The updated guideline from NICE on Management of type 2 diabetes in primary and secondary care was published earlier this year. It revises and combines previous NICE guidance on certain aspects of the disease, which are retinal screening, renal disease, blood glucose levels, and hypertension with lipids. It has also amalgamated earlier technology appraisal advice on long-acting insulin analogues, patient education models, and glitazones.1,2
The guideline only considered evidence published by May 2007, and which related to agents licensed by the anticipated publication date for UK use. Some ‘newer agents’, such as the dipeptidyl peptidase 4 (DPP-4) inhibitors sitagliptin and vildagliptin were not included. The glucagon-like peptide 1 (GLP-1) mimetic exenatide was considered in the guideline, despite the relative paucity of randomised, controlled, clinical trials of adequate quality and size. In what many consider an awkward anomaly, the long-acting insulin analogue detemir was excluded for the same reason.
These exclusions and limitations have been of immense interest, and some frustration, to practising clinicians and to patients, and NICE has commissioned a further guideline to consider these ‘newer agents’ under a rapid update process.
This article discusses recommendations in the published guideline and also the proposals for the newer agents, due to be published in March 2009 (www.nice.org.uk/guidance/index.jsp?action=folder&o=42277). However, it must be borne in mind that changes to the ‘rapid update’ may still be made following the stakeholder consultation, which has just started.
Who will use the guideline?
The guideline will principally be used by healthcare professionals working with patients with type 2 diabetes (T2D). These healthcare professionals will include clinicians, managers, and commissioners of services who are responsible locally for implementation of the guidelines.
The guideline, in addition to the available patient information, should also be of interest to patients with T2D, as an indicator of expected standards and methods of care.
The NICE guideline recommends that structured education should be offered to every person diagnosed with T2D, and/or their carer, at or around the time of diagnosis as an integral part of care, and that such education should be reinforced and reviewed annually. This is not new advice, but despite a similar recommendation in the National Service Framework (NSF) of 20013 and in NICE Technology Appraisal 60 from 2003 on the use of patient-education models for diabetes,4 such provision remains the exception rather than the rule.
The Health Commission Survey of 2006 reported that only 11% of people with diabetes recalled participating in structured education and that the availability of such provision varied widely by geographical area.5 Despite continuing debate about the specific merits and outcome benefits of particular education programmes, the continuing lack of adequate provision in line with criteria laid down by the Department of Health and Diabetes UK Patient Education Working Group requires urgent attention by commissioners in most districts.6
The optimisation of lifestyle (including physical activity) and diet remains a cornerstone of T2D management, and the guideline recommends that nutritional advice individualised to the patient should be provided by a suitably qualified healthcare professional. Nevertheless, in many places similar deficiencies in provision to those in the area of diabetes education persist. Again, commissioners bear the responsibility for ensuring that people with diabetes can be offered adequate information and support to achieve their goals.
There is plentiful evidence of the benefits of maintaining near-normal glycated haemoglobin (HbA1c) levels in terms of minimising at least the microvascular complications of T2D, even if this has recently been shown to raise the possibility of significant risks if this is attempted overzealously.7 Sensibly, the guideline accepts that appropriate targets may vary from person to person according to their circumstances, and that account should also be taken of the personal costs (e.g. hypoglycaemia) resulting from overambitious glycaemic control.1,2 Many have noted an apparent anomaly within the glycaemic control algorithm whereby in the early stages of therapy an HbA1c of ?6.5% is quoted as the threshold for action but in the later stages this rises to ?7.5%. This actually reflects the reality that the use of insulin, or even the more costly oral antidiabetic agents, is not demonstrably cost-effective at HbA1c levels below 7.5% when balanced against the incidence of preventable complications in this group. Further discussion of choice of glycaemic control agents follows later.
The guideline includes a helpful discussion on this often contentious topic, and recommends that self-monitoring of blood glucose (SMBG) should be available as part of an integrated management plan where identified goals are set and results acted upon. Already expensive, SMBG is all the more so if results are simply archived rather than used in an informed way to achieve or maintain optimal glycaemic control. Equally, arbitrary restrictions on SMBG can induce insecurity and deny patients information that is useful or even essential to their effective self-management.1,2
Implementation of SMBG is recommended:
- for people using insulin
- for those at risk of hypoglycaemia who are using oral antidiabetic agents
- when making changes in lifestyle or medication to monitor changes in glucose control
- during intercurrent illness to monitor changes
- to ensure safety during activities such as driving.
