Guidelines identified a need for clinical guidance in a specific area and approached Sanofi Ltd for an educational grant to support the development of a working party guideline. This working party guideline was developed by Guidelines, and the Chair and members of the group were chosen by and convened by Guidelines. The content is independent of and not influenced by Sanofi Ltd, who checked the final document for technical accuracy and to ensure compliance with regulations. The views and opinions of the contributors are not necessarily those of Sanofi Ltd, or of Guidelines, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher.

Guideline for the managed introduction of biosimilar bolus insulin in individuals with type 2 diabetes

Download a PDF of the guideline

Download a PDF of the algorithm

Working party group members

Su Down (Chair) —Diabetes Nurse Consultant, Somerset Partnership NHS Foundation Tust

Hannah Beba —Senior Pharmacist for Diabetes and Endocrinology, County of Durham and Darlington NHS Foundation Trust; UKCPA Diabetes and Endocrinology Co-Chair

Sarah Davies —General Practitioner with Special Interest in Diabetes, Woodlands Medical Centre, Cardiff

Jane Diggle —Specialist Practitioner Practice Nurse, West Yorkshire

Sonica Goel —General Practitioner, Abbey Field Medical Centre, Colchester

Introduction

Diabetes mellitus is a group of metabolic disorders characterised by the inability to produce enough insulin and/or the inability to respond appropriately to the insulin produced. In time, this can lead to prolonged periods of hyperglycaemia, which increases the risk of developing serious complications including cardiovascular disease, chronic kidney disease, foot ulcers, and blindness.1 In the UK, more than 4.9 million people have diabetes, and 5.5 million are predicted to have diabetes by 2030.2,3 About 90% have type 2 diabetes and about 8% have type 1 diabetes; the remaining 2% have rarer types.2

Diabetes-related care represents about 10% of the NHS budget (£9.8 billion) –  £1 billion for type 1 diabetes and £8.8 billion for type 2.4 About 80% of this (£7.7 billion) is spent on complications and 20% (£2.1 billion) on treatment, primarily related to primary care and prescriptions.4 If the costs of treating an individual with diabetes stays the same, demographic changes and high levels of obesity mean that the overall costs of diabetes are projected to increase to 17% of the NHS budget over the next 20 years.

Lifestyle management is often the first step in the treatment of diabetes, with oral treatments the first-line pharmacological treatment, although lifestyle management should continue irrespectively.5 Some patients may need to progress to insulin therapy quickly.5 The role of insulin is to lower blood-glucose concentrations in order to prevent hyperglycaemia and its associated microvascular, macrovascular, and metabolic complications.6 Basal insulins are longer-acting insulins that cover the body’s basal metabolic insulin requirement (regulating hepatic glucose production), while bolus insulin targets glycaemic excursions after meals.5 Bolus insulins are the focus of this guideline, and the currently available options are shown in Table 1.

Table 1: Bolus insulin formulations
PreparationManufacturer SpeciesFormOnset (approximate, min) Peak activity (approximate, min)Duration of action (approximate, hours)

Actrapid

Novo Nordisk Human V <30 1.5–3.5 7–8 
Apidra (insulin glulisine) Sanofi Human  V, P, C4, C5  10–20  55 mins  1.5–4 
Fiasp (insulin aspart) Novo Nordisk  Human  V, P, C1 4 1–3  3–5 
Humalog (insulin lispro) Lilly  Human  V, P, C3 15  1.5  2–5 
Humulin S Lilly  Human  V, C3 30–60  1–6  6–12 
Hypurin Porcine Neutral Wockhardt  Porcine V, C2 30–60  1.5–4.5 6–8 
Insulin Lispro Sanofi▼ (insulin lispro)[A], [B] Sanofi Human  V, P, C5  15  1.5  2–5 
Insuman Rapid Sanofi  Human  P, C4, C5  <30  1–4 7–9
Lyumjev (insulin lispro) Lilly  Human  V, P, C3  20  1–3 
NovoRapid (insulin aspart) NovoNordisk  Human  V, P, C1  10–20  1–3  3–5 
Trurapi▼ (insulin aspart)[B] Sanofi  Human P, C5  10–20  1–3  3–5 
C1=compatible with NovoPen range; C2=compatible with Autopen Classic; C3=compatible with Humapen Savvio; C4=compatible with Autopen 24; C5=compatible with AllStar Pro, JuniorSTAR; P=prefilled pen; V=vial.
[A] In November 2021, the name of Insulin Lispro Sanofi will be changed to Admelog.
[B] Insulin Lispro Sanofi and Trurapi are biosimilars of insulin lispro and insulin aspart, respectively.

