Dr Stephen Lawrence discusses the NICE guideline recommendations on the use of newer agents for diabetes in the control of blood glucose levels

Many professionals who work in the field of healthcare and, in particular, diabetes, will be familiar with the term epidemic being applied to the burden associated with a disease. The phrase ‘a worldwide epidemic of diabetes’ is often used even though traditionally, the word ‘epidemic’ has been synonymous with infectious diseases such as typhoid or in more modern times, human immunodeficiency virus. It is highly appropriate that the term epidemic is applied to the current challenge of diabetes.

Prevalence and burden

The estimated global prevalence of diabetes is 285 million cases, which is set to increase to 438 million by 2030. The burden of disease in the UK is 2.6 million individuals of whom over 90% have type 2 diabetes, with up to
1 in 20 remaining undiagnosed.1

Diabetes is associated with serious complications:1

  • Cardiovascular disease is responsible for 44% of fatalities in people with type 1 diabetes and 52% in people with type 2 diabetes
  • Diabetes is the most common cause of end-stage renal disease
  • Diabetes is the leading cause of blindness in people of working age in the UK.

These statistics indicate that the ‘diabetes epidemic’ will continue even if levels of obesity remain constant. Given the increasing prevalence of obesity, it is likely that these figures underestimate the future numbers of people with diabetes. The economic impact of diabetes is estimated to be around £9 billion, which represents approximately 10% of the national health budget.1 In the light of such enormous and rising cost, an objective review of the cost effectiveness of healthcare interventions for diabetes is of paramount importance.

Tailored care

Clinical Guideline (CG) 87 on newer agents for type 2 diabetes was published by NICE in May 20092 and is a partial update of CG66, which it replaces.3 As with other guidelines, the preface of the NICE guideline on newer agents for type 2 diabetes states: ‘This guidance represents the view of NICE, which was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer and informed by the summary of product characteristics of any drugs they are considering.’2

It is not accidental that NICE has as its focus, and indeed opening paragraph, the issue of patient-centered care. This theme, repeated throughout the document, places heavy emphasis on the principle of individualised care, which (as will be discussed later on in this article) needs to underpin interpretation of the data from recent clinical trials.

Lifestyle modifications

While the focus of this article is on pharmacological treatment, the importance and positioning of lifestyle advice and modifications should not be overlooked and NICE CG87 advises that there should be a trial of lifestyle modification (3 months) before reassessing glycated haemoglobin (HbA1c). It is the persistence of HbA1c values >6.5% (48 mmol/mol) that would trigger initiation of pharmacological treatment.2

Newer agents for diabetes

Clinical Guideline 66 was rather restrictive in regard to identifying treatment beyond metformin, advocating a sulfonylurea as the second-line agent followed by a thiazolidinedione (now only pioglitazone—see Box 1). Clinical Guideline 87 on newer agents still advocates the addition of a sulfonylurea as second-line treatment but also now significantly extends the choice of the prescriber to consider use of a dipeptidyl peptidase-4 (DPP-4) inhibitor or a thiazolidinedione (pioglitazone) see Figure 1, below) provided that a prior detailed assessment of the person’s personal and pharmacological needs has taken place.2

NICE recommends adding a DPP-4 inhibitor, a thiazolidinedione (pioglitazone), or a glucagon-like peptide-1 (GLP-1) mimetic as third-line therapy (see Figure 1).2

It is pertinent to note at this stage that while these particular sections of the guideline do not cover the GLP-1 mimetic, liraglutide, the use of this agent has been reviewed by NICE through a Single Technology Appraisal very recently and it is anticipated final guidance will be published in October 2010. The draft version of this appraisal recommends that this agent be used in accordance with existing recommendations on GLP-1 mimetics.6

Continuation of treatment
The NICE guideline also puts in place provisos for the continuation of the newer therapies. Although some prescribers may deem these steps as restrictive they do perform an essential role. Given the relative expense of the newer agents it is important to ensure that the prescriber monitors the response to treatment. This will help to avoid the situation in which a patient is started on costly medication and remains on the treatment by default despite receiving no significant benefit.

However, what happens when these provisos are only partially met? For example, there may arise a situation where a patient manages to achieve one monitoring goal but not another (such as significant weight loss exceeding the required limit of 3% of initial body weight without any significant improvement in glycaemic control). Under such circumstances in accordance with the principles of NICE guidelines, it would be sensible to actively involve the patient in a discussion regarding continuation of treatment.

Cost implications
The introduction of DPP-4 inhibitors is predicted to have had a national cost impact of approximately £37 million.7 This cost is likely to be offset to some extent by cost savings resulting from reduced use of other treatments (e.g. thiazolidinediones and insulin).

It is predicted that the overall number of people being treated with thiazolidinediones is likely to remain constant because the only change expected is an increase in the number using pioglitazone rather than rosiglitazone. As both drugs are similarly priced, there is unlikely to be a significant cost impact in the medium term. In the longer term, however, there may be less resistance to prescribing pioglitazone once the manufacturing patent expires in 2011.

