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Foreword

Professor Wasim Hanif 
Professor of Diabetes & Endocrinology, Consultant Physician and Head of Service in Diabetes at University Hospital Birmingham

The recently published cardiovascular outcome trials (CVOT) with glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) have led to updating of a number of guidelines, including the American Diabetes Association and the European Association for the Study of Diabetes consensus statement,1,2 placing GLP-1 RA and SGLT-2i as preferred second-line agents in patients with underlying cardiovascular and renal disease. In spite of these recommendations, dipeptidyl peptidase-4 (DPP-4) inhibitors are still commonly prescribed as second-line agents, second only to sulfonylureas (the use of which is decreasing).3

In many clinical scenarios, DPP-4 inhibitors may be considered the class of choice after metformin in the treatment of type 2 diabetes. The COVID-19 pandemic has forced the NHS to dramatically change the way in which diabetes care is offered. Remote consultations and prescribing have become routine and the benefits of therapies that are straightforward to prescribe are more apparent than before. The DPP-4 inhibitor linagliptin (Trajenta®) appears particularly well suited to remote prescribing given its broad spectrum of patient suitability (including elderly/frail and renally impaired patients), simplicity of dosing, and established safety profile. It also has no requirement for additional drug-related renal monitoring.4 This may, in turn, lead to important clinical and cost benefits to the NHS resulting from fewer follow-up appointments with the practice nurse or GP, and reduced need for blood tests. 

At a time when there is a heightened need to reduce unnecessary referrals, primary care-led management of patients with type 2 diabetes is more important than ever. DPP-4 inhibitors are a well-established drug class and important agents in the armamentarium available for the treatment of type 2 diabetes, and one that not only specialists but also generalist GPs, pharmacists, and nurses will feel comfortable and confident in prescribing. Their safety profile, including cardiovascular outcomes, coupled with suitability for use in a wide variety of patients, especially during the COVID-19 pandemic, makes this class perhaps the ‘dark horse’ of diabetes therapy. 

References 

  1. Davies M, D’Alessio D, Fradkin J et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018; 41 (12): 2669–2701. 
  2. Buse J, Wexler D, Tsapas A et al. 2019 update to: 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). Diabetes Care 2020; 43 (2): 487–493. 
  3. Boehringer Ingelheim Limited. Data on File LIN 20-01, June 2020 
  4. Boehringer Ingelheim Limited. Trajenta (linagliptin) 5 mg film-coated tablets. Summary of product characteristics. Updated December 2019. Available at: www.medicines.org.uk/emc/product/4762/smpc 

Dipeptidyl peptidase-4 inhibitors—still a major player in type 2 diabetes care

The positioning of DPP-4 inhibitors within clinical guidelines and the evolving NHS landscape 

Professor Wasim Hanif 
Professor of Diabetes & Endocrinology, Consultant Physician and Head of Service in Diabetes at University Hospital Birmingham 

Introduction 

Dipeptidyl peptidase-4 (DPP-4) inhibitors retain an important position within current clinical guidelines for the management of adult patients with type 2 diabetes and continue to be a main part of the overall treatment armamentarium. Most recently, they have come to the fore as a crucial treatment option for patients with type 2 diabetes and confirmed or suspected SARS-CoV-2 (COVID-19) infection, and look set to play a key role in the reshaped NHS landscape of the future.1

The current treatment landscape 

A key benefit of DPP-4 inhibitors is their suitability for use across a wide spectrum of adult patients with type 2 diabetes, including elderly and frail patients and individuals in whom other drug classes may be contraindicated or poorly tolerated.3–7 DPP-4 inhibitors benefit from a tolerable safety profile and relatively little additional renal monitoring.3–7 The safety profile of DPP-4 inhibitors makes them suitable for prescribing in primary care, and this, in turn, makes them easier for physicians to prescribe and easy for patients to take, with little need for initial education or ongoing follow-up. 