It is the responsibility of commissioners and prescribers to ensure that appropriate facilities and resources are available to people with diabetes. Likewise it is the responsibility of prescribers, educators, and people with diabetes themselves, to ensure that such resources are used effectively. It may be entirely appropriate, for example, to encourage and facilitate the use of SMBG by a person using metformin alone (or even no medication at all) during their initial adjustment period to their T2D, if this enables them to gain insight into the effects of different foods and activities on their glycaemia. On the other hand, mechanistic, frequent SMBG when management and situations are stable may be inappropriate even for someone using insulin.
The guideline emphasises the importance of an organised programme of information, support, and dose titration when insulin is started and continued. With the initiation of insulin therapy increasingly taking place outside of specialist units, this recommendation is of key importance. For patients and clinicians alike the use of insulin can be a daunting prospect. There is plentiful scope for serious mishap and both patients and those involved in their care need to be able adequately to anticipate, avoid, or, at worst, deal with such problems. A variety of ways to address the potential difficulties of providing an adequate service have been tried, including starting a group of patients together on insulin, but whatever model is adopted by individual service providers the criteria set out by NICE must be met.1,2
Blood glucose-lowering pharmacotherapy
The NICE guideline contains an algorithm for the use of glucose-lowering medicines in people with T2D (see Figure 1).
Since the UK Prospective Diabetes Study, where subgroup analysis suggested that metformin may be superior in terms of cardiovascular mortality to other oral antidiabetic agents, it has remained the first-choice agent for glycaemic control in T2D.8 (Given the attributes of effectiveness, safety, and economy, its place seems secure for some time to come.) It does, however, bring well-known problems of tolerability for some patients and is contraindicated in the presence of renal impairment and at times of severe acute illness where lactic acidosis may be a risk.2
While the NICE guideline was being developed, the storm of adverse publicity over use of rosiglitazone arose, and by association the possible doubts about glitazones as a class. The DPP-4 agents were not then licensed, so the sulfonylureas, in the light of their favourable cost profile and effectiveness, were in a strong position to secure their place as the next oral anti-diabetic agent of choice.
Caution needs to be exercised with the use of sulfonylureas where hypoglycaemia would be a particular danger (for example, in people with certain occupations, such as those driving or operating machinery; and the elderly living alone), although accurate figures for the occurrence of hypoglycaemia attributable to the use of sulfonylureas are hard to obtain. Less well known, but mentioned in the guideline, is the increased risk of hypoglycaemia with sulfonylureas when used in the presence of renal impairment, due to their delayed clearance.
Rapid-acting insulin secretagogues such as repaglinide and nateglinide fall foul of health economic modelling in the absence of marked clinical advantages. The guideline says acarbose should be considered when other oral glucose-lowering medicines cannot be taken by the patient. Acarbose is relatively unpopular with prescribers in England and Wales, as well as being expensive and lacking significant advantages.
Thiazolidinediones (glitazones) and ‘newer agents’
After careful study by the guideline development group of the evidence regarding thiazolidinediones (glitazones) there was not felt to be sufficient certainty to differentiate between them—a situation that persists through to the recent draft NICE guidance on the ‘newer agents’ group.2,9 Pioglitazone and rosiglitazone therefore retain their places as third-line oral alternatives to insulin, or as second-line agents if metformin or sulfonylureas cannot be used together. However, only pioglitazone is suitable for use with insulin therapy.
The ‘newer agents’ draft update proposes that sitagliptin, the first DPP-4 inhibitor available in the UK, also be considered. It is placed in the same role as the glitazones.9 So far, both glitazones and gliptins appear generally similar in terms of efficacy and cost, and the choice between them may come down to individual circumstances. Renal impairment is a contraindication to the use of DPP-4 inhibitors,10 and the need to avoid oedema or weight gain, or the presence of active cardiac ischaemia counsels against choosing a glitazone.10 Some clinicians will take the view that neither group of third-line agents has clinical benefits sufficient to delay the use of insulin therapy after metformin and sulfonyureas have reached their limits. However, in primary care and for many patients the ease of use and avoidance of injections will make the choice for them.