The use of GLP-1 mimetics (exenatide) will have the largest cost impact because the high unit price (e.g. exenatide costs £830 per person per year),8 which means that even relatively low-level use would result in significant costs. It is estimated that 2% of people with type 2 diabetes will be prescribed exenatide,7 although this figure may increase over time. Local circumstances may vary from national assumptions. The cost of a year’s treatment with liraglutide 1.2 mg daily is approximately £921.9

Box 1: Withdrawal of rosiglitazone4
The European Medicines Agency has completed a review of the benefit and risk profile of products containing rosiglitazone, with a focus on cardiovascular safety. The Agency’s Committee for Medicinal Products for Human Use concluded that the benefits of rosiglitazone no longer outweigh the risk and has recommended the suspension of the marketing authorisations across the European Union. These medicines will stop being available within the next few months. Prescribers are advised not to issue any new or repeat prescriptions of rosiglitazone. As a result of this decision, NICE has temporarily withdrawn its recommendations on the use of rosiglitazone.

Figure 1: Blood glucose-lowering therapy5

Blood glucose lowering therapy

Blood glucose lowering therapy

HbA1c=glycated haemoglobin; DPP-4=dipeptidyl peptidase-4; BMI=body mass index
National Institute for Health and Care Excellence (NICE) (2009) CG87. Type 2 diabetes: the management of type 2 diabetes. London: NICE. Reproduced with permission. Available from www.nice.org.uk/CG87

Blood glucose targets

Table 1 shows the target HbA1c values as set by different bodies; the NICE guideline conspicuously quotes a range of HbA1c from 6.5%–7.5% (48–58 mmol). Unfortunately there is potential for confusion because the targets for HbA1c differ between NICE and the quality and outcomes framework (QOF).2,10 The QOF appears to incentivise prescribers to aim for a HbA1c value of <7% (53 mmol/l) since reaching this goal attracts the maximum number of points (17 points for 50% of patients reaching this target).10 While this target may be appropriate for many people receiving treatment there are possible risks in applying such a stringent target in a cavalier fashion.

Table 1: Recommended glycaemic targets (clinical and non-clinical)
Guideline HbA1c (%)
NICE CG872 6.5–7.5 (48–58 mmol/mol)
GMS contract10 ?7.0 (53 mmol/mol)
Joint British Societies 2 (JBS2)11 ?6.5 or ?7.5 (for audit standard)
(48–58 mmol/mol)
European Diabetes Policy Group12 ?7.0 (53 mmol/mol)
International Diabetes Federation13 ?6.5 (48 mmol/mol)

Intensive therapy to lower HbA1c

The patients in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study had the characteristics of greater longevity of diabetes (median period of 10 years) and pre-existing cardiovascular disease.14 The aim of this trial was to determine if intensive therapy to reduce HbA1c in patients with type 2 diabetes resulted in a decrease in cardiovascular events. The measured primary outcome was the first occurrence of nonfatal myocardial infarction or nonfatal stroke or death from cardiovascular causes.14

A greater number of patients died in the intensive-therapy group compared with patients in the standard therapy group. Hypoglycaemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (p<0.001).14 This study cautions that the use of intensive therapy to target normal HbA1c levels runs the risk of increasing mortality. These findings identify a previously unrecognised harm of intensive glucose lowering in high-risk patients with type 2 diabetes.

The UK Hypoglycaemia Study Group revealed that the incidence of hypoglycaemia is often unrecognised and may exist to a greater degree than is officially reported.15 It is important that prescribers acknowledge that not all patients with diabetes should be treated to an HbA1c level <6.5%.

In contrast to the QOF, the NICE guideline recognises that any reduction in HbA1c is beneficial, even if patients do not reach their target thus softening the trend of the slavish pursuit of an ever lower HbA1c target.

Healthcare professionals are advised to offer therapy (lifestyle and medication) to help achieve and maintain the HbA1c target level.2 The NICE guideline encourages discussion with the patient with diabetes, and permits settling at a level greater than 6.5% with the proviso that these loose targets do not impair their quality of life. We are specifically advised to avoid pursuing highly intensive management to achieve HbA1c levels <6.5%.2

Implications for primary care

The NICE guideline has significant implications for primary care including the requirement to update existing protocols to take account of the new therapies. There is also a need to review practice protocols for both existing and newly diagnosed cases of diabetes.

In the short term, there will be an increase in workload for primary care as patients will need to be assessed and reassessed after being given a newer agent. However, it is likely that in the long-term, the workload will decrease as these agents are effective in controlling blood glucose.

The ethos of the White Paper Equity and excellence: Liberating the NHS is synonymous with that of the NICE guideline CG87 with regard to individualising the evolution and delivery of commissioned services.16 This is epitomised by the phrase in the White Paper, ‘no decision about me without me’.16 The GP community is being handed a golden opportunity to shape the development and provision of primary care as they take over the helm from failing PCTs. This has challenging implications for diabetes care since we are faced with the dichotomy of widening treatment options for a disease that is widely accepted to be at epidemic proportions and is increasing conjoined with a climate of increasingly tight financial restrictions.

