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The current National Institute for Health and Care Excellence (NICE) guideline covering glucose lowering in type 2 diabetes is Clinical Guideline CG87,1 which was published in 2009. This and the other three NICE diabetes clinical guidelines (covering type 1 diabetes, diabetes foot care, and diabetes and pregnancy2-4) are currently being revised ready for publication in the summer of 2015.
In this article, I give a personal view of some of the major issues that have arisen since 2009 in glucose lowering in type 2 diabetes. I believe these issues need to be reflected in the revised CG87 guideline.
Note: The author, Prof R Gadsby, has had no connection with the development of the new guideline and has had no information about the work of the guideline development group other than that which is in the public domain.
Developements that need to be included in the revised NICE type 2 diabetes guideline
Since 2009, the importance of, and potential harms from, aggressive glucose lowering in people with established type 2 diabetes has become more clear and established. NICE CG87 recommends a target glycated haemoglobin (HbA1c), ‘at or below 48 mmol/mol (6.5%)’, and ‘straight after diagnosis and when 1 or 2 glucose lowering agents are prescribed’.1 It recommends that a third glucose lowering agent should not be added unless the HbA1c is, ‘at or above 58 mmol/mol (7.5%)’. The guideline does not specifically discuss modifications of these goals in older people, in situations of multimorbidity, or where there is frailty, or dementia, or during end-of-life care.1 In my opinion, the revised guideline needs to include those situations in which recommendations for glucose control targets do not apply.
The sequence in which agents are used
NICE guidelines usually incorporate information on the clinical effectiveness and cost effectiveness of the treatments being discussed. NICE CG87 currently recommends the use of metformin as initial monotherapy followed by the addition of a sulphonylurea, unless hypoglycaemia is considered to be a significant risk.1 Both of these agents cost £1–£3/month, and all other glucose lowering agents considered in CG87 are priced at £30 or more per month. The glucose lowering agent pioglitazone has come off patent recently and is now available generically at a few pounds per month. How should the revised guideline recommend the sequencing of glucose lowering agents, given the difference in acquisition costs? This is something that needs some thought.
Since the publication of CG87 in 2009, there has been a considerable increase in the number of glucose lowering agents currently available in the UK. These include an additional two agents in the GLP-1 class (NICE CG87 only covered exenatide), four additional agents in the DPP4 class (NICE CG87 only covered sitagliptin), and a further two agents in a completely new class, the SGLT2 inhibitors (not previously covered in NICE CG87).
The question, therefore, arises as to how the updated guideline might handle this ‘explosion’ of new glucose lowering therapies, and which it will recommend.
How new international guidelines have addressed these issues
American Diabetes Association/European Association for the Study of Diabetes guideline
One of the major international guidelines for type 2 diabetes that has been published since 2009 is that of the joint American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) for glycaemic control in type 2 diabetes.5 This guideline, like CG87, recommends metformin as the initial monotherapy of choice for most people with type 2 diabetes published in 2012. However, it then recommends that the add-on therapy to metformin should be decided based on what is best for the individual. So, for example, in someone who is symptomatic due to hyperglycaemia and in whom hypoglycaemia is not deemed a significant risk, a sulphonylurea agent—which as a class will reduce glucose and hence symptoms within 1 or 2 days—may be appropriate. For the individual who is significantly obese, a GLP-1 agent that gives weight loss as well as lowering glucose may be an appropriate option. This ADA/EASD guideline is not specifically one of cost-effectiveness, but it does mention agent cost as an issue, especially in resource-limited healthcare systems.
This guideline also tackles the issue of glucose targets, suggesting that there is a continuum between more stringent and less stringent goals; this is based on disease duration, the presence or absence of co-morbidities, life expectancy, established vascular complications, available healthcare resources, hypoglycaemia risk, and patient attitudes.
This guideline was written before the launch of the SGLT2 agents and so these are not mentioned.
International Diabetes Federation guideline on managing older people with type 2 diabetes
This guideline, published by the International Diabetes Federation (IDF) in December 2013,6 stratifies its recommendations into categories:
- Category 1 for older people who are functionally independent
- Category 2 for people who are functionally dependent, including sub categories for those with frailty and those with dementia
- Category 3 for end-of-life care (defined as those with a reduced life expectancy, of less than 1 year).