The broad therapeutic utility of DPP-4 inhibitors is underpinned by their current positioning within UK guidance from NICE and the Scottish Intercollegiate Guidelines Network (SIGN), and in leading international consensus reports and treatment guidelines from the American Diabetes Association/ European Association for the Study of Diabetes and the European Society for Cardiology (ADA/ESC; see Box 1).8–12 Primarily used as supplemental second-line agents, most DPP-4 inhibitors, such as linagliptin, can also be prescribed as monotherapy (when metformin is contraindicated or not tolerated), or as part of combination therapy for type 2 diabetes.3

One of the current challenges in management of type 2 diabetes is the tendency to adopt a ‘one-size-fits-all’ approach. However, in real-world clinical practice, the individualisation of treatment—choosing medication that best suits an individual patient or group of patients with similar clinical characteristics—remains critical. In this respect, not all DPP-4 inhibitors are equivalent, and it is important to consider comorbidities, such as renal impairment, when selecting treatment from within this drug class. 

Selecting a DPP-4 inhibitor 

The number of people over the age of 70 years with diabetes is growing worldwide and a high prevalence of comorbidities, polypharmacy, and frailty can make treatment in this population particularly challenging.13,14 In elderly patients who do not require stringent HbA1c control but often suffer with complex comorbidities, DPP-4 inhibitors represent an important treatment option. While some drugs for type 2 diabetes are contraindicated in the elderly, DPP-4 inhibitors have been shown to be well tolerated in older adults.15 Some other classes are associated with an increased risk of side effects that may be particularly problematic in elderly patients—for example hypoglycaemia with sulfonylureas,16 and thrush and other genital infections with sodium-glucose co-transporter-2 inhibitors (SGLT-2i).17 Linagliptin should be used with caution in combination with a sulfonylurea and/or insulin (which are known to cause hypoglycaemia). A dose reduction of the sulfonylurea or insulin may be considered.3 When used alone or in combination with non-hypoglycaemia-causing drugs (such as metformin), linagliptin shows an incidence of hypoglycaemia that is comparable to placebo.3

Renal impairment is a common comorbidity among patients with type 2 diabetes, especially the elderly. Linagliptin is particularly well suited for use in adults with type 2 diabetes and renal impairment as it can be prescribed at estimated glomerular filtration rates <30 ml/min and is also suitable without dose adjustment for patients with renal failure who are on dialysis.3

Unlike other DPP-4 inhibitors, linagliptin does not require dose adjustment based on renal function or additional renal function monitoring,3 whereas sitagliptin, vildagliptin, saxagliptin, and alogliptin require both.4–7 This makes linagliptin simple to prescribe at a single dose of 5 mg daily, irrespective of renal function. In clinical trials, linagliptin has demonstrated efficacy as an add-on therapy both for patients with severe renal impairment and elderly patients ≥70 years of age.Renal and other monitoring in adult patients with type 2 diabetes should be undertaken as per NICE guidelines.8

Based on compelling evidence of renal and cardiovascular (CV) benefits from cardiovascular outcome trials (CVOT), recently published guidelines have placed SGLT-2i and glucagon-like peptide-1 receptor agonists (GLP-1 RA) as preferred second-line therapy choices for patients with underlying CV and renal disease;10,11 although data suggest that the proportion of the total number of patients with type 2 diabetes who may benefit may be up to around 25–30%.10,18,19 

The CV safety of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin and sitagliptin has been assessed across five CVOTs.20–24 Across these trials, there was no increase in the risk of primary three- or four-point major adverse cardiac events outcomes (3P-MACE and 4P-MACE). 

