Updated NICE guidance on using newer agents for glycaemic control in type 2 diabetes permits flexible treatment, says Dr Roger Gadsby


The revision of the glycaemic control section of NICE Clinical Guideline 66 on The management of type 2 diabetes1 was published in May 2009 in two forms: as NICE Clinical Guideline 87 (a partial update of the original guideline) and as a short clinical guideline on Newer agents for blood glucose control in type 2 diabetes.2,3 These updates were developed because several new glucose-lowering therapies have recently been approved that were not covered in the previous guideline.

The new recommendations cover:

  • dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin)
  • thiazolidinediones (pioglitazone, rosiglitazone)
  • exenatide, a glucagon-like peptide-1 (GLP-1) mimetic
  • long-acting insulin analogues (insulin detemir and insulin glargine).

The guideline recommendations on lifestyle and monotherapy are unchanged, but new advice on pharmacotherapy in terms of dual therapy and triple therapy is provided.2,3 An algorithm on the pharmacological treatments available for lowering blood glucose has also been developed and is shown in Figure 1.4

Figure 1: Blood glucose-lowering therapy4

algo

(Figure 1 continued)
algo 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

Lifestyle interventions

The NICE guideline development group highlights (in line with the previous NICE guideline) that good adherence to lifestyle changes is fundamental to effective control of diabetes; it recommends that lifestyle interventions should be used as first-line treatment before any oral glucose-lowering therapy is prescribed.2 This differs from US guidelines where metformin along with lifestyle interventions are recommended as first-line management.5

Monotherapy

Metformin should be the initial monotherapy of choice for the majority of patients. A sulfonylurea should be considered in those:2

  • who are not overweight
  • in whom metformin is contraindicated or not tolerated
  • in whom a rapid therapeutic response is required because of hyperglycaemic symptoms.

Dual therapy

The guideline recommends that if a second agent is needed for the control of blood glucose, a sulfonylurea should be the usual choice to add to the maximum tolerated dose of metformin.2

A DPP-4 inhibitor or a thiazolidinedione can be added to metformin first-line treatment instead of a sulfonylurea if:2,3

  • the patient is at significant risk of hypoglycaemia or its consequences; for example, older people and people in certain jobs (e.g. those working at heights or with heavy machinery), or people in certain social circumstances (e.g. living alone)
  • a sulfonylurea is not tolerated or is contraindicated.

This advice allows therapy to be tailored to the individual, and as such, is very helpful.

Triple therapy

There are a number of options available if maximum tolerated doses of metformin and a sulfonylurea do not give adequate glycaemic control. These include the addition of a third-line therapy, such as basal insulin, exenatide, sitagliptin (the only DPP-4 inhibitor with a licence to be used in triple therapy), or a thiazolidinedione. These are discussed below in more detail.

Insulin
The guideline recommends that insulin should be considered as the main option if there is marked hyperglycaemia, unless there is a strong case for not doing so. Treatment should be initiated using a structured education programme employing active insulin dose titration. Human neutral protamine Hagedorn (NPH) insulin is recommended as a starting point, but consideration should be given to a long-acting insulin analogue (insulin detemir or insulin glargine) if the person:2,3

  • requires assistance from a carer or healthcare professional to inject insulin, and the use of a long-acting insulin analogue would decrease the frequency of injections from twice to once daily
  • is confined by recurrent symptomatic hypoglycaemic episodes
  • would otherwise need twice-daily NPH insulin injections in combination with oral glucose-lowering drugs
  • is unable to use the device to inject NPH insulin.

These recommendations again allow a degree of flexibility in choosing insulin type so that the most appropriate long-acting insulin analogue can be used.

Thiazolidinedione or a DPP-4 inhibitor (sitagliptin)
The NICE guideline suggests that either a thiazolidinedione (pioglitazone or rosiglitazone) or sitagliptin can be considered as third-line treatment options to first-line metformin and a second-line sulfonylurea if treatment with insulin is unacceptable or inappropriate.2,3

The choice of thiazolidinedione (pioglitazone or rosiglitazone) should take into account:2,3

  • up-to-date advice from relevant regulatory bodies (e.g. the European Medicines Agency and the Medicines and Healthcare products Regulatory Agency)
  • cost
  • safety
  • prescribing issues.

