Professor John Petrie (left), Dr Richard Quigley, and DrMoray Nairn discuss the SIGN 116 guideline on diabetes and the influence of recent trial data and advances in drug therapy
- Targets for HbA1c should be tailored to the individual patient (usually <7.0%)
- GPs should engage with managed clinical networks to ensure provision of appropriate structured education and psychological support for people with diabetes
- The pharmacological management of glycaemia can be guided by the algorithm in the SIGN guideline
- There will be an increased use of injectable agents in primary care, particularly GLP-1 agonists
- Aspirin is no longer indicated for the primary prevention of cardiovascular disease in patients with diabetes (based on recent trial evidence)
- The blood pressure target for patients with diabetes is <130/80 mmHg
- The frequency of eye screening has been reduced to once every 2 years in patients with no diabetic retinopathy
The SIGN guideline on the management of diabetes (SIGN 55),1 published in 2001, was one of the first guidelines on diabetes that was developed neither by ‘good old boys sitting around the table’ nor in an ivory tower by faceless civil servants. Instead, it was developed on the basis of the unique SIGN process (www.sign.ac.uk/methodology/index.html), which supports volunteer professionals from a wide range of care disciplines—along with individuals affected by diabetes—to undertake comprehensive and systematic tabulating and grading of clinical evidence, largely independent of cost-considerations (these are the remit of a different body in Scotland). This process is designed so that SIGN guidelines are read and used by the clinical community rather than being filed under ‘W’ (for waste paper).
By the mid ‘noughties’, many sections of SIGN 55 were becoming outdated in the face of a rapid accumulation of new agents and evidence. However, SIGN was aware that a new NICE guideline on diabetes treatment was in development. Although NICE guidance has no formal status in Scotland, it was considered timely by SIGN to await the NICE publication, as its evidence review could potentially inform the SIGN process.
NICE Clinical Guideline 66 on the management of type 2 diabetes was launched in May 2008,2 however some sections were already outdated at publication3—mainly due to the timing of product launches. Although NICE CG87 on newer agents was provided as a rapid update in May 2009,4 busy healthcare professionals can find it challenging to cross-refer between two documents.
Revision of the SIGN 55 guideline in 2008 provided an opportunity to draw guidance on drug therapy into a single document, while taking account of key clinical trials that had subsequently been published and the launch of various new agents onto the market. Another aim was to go well beyond a simple review of drug treatment, with coverage of both type 1 and 2 diabetes across a range of topics including lifestyle management, pregnancy, renal disease, prevention of visual impairment, and management of foot disease.5 The process in itself was seen as having added benefit in once again drawing together the Scottish diabetes community to promote evidence-based practice.
Guideline Development Groups (GDGs) for each of the nine chapters of the SIGN guideline were established by late 2008. A tight timetable was specified for a draft to be available for peer review and consultation by September 2009 for formal launch in March 2010 (which was achieved). A novel SIGN methodology was adopted that allowed retention of unaltered sections in which the evidence base was judged unchanged, reserved formal review of evidence for specific areas, and permitted incorporation of NICE evidence tables into the review process as per the rules of the Appraisal of Guidelines, Research, and Evaluation Collaboration (AGREE: www.agreecollaboration.org). A total of 1945 papers were reviewed and 759 references were cited in the final guideline.
In addition to the main guideline, the SIGN guidance is also available as a Quick Reference Guide along with an excellent Plain English booklet for patients and carers (www.sign.ac.uk/guidelines/fulltext/116/index.html). Some of the key recommendations of SIGN 116 on Management of diabetes are summarised below. Grades relating to the strength of the supporting evidence on which recommendations are based, along with good practice points (GPP), are shown in brackets.
Improving diagnosis and assessment of diabetes
There are no changes in SIGN 116 on the recommendations from SIGN 55 