The inclusion of exenatide in the glucose control algorithm in Figure 1 depends partly on cost-effectiveness, and this depends very strongly upon the utility value associated with its weight-reducing characteristics. Exenatide is recommended for use in people with a body mass index (BMI) over 35 kg/m2 adjusted according to ethnic group, and where other criteria, such as specific problems relating to high weight, cost, and inadequate blood glucose control, are satisfied. The ‘newer agents’ draft supports these recommendations but also proposes exenatide be used in other clinical scenarios related to obesity, such as obstructive sleep apnoea, and in people whose occupations raise particular problems with insulin use, for example HGV drivers. Both the published guideline and the draft update recognise that exenatide is an expensive alternative to insulin and recommend that its use is justified by effectiveness, defined as a reduction in HbA1c of 1% at 6 months (when its effect is likely to be maximal) and in body weight of at least 5% at 1 year.1,2,9
The use of insulin is discussed in the NICE guideline and a preference stated for starting treatment with neutral protamine hagedorn (NPH) rather than a long-acting insulin analogue. The reasoning here, of which many prescribers may be unaware, is that NPH is half the price.10 Available evidence shows the analogues to be superior in minimising hypoglycaemic events but not in HbA1c reduction, and so NPH is recommended as first choice unless hypoglycaemia becomes problematic.1,2 The ‘newer agents’ draft, expected to be published early in 2009, considers detemir alongside glargine, but finds little real difference between them.9
Where more complex insulin regimens are required, human mixed insulins are again preferred over analogues on grounds of cost. Here though, the facility of the analogues to be given at mealtimes rather than 20–30 minutes in advance will sway many patient and provider preferences.
Figure 1: Algorithm for use of glucose-lowering medicines in people with type 2 diabetes
Adapted from National Institute for Health and Care Excellence (NICE) (2008) CG 66 Type 2 diabetes—the management of type 2 diabetes (update). London: NICE. Reproduced with permission. Available from www.nice.org.uk.
For details on glucose-lowering targets, clinical monitoring, use of oral agents, and use of insulin, refer to the full NICE guideline.
Blood pressure management
Broadly the management of hypertension in people with diabetes differs in few respects from that of the general population,11 except that target levels are lower, the priority even greater, and angiotensin-converting enzyme inhibitor (ACEI) drugs are emphasised as first-choice agents. In people of African–Caribbean descent, who tend to be less responsive to the blood pressure-lowering effects of ACEIs, a diuretic or calcium channel antagonist (blocker) is suggested as joint first-line treatment. A general target of below 140/80 mmHg is set, reducing to below 130/80 mmHg for those with renal, retinal, or cerebrovascular damage.
Setting precise levels for blood pressure management is somewhat arbitrary, with a general acceptance that ‘lower is better,’ and the clinical situation is always complicated by the difficulty of ascribing a precise single blood pressure to any individual when the measurement varies significantly according to circumstance.
Again the methodology for achieving target lipid levels differs little between people with and without diabetes. In the NICE guideline on lipid modification there is no target level for total cholesterol (TC) or low density lipoprotein cholesterol (LDL-C)for primary prevention.12 That guideline was developed simultaneously with the T2D guidance though with no formal crossover between the groups. Views differ as to the precise relative increase in risk of cardiovascular events for people with T2D. Estimates vary from a risk equivalent to that of someone without diabetes who has already had a cardiovascular event, to one somewhat lower than this but still markedly elevated above that of the general population. Nevertheless, many studies, such as the CARDS study,13 have confirmed the significant risk reduction conferred by statins in T2D.
The new NICE guideline on management of T2D advocates routine use of a baseline statin (generic simvastatin to 40 mg) in all people over the age of 40 years with diabetes (and those below 40 years with a poor risk factor profile), unless all of the following risk-reducing conditions apply:
- not overweight, normotensive—BP <140/80 mmHg without treatment
- no microalbuminuria, non-smoker without high-risk lipid profile
- no family history of cardiovascular disease.
In practice there will be few people aged over 40 years with T2D who should not receive a statin. The target for lipid lowering is set at a TC of below 4 mmol/l and an LDL-C of below 2 mmol/l if this can be achieved with simvastatin up to 80 mg/day. The use of other statins or ezetimibe only becomes cost effective in people with existing or newly diagnosed cardiovascular disease, or if there is an increased albumin excretion rate.1,2 This is clearly a cost-sensitive issue, with the clinical message being that the 4/2 mmol/l target for TC/LDL-C is aspired to.
Fibrates are suggested by the guideline for use in addition to a statin in the presence of raised triglycerides. Women who may become pregnant should be informed of the need to avoid statins.
The role of aspirin in reducing cardiovascular events in those at high risk is well established, but direct evidence of the applicability of this to those with diabetes is relatively sparse. At least one trial studying this specific question is in progress, but for the moment the guideline recommends daily low-dose (75 mg) aspirin for people with diabetes aged over 50 years, and for those under 50 years with diabetes if significant cardiovascular risk factors are present. Clopidogrel is suggested for use only where aspirin is clearly not tolerated, with the combination of clopidogrel with aspirin not endorsed in the light of additional risks.2
Renal disease and eye screening
Annual measurement of creatinine and of urinary albumin/creatinine ratio, and annual retinal screening are suggested in line with current practice.1,2
Few major changes to established practice were expected from the updated NICE guideline on The management of type 2 diabetes, with interest centring on the role of the glitazones (pioglitazone; rosiglitazone), DPP-4 inhibitors (sitagliptin), and GLP-1 agonists (exenatide), which will now be dealt with in the forthcoming ‘newer agents’ update.