Biosimilar alternatives to originator diabetes treatments (also known as ‘reference products’) offer the opportunity to make significant cost savings and support the NHS in meeting its affordability challenge while maintaining excellent diabetes care, as they are typically offered at a discount compared with the originators.8 Biosimilars have been available to the NHS for over a decade,9 although their use was not widespread until 2015, when biosimilar infliximab was first approved.10 They were initially used largely in secondary care for rheumatoid arthritis, cancer, severe anaemia, and chronic kidney disease; however, biosimilar insulins are now available, with the first basal biosimilar insulin glargine launched in 2018.

Insulin is classified as a high-risk medication, as it can cause hypoglycaemia, which is life threatening. Its use is more complex than with most other drugs and individualisation of dose can be time consuming and multifactorial. This complexity can lead to clinical inertia from healthcare professionals in progressing with insulin therapy, e.g. increasing the dose or switching to a ‘new’ insulin such as a biosimilar.11 Lack of awareness of, familiarity with, and confidence in biosimilars can also lead to reluctance to use these products. Clinicians may also anticipate that individuals will be reluctant to take biosimilars, but they are often more receptive than might be anticipated—especially if they feel they are helping the NHS to get value for money.12

At the time of writing, national guidance for biosimilar insulin use in the UK remains restricted to a position statement from Diabetes UK8 and an evidence review from NICE on Abasaglar (biosimilar insulin glargine).13 The NICE review concluded that evidence from two phase 3 studies in type 1 and type 2 diabetes—ELEMENT 1 and ELEMENT 2, respectively—showed that basal biosimilar insulin glargine was as effective as the originator insulin glargine (Lantus) at reducing HbA1c levels in people with type 1 and type 2 diabetes and with a safety profile comparable to that of the originator.13 The same results were later obtained in two additional studies, INSTRIDE 1 and INSTRIDE 2 for Semglee, basal biosimilar insulin glargine, compared to the originator.14,15 An equivalent NICE review is not yet available for biosimilar bolus insulins, but clinical studies found that:

  • biosimilar insulin aspart (Trurapi t) had similar pharmacokinetic exposure profiles, glucodynamic potency, and immunogenicity to originator insulin aspart (NovoRapid®) and produced effective glycaemic control, with a similar efficacy and safety profile16,17 
  • biosimilar insulin lispro (Insulin Lispro Sanofi t) had similar exposure profiles, pharmacodynamic activity, efficacy, and safety, including immunogenicity, to originator insulin lispro (Humalog®).18,19

When biosimilar basal insulins first became available in 2018, this working party group developed an algorithm for their managed introduction.20 As biosimilar bolus insulins are now available, the group was reconvened to offer similar guidance for introducing these new bolus biosimilar insulins. It aims to offer concise, easy-to-follow, practical guidance to inform and support primary care clinicians to initiate or transfer suitable individuals to biosimilar bolus insulin. It is intended to be used only for people with type 2 diabetes, because, although biosimilar insulins are suitable for those with type 1 diabetes, insulins in this population should be managed by their specialist. 

