Professor Philip Home discusses current NICE treatment strategies and recent and future developments in the control of blood-glucose levels in type 2 diabetes


NICE published a guideline on the management of diabetes in 2008 (Clinical Guideline 66). A rapid update to this guideline was published in May 2009, reflecting changes in one area of pharmaceutical management of the condition, namely glucose-lowering drugs. This resulted in some confusion in the available documentation as the publications fall into two sets:

  • NICE Short Clinical Guideline 87 entitled Type 2 diabetes: newer agents, which has a strictly limited coverage, determined by the scope of the update.1 The reality is better addressed by its subtitle Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes as the guideline does not address the majority of drugs used to treat the disease (e.g. lipid-lowering medications, antihypertensives, antiplatelet agents) or even the commonest medication used in diabetes (metformin), while sulfonylureas only appear as an economic comparator
  • NICE Clinical Guideline 87 entitled Type 2 diabetes: the management of type 2 diabetes merges the updated recommendations on newer agents with those of Clinical Guideline 66 on type 2 diabetes, thus comprehensively covering most of diabetes care.2 However, it noticeably lacks recommendations on diabetes footcare (to be found in Clinical Guideline 103) and pre-pregnancy care (not covered comprehensively by NICE for type 2 diabetes).

This article covers Clinical Guideline 872 rather than the short guideline, however much of the commentary regarding therapy will be limited to glucose-lowering medications, partly because this is a more complex area than lipid or blood-pressure control in people with diabetes, and partly because the diverse changes that have occurred since 2009, and that are still occurring, are mainly in this area.

Education and self-management

Three of the first four chapters of Clinical Guideline 87 emphasise the importance of self-management issues and cover patient education, lifestyle management (including the all-important nutritional education), and self-monitoring. The other chapter covers glucose target levels, an area that overlaps between self-management and medications;2 this information can then be used as a basis for people with diabetes to hone their own behaviour.

Structured education for diabetes has been endorsed repeatedly by NICE in its guidance and is a common theme in the management of other conditions—this reflects the cost effectiveness of structured education. The NICE guideline recognises that there is useful literature summarising the nationally agreed criteria and nature of the curriculum of education programmes that must be available to all people with type 2 diabetes. Formal recommendations are made as to the timing of initial education, its review, and follow up.2

Regarding the difficult issue of self-monitoring, the NICE guideline does seek to go beyond the simplistic idea that this is an intervention designed to improve blood-glucose control. Both the evidence base and the guideline view self-monitoring as a support tool to self-management, and thus it can support improved quality of life throughout the lifetime of a person with diabetes; the best evidence being for the time after diagnosis. Unfortunately the usefulness of self-monitoring in practice varies enormously from individual to individual, making it impossible for the guideline to dictate frequency and practice.

Commissioning

Individuals involved in commissioning and providing care for people with type 2 diabetes must be aware of the need to provide structured care in a number of areas rather than relying on the ad hoc deployment of current primary or secondary care staff into diabetes clinics that provide medications such as those covered in Clinical Guideline 87. One obvious example is podiatry services for people with diabetes as a whole (thus including type 1, secondary, and gestational diabetes), which can largely obviate the need for amputation, but are not discussed in Clinical Guideline 87 (covered in CG103). A general summary of areas of care that need consideration when commissioning diabetes services, and are included in Clinical Guideline 87 and other NICE guidance, is shown in Table 1.

As with the advice on nutrition, a critical issue is the expertise of the professionals involved in providing education, with a requisite overlap of diabetes expertise and knowledge of the principles of assisting behavioural changes in adults. Commissioners will want to see that structured-education programmes are available to both primary and secondary care, fulfil national standards, and are staffed and organised by professionals with the relevant expertise (usually diabetes nurse specialists and accredited dietitians).