Much has been achieved in the provision of high quality diabetes care in the UK. Clinical trials do not reach endpoints as they are being thwarted by cardiovascular event rates being significantly below predicted levels as the result of statin and possibly ACEI use. Excellent news for people saved from cardiovascular events! Annual digital retinal screening is widespread for people with diabetes, although not yet universal. The quality and outcomes framework in primary care has yielded accurate data showing improvements in glycaemic control and other clinical indicators, however much remains to be done, especially in the fields of patient education and support. Commissioners take note!
NICE implementation tools
NICE has developed the following tools to support implementation of its guideline on the management of type 2 diabetes. They are now available to download from the NICE website: www.nice.org.uk.
The recommendations regarding the prescribing of blood glucose-lowering pharmacotherapy were identified as having possible significant resource implications. The recommendations for newer drugs for type 2 diabetes and their associated costs may change depending on the rapid update that is currently in development (Newer agents for blood glucose in type 2 diabetes). The cost of patient education is unlikely to change above that already identified. However, the cost implications of patient education programmes will depend on the extent to which NICE Technology Appraisal 60 has been implemented locally, and this may have significant consequences on resources.
Audit support (organisational and clinical)
Audit support has been developed to assess current practice in the management of type 2 diabetes compared with the guideline recommendations. Audit criteria based on key priorities for implementation in the guideline are provided, which can be adapted for use locally. Although the given standard should be aimed for, a more realistic local short-term standard can be set based on discussion with clinicians.
The slides are aimed at supporting organisations to raise awareness of the guideline at a local level and can be edited to cater for local audiences. They do not cover all the recommendations from the guideline but contain key messages, and should be used in conjunction with the Quick Reference Guide.
- National Institute for Health and Care Excellence. Type 2 diabetes—the management of type 2 diabetes (update). Clinical Guideline 66. London: NICE, 2008.
- 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.
- Department of Health. National Service Framework for diabetes: standards. London: DH, 2001.
- National Institute for Clinical Excellence. Guidance on the use of patient-education models for diabetes. Technology Appraisal 60. London: NICE, 2003.
- Healthcare Commission. Diabetes: The view of people with diabetes—key findings from the 2006 survey. www.healthcarecommission.org.uk/publicationslibrary.cfm
- Diabetes UK, Department of Health. Structured patient education in diabetes—report from the Patient Education Working Group. London: DH, 2005.
- National Heart, Lung, and Blood Institute. For safety, NHLBI changes intensive blood sugar treatment strategy in clinical trial of diabetes and cardiovascular disease. public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2551
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352 (9131): 854–865.
- National Institute for Health and Care Excellence. Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes. Draft for consultation. London: NICE, 2008.
- British National Formulary. BNF 56. London: Royal Pharmaceutical Society, 2008.
- National Institute for Health and Care Excellence. Hypertension: management of hypertension in adults in primary care (partial update). Clinical Guideline 34. London: NICE, 2006.
- National Institute for Health and Care Excellence. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Clinical Guideline 67. London: NICE, 2008.
- Colhoun H, Betteridge D, Durrington P et al; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364 (9435): 685–696. G
Click here for CPD questions on this article and the NICE guideline on the management of type 2 diabetes
- The NICE guideline update on diabetes will result in significant inflationary pressures on PBC prescribing budgets and these will need to be budgeted for
- More stringent targets for glycaemic control and lipid modification have been set
- Metformin and sulfonylurea should be used to achieve an HbA1c target of 6.5%
- Insulin or thiazolidinedione can be added to meet a target of 7.5% if control to this level has not been achieved
- The updated QOF for 2009/2010 will reward practices in which 40-50% of patients with diabetes have achieved an HbA1c target of 7.0%1
- The NICE guideline provides specific guidance for when SMBG is appropriate, as the cost involved can exceed those of the drugs
- Higher intensity statins and ezetimibe should only be considered to meet the targets of TC (4 mmol/l) or LDL-C (2 mmol/l) in those individuals with CVD or microalbuminuria, but these drugs are expensive
- Neutral protamine hagedorn insulin should be used as first-line therapy over analogue insulins due to the cost benefit
- PBC incentive schemes could be designed to ensure practices keep to this guidance and moderate use of expensive statins and insulins