Guideline for the managed introduction of biosimilar bolus insulin

Figure 1 provides an algorithm summarising the working party group’s consensus guideline for the managed introduction of biosimilar bolus insulin. 

Biosimilar insulin algorithm

Figure 1: Guideline for the managed introduction of biosimilar bolus insulin

Who should be prescribing biosimilar insulins?

  • The guideline aims to support initiation of and switches to biosimilar bolus insulins in individuals with type 2 diabetes by primary care clinicians who are competent to prescribe bolus insulins, including physicians, nurses, pharmacists, and other non-medical prescribers, and medicine optimisation teams 
  • All prescribers should have the competencies defined in Diabetes UK’s competency framework for healthcare professionals working with people with diabetes,21 as determined by the local lead and in line with local policies
  • The working party group strongly recommends that insulin prescribers, especially those in primary care, undertake mandatory training via the Six Steps programme (or a similar accredited programme).

Considerations when selecting a biosimilar

  • Setting a precedent, a NICE review of the use of human growth hormone when a biosimilar is available recommends that:22
    • ‘the choice of product should be made on an individual basis after informed discussion between the responsible clinician and the patient and/or their carer about the advantages and disadvantages of the products available, taking into consideration therapeutic need and the likelihood of adherence to treatment. If, after that discussion, more than one product is suitable, the least costly product should be chosen’. 

Who should be receiving biosimilar bolus insulins?

  • The working party group recommends a phased introduction of biosimilar bolus insulins:
    • new starters naïve to bolus insulin who are identified during diabetes review as highly likely to need bolus insulin due to optimal fasting glucose with suboptimal glycosylated haemoglobin (HbA1c) or other markers of poor postprandial glycaemic control
    • individuals who are ‘optimised’ on bolus insulin who are identified during diabetes review or via a search for originator insulin + type 2 diabetes (to exclude patients taking insulin for other indications):
      • no blood glucose levels <4 mmol/l in past 2 weeks
      • no signs or symptoms of hypoglycaemia (see Box 123)
      • individualised HbA1c target met
      • individualised blood glucose levels within target ranges
    • individuals with suboptimal control (either above or below individualised targets) on bolus insulin who are identified during diabetes review or via a search for originator insulin + type 2 diabetes (to exclude patients taking insulin for other indications): 
      • blood glucose levels <4 mmol/l in past 2 weeks
      • signs or symptoms of hypoglycaemia (see Box 123)
      • individualised HbA1c target not met
      • individualised blood glucose levels not within target ranges.

Box 1: Most common symptoms of hypoglycaemia

  • Sweating 
  • Trembling
  • Hunger
  • Palpitations
  • Confusion
  • Drowsiness
  • Lack of coordination
  • Difficulty speaking

NB Elderly people, frail individuals, and people with longstanding diabetes or frequent hypoglycaemia may not experience or recognise these symptoms.

New initiation of bolus insulin

All bolus insulin-naïve individuals with type 2 diabetes suitable for starting bolus insulin may be initiated on biosimilar bolus insulin.

  • Identify individuals on optimised basal insulin who may require new initiation of a bolus insulin through diabetes review:
    • have a high level of suspicion of requiring bolus insulin due to:
      • optimal fasting glucose with suboptimal HbA1c
      • other markers of poor postprandial glycaemic control, e.g. post-prandial self-monitored blood glucose
  • Undertake targeted testing — before and 2 hours after one or all meals — to establish which meal or meals would benefit from bolus insulin 
  • Identify potential reasons why postprandial glucose is suboptimal (Box 2) and address, where possible, before initiating biosimilar bolus insulin
  • When addition of biosimilar bolus insulin is indicated:
    • agree rationale for initiation of new drug with individual
      • Box 3 provides discussion points and Box 4 provides practical tips
    • start with 4 units to be given 20 minutes before the start of eating5
    • titrate dose according to local protocol until postprandial glucose is within individual’s target range
  • Targeted testing should be encouraged until optimal glycaemic control is achieved
    • the ongoing need for increased monitoring after optimal control is achieved should be discussed and agreed with individual
    • ensure the individual has an adequate supply of monitoring equipment to meet increased needs
  • Review and follow up at 3 months.

