Dr Brian Karet reviews the 2009 NICE guideline on newer agents for diabetes and the implications for primary care management

Diabetes is a common and expensive condition to manage. Most healthcare experts agree that the UK is facing a huge rise in the number of people with diabetes: since 1996 the number of people diagnosed has increased from 1.4 million to 2.6 million and there are around another 500,000 who have not been diagnosed. By 2025 it is estimated that over 4 million people will have diabetes.1

Most of these cases will be type 2 diabetes because of the ageing population and the rapidly rising numbers of people who are overweight and obese. The prevalence of diagnosed diabetes is approximately 5.1% in England and 4.6% in Wales; with around 90% of these individuals having the type 2 form.1 Diabetes is estimated to account for at least 10% of healthcare expenditure in the UK and the drug costs associated with this condition are a staggering £650 million in England alone—up by 40% in the last 5 years and comprising almost 8% of all drugs prescribed.2

It is therefore appropriate that this article reviews what developments have taken place in the year following publication of the NICE guideline on newer agents for glucose control in type 2 diabetes (Clinical Guideline 87 [CG87]).3 It is important to note that NICE was asked to give advice only on the use of licensed drugs available in September 2008 that had not been accessible in the 2 years preceding this time, and not to judge whether these drugs had any benefit in terms of vascular risk. The importance of this has been demonstrated by the very recent debate about the increased cardiovascular risks associated with rosiglitazone—the European Medicines Agency (EMA) has now recommended the suspension of the marketing authorisations for rosiglitazone-containing anti-diabetes medicines; doctors should stop prescribing these medications; and patients taking rosiglitazone-containing medicines should be reviewed in a timely manner to amend their treatment.4

Supporting self management

The NICE guideline emphasises the importance of giving every patient with diabetes the opportunity to engage in a structured education programme that focuses on the importance of lifestyle changes.3

Glycaemic control

Although lifestyle interventions (diet and physical activity) are the first-line treatments in the management of type 2 diabetes, most patients subsequently need sequential addition of oral glucose-lowering drugs.3 The guideline has not altered the targets for glycated haemoglobin (HbA1c):3

  • <6.5% (48 mmol/mol) in people who are receiving no pharmacological treatment or just one medication for their diabetes
  • <7.5% (58 mmol/mol) in people receiving two or more glucose-lowering medications.

The previous NICE guideline (Clinical Guideline 66) on diabetes reiterated the almost worldwide unanimity that metformin should be used as a first-line oral therapy. Treatment should start at a dose of 500 mg and build up slowly to minimise side-effects, with the sulfonylureas added as second-line therapy if glycaemic control remains poor or deteriorates.

Newer agents

In recent years several new agents have been developed to control blood glucose levels and CG87 covers the following of these in detail:3

  • dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin—also known as gliptins or incretin enhancers)
  • thiazolidinediones (pioglitazone, rosiglitazone—however NICE has since withdrawn its recommendations on the use of rosiglitazone, in line with the EMA)
  • GLP-1 mimetics also known as incretin mimetics (exenatide)
  • long-acting insulin analogues (insulin detemir and insulin glargine).

Neither the DPP-4 inhibitor, saxagliptin, nor the GLP-1 mimetic, liraglutide, were covered in CG87 as these drugs had not received marketing authorisation at the time of publication. NICE published a technology appraisal on liraglutide in October 2010.5

For several years, thiazolidinediones were believed to be the natural next step after and possibly instead of sulfonylureas. However, given the problems associated with thiazolidinediones (weight gain, heart failure, and fractures3), the arrival of drugs that mimic the incretin effect of prandial release of an enzyme which stimulates insulin production and suppresses glucagon, seemed highly appealing.

