected one to three years after commenc- ing CSII therapy. (Figures 1 and 2.) No detrimental effect of LA on the glycated haemoglobin (HbA1c) was demonstrated; however, the cosmetic effects were disturbing to patients and carers. All patients were advised to rest the lipoatrophic sites and avoid administering insulin into the areas. In all patients LA persisted at the most recent follow up, albeit with some improve- ment. To help elucidate an immunological basis for LA we looked for co-existing autoimmune disorders and noted that patient number two had coeliac disease. Discussion Lipoatrophy is a rare and likely under-reported complication of insulin therapy, which appears to be re-emerging. Lipoatrophy repre- sents destruction of subcutaneous fat and presents with well demar- cated, depressed areas at sites of insulin administration, typically fol- lowing 6–24 months of regular insulin treatment. We present four cases of LA: all female, and all on CSII with insulin aspart. This raises a number of interesting points. Lipoatrophy: re-emerging with analogue insulins. Is there a link with CSII? Abstract Over the last decade, there has been an increase in reported cases of lipoatrophy as a complication of treatment with analogue insulin preparations. Lipoatrophy causes undesirable cosmetic appearances and may cause variable glycaemic control. We report a case series of four female patients from a tertiary paediatric diabetes unit presenting with lipoatrophy while on treatment with insulin aspart via a continuous subcutaneous insulin infusion (CSII) pump for the management of type 1 diabetes. We did not observe any cases of lipoatrophy in patients receiving multiple daily insulin injections. In examining the effect of lipoatrophy on glycaemic control, we found no detrimental effect of lipoatrophy on the patients’ glycated haemoglobin. Cases of lipoatrophy should be reported to drug manufacturers and through the appropriate national adverse drug reaction reporting system. This will facilitate observation of trend, and help monitor for associations, informing future research. Copyright © 2014 John Wiley & Sons. Practical Diabetes 2014; 31(4): 164–166 Key words diabetes; lipoatrophy; paediatrics; CSII Dr Marcelle Simeonovic Medical Doctor, University of Melbourne, Medical School, Victoria, Australia Dr Azriyanti Anuar Clinical Fellow in Paediatric Diabetes, Paediatric Department, University Malaya, Kuala Lumpar, Malaysia; and Paediatric Diabetes, Oxford Children’s Hospital, Oxford, UK Dr Julie Edge Consultant in Paediatric Diabetes, Oxford Children’s Hospital, Oxford, UK Dr Tafadzwa Makaya Consultant in Paediatric Endocrinology, Oxford Children’s Hospital, Oxford, UK Correspondence to: Dr T Makaya, Consultant in Paediatric Endocrinology, Oxford Children’s Hospital, Headley Way, Oxford OX3 9DU, UK; email: [email protected] Received: 11 February 2014 Accepted in revised form: 14 March 2014
Transcript of Lipoatrophy: re-emerging with analogue insulins. Is there a link with CSII?
164 PRACTICAL DIABETES VOL. 31 NO. 4 COPYRIGHT © 2014 JOHN WILEY & SONS
Case report
IntroductionLipoatrophy (LA) was commonlyseen with insulin use prior to the1970s, occurring in 25–55% ofpatients using conventional bovine orporcine insulin.1 The incidence of LAfell to less than 10% with the intro-duction of highly purified insulin1
and it has been largely unreportedand hence considered extremely raresince the development of recombi-nant human insulin and insulin ana-logues. In the past decade, however,there has been in an increase inreports of LA among patients usingvarious rapid- and long-acting analogue insulin preparations. Lipo -atrophy is more commonly seen inyoung people,1 therefore its inci-dence is particularly relevant in a paediatric setting. The presence ofLA is clinically significant because itmay lead to impaired insulin absorp-tion and instability of blood glucosecontrol. Furthermore, its adverse cosmetic effects can cause distress to patients and their carers.