It should be noted that treatment with thiazolidinediones should not be started or continued in people who have heart failure, or who are at higher risk of fracture.2,3

Clinical Guideline 87 does not clearly distinguish between the two available thiazolidinediones in either dual or triple therapy, and the guideline has been criticised for not providing a clear lead on the issues surrounding the cardiovascular safety of rosiglitazone.6

In choosing between a thiazolidinedione (pioglitazone, rosiglitazone) or sitagliptin in triple therapy, the guideline states that a thiazolidinedione may be preferable if the person has marked insulin insensitivity. Furthermore, there may be some people for whom either a thiazolidinedione (pioglitazone, rosiglitazone) or a sitagliptin may be suitable as triple oral therapy and, in this case, the choice of treatment should be based on patient preference.2,3

Again in my opinion, the guideline gives sufficient flexibility to fit therapy to the needs of the individual.

Exenatide
As in the previous version, the updated NICE guideline recommends that exenatide should be considered as a third-line therapy to first-line metformin and a second-line sulfonylurea in patients with a body mass index (BMI) of ?35 kg/m2 (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight.2,3 Exenatide can be considered if BMI is <35 kg/m2 and insulin is unacceptable because of occupational implications or weight loss would benefit other co-morbidities. In my opinion, this restriction is largely driven by concerns over the costs of this therapy.

HbA1c targets and continuing therapy

The guideline continues to use a target glycated haemoglobin (HbA1c) level of 6.5% for patients on monotherapy, but a target of 7.5% for patients on two or more glucose-lowering drugs.2 There are also recommendations for continuing certain pharmacological treatments:

  • thiazolidinediones should only be continued if there is a reduction of at least 0.5 percentage points in HbA1c in 6 months
  • DPP-4 inhibitors should only be continued if there is a reduction of at least 0.5 percentage points in HbA1c in 6 months
  • exenatide should only be continued if there is a reduction of at least 1.0 percentage point in HbA1c and a decrease of 3% or more of initial body weight at 6 months.

This is an interesting development as in the past, oral agents with different mechanisms of action have been used additively (i.e. when one agent fails to achieve control, a second is added, and then a third). These discontinuation recommendations imply that some people may not respond to a particular agent, and if this is the case it should be stopped rather than continued.

Summary

In my opinion, the guideline does not contain any recommendations that are particularly surprising or controversial. They place the new DPP-4 inhibitors and thiazolidinediones for consideration in limited circumstances as secondary options, while suggesting that for the majority of patients, metformin plus a sulfonylurea is the usual choice. These generic therapies at around £2 to £3 a month are far cheaper than the newer glucose-lowering therapies,7 and are therefore likely to be the most cost effective.

In terms of adding a third agent to dual therapy: insulin, a thiazolidinedione, a DPP-4 inhibitor (sitagliptin), or exenatide can all be considered depending on patient circumstances. After a thorough discussion of the benefits and disadvantages of each option with a healthcare professional, patient preference will determine which option needs to be used, and the recommendations allow therapy to be determined according to the individual.

  1. National Institute for Health and Care Excellence. Type 2 diabetes: the management of type 2 diabetes. Clinical Guideline 66. London: NICE, 2002. Available at: www.nice.org.uk/guidance/CG66/Guidance/pdf/English
  2. National Institute for Health and Care Excellence. Type 2 diabetes: the management of type 2 diabetes (partial update). Clinical Guideline 87. London: NICE, 2009. Available at: www.nice.org.uk/guidance/CG87/NiceGuidance/pdf/English
  3. National Institute for Health and Care Excellence. Type 2 diabetes: newer agents (short clinical guideline). Clinical Guideline 87. London: NICE, 2009. Available at: www.nice.org.uk/guidance/index.jsp?action=download&o=44318
  4. 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
  5. Nathan D, Buse J, Davidson M et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009; 32 (1): 193–203.
  6. Barnett A. NICE should speak up on rosiglitazone. Pulse. 4 June 2009.
  7. British National Formulary. BNF 57 March 2009. London: BMJ Group and RPS Publishing, 2009.G