For example, the IDF guideline specifies glycaemic targets according to functional category (see Table 1).6
The guideline also states that glycaemic targets should be individualised to take into account functional status, co-morbidities (especially the presence of established cardiovascular disease), history and risk of hypoglycaemia, and presence of microvascular complications.1 In terms of agent sequencing, the IDF guideline broadly follows that of the ADA/EASD guideline in recommending metformin first and then individualising secondary therapy. However, it also includes the use of SGLT2 agents second to metformin, or third to metformin plus one other glucose lowering agent.
I believe this is now the definitive guideline for older people with type 2 diabetes. I hope that the 2015 NICE guideline will explicitly state that for older people with frailty and/or dementia, or who are in their last year of life, the recommendations of the IDF guideline should be the ones to use to guide practice.
|Functional category||General glycated haemoglobin (HbA1c) target|
|Functionally independent||53–64 mmol/mol (7%–8%)|
| Functionally dependent
||53–59 mmol/mol (7%–7.5%)
up to 70 mmol/mol (8.5%)
up to 70 mmol/mol (8.5%)
|End of life||Avoid symptomatic hyperglycaemia|
Using a sulphonylurea second to metformin in the majority of people with type 2 diabetes
This is what currently happens in the UK as a result of the NICE CG87 guideline recommendations.1 However, the major side-effect of sulphonylurea therapy is hypoglycaemia. NICE CG87 recognises this and states, ‘consider substituting a DPP4 inhibitor or a thiazolidinedione [pioglitazone is now the only available agent in this group] if there is a significant risk of hypoglycaemia (or its consequences)’. Older people living alone and people with particular employment issues, for example, commercial drivers, are identified as groups in whom sulphonylurea-induced hypoglycaemia may pose a significant risk.
Since 2009 it has been shown that, although the acquisition cost of a sulphonylurea is low, the total health costs may be high. This is due to the combined cost of self-monitoring blood glucose (SMBG) in people taking sulphonylurea who drive, and that of severe hypoglycaemia requiring ambulance call outs and hospital admissions. There are additional potential costs owing to the incidence of mild to moderate hypoglycaemia and weight gain that occurs with sulphonylurea therapy. Those who support more frequent prescribing of the newer glucose lowering agents, particularly DPP4, GLP-1, and SGLT2, suggest it is cheaper, overall, to use one of these newer agents at an acquisition cost of £30–£40 per month than sulphonylurea when costs for hypoglycaemia, weight gain, and SMBG are included.
The place of SGLT2 agents
Dapagliflozin (the first SGLT2 agent to be launched in the UK), and canagliflozin (the second to be launched) have undergone NICE technical appraisals.7,8 Dapagliflozin was recommended as a second therapy to metformin or as an add-on to insulin therapy.7 Canagliflozin was recommended as a second therapy to metformin, third with metformin plus sulphonylurea, or third with metformin and pioglitazone. Canagliflozin was also recommended as an add-on to insulin.8 In my opinion, the revised NICE CG87 guideline will need to include these agents to be in line with these technical appraisal recommendations.
What should the revised 2015 NICE guideline on type 2 diabetes include?
The benefits of good glycaemic control in the first few years following diagnosis of type 2 diabetes has, in the author’s opinion, become well established over recent years. This control needs to be achieved without causing hypoglycaemia. However, once type 2 diabetes is established, especially when there are cardiovascular complications, there are no benefits to intensive glucose control. This is highlighted by the outcomes of the ADVANCE9 and ACCORD10 trials, which investigated the effects of intensive glucose control on cardiovascular events compared with standard glucose control. Intensive glucose control reduced HbA1c to levels at or below 48 mmol/mol (6.5%), compared with an HbA1c of 54–59 mmol/mol (7.3%–7.5%) following standard control. In the ADVANCE trial there was no difference in the number of deaths between the normal and intensive glucose control groups, while in the ACCORD study, more people died in the intensive control arm.9,10
Therefore, glycaemic control targets clearly need to be discussed, agreed, and individualised. Below, I have provided suggestions for what could be included in the revised guideline in relation to blood glucose targets, sequencing of agents, and newer agents.