Table 1: Type 2 diabetes—areas for commissioning
Included in Clinical Guideline 87 Not included in Clinical Guideline 87
Structured education:
  • Initial and review
Lifestyle support issues:
  • Nutritional education and information:
    • Initial and review
  • Physical activity education
  • Self-monitoring:
    • Insulin therapy
    • Newly diagnosed
    • Sulfonylurea therapy
    • Other oral agents
    • Poor glucose control

Initiation of insulin:

  • Education
  • Dose titration
  • Telephone support lines

Eye disease surveillance

Kidney disease surveillance

Cardiovascular disease risk assessment

Pre-pregnancy assessment and education Diabetes foot care (CG10)3 Young people with type 2 diabetes Obesity management (CG43):4
  • Pharmacological and behavioural
  • Bariatric surgery
Neuropathic pain (CG96)5
This table does not include tertiary services, such as vascular surgery, renal disease clinics, or ophthalmology

 

Education should be interpreted as enabling behavioural self-management, and not simply provision of information

Current strategies for control of blood glucose

The necessity for an update of CG66 after 12 months was driven by the appearance of the dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) and the recent introduction of the glucagon-like peptide-1 (GLP-1) receptor agonists, together with an anomaly in the handling of the long-acting insulin detemir in the CG66 process.

A simple algorithm demonstrating the sequential add on of glucose-lowering therapies (adapted from Clinical Guideline 87) is shown in Figure 1.

Clinical Guideline 87 endorses the use of sulfonylureas and even sometimes insulin first line in cases of marked hyperglycaemia. Metformin is poorly tolerated in many people and the guideline recommends considering a trial of an extended-absorption formulation.2 As sulfonylureas can cause hypoglycaemia, alternative therapies such as DPP-4 inhibitors or thiazolidinediones can be offered to some occupational groups, and may be safer in high-risk groups, for example the thin elderly with cognitive impairment and erratic eating habits or instability. NICE recognises that expensive GLP-1 medications can be used third line in obese people who meet the criteria or people with an occupational risk of hypoglycaemia, although the cost-effectiveness rationale for this latter group seems weak compared with DPP-4 inhibitor and thiazolidinedione therapy.

The commissioning message here is obvious—the standard recommendations only apply to a proportion of people, and the alternative medications, while much more expensive, are recommended for many other patients. This situation extends to third-line medication where insulin is the standard comparator, but the costs of which are driven up by the need for educational and continuing support and a higher frequency of self-monitoring. This allowed thiazolidinediones and DPP-4 inhibitors to become cost-effective third-line agents, although as discussed later, generic pioglitazone may come to undermine these calculations.

In many parts of the UK, it is standard practice to use neutral protamine hagedorn (NPH) as the starter insulin in line with NICE recommendations; however, the progressive nature of diabetes is such that further intensive-insulin regimens often using more modern formulations become inevitable with time in surviving patients and occur more rapidly when insulin is started late.

Targets
NICE does endorse treatment to glucose targets, not just in CG87, but in its quality standard for diabetes.6 Indeed, targets for glycated haemoglobin (HbA1c) have been a core part of quality and outcomes framework payments in diabetes.

As mentioned previously, lifestyle measures supported by structured education and technologies to support self-management (e.g. self-monitoring) should be offered first line. However, in most people, this will not be sufficient to obtain target control without the addition of one or both metformin or sulfonylurea.

Challenges in blood-glucose management
Care must be taken in diabetes management to allow for:

  • deterioration of endogenous insulin production over time and therefore the need for continual monitoring of glycated haemoglobin and uptitration of the number and types of pharmacological therapies with time to achieve plasma glucose targets
  • drug-specific problems:
  • A high level of intolerance to agents (e.g. immediate-release metformin)
  • The problems of hypoglycaemia with sulfonylureas
  • Potential risk of fractures with thiazolidinediones
  • Weight-gain issues with thiazolidinediones and insulins.
Figure 1: Algorithm on blood-glucose-lowering therapy*

graph

*This algorithm is deliberately concise and assumes prescribers will be aware of relevant information including contraindications, drug interactions, and the latest safety data; †or other individually agreed target; †continue with metformin and sulfonylurea, but only continue other drugs if they are licensed for use with insulin

HbA1c=glycated haemoglobin; DPP-4=dipeptidyl peptidase; NPH=neutral protamine hagedorn; GLP-1=glucagon-like peptide-1; BMI=body mass index

Developments in the control of glucose control

It is difficult to discuss Clinical Guideline 87 with regard to glucose-lowering medications without first recognising the areas in which the guidance is now out of date (see Table 2). Indeed recommendations to NICE to have the guideline updated were accepted by the Institute in August 2011. There would also be a good case for making this a living guideline, which is updated yearly, given the pace of change in this complex area.