Box 2: Reasons for suboptimal glycaemic control

  • Adherence 
  • Diet – carbohydrate intake in particular and alcohol consumption
  • Activity levels
  • Injection technique/site 
  • Injection timing
  • Psychological causes 
  • Intercurrent or concurrent illness
  • Interacting drugs, e.g. recent steroid therapy or antipsychotic drugs

Switching to biosimilar bolus insulin

  • Biosimilar insulins should never be introduced as part of a whole-population switch. Insulin prescribing should be tailored to each individual. This position is supported by Diabetes UK8
  • Identify individuals with type 2 diabetes on optimised basal insulin plus bolus insulin who are suitable for the switch to biosimilar bolus insulin via diabetes review or via a search for originator insulin + type 2 diabetes (to exclude patients taking insulin for other indications)
  • Assess current glycaemic control using the following questions: 
    • any blood glucose levels <4 mmol/ml in past 2 weeks?
    • any signs or symptoms of hypoglycaemia (see Box 123)
    • is individualised HbA1c target NOT being met?
    • are individualised blood glucose levels NOT within target ranges?
    • if the answer to ANY of the above questions is YES, the individual should be managed as having suboptimal control

Box 3: Discussion points for individuals

  • The switch should be discussed in a way that gives the individual confidence in the new drug

Pre-decision 

  • Explain the rationale for the switch, as relevant:
    • offer information on biosimilars that is appropriate to the individual 
    • explain that the switch will allow cost savings with no anticipated difference in day-to-day control, without comprising efficacy or safety 
  • Allow individual to raise and address their concerns

Post-switch

  • Emphasise that it is good practice to be vigilant after any change to medicines

Box 4: Practical tips

Give the individual an information sheet (e.g. Truapi patient information leaflet: www.medicines.org.uk/emc/files/pil.12738.pdf; Insulin Lispro Sanofi patient information leaflet: www.medicines.org.uk/emc/files/pil.9264.pdf)

  • Increased risk of hypoglycaemia with addition of intensified regimen
    • discuss need for increased monitoring to maintain safe levels of glucose 
    • revisit sick day rules, Driver Vehicle and Licensing Authority (DVLA) guidance, and management of hypoglycaemia
  • Tell them what to do if there is a problem:
    • avoid initiating any new drug just before or over a weekend, so they can access help if they have any problems or questions
  • Ensure they can visually recognise their insulin and device 
  • Make sure not to mix different insulins

Well-controlled diabetes

In its position statement, Diabetes UK recommends against switching people well controlled on an insulin to a biosimilar.8 However, given the equivalent efficacy and safety demonstrated by biosimilar bolus insulins in comparison to their originators,9–16 the working party group believes that appropriately selected individuals in this cohort may be suitable from switching to a biosimilar bolus insulin. Switching stable individuals with diabetes to a biosimilar insulin would also support the NHS England commissioning framework, which aims to achieve savings by switching at least 80% of existing individuals to a biosimilar within 12 months from launch, in a proactive, systematic and safe way.24

  • In individuals with optimal control, switch only to the biosimilar for the originator product they are currently using:
    • agree the switch with the individual and obtain and document the discussion (see Boxes 3 and 4 for discussion points and practical tips) 
    • switch dose for dose
  • Continue with usual monitoring and titrate, where indicated
    • it is good practice to be vigilant after any change to medicines
  • Review and follow up as per standard of care 

Poorly-controlled diabetes 

Although guidelines recommend switching individuals with poor control on their current insulin, the working party group feels that the complex reasons for suboptimal control (see Box 3), the challenges associated with adjusting bolus insulins, and the fact that non-insulin drugs may be indicated means that referral for specialist advice and guidance should be considered, depending on the prescriber’s competencies, experience, and confidence with bolus insulins.