Blood glucose targets
In the first 5–10 years from diagnosis, individualise the glycaemic control target in discussion with the person with diabetes, with the aim of achieving an HbA1c level of below 53 mmol/mol (7%) when this can be safely done without risk of hypoglycaemia.
Ten years plus after diagnosis, individualise the glycaemic control target in discussion with the person with diabetes with the aim of achieving an HbA1c between 53 and 64 mmol/mol (7%–8%) when this can be safely done without risk of hypoglycaemia.
The sequence in which agents are used
Metformin should be the usual first choice for monotherapy in the majority of people with type 2 diabetes. Levels can be up titrated, if necessary, to a usual maximum of 1 g twice daily.
When an additional glucose lowering agent is required, an oral agent appropriate to the needs of the individual should be chosen. This might include a DPP4 inhibitor, an SGLT2 inhibitor, pioglitazone, or a sulphonylurea. I am not sure how much the guideline wording should encourage the use of pioglitazone, as an add-on agent to metformin. Pioglitazone is a relatively cheap, generic agent, but there have been concerns due to an increased risk of fractures and bladder cancer following its use; however, pioglitazone data from one randomised control trial11 and from observational studies12 suggest that it protects against cardiovascular ischaemic events.
If a third glucose lowering agent needs to be added, a GLP-1 agonist or insulin therapy should be considered or the use of a third oral agent, depending on the circumstances and wishes of the individual.
I expect the updated guideline will treat DPP4 agents generically and recommend them either as second- or third-line therapy, or, in someone on insulin, as an add-on in line with the licence of each individual DPP4 agent. I also speculate that SGLT2 agents will be recommended as second- and third-line agents, or as an addition to insulin in line with the licence of each individual SGLT2 agent.GLP-1 agents are likely to be treated generically and be recommended for use as third-line glucose lowering therapies in line with their individual licences.
This has been my personal view on the area of glucose control in type 2 diabetes.
It will be interesting to see how the revised CG87 NICE guideline on type 2 diabetes deals with the issues I have outlined and how many of my speculations are realised. The release of the draft for consultation is expected around December 2014.
- NICE. Type 2 diabetes: the management of type 2 diabetes. Clinical Guideline 87. London: NICE, 2009. Available at: www.nice.org.uk/guidance/cg87/resources/cg87-type-2-diabetes-newer-agents-a-partial-update-of-cg66-short-guideline2
- NICE. Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young people and adults. Clinical Guideline 15. London: NICE, 2004. Available at: www.nice.org.uk/guidance/cg15
- NICE. Type 2 diabetes foot problems: prevention and management of foot problems. Clinical Guideline 10. London: NICE, 2004. Available at: www.nice.org.uk/guidance/cg10
- NICE. Diabetes in pregnancy: management of diabetes and its complications from pre-conception to the postnatal period. Clinical Guideline 63. London: NICE, 2008. Available at: www.nice.org.uk/guidance/CG63
- Inzucchi S, Bergenstal R, Buse J et al. Management of hyperglycaemia in type 2 diabetes: A patient centered approach. Diabetes Care 2012; 35 (6): 1364–1379.
- IDF Global Guideline. Managing older people with type 2 diabetes. Brussels: IDF, 2013. Available at: www.idf.org/global-guideline-type-2-diabetes-2012
- NICE. Dapaglifozin in combination therapy for treating type 2 diabetes. Technology Appraisal 288. NICE, 2013 Available at: www.nice.org.uk/guidance/TA288
- NICE. Canagliflozin in combination therapy for treating type 2 diabetes. Technology Appraisal 315. NICE, 2014. Available at: www.nice.org.uk/guidance/TA315
- The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560–2572.
- The Action to Control Cardiovascular Risk in Diabetes Study (ACCORD). Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545–2559.
- Dormandy J, Charbonnel B, Eckland D et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–1289.
- Tzoulaki I, Molokhia M, Curcin V et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ 2009; 339: b4731.G