Case reportsWe retrospectively collected data onpatients identified with LA from ourclinic population of 328 patients.Over a two-year period, fourpatients with type 1 diabetes pre-sented with LA (see Table 1). Allfour patients were female, and
receiving treatment with insulinaspart (NovoRapid) via continuoussubcutaneous insulin infusion(CSII). Lipoatrophy was detectedone to three years after commenc-ing CSII therapy. (Figures 1 and 2.)
No detrimental effect of LA onthe glycated haemoglobin (HbA1c)was demonstrated; however, the cosmetic effects were disturbing topatients and carers. All patientswere advised to rest the lipoatrophicsites and avoid administeringinsulin into the areas. In all patientsLA persisted at the most recent follow up, albeit with some improve-ment. To help elucidate animmunological basis for LA welooked for co-existing autoimmunedisorders and noted that patientnumber two had coeliac disease.
DiscussionLipoatrophy is a rare and likelyunder-reported complication ofinsulin therapy, which appears to bere-emerging. Lipoatrophy repre-sents destruction of subcutaneousfat and presents with well demar-cated, depressed areas at sites ofinsulin administration, typically fol-lowing 6–24 months of regularinsulin treatment. We present fourcases of LA: all female, and all onCSII with insulin aspart. This raises anumber of interesting points.
Lipoatrophy: re-emerging with analogueinsulins. Is there a link with CSII?
AbstractOver the last decade, there has been an increase in reported cases of lipoatrophy as acomplication of treatment with analogue insulin preparations. Lipoatrophy causes undesirablecosmetic appearances and may cause variable glycaemic control.
We report a case series of four female patients from a tertiary paediatric diabetes unitpresenting with lipoatrophy while on treatment with insulin aspart via a continuoussubcutaneous insulin infusion (CSII) pump for the management of type 1 diabetes. We did notobserve any cases of lipoatrophy in patients receiving multiple daily insulin injections. Inexamining the effect of lipoatrophy on glycaemic control, we found no detrimental effect oflipoatrophy on the patients’ glycated haemoglobin.
Cases of lipoatrophy should be reported to drug manufacturers and through theappropriate national adverse drug reaction reporting system. This will facilitate observation oftrend, and help monitor for associations, informing future research. Copyright © 2014 JohnWiley & Sons.
Practical Diabetes 2014; 31(4): 164–166
Key wordsdiabetes; lipoatrophy; paediatrics; CSII
Dr Marcelle SimeonovicMedical Doctor, University of Melbourne, MedicalSchool, Victoria, Australia
Dr Azriyanti AnuarClinical Fellow in Paediatric Diabetes, Paediatric Department, University Malaya, KualaLumpar, Malaysia; and Paediatric Diabetes, Oxford Children’s Hospital,Oxford, UK
Dr Julie EdgeConsultant in Paediatric Diabetes, Oxford Children’sHospital, Oxford, UK
Dr Tafadzwa MakayaConsultant in Paediatric Endocrinology, OxfordChildren’s Hospital, Oxford, UK
Correspondence to: Dr T Makaya, Consultant in Paediatric Endocrinology,Oxford Children’s Hospital, Headley Way, Oxford OX39DU, UK; email: [email protected]
Received: 11 February 2014Accepted in revised form: 14 March 2014
The precise mechanism of LA isstill unknown, although it is consid-ered to be an immunological phe-nomenon. This theory is supportedby the presence of IgM, IgA, C3 andfibrin in LA lesions and a responseto steroid therapy in a number ofcases.2,3 Our case series suggests thatthe continuous exposure to insulinvia CSII may play a role in inducingthe immunogenic response. Reportsof LA occurring with insulin ana-logues via injections2,3 and pumptherapy4,5 imply that the mechanismmay be independent of the deliverysystem. However, this observationmay not necessarily be applicable toa paediatric population. In theory,infusion of insulin and maintainingthe catheter at the same site over anumber of days could predispose tothe development of LA, since therepeated administration of insulin toa particular area has been identifiedas a contributing factor.1,2 It is con-ceivable that, in young children,sites for cannula insertion for CSII may be limited, leading to adecrease in the recommended rota-tion of insertion sites, compared torotation of injection sites with multi-ple daily injections. This is sup-ported by our data series where LApresented only in patients on CSII.