In the CARMELINA non-inferiority study, there was no difference in risk for linagliptin versus placebo for both CV (HR 1.02, 95%, CI 0.89, 1.17, p<0.001 for non-inferiority, p=0.74 for superiority) and renal (HR 1.04, 95%, CI 0.89, 1.22, p=0.62) outcomes in patients with type 2 diabetes.3,23 Similarly, in the CAROLINA study of adults with early type 2 diabetes and elevated CV risk, use of linagliptin demonstrated non-inferiority compared to glimepiride with regard to the risk of major CV events (HR 0.98, 95.47%, CI 0.84, 1.14, p<0.0001 for non-inferiority, p=0.76 for superiority).24 

DPP-4 inhibitors in the evolving NHS landscape 

In addition to treatment individualisation, it is important for diabetes management to reflect the evolving NHS landscape. The NHS Long Term Plan sets out a number of key primary care goals, of which primary care networks are a central pillar.25 As the prevalence of type 2 diabetes continues to rise, there will be an increasing focus on this primary care-led diabetes management, incorporating initiatives such as Structured Medication Reviews and Enhanced Health in Care Homes.26 Upskilling primary care professionals will also be important for further improving diabetes patient care, as the management of type 2 diabetes is becoming more complex, with improvements in care. The increasing prevalence of type 2 diabetes makes it imperative that primary care physicians, pharmacists, and nurses have the necessary skills to manage these patients, and thereby avoid unnecessary referrals to specialist consultants. Clear, clinical pathways are needed, with dissemination and training of all healthcare teams. 

Within the new primary care-focused landscape, DPP-4 inhibitors represent a good fit as a well-established drug class for the treatment of type 2 diabetes, and one that not only specialists but also generalist GPs will feel comfortable and confident in prescribing. With its suitability for use across a broad spectrum of patients, including those with renal failure, linagliptin has a lower burden of monitoring than many other antidiabetic drugs.3 This may, in turn, lead to important clinical and cost benefits to the NHS resulting from fewer follow-up appointments with the practice nurse or GP, and reduced need for blood tests. 

Diabetes management in care homes can be supported by use of DPP-4 inhibitors, which provide a treatment option well suited to elderly, frail patients. They may prove particularly valuable in this population as they are associated with a low risk of hypoglycaemic episodes, which contribute to falls and hospital admissions in elderly patients (reduction of which is a key NHS priority).27 

Structured medication reviews are intended to eliminate issues with existing medication such as side-effects, and optimise overall treatment efficacy.26 In cases where treatment needs to be escalated or changed, DPP-4 inhibitors have the flexibility for use as alternative or add-on therapies. Choosing linagliptin also eliminates the need for additional monitoring of renal function as it is the only DPP-4 inhibitor that does not require dose adjustment according to renal function.3 Renal and other monitoring in adult patients with type 2 diabetes should be undertaken as per NICE guidelines.8 Switching to or adding DPP-4 inhibitors during medication reviews is typically straightforward and requires minimal patient education or follow-up. 

Impact of the COVID-19 pandemic 

The COVID-19 pandemic has helped shine a spotlight on the important role that DPP-4 inhibitors still occupy within the type 2 diabetes treatment landscape. The pandemic has also highlighted glycaemic control and risk factor modification as key priorities, with patients with type 2 diabetes at twice the risk of dying in hospital with COVID-19 compared to the general population.28

During the pandemic, DPP-4 inhibitors have become the default drugs for the treatment of type 2 diabetes after NHS England issued guidance to halt treatment with metformin, sulfonylureas, GLP-1 RA, and SGLT-2i during concurrent COVID-19 infection.2 Patients with type 2 diabetes hospitalised with COVID-19 will be prescribed insulin, with DPP-4 inhibitors as an addition or an option, although many patients will be restarted on their usual medications when they have recovered. 

