GPs should familiarise themselves with newer agents for diabetes

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Type 2 diabetes is a metabolic disorder characterised by insulin insensitivity, gradual beta cell failure, and consequent hyperglycaemia. The current prevalence of type 2 diabetes is estimated to be 3.5%–5.0% of the population, but this is increasing along with the prevalence of obesity.¹ The number of patients with type 2 diabetes, and the shift of chronic disease management to the community, has meant that the vast majority of this group of patients are now managed within primary care. The combined direct and indirect costs of type 2 diabetes to the health economy is approximately 7%–12% of total NHS expenditure.¹ The recent publication Prescribing for diabetes in England by the Yorkshire and Humber Public Health Observatory and National Diabetes Support Team noted that: ‘… the numbers and costs of diabetes-related prescriptions have increased to the extent that such items are now the highest single cost in the NHS prescribing budget’.²

Need for guidance on newer agents for blood-glucose control

Patients with type 2 diabetes are at increased risk of developing microvascular (e.g. retinopathy, nephropathy, and neuropathy) and macrovascular (e.g. ischaemic heart disease, cerebrovascular disease, and peripheral vascular disease) complications. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that effective glycaemic control resulted in a reduction in these complications.^3,4 In this trial, traditional agents—including metformin, sulfonylureas and intermediate-acting human insulin (Neutral Protamine Hagedorn or NPH insulin)—were used to achieve blood-glucose control. However, in recent years several newer blood glucose-lowering drugs have become available including dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin and vildagliptin), glucagon-like peptide-1 (GLP-1) mimetics (exenatide and liraglutide), and long-acting insulin analogues (levemir and glargine). The emergence of these newer agents together with the safety concerns expressed about the use of rosiglitazone⁵ has made the glycaemic treatment pathway for type 2 diabetes far more complex than ever before.

In May 2008, NICE published Clinical Guideline 66 on the management of type 2 diabetes.¹ The development and publication of such a comprehensive document was a major achievement, particularly bearing in mind the large amount of information that needed to be condensed. However, because of the limitations of the original scope, the newer incretin-based agents for lowering blood glucose and insulin detemir were not included in the guideline. Therefore, there were significant concerns expressed by various stakeholders that the glycaemic pathway in the guideline was out of date at publication.⁶ To address these concerns, NICE commissioned a short clinical guideline specifically to look at the role of newer agents in controlling blood glucose type 2 diabetes. This short clinical guideline (CG87)⁷ was published in May 2009 and included an updated glycaemic pathway (see Figure 1).

Figure 1: Blood glucose-lowering therapy8

Figure 1 continued

Scope of Clinical Guideline 87

Clinical Guideline 87 covers adult patients (aged over 18 years) with type 2 diabetes; patients younger than 18 years of age and pregnant women are not covered. The newer blood glucose-lowering agents that are considered include:⁷

• DPP-4 inhibitors (sitagliptin and vildagliptin)
• thiazolidinediones (TZDs) (pioglitazone and rosiglitazone)
• GLP-1 mimetic (exenatide)
• long-acting insulin analogues (detemir and glargine).

The key recommendations from the guideline regarding the use of these agents are summarised in Box 1 and discussed below.

At the time of developing the guideline, exenatide was the only GLP-1 analogue that was licensed for use and hence liraglutide was not reviewed. Thiazolidinediones were only examined from a safety point of view.

Box 1: Key recommendations for use of newer agents for blood-glucose control7

DPP-4 inhibitors and TZDs Consider a DPP-4 inhibitor or a TZD as second-line treatment with metformin instead of a sulfonylurea if blood glucose control is unsatisfactory (HbA1c >6.5% or a higher level agreed with the individual), if the person is at serious risk of hypoglycaemia and its consequences, or a sulfonylurea is not tolerated or is contraindicated Consider a DPP-4 inhibitor or a TZD as second-line treatment with a sulfonylurea if blood-glucose control is unsatisfactory (HbA1c >6.5% or a higher level agreed with the individual) if the person does not tolerate metformin or it is contraindicated Consider sitagliptin* or a TZD as a third-line treatment when a trial of metformin with a sulfonylurea does not control blood glucose (HbA1c >7.5% or a higher level agreed with the individual) and human insulin is unacceptable or inappropriate Continue treatment with a DPP-4 inhibitor or a TZD only if a beneficial metabolic response occurs (a reduction of at least 0.5 percentage points in HbA1c in 6 months) Consider combining pioglitazone with insulin therapy for patients who have previously had a good response to TZD therapy or are taking high-dose insulin with unsatisfactory control of blood glucose† A DPP-4 inhibitor may be preferable to a TZD if: further weight gain would cause or exacerbate serious problems associated with a high-body weight a TZD is contraindicated or not tolerated the person has previously had a poor response to TZD therapy A TZD may be preferable to a DPP-4 inhibitor if: the patient is likely to have marked insulin insensitivity a DPP-4 inhibitor is contraindicated or not tolerated the person has previously had a poor response to treatment with a DPP-4 inhibitor Exenatide Consider exenatide as third-line treatment (HbA1c >7.5% or a higher level agreed with the individual) to metformin and a sulfonylurea if a patient has a body mass index >35.0 kg/m2 in those of European descent (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight Consider exenatide as third-line treatment (HbA1c >7.5% or a higher level agreed with the individual) to metformin and a sulfonylurea if a patient has a body mass index <35.0 kg/m2 but in whom insulin would have substantial occupational implications, or weight loss would benefit other serious co-morbidities related to obesity Only continue treatment with exenatide if a beneficial metabolic response occurs (a reduction of at least 1.0 percentage point in HbA1c and a weight loss of at least 3% of initial body weight over 6 months) Long-acting insulin analogues Consider switching from NPH insulin to a long-acting insulin analogue in patients who: need help from a healthcare professional (e.g. district nurses) to administer insulin injections (as this has the potential to reduce the amount of visits needed from twice to once daily) would otherwise need twice-daily NPH insulin injections in combination with oral glucose-lowering drugs cannot use the device for injecting NPH insulin do not reach their target HbA1c because of hypoglycaemia or experience severe hypoglycaemia irrespective of the level of HbA1c reached