In addition, previous studies andreports have described an increasedincidence of LA in females,2,3 a pointhighlighted by the demographics ofour case series. Further research bySalgin et al. in 20136 showed thatHashimoto’s thyroiditis and coeliacdisease – both autoimmune condi-tions, and with a higher prevalence infemales – were more prevalent inpatients with LA. Lipoatrophy wasalso associated with an increased riskof Hashimoto’s thyroiditis andcoeliac disease in female patients.
The authors concluded that theirfindings support the hypothesis that an immune complex-mediatedinflammatory process may be impor-tant in the development of LA. Onlyone of our four patients currently hasa co-existing autoimmune condition.All patients will continue to be moni-tored for the possible development
of Hashimoto’s thyroiditis and/orcoeliac disease.
Management of LA presents a seri-ous challenge, particularly in adultswhere spontaneous resolution is lesscommon than in children.5 Variousmanagement strategies have beenemployed and postulated. Theseinclude rotating away from affected
PRACTICAL DIABETES VOL. 31 NO. 4 COPYRIGHT © 2014 JOHN WILEY & SONS 165
Lipoatrophy re-emergence: link with CSII?
Case report
1 F 3 1.5 1.3 0.7 Buttock 7.1 6.9 4 N
2 F 7 3.3 3.25 0.8 Abdomen 8.3 7.8 8 N
3 F 8 5.6 2.45 0.7 Thigh 8.9 7.7 25 N
4 F 10 4.9 1.6 0.4 Abdomen 6.8 7 9 N
Patient Sex Age Duration Duration Total daily Site of LA HbA1c (%) HbA1c (%) at Follow up LA(years) of diabetes of CSII use dose 3 months prior LA diagnosis (months) resolved
(years) (years) (units/kg) to LA diagnosis (Y/N)
Table 1. Demographic data in patients identified with lipoatrophy (LA)
Figure 1. Patient 1: lipoatrophy on buttock (arrowed)
Figure 2. Patient 2: lipoatrophy on abdomen (arrowed)
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Lipoatrophy re-emergence: link with CSII?
Case report
sites, substituting insulin brands, theuse of oral or injected corticosteroids,and the use of topical disodium cro-moglycate ointment.2,3,5,7 Noud et al.in 20098 also suggested the novelapproach of peritoneal insulin in apatient with intractable LA. At thistime, the use of corticosteroidsappears to be the most effectivemethod for achieving completeremission of LA.5 In our case series,we advised rotation away from theareas of LA as the initial managementstrategy allowing for a period of obser-vation before resorting to alternativeforms of management. All patientscontinue to be followed up.
ConclusionsUnderstanding the risk factors fordeveloping LA and ultimately under-standing the pathogenesis of LA willbe useful in modifying the treatmentoptions in the future.
We recommend further researchin this area. Cases of LA should alsobe reported to drug manufacturersand through the appropriate nationalreporting system for adverse drugeffects. This will facilitate observation
of trend, and help monitor for associ-ations, informing further research.
AcknowledgementsWe would like to thank the patientsand/or carers for providing their con-sent in allowing their information tobe used in the production of thismanuscript. We would like to thankDr Rosemary London, Dr Fiona Ryan
and Mrs Andrea Savidge (all of Oxford Children’s HospitalPaediatric Department) for helpingto obtain the patient/parent consent.
Declaration of interestsThere are no conflicts of interestdeclared. Source of funding: none.
References1. Richardson T, Kerr D. Skin-related complications of
insulin therapy: epidemiology and emerging man-agement strategies. Am J Clin Dermatol 2003;4:661–7.