The DPP-4 inhibitors have proven to be well tolerated during coronavirus infection and provide a ‘safety net’ for prescribers and patients that avoids the need to switch medications if COVID-19 symptoms develop or are suspected.1

As a result, DPP-4 inhibitors look set to remain an important drug class in the post-COVID world. Coronavirus has caused patients with type 2 diabetes, particularly those who are vulnerable and shielding, to become more cautious about accessing diabetes care. Remote consultations have also complicated the logistics around accessing prescriptions. A degree of therapeutic inertia may therefore have crept in as patients stay at home and doctors delay treatment changes. Linagliptin appears particularly well suited to remote prescribing given its broad spectrum of patient suitability (including elderly/frail and renally impaired patients), simplicity of dosing, and established safety profile.3 While other antidiabetic drugs (notably insulin and GLP-1 RA) may entail training in injection techniques and/or complex dosing protocols, DPP-4 inhibitors are administered orally and require limited patient education. Linagliptin also has lower need for the additional monitoring that may be required for other agents, both for glycaemic control and renal function.3

With the wider changes to the NHS resulting from the COVID-19 pandemic likely to remain in place over the longer term, DPP-4 inhibitors, like linagliptin, will continue to play an important role in ensuring good control in patients with type 2 diabetes in order to help optimise their clinical outcomes. 

Summary 

Dipeptidyl peptidase-4 inhibitors continue to be an important treatment option for type 2 diabetes and are recommended in many clinical guidelines. These well-established drugs are familiar to primary care prescribers and suitable for use across a broad spectrum of patients with type 2 diabetes. Linagliptin, in particular, benefits from simple, once-daily dosing at a dose of 5 mg, with no requirement for renal dose adjustment or additional monitoring, making it suitable for use in the elderly/frail and renally impaired. As a class, DPP-4 inhibitors have played a pivotal part in treatment of type 2 diabetes during the coronavirus pandemic and look set to retain a key role in the evolving NHS landscape of diabetes care post-COVID. 

Conflicts of interest 

Professor Wasim Hanif has received research funding, travel grants, and consultancy fees from Boehringer Ingelheim Ltd, as well as other companies. He has received an honorarium for his contribution to this supplement. 

