Overview 

Cutaneous amyloidosis is a clump of abnormal amyloid proteins buildup in wave-like projections (dermal papillae) between the dermis and the epidermis.¹ It may be associated with the use of insulin injection and could be a class effect for all insulins.² 

Comparing to lipohypertrophy, amyloid lumps are firmer and more solid, and take a longer time to regress once insulin is no longer injected to the area.² As both are local site reactions occurring in patients on subcutaneous insulin therapy, there is a possibility that amyloid lumps are misdiagnosed as lipohypertrophy, and cases of cutaneous amyloidosis associated with insulin injection may have been underreported.³

When insulin is injected at the amyloid lump, the absorption of insulin into the bloodstream may be reduced or delayed, leading to poor glycaemic control.⁴ Unknowingly, to compensate for the high blood glucose levels, the dose of the insulin administered may be increased. This is clinically important as there have been reports where patients developed severe hypoglycaemia when there is a sudden change in the injection site to an unaffected area.⁵

Background of the safety issue

In May 2020, the National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) on reports of cutaneous amyloidosis following insulin administration.^5,6 Considering all available evidence in database and literature, both EMA and PMDA have requested the product registration holders to update insulin products’ information with the risk of cutaneous amyloidosis.

Adverse Drug Reaction (ADR) Reports: 

To date, NPRA has received 1,788 reports with 3,646 adverse events suspected to be related to insulin. Among these, 50 cases were injection site swelling, injection site mass (1), injection site abscess (1), lipohypertrophy (1) and lipodystrophy (1). However, no event regarding cutaneous amyloidosis or skin hypertrophy has been reported.⁷

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (28)] has been issued for registration holders of insulin-containing products (including combination products) to update the local package inserts with this new safety information.

Advice for Healthcare Professionals: 

• Advise patients to routinely check for any dermatologic changes and to continuously rotate the injection site to reduce or prevent the development of amyloidosis.
• Counsel patients to:
  • avoid injecting into the affected area.
  • monitor their blood glucose levels particularly after there is a change in the injection site, and to consider adjusting the dose accordingly.
• Report all adverse events suspected to be related to the use of insulin to NPRA.

References: 

1. U.S. National Library of Medicine. Primary localized cutaneous amyloidosis [Internet]. Bethesda, USA: National Institutes of Health, U.S Department of Health and Human Services. 2020 July 7 [Cited on 2020 June 30]. Available from: https://www.ghr.nlm.nih.gov/condition/primary-localized-cutaneous-amyloidosis
2. Sullivan CA, Gedik R and Haddady S. An atypical presentation of insulin amyloidosis: An uncommon but important complication of insulin therapy. AACE Clinical Case Reports Volume 4 No. 1 January/February 2018 [Internet]. 2018 Feb [Cited on 2020 June 30] 4(1):80-3. Available at: https://www.doi.org/10.4158/EP171865.CR
3. Gupta Y, Singla G, Singla R. Insulin‑derived amyloidosis. Indian Journal of Endocrinology and Metabolism [Internet]. 2015 [Cited on 2020 June 30] 19:174-7. Available from: http://www.ijem.in/text.asp?2015/19/1/174/146879
4. Nakamura M, Misumi Y, Nomura T, Oka W, Isoguchi A, Kanenawa K et al. Extreme Adhesion Activity of Amyloid Fibrils Induces Subcutaneous Insulin Resistance. Diabetes [Internet]. 2019 [Cited on 2020 June 30]; 68(3): 609-616. Available from: https://www.doi.org/10.2337/db18-0846
5. European Medicines Agency. PRAC recommendations on signals: Adopted at the 14-17 April 2020 PRAC meeting. 2020 May 11 [Cited on 2020 June 30]. EMA/PRAC/201784/2020.
6. Pharmaceuticals and Medical Devices Agency (PMDA). Revision of Precautions [Internet]. 2020 May 19 [Cited on 2020 June 30]. Available from: https://www.pmda.go.jp/english/safety/info-services/drugs/revision-of-precautions/0008.html
7. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2020 [Cited 2020 June 01; Updated 2021 September 02]. Available from: https://www.npra.gov.my

DISCLAIMER:

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.