DPP-4 inhibitors
Since publication of Clinical Guideline 87, which included recommendations on sitagliptin and vildagliptin, a further DPP-4 inhibitor (saxagliptin) has been marketed, with an additional indication in renally compromised people;7 in addition, the indications for the use of sitagliptin have been extended to include combination with insulin therapy (see Table 2, below).10,11 It is not clear that this latter indication would have been considered cost effective had it been subjected to economic modelling as part of the NICE review process.

GLP-1 mimetics
For the new GLP-1 receptor agonist, liraglutide, the situation is somewhat different. Although marketed after publication of Clinical Guideline 87, it was subject to prolonged review by NICE as a technology appraisal (TA203);8 its advantages over exenatide being sufficient for it to be cost effective at the 1.2 mg dose under the same circumstances as exenatide. NICE has recommended that liraglutide should be made available on the NHS for the same indications as exenatide.10

The once-weekly version of exenatide, marketed in July 2011 (although approved earlier),9 poses new challenges in decision making regarding the advantages of administering an injectable at this frequency and in comparison with liraglutide. NICE guidance on the use of this product is expected in February 2012.12

The GLP-1 mimetics are increasingly being used in combination with insulin, a use that is off licence (and which is entirely unpromoted by the manufacturers). These individuals are often obese and the weight gain that accompanies insulin therapy, in particular that targeted at meal-time glucose control, is then often a further barrier to achieving blood-glucose targets. As GLP-1 mimetics target body weight reduction and post-prandial glucose control, combining this therapy with insulin can be useful, particularly when the patient–doctor–nurse team are in despair over the difficulties in even coming close to plasma-glucose target levels.

Insulins
New long-acting insulins are shortly being submitted to European Medicines Agency (EMA) on the basis of reductions in hypoglycaemia comparable to insulin glargine. This drug area is further complicated by insulin glargine coming off patent in the next 3 years (it is governed by a series of patents). Competitors to the proprietary form of glargine will be biosimilar rather than a generic form, with more rigorous licensing requirements and therefore cost reductions are likely to be limited to 50%. However, this would still make them competitive against current human NPH insulin preparations.

Sodium-glucose co-transporters type 2 inhibitors
Sodium-glucose co-transporters type 2 (SGLT2) inhibitors are a new class of glucose-lowering agents. Dapagliflozin is currently with the regulators but it is uncertain whether it will be approved.

Thiazolidinediones
On a negative note, rosiglitazone currently has its marketing licence suspended in Europe. The EMA Committee for Medicinal Products for Human Use indicated that this was because of concern over benefit:risk by comparison with pioglitazone.13 It has also been noted that pioglitazone leads to a marginal increase in the risk of bladder cancer, leading to advisory restrictions on its use.14 However, rosiglitazone and pioglitazone are the only two peroxisome proliferator-activated receptor gamma (PPAR-?) agonists ever licensed. These drugs have a unique insulin-sensitising property particularly in people with abdominal obesity and those with fatty liver (the majority of people with type 2 diabetes), so clinically a role for pioglitazone still remains. To complicate the issue, this drug will soon go off patent, and cost reductions are likely to mean it trumps insulin therapy and DPP-4 inhibitors on cost-effectiveness grounds. If this occurs, Clinical Guideline 87 will clearly require an update.

Table 2: Recent and upcoming development in glucose-lowering medications (not covered by Clinical Guideline 87)
Drug name Drug category

Use/indication

Cost effectiveness*

New medications licensed
saxagliptin7 DPP-4 inhibitor General and in renal impairment Similar to other
DPP-4 inhibitors
liraglutide8 GLP-1 receptor agonist As exenatide 1.2 mg dose endorsed by NICE
exenatide once-weekly9 GLP-1 receptor agonist As exenatide Similar to exenatide
New indications of already licensed medications
sitagliptin10,11 (and expected for other drugs in this class) DPP-4 inhibitors Use in combination with insulin therapy Unlikely without evidence of cardiovascular risk protection
Projected new indications
DPP-4 inhibitors Cardiovascular risk protection as first-line glucose-lowering therapy Likely when outcome studies completed
GLP-1 receptor agonists In combination with insulin Likely in some circumstances
Projected new licences
linagliptin (and expected for other drugs in this class) DPP-4 inhibitors As sitagliptin/saxagliptin Likely
SGLT2 inhibitors Third line Depends on pricing
insulin degludec Long-acting insulin analogue Basal insulin therapy Limited to current glargine indications
generic pioglitazone PPAR-? agonist All steps except first line Highly likely; may displace other therapies
biosimilar insulin glargine Long-acting insulin analogue Basal insulin therapy Highly likely; may displace NPH insulin