Box 5 provides current guidance during the COVID-19 pandemic, and Box 6 lists some useful resources.

Box 5: Diabetes during the COVID-19 pandemic

  • The COVID-19 pandemic forced practices (and community teams) to focus on delivering acute care, often at the expense of chronic disease management, including diabetes reviews
    • there is a risk that fear of exposure to COVID-19 or difficulty accessing clinical services may contribute to late clinical presentations or assessment of diabetes complications 
    • many practices find that many people’s HbA1c has risen significantly during lockdown 
  • As the acute phase of the pandemic recedes, teams now face significant backlogs of diabetes reviews, and it is likely to take at least 6–12 months for services to catch up
    • practices should maintain clinically important diabetes reviews  
    • it is important to prioritise care delivery to those who need more urgent reviews
      • as higher HbA1c increases the risk of worse outcomes and mortality from COVID-19 and the risk of diabetes-related complications, prioritisation by HbA1c may be a good place to start 
      • practices should collaborate with local specialist diabetes teams to maximise opportunity for reviewing people with diabetes whilst minimising duplication
  • Some people with diabetes, including those not previously diagnosed, may be discharged from hospital on higher doses or additional glucose-lowering therapies, including insulin, that may need adjustment in subsequent days or weeks
    • where possible, follow-up and de-escalation should be picked up by specialist services, but where not possible (due to demands of supporting the acute pandemic response), clear communication and collaboration between specialists and primary care or community teams is vital 
  • People with diabetes report additional stress and increasing concern about access to routine diabetes care as a consequence of the pandemic
    • stress may be made worse by a lack of communication about local service provision and how to access care in the event of clinical concern 
    • practices should recognise that some people with diabetes may be concerned about attending for face-to-face review because of the risks associated with COVID-19 
    • people with diabetes should be supported in preparation for their review and afterwards 
    • use telephone, video and e-consultation tools to support attendance 
    • make use of remotely gathered information (e.g. self-reported weight, home capillary glucose or blood pressure data) ensuring that face-to-face consultations continue to be offered where clinically appropriate or for those with limited digital access

Box 6: Useful resources

For healthcare professionals

For individuals with diabetes 

Conflict of interests

The group members have received an honorarium to develop this working party guideline. Some of the group members have also received consultancy fees from other pharmaceutical companies, which may include Sanofi Ltd, for activities other than the development of this working party guideline.

Acknowledgements

Jemma Lough, Medical Writer, drafted the article in this supplement, which was reviewed by the members of the expert working group.