Although CG87 covers DPP-4 inhibitors and injectible GLP-1 mimetics separately, both of these drugs essentially do the same thing. The difference is that DPP-4 inhibitors are oral drugs with few side-effects6 and no effect on weight, and GLP-1 mimetics are injectable, with significant side-effects (predominantly nausea although it was generally mild and usually subsided) and profound weight loss, but not in all patients.3 The reason being that GLP-1 mimetics result in a level of circulating incretin that is approximately three times as high as that achieved with DPP-4 inhibitors.7 Both drug types result in very low rates of hypoglycaemia except when used with sulfonylureas.3,8 Dipeptidyl peptidase-4 inhibitors are excreted renally and should be used with caution in patients with a low estimated glomerular filtration rate.9

The main differences between the DPP-4 inhibitors are as follows: sitagliptin is used once a day and has a licence for triple oral therapy; saxagliptin is a once a day therapy but does not have a licence for triple oral therapy or for use with insulin; and vildagliptin is taken twice a day and, like saxagliptin, also does not have a licence for triple oral therapy or use with insulin.3 In the GLP-1 mimetics group, liraglutide is used once a day compared with twice a day for exenatide, and may cause less nausea.5,10 The possible risk of pancreatitis with GLP-1 mimetics (and possibly DPP-4 inhibitors too) is mentioned in the NICE guideline, but so far this does not seem to be a significant problem.3

The NICE guideline makes it clear that GLP-1 mimetics are licensed at present as drugs to treat diabetes and not as weight-loss drugs and should only be used in people with a body mass index over 35 kg/m2, except in exceptional circumstances, which include occupational issues arising out of insulin use. These therapies are an option if weight loss would benefit other significant obesity related co-morbidities.3

Other oral drugs for lowering blood glucose include alpha-glucosidase inhibitors (acarbose) and meglitinides (repaglinide and netaglinide), which are essentially very short-acting sulfonylureas.11

Treatment continuation

Both DPP-4 inhibitors and GLP-1 mimetics should be continued only if they have demonstrated efficacy within 6 months (see Table 1).3 The NICE guideline emphasises that the target for blood glucose level may be above that of 6.5% set for people with type 2 diabetes.3

Table 1: Thresholds for continuing treatment with the newer agents3
  Reduction in HbA1c (%) Timing
DPP-4 inhibitor ?0.5 Within 6 months
Thiazolidinedione ?0.5 Within 6 months
Exenatide ?1.0 AND 3% weight loss Within 6 months

Insulin therapy

As type 2 diabetes is a progressive condition, with secretion of insulin decreasing over time, most people will eventually need therapy with insulin. Healthcare professionals can prescribe a variety of insulin formulations, including long- or short-acting formulations, or a pre-mixed (biphasic) combination of short- and long-acting insulins and there is recent evidence that the use of insulin early in the course of type 2 diabetes significantly reduces disease progression and improves quality of life.12

The long-acting human insulin analogues have made life much easier for the GP generalist to become familiar with a straightforward insulin regimen. Large trials, such as the 4-T study13 and AT.LANTUS14 have shown that use of a long-acting analogue results in effective achievement of glycaemic control with less hypoglycaemia (compared with older NPH insulins and more complex regimens) and less weight gain with the added benefit of once-daily injections. They are however, more expensive than older NPH insulin and the guideline makes a valiant if somewhat futile attempt to encourage first-line use of older insulin;15 sales and usage of analogue insulins are rising while those of NPH insulins are falling.16

A structured programme for patients on insulin therapy is recommended by NICE (see Box 1, below).

Summary

Overall, this is a useful guideline covering new (and expensive) therapies and makes a good case for the early use of insulin, which is to be applauded. Unfortunately it does not take a dispassionate view as to whether throwing more and more medications at people with type 2 diabetes works in the long run and is cost effective. New initiatives like care planning, where patient engagement in treatment is truly supported, may do more to improve the lives of people with diabetes and control the spiralling cost and impact of diabetes.

Box 1: Structured programme for insulin therapy3

People starting on insulin need:

  • structured education
  • continuing telephone support
  • frequent self-monitoring
  • dose titration to target
  • dietary understanding
  • management skills for hypoglycaemia
  • management of acute changes in plasma glucose control
  • management of intercurrent illness (sick day rules)
  • support from an appropriately trained and experienced healthcare professional.