*Informal cost-effectiveness estimate by criteria used in Clinical Guideline 87, for same steps in the glucose-lowering algorithm as other medications in class

DPP-4=dipeptidyl peptidase; GLP-1=glucagon-like peptide-1; SGLT-2=sodium-glucose co-transporters type 2 inhibitors; PPAR-?=peroxisome proliferator-activated receptor gamma


Other areas of diabetes care

Diabetes care goes beyond plasma-glucose control and pharmacological management extends to blood-lipid control, blood-pressure control, and antithrombotic therapy. Clinical Guideline 87 provides recommendations on these areas, and it is important to note that its advice differs from guidance for people who do not have diabetes. This is on the basis of cost-effectiveness—people with diabetes are at higher risk and more intensive (and if necessary, expensive) interventions are indicated (e.g. tight lipid-lowering targets).

The basis of decision making in Clinical Guideline 66 (not updated in these areas when incorporated into Clinical Guideline 87) has changed, in some ways improving cost effectiveness. Some of the angiotensin-2 receptor blockers (sartans) are coming off patent in 2011, as is atorvastatin. Additionally, there is some evidence for microvascular protection that favours the renin-angiotensin system medications, although the nature of arterial disease in people with type 2 diabetes generally demands that multiple therapy (two to five agents) is in any case needed to keep blood pressure to target.There is less clarity around the role of aspirin and its cardiovascular protective dose in people with type 2 diabetes. The NICE advice on using clopidogrel if there is aspirin intolerance may be overtaken by the introduction of newer agents.

Referral patterns

Referral patterns are not addressed by Clinical Guideline 87, which was constructed specifically to be blind to site of care. Many (but not all) in primary care, however, currently request help:

  • when insulin therapy is under consideration
  • before starting expensive GLP-1 receptor agonists
  • when drug intolerance, which is common, leads to a need to deviate from the standard algorithm
  • in the management of hypertriglyceridaemia
  • for people with more advanced insulin-secretory failure requiring
    full insulin-replacement regimens similar to people with type 1 diabetes
  • for microalbuminuria, as both a cardiovascular and renal risk state.

In the last decade, there has been a noticeable trend for early referral of younger adults and even late teenagers with type 2 diabetes, with the correct understanding that the lifetime risk of vascular complications in such people is extreme, and the exposure to metabolic damage thus needs to be mitigated from the time of diagnosis.

Implementation

The NICE guideline itself offers priorities for implementation, but this is perhaps a little naive given the devastating and costly endpoints of inadequate preventative care of people with diabetes (blindness, amputation, ischaemic heart disease, stroke, renal failure), nearly all of which are either preventable in the majority, or have the possibility of having their incidence reduced by over 50%.15 According to the Steno-2 study, the number needed to treat to prevent one major outcome was around two for people at high risk, and the health economic analysis at 8 years suggested it could be cost saving.16

The mix of needs in pharmacological management is difficult to predict for any group of individuals with diabetes, varying for example with deprivation index. This makes specifying a more detailed approach than that provided in the NICE guideline (including glucose, lipid, and blood-pressure targets) difficult. Assurance of due process in areas such as structured education and surveillance of complications, however, will be easier.

Conclusion

It is to be hoped that future NICE guideline activity will:

  • bring together all aspects of care managed by the same team for the same patients, rather than fragmenting it into guidelines linked to other care teams (currently a problem for foot care, neuropathic pain, and pre-pregnancy care)
  • find a methodology to keep the guideline up to date, perhaps by making it a living guideline, bringing the guideline development group together every year to review new technologies, evidence, and safety issues, and patent-related price changes.

 

Philip Home and institutions with which he is connected, receive funding from most pharmaceutical manufacturers interested in diabetes care, including the medications and diagnostic devices discussed in this article. He has held various positions at NICE, and is diabetes guidelines consultant to the Royal College of Physicians, but the views expressed here are his own, and do not in any way seek to represent the views of the Institute or the College.

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