References 

  1. Bornstein SR, Rubino F, Khunti K, et al. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol 2020; 8: 546–550. 
  2. NHS. Sick day rules: how to manage Type 2 diabetes if you become unwell with coronavirus and what to do with your medication. April 2020. Available at: www.england.nhs.uk/london/wp-content/uploads/sites/8/2020/04/3.-Covid-19- Type-2-Sick-Day-Rules-Crib-Sheet-06042020.pdf 
  3. Boehringer Ingelheim Limited. Trajenta (linagliptin) 5 mg film-coated tablets. Summary of product characteristics. Updated December 2019. Available at: www.medicines.org.uk/emc/ product/4762/smpc 
  4. Merck Sharp & Dohme Limited. Januvia (sitagliptin) 100 mg film-coated tablets. Summary of product characteristics. Updated 17 Jun 2020. Available at: www.medicines.org. uk/emc/product/7887/smpc 
  5. Novartis Pharmaceuticals UK Ltd. Galvus (vildagliptin) 50 mg film-coated tablets. Summary of product characteristics. Updated 14 May 2018. Available at: www.medicines.org. uk/emc/product/6225/smpc 
  6. AstraZeneca UK Limited. Onglyza (saxagliptin) 5 mg film-coated tablets. Summary of product characteristics. Updated 24 Mar 2020. Available at: www.medicines.org.uk/emc/ product/6675/smpc 
  7. Takeda UK Ltd. Vipidia (alogliptin) 6.25 mg film-coated tablets. Summary of product characteristics. Updated 12 Jul 2018. Available at: www.medicines.org.uk/emc/ product/5235/smpc 
  8. NICE. Type 2 diabetes in adults: management. NICE guideline 28. NICE, 2015 (last updated August 2019). Available at: nice.org.uk/ guidance/ng28 
  9. Scottish Intercollegiate Guidelines Network. Pharmacological management of glycaemic control in people with type 2 diabetes. SIGN 154. SIGN, 2017. Available at: www.sign.ac.uk/ assets/sign154.pdf 
  10. Davies M, D’Alessio D, Fradkin J et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018; 41 (12): 2669–2701. 
  11. Buse J, Wexler D, Tsapas A et al. 2019 update to: 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). Diabetes Care 2020; 43 (2): 487–493. 
  12. Cosentino F, Grant P, Aboyans V et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the task force for diabetes, pre-diabetes, and cardiovascular disease of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). Eur Heart J 2020; 41 (2): 255–323. 
  13. Pratley R. Linagliptin use in older individuals with type 2 diabetes. Clin Interventions Aging 2014; 9: 1109–1114. 
  14. Gadsby R, Hope S, Hambling C, Carnegie A. Frailty, older people and type 2 diabetes. J Diabetes Nursing 2017; 21: 138–142. 
  15. Du Y, Ou H, Beverly E, Chiu C. Achieving glycemic control in elderly patients with type 2 diabetes: a critical comparison of current options. Clin Interventions Aging 2014; 9: 1963–1980. 
  16. Van Dalem J, Brouwers M, Stehouwer C et al. Risk of hypoglycaemia in users of sulphonylureas compared with metformin in relation to renal function and sulphonylurea metabolite group: population based cohort. BMJ 2016; 354: i3625. 
  17. McGovern A, Hogg M, Shields B et al.; MASTERMIND consortium. Risk factors for genital infections in people initiating SGLT2 inhibitors and their impact on discontinuation. BMJ Open Diab Res Care 2020; 8: e001238. Doi: 10.1136/bmjdrc-2020-001238. 
  18. Leon BM and Maddox TM. Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes 2015; 6: 1246–1258. 
  19. Diabetes UK. Position Statement: Preventing kidney failure in people with diabetes. August 2016. Available at: www.diabetes.org.uk/ professionals/position-statements-reports/ specialist-care-for-children-and-adults-and-complications/preventing-kidney-failure-in-people-with-diabetes 
  20. Scirica B, Bhatt D, Braunwald E et al. for the SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317–1326. 
  21. White W, Cannon C, Heller S et al. for the EXAMINE Investigators. N Engl J Med 2013; 369: 1327–1335. 
  22. Green J, Bethel M, Armstrong P et al. for the TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 373: 232–242. 
  23. Perkovic V, Toto R, Cooper M et al. on behalf of the CARMELINA investigators. Effects of linagliptin on cardiovascular and kidney outcomes in people with normal and reduced kidney function: secondary analysis of the CARMELINA randomized trial. Diabetes Care 2020; 43: 1803–1812. 
  24. Rosenstock J, Kahn S, Johansen O et al. for the CAROLINA investigators. Effect of linagliptin vs glimepride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA 2019; 322 (12): 1155–1166. 
  25. NHS England. The NHS Long Term Plan. NHS, 2019. Available at: www.longtermplan.nhs.uk/ wp-content/uploads/2019/08/nhs-long-term-plan-version-1.2.pdf 
  26. NHS England and NHS Improvement. Network Contract Directed Enhanced Service. Contract Specification 2020/21—PCN Requirements and Entitlements. NHS, 2020. Available at: www. england.nhs.uk/wp-content/uploads/2020/03/ network-contract-des-specification-pcn-requirements-entitlements-2020-21.pdf 
  27. Schott G, Martinez Y, de Silva R et al. Effectiveness and safety of dipeptidyl peptidase 4 inhibitors in the management of type 2 diabetes in older adults: a systematic review and development of recommendations to reduce inappropriate prescribing. BMC Geriatrics 2017; 17 (Suppl. 1): 226. 
  28. Barron E, Bakhai C, Kar P et al. Associations of type 1 and type 2 diabetes with COVID-19- related mortality in England: a whole-population study. Lancet Diabetes Endocrinol 2020; 8: 813-822. 

This supplement has been commissioned and funded by Boehringer Ingelheim Limited and developed in partnership with Guidelines in Practice. Boehringer Ingelheim Limited suggested the topic and authors, and carried out full medical approval on all materials to ensure compliance with regulations. The funding of the project included honoraria for the authors. The views and opinions of the authors are not necessarily those of Guidelines in Practice, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher. 

PC-GB-102715

Date of preparation: January 2021