The welcome extension of treatment choices proffered by the NICE guideline may be seen by some as a poisoned chalice given that our armamentarium now largely consists of drugs that are in the early stages of their patent and are likely to remain expensive for several years to come. With regard to diabetes care we may consequently struggle to completely embrace the principle of individualised care so enshrined in the White Paper and CG87.


The care of people with diabetes has come a long way from the most ancient of scripts on record in the Papyrus of Ebers 1500 BC17 to the polished periodically updated guideline that we associate with NICE. In particular, CG87 has for the first time greatly extended the pharmaceutical tools at our disposal to manage our patients’ hyperglycaemia in a tailored fashion.

In recognition of the relatively high cost of the new treatment rapidly becoming available, NICE has embedded in the guideline the requirement to assess and reassess patients’ responses to medication and to be prepared to consider stopping treatment in favour of an alternative approach should no measurable benefit be observed. We are guided to use these agents to aim for good glycaemic control with an algorithm that may at first sight appear unwieldy. However it illustrates the potential offered with the current agents for individualising treatment according to the person in front of us. We are also given a range of acceptable glycaemic control values rather than an inflexible ‘treatment to target’. The real challenge, however, is to deliver this gold standard of care endorsed in the White Paper in the climate of financial austerity that now dominates the NHS.


  1. Diabetes in the UK 2010: Key statistics on diabetes. London: Diabetes, 2010
  2. National Institute for Health and Care Excellence. Type 2 diabetes: Newer agents. Clinical Guideline 87. London: NICE, 2009. Available at: www.nice.org.uk/guidance/CG87
  3. The National Collaborating Centre for Chronic Conditions. Type 2 diabetes. London: RCP, 2009. Available at: www.nice.org.uk/guidance/CG66
  4. European Medicines Agency. European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim. London: EMA, 2010.
  5. National Institute for Health and Care Excellence. Type 2 diabetes: the management of type 2 diabetes. Quick reference guide. Clinical Guideline 87. London: NICE, 2009. Available at: www.nice.org.uk/guidance/CG87/QuickRefGuide/pdf/English
  6. National Institute for Health and Care Excellence. Final appraisal determination. Liraglutide for the treatment of type 2 diabetes mellitus. London: NICE, 2010. Available at: www.nice.org.uk/guidance/TA/Wave20/68#keydocs
  7. National Institute for Health and Care Excellence. CG87 Type 2 diabetes—newer agents (a partial update of CG66): slide set. London: NICE, 2009.
  8. Waugh N, Cummins E, P Royle et al. Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation. Health Technology Assessment 2010; 14 (36).
  9. North Yorkshire and York NHS. PCT service specification—liraglutide. North Yorkshire and York NHS, 2010.
  10. British Medical Association. Quality and outcomes framework guidance for GMS contract 2009/10. London: BMA, NHS Employers, 2009.
  11. British Cardiac Society, British Hypertension Society, Diabetes UK et al. JBS2: Joint British societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 (5): 1–52.
  12. European Diabetes Policy Group. A desktop guide to type 2 diabetes mellitus. Diabetic Medicine 1999, 16: 716–730.
  13. International Diabetes Federation Clinical Guidelines Task Force. Global guideline for type 2 diabetes. Brussels: IDF, 2005.
  14. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358 (24): 2545–2559.
  15. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007; 50 (6): 1140–1147.
  16. Department of Health. Equity and excellence: Liberating the NHS. London: DH, 2010.
  17. Carpenter S, Rigaud S, Barile M. An interlinear transliteration and english translation of portions of the ebers papyrus possibly having to do with diabetes mellitus. Bard College Annandale-on-Hudson, NY: 1998.G

A checklist to aid the implementation of the NICE guideline on newer agents for blood glucose control in
type 2 diabetes is availble to download. Please click here for the Checklists section of eGuidelines.co.uk.

  • The NICE guideline could potentially represent a major cost pressure to PBC consortia and PCTs through the increased use of the newer more expensive agents
  • There is confusion as to the HbA1c level for progressing to newer agents or insulin; in most cases, this will be 7.5% unless metformin or sulfonylurea is contraindicated or not tolerated (pioglitazone or a DPP-4 inhibitor can be used second line if this is the case)
  • An educational program around this guidance, supported by audits and a local prescribing incentive scheme for the newer agents, could help reduce costs and support NICE implementation
  • Such an incentive scheme could also focus on ensuring that the target HbA1c reductions with newer agents are met after 6 months and that these agents are withdrawn where this is not met
  • PCTs, PBC consortia, and LMCs could consider agreed exception criteria for the QOF DM23 indicator for individuals whose HbA1c lies between 7% and 7.5% and cannot be lowered further without breaching NICE guidance (for this year only as this target is likely to be changed back to 7.5% in 2011)
  • GP commissioners should consider commissioning a specialist diabetic nurse and/or GPwSI service to support primary care prescribers in the effective use of the newer agents

HbA1c=glycated haemoglobin; LMC=local medical committees; QOF=quality and outcomes framework