References

  1. World Health Organization. Diabetes fact sheet. Geneva, Switzerland: WHO, 2021. www.who.int/news-room/fact-sheets/detail/diabetes (accessed 26 July 2021)
  2. Diabetes UK. Diabetes statistics. Diabetes UK, 2021. www.diabetes.org.uk/professionals/position-statements-reports/statistics (accessed 26 July 2021)
  3. Diabetes UK. Diabetes prevalence 2020. Diabetes UK, 2021. www.diabetes.org.uk/professionals/position-statements-reports/statistics/diabetes-prevalence-2019 (accessed 26 July 2021)
  4. Diabetes UK. The cost of diabetes – report. Diabetes UK, 2014. Available at: www.diabetes.org.uk/resources-s3/2017-11/diabetes%20uk%20cost%20of%20diabetes%20report.pdf
  5. Davies M, D’Alessio D, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018; 61: 2461–2498.
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  8. Diabetes UK. Diabetes position on the use of biosimilar insulin. Diabetes UK, 2019. Available at www.diabetes.org.uk/resources-s3/2019-09/Biosimilars%20PS%20Final.pdf 
  9. Tyler D. Biosimilars in the UK: where are we now and where does the NHS want to go? Available at: https://pharmaphorum.com/views-analysis-market-access/biosimilars-in-the-uk/ (accessed 26 July 2021)
  10. Moorkens E, Vulto A, Kent J et al. A look at the history of biosimilar adoption: characteristics of early and late adopters of infliximab and etanercept biosimilars in subregions of England, Scotland and Wales – a mixed methods study. BioDrugs 2021; 35: 75–87.
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  12. Wilkins A, Venkat M, Brown A et al. Patient perspectives on biosimilar insulin. J Diabetes Sci Techno l 2014; 8: 23–25.
  13. NICE. Diabetes mellitus type 1 and type 2: insulin glargine biosimilar (Abasaglar). Evidence Summary (ESNM) 64. NICE, 2015. www.nice.org.uk/advice/esnm64/chapter/Key-points-from-the-evidence
  14. Blevins T, Barve A, Sun B et al. Efficacy and safety of MYL-1501D vs insulin glargine in patients with type 1 and 2 diabetes after 52 weeks: results of the INSTRIDE 1 phase III study. Diabetes Obes Metab 2018; 20: 1944–1950.
  15. Blevins T, Barve A, Sun B et al. Efficacy and safety of MYL-1501D versus insulin glargine in patients with type 2 diabetes after 24 weeks: results of the phase III INSTRIDE 2 study. Diabetes Obes Metab 2019; 21: 129–135.
  16. Garg SK, Wernicke-Panten K, Wardecki M et al. Efficacy and safety of insulin aspart biosimilar SAR341402 versus originator insulin aspart in people with diabetes treated for 26 weeks with multiple daily injections in combination with insulin glargine: a randomized open-label trial (GEMELLI 1). Diabetes Technol Ther 2020; 22: 85–94.
  17. Kapitza C, Nosek L, Schmider W et al. Single-dose euglycemic clamp study demonstrating pharmacokinetic and pharmacodynamic similarity between SAR341402 insulin aspart and US- and EU-approved versions of insulin aspart in subjects with type 1 diabetes. Diabetes Technol Ther 2020; 22: 278–284.
  18. Garg S, Wernicke-Panten K, Rojeski M et al. Efficacy and safety of biosimilar SAR342434 insulin lispro in adults with type 1 diabetes also using insulin glargine—SORELLA 1 study. Diabetes Technol Ther 2017; 19: 516–526. 
  19. Kapitza C, Nowotny I, Lehmann A et al. Similar pharmacokinetics and pharmacodynamics of rapid-acting insulin lispro products SAR342434 and US- and EU-approved Humalog in subjects with type 1 diabetes. Diabetes Obes Metab 2016; 19: 622–627.
  20. Down S et al. Guideline for the managed introduction of biosimilar basal insulin. Guidelines, 2019. Available at www.guidelines.co.uk/diabetes/guideline-for-the-managed-introduction-of-biosimilar-basal-insulin/454932.article
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  24. NHS England. Commissioning framework for biological medicines (including biosimilars). September 2017. Available at: www.england.nhs.uk/wp-content/uploads/2017/09/biosimilar-medicines-commissioning-framework.pdf 
  25. Brown P, Diggle J. How to prioritise primary care diabetes services during and post covid-19 pandemic. Diabetes Primary Care 2020; 22
  26. Hamblin C, Patel D, Turner B. COVID-19 and diabetes: update for primary care in response to the ongoing coronavirus pandemic. Diabetes Primary Care 2021; 23: 9–12

Guidelines identified a need for clinical guidance in a specific area and approached Sanofi Ltd for an educational grant to support the development of a working party guideline. This working party guideline was developed by Guidelines, and the Chair and members of the group were chosen by and convened by Guidelines. The content is independent of and not influenced by Sanofi Ltd, who checked the final document for technical accuracy and to ensure compliance with regulations. The views and opinions of the contributors are not necessarily those of Sanofi Ltd, or of Guidelines, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher.

Date of preparation: August 2021