* sitagliptin is currently the only DDP-4 inhibitor with UK marketing authorisation for use in this combination † pioglitazone is currently the only TZD with UK marketing authorisation for use in this combination DPP-4=dipeptidyl peptidase-4; TZD=thiazolidinedione; HbA1c=glycated haemoglobin; NPH=neutral protamine Hagedorn

Dipeptidyl peptidase-4 inhibitors

Sitagliptin and vildagliptin are insulin secretagogues that prevent breakdown of endogenous GLP-1 by inhibition of the enzyme DPP-4. The current evidence suggests that these DPP-4 inhibitors are weight neutral and do not cause hypoglycaemia (unless used in conjunction with a sulfonylurea).⁹ Both sitagliptin and vildagliptin were found to be cost effective when compared to higher cost comparators such as TZDs, insulin, or exenatide.⁷ These DPP-4 inhibitors are positioned as a possible alternative second-line therapy (in conjunction with metformin or a sulfonylurea) in certain limited circumstances (see Box 1). Sitagliptin (but not vildagliptin) is also recommended for use as a third-line agent (in conjunction with metformin and a sulfonylurea) as an alternative to insulin, TZDs, or exenatide treatment.⁷

Thiazolidinediones

Thiazolidinediones (rosiglitazone and pioglitazone) are agonists for peroxisome proliferator-activated receptor-? (PPAR?) and are insulin sensitisers. It has been suggested that these drugs might reduce cardiovascular risk, however they can cause weight gain and fluid retention, which may result in symptomatic oedema in some individuals.^7,10 The use of these drugs was addressed in the original guideline (Clinical Guideline 66),¹ and they were only re-examined in the guideline on newer agents (Clinical Guideline 87) because of emerging concerns regarding the cardiovascular safety of rosiglitazone⁵ and the possible propensity of these drugs to result in fractures.¹¹ The updated guideline addresses these safety concerns by warning against the use of these drugs in patients who have heart failure or are at high risk of fractures; and recommends that prescribers take into account the latest advice from the European Medicines Agency and the Medicines and Healthcare products Regulatory Agency when considering which TZD to prescribe.⁷

Exenatide

Exenatide is an injectable synthetic version of exendin-4 and is the first commercially available GLP-1 mimetic. It is resistant to DPP-4 breakdown and acts as a glucose-dependent insulin secretagogue. Exenatide does not cause hypoglycaemia (unless used in conjunction with a sulfonylurea) and results in modest mean weight loss of 1.5–3.0 kg over 6–12 months.⁹ Despite its beneficial effects on body weight, exenatide should be used as a drug for blood-glucose control rather than weight loss. It should be considered for use as a third-line agent (in conjunction with metformin and a sulfonylurea) as an alternative to insulin, TZDs, or DPP-4 inhibitors only in certain situations where weight loss is a particularly important clinical factor.⁷

Long-acting insulin analogues

The NICE guideline recommends that insulin should be started in preference to adding other drugs for blood-glucose control in patients who are markedly hyperglycaemic and are taking oral dual therapy (metformin and a sulfonylurea). The main benefit of the use of the long-acting insulin analogues is a reduction of nocturnal hypoglycaemia (when compared with NPH insulin),⁷ as the current evidence suggests that they do not lower HbA_1c significantly more than NPH insulin.¹² Due to the considerable cost difference between the newer long-acting insulin analogues and NPH insulin, the recommendation from the previous version of the guideline, which proposes the use of NPH insulin as a starting point in most cases, has not been changed. It should be noted that, in current practice, the long-acting insulin analogues are often used in preference to NPH insulin at the start of insulin therapy; if prescribing advisers enforce the NICE recommendation that NPH insulin should be used first, then this could potentially lead to significant savings in drug budgets.⁷