References

  1. Diabetes UK. Diabetes in the UK 2010: Key statistics on diabetes. Diabetes UK, 2010.
  2. The Information Centre for Health and Social Care. Prescribing for diabetes in England 2004/5 to 2009/10. Leeds: The Health and Social Care Information Centre, Prescribing Support and Primary Care Services, 2010.
  3. National Institute for Health and Care Excellence. Type 2 diabetes—newer agents (partial update of CG66). Clinical Guideline 87. London: NICE, 2009. Available at: www.nice.org.uk/guidance/CG87 nhs accred
  4. European Medicines Agency. European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim. London: EMA, 2010.
  5. National Institute for Health and Care Excellence. Liraglutide for the treatment of type 2 diabetes mellitus. Technology Appraisal 203. London: NICE, 2010. Available at: www.nice.org.uk/guidance/TA203 nhs accred
  6. Stein P, Williams-Herman D, Khatami H et al. Sitagliptin, a selective DPP-4 inhibitor, is well tolerated in patients with type 2 diabetes: pooled analysis of 5141 patients in clinical trials for up to 2 years. (Abstract 534). Presented at the American Diabetes Association (ADA) 67th Scientific Sessions; June 22–26, 2007; Chicago, Illinois.
  7. Boyle P, Freeman J. Application of incretin mimetics and dipeptidyl peptidase IV inhibitors in managing type 2 diabetes mellitus. J Am Osteopath Assoc 2007; 107 (Suppl): S10–16.
  8. Marre M, Shaw J, Brändle M et al; LEAD-1 SU study group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med 2009; 26 (3): 268–278.
  9. White J. Dipeptidyl peptidase-IV inhibitors: pharmacological profile and clinical use. Clinical Diabetes 2008; 26 (2) 53–57.
  10. Buse J, Rosenstock J, Sesti G et al; LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6).Lancet 2009; 374 (9683): 39–47.
  11. National Collaborating Centre for Chronic Conditions. Type 2 diabetes: National clinical guideline for management in primary and secondary care (update). London: RCP, 2008. Available at: www.nice.org.uk/guidance/CG87 nhs accred
  12. Opsteen C, Qi Y, Zinman B, Retnakaran R. Effect of short-term intensive insulin therapy on quality of life in type 2 diabetes. J Eval Clin Pract 2010; Sep 16 (Epub ahead of print).
  13. Holman R, Thorne K, Farmer A et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007; 357 (17): 1716–1730.
  14. Davies M, Lavalle-Gonzalez F, Storms F et al; AT.LANTUS Study Group. Initiation of insulin glargine therapy in type 2 diabetes subjects suboptimally controlled on oral antidiabetic agents: results from the AT.LANTUS trial. Diabetes Obes Metab 2008; 10 (5): 387–399.
  15. British National Formulary. BNF 60—September 2010. London: BMJ Group, Pharmaceutical Press, 2010.
  16. McEwan P, Poole C, Tetlow T et al. Evaluation of the cost-effectiveness of insulin glargine versus NPH insulin for the treatment of type 2 diabetes in the UK. NHS Economic Evaluation Database, 2007.G
  • The NICE guideline could potentially represent a major cost pressure to PBC consortia and PCTs through the increased use of the newer more expensive agents
  • There is confusion as to the HbA1c level for progressing to newer agents or insulin; in most cases, this will be 7.5% unless metformin or sulfonylurea is contraindicated or not tolerated (pioglitazone or a DPP-4 inhibitor can be used second line if this is the case)
  • An educational program around this guidance, supported by audits and a local prescribing incentive scheme for the newer agents, could help reduce costs and support NICE implementation
  • Such an incentive scheme could also focus on ensuring that the target HbA1c reductions with newer agents are met after 6 months and that these agents are withdrawn where this is not met
  • PCTs, PBC consortia, and LMCs could consider agreed exception criteria for the QOF DM23 indicator for individuals whose HbA1c lies between 7% and 7.5% and cannot be lowered further without breaching NICE guidance (for this year only as this target may be changed back to 7.5% in 2011)
  • GP commissioners should consider commissioning a specialist diabetic nurse and/or GPwSI service to support primary care prescribers in the effective use of the newer agents
  • Liraglutide is now approved for use with conditions similar to that of exenatide.

HbA1c=glycated haemoglobin; LMC=local medical committees; QOF=quality and outcomes framework