2. Holstein A, et al. Lipoatrophy associated with the useof insulin analogues: a new case associated with theuse of insulin glargine and review of the literature.Expert Opin Drug Saf 2010;9:225–31.
3. Babiker A, Datta V. Lipoatrophy with insulin analoguesin type I diabetes. Arch Dis Child 2011;96:101–2.
4. Griffin ME, et al. Lipoatrophy associated with lisproinsulin in insulin pump therapy: an old complication,a new cause? Diabetes Care 2001;24:174.
5. Chantelau EA, et al. Relapsing insulin-induced lipoat-rophy, cured by prolonged low-dose oral prednisone:a case report. Diabetol Metab Syndr 2011;3:33.
6. Salgin B, et al. Lipoatrophy is associated with anincreased risk of Hashimoto’s thyroiditis and coeliacdisease in female patients with type 1 diabetes.Horm Res Paediatr 2013;79:368–72.
7. Lopez X, et al. Human insulin analog-induced lipoatrophy. Diabetes Care 2008;31:442–4.
8. Noud MN, et al. Benefits of intra-peritoneal insulin administration in a child with severeinsulin-induced lipoatrophy. Pediatric Diabetes2009;10(Suppl 11):100.
Book review
l Reported cases of lipoatrophy inpatients using analogue insulinpreparations are on the increase. Ourcase series describes four patients withlipoatrophy who were all usingcontinuous subcutaneous insulininfusion (CSII) therapy
l We review the proposedpathophysiology of lipoatrophy anddiscuss how this may link to CSIItherapy
l Reporting cases of lipoatrophy isrecommended – in particular reportingto drug manufacturers and throughappropriate national adverse drugreaction reporting systems
Key points
Ilike this book. The previous editionswere excellent; this third edition
is superb. The introduction is comprehen-
sive, providing a good overview of dia-betic foot pathology, and concludes byemphasising the importance of boththe multidisciplinary diabetic foot clin-ics and the foot protection teams.
This introductory chapter is fol-lowed by six chapters on the staginglevels, from the ‘normal’ foot to theunsalvageable foot. Each section hasgood, clear photographs to reinforcethe clinical presentation.
There is a mention in chapterthree, the high-risk foot, about painful
neuropathy, an area often neglectedby health professionals. The variousdrugs, together with their dosages, aredocumented. The longest chapters,four and five, are concerned withStage 3, the ulcerated foot, and Stage4, the infected foot. In the formerthere is salient, updated informationon ischaemic disease with the additionof arterial therapies mentioned suchas percutaneous transluminal angio-plasty and sub-intimal angioplasty.There is also a good section in chapterfour on ‘off loading’ devices.
There is updated information onCharcot’s neuroarthropathy and a wel-come mention of surgical procedures
that can be done to restore foot archi-tecture. This is an area of controversy,in that surgical intervention mayinvoke further development ofCharcot’s pathology.
In chapter five, there is a very use-ful table relating to antibiotic prescrib-ing aligned to the micro-organismsinvolved in the infection. Further -more, there is a comprehensive tableon antibiotic suitability and dosage levels for those diabetic patients whohave nephropathy.
The final chapter relates to Stage6, the unsalvageable foot. It mentionsthe team approach in dealing withamputation and includes a section onrehabilitation for the amputee.
Finally, there is a useful appendixon differential diagnosis, with keyterms, followed by the likely pathol-ogy. In addition, there is also a goodreading list to allow the reader todelve further.
John Bardwell, Bank Podiatrist,Lincolnshire Community Health Trust,Johnson Community Hospital, Spalding,Lincolnshire, UK
Third edition By Michael E Edmonds and Alethea VM FosterPublished by Wiley-Blackwell, 2014246 pages, price £39.99 paperbackISBN: 0 470 655054Website: www.wiley.com
Managing the diabetic foot