Patient-centred care

A key part of the guideline on the use of newer agents for blood-glucose control is the increased importance of patient-centred care. There is a clear emphasis on individualising treatment to a patient’s own specific clinical and personal requirements. For example, DPP-4 inhibitors and TZDs are positioned equally throughout the pathway; and a patient who requires third-line treatment after metformin and sulfonylurea use could be prescribed several treatments including a TZD, a DPP-4 inhibitor, NPH insulin, a long-acting insulin analogue, or exenatide, depending on their own individual circumstances. The choice of treatment is left to the prescribing clinician who should make this decision in consultation with the patient. This should include a discussion of the potential benefits and risks of treatment so that a fully informed choice can be made. Hopefully, this will encourage effective clinical decision making in the best interests of the individual patient, rather than promoting the practice of rigid protocol-driven medicine.⁷

Key points and priorities for implementation

There are a number of key messages in the guidance for GPs and commissioners, including:

• lifestyle interventions (such as dietary modification, exercise, and structured diabetes education) remain as first-line treatment and should not be forgotten
• current glycaemic pathways need to be updated to take into account the newer agents that are available for lowering blood glucose
• the choice of treatment should be individualised to suit the best interests of the patient
• clinicians need to be capable of having an informed discussion with patients regarding the pros and cons of various treatments. This requires some familiarity of the newer agents and this familiarity may not currently exist in all primary care settings. Therefore provision of education to healthcare professionals in order to address this is crucial to implementation
• NPH insulin should be the starting insulin of choice for most patients when basal insulin is required
• TZDs and DPP-4 inhibitors are positioned equally and at the same points in the glycaemic pathway; the choice of which drug to use would depend on the clinician and patient
• treatment with TZDs, DPP-4 inhibitors, or exenatide should only be continued if shown to be effective (as determined by reduction in percentage points in HbA_1c)
• exenatide should be considered as a third-line option in situations where weight loss is particularly important. This will often require referral and initiation in a specialist setting (as there remains limited experience with the use of these drugs) and ensures that experience can be shared among diabetes centres (e.g. the Association of British Clinical Diabetologists [ABCD] nationwide exenatide audit).¹³ This in turn allows local practice to be benchmarked against comparable centres, which is a valuable governance tool for an expensive new drug. However, it may be necessary to develop local shared care agreements if prescribing is to be continued in primary care.

Conclusion

The newer agents for blood-glucose control, in particular incretin-based therapies, are potentially valuable tools to help achieve good glycaemic control while avoiding hypoglycaemia and weight gain. However, the advent of these agents has made the glycaemic treatment algorithm for type 2 diabetes far more complex. The NICE guideline on newer agents (CG87) updates the existing glycaemic pathway and aims to encourage clinicians to tailor blood glucose-lowering treatment to the individual circumstances of each patient.

Conflicts of interest statement

Dr Niru Goenka has previously given lectures at meetings sponsored by Eli Lilly, MSD, Novartis, GlaxoSmithKline, and Takeda. Any honoraria from these activities have been paid either to the departmental diabetes trust fund or to other registered charities. Dr Niru Goenka’s department is receiving support from Eli Lilly for the development of a diabetes website. Dr Niru Goenka was a member of the Guideline Development Group for the NICE short clinical guideline on Type 2 diabetes: newer agents.

NICE implementation tools

NICE has developed the following tools to support implementation of its guideline on Type 2 diabetes—newer agents (partial update of CG66). They are now available to download from the NICE website: www.nice.org.uk Slide set The slides are aimed at supporting organisations to raise awareness of the guideline and resulting implementation issues at a local level, and can be edited to cater for local audiences. This information does not supersede or replace the guidance itself. Audit support This tool has been developed to support the implementation of the NICE guideline on type 2 diabetes. The aim is to help NHS organisations with a baseline assessment and to assist with the audit process, thereby helping to ensure that practice is in line with the NICE recommendations. The audit support is based on the key recommendations of the guidance and includes criteria and data collection tools.

References

1. National Collaborating Centre for Chronic Conditions. Type 2 diabetes: national clinical guideline for management in primary and secondary care (update). London: Royal College of Physicians, 2008. Available at: www.nice.org.uk/guidance/CG66
2. The Information Centre and Yorkshire & Humber Public Health Observatory. Prescribing for diabetes in England: An analysis of volume, expenditure and trends. November 2007. The Information Centre, 2007.
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4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352 (9131): 837–853.
5. Nissen S, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356 (24): 2457–2471.
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7. National Institute for Health and Care Excellence. Type 2 Diabetes: newer agents. Short Clinical Guideline 87. London: NICE, 2009. Available at: www.nice.org.uk/guidance/CG87
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13. Edwards C, Winocour P, Association of British Clinical Diabetologists (ABCD). ABCD position statement on incretin mimetics and DPP-4 inhibitors. Practical Diabetes International 2009; 25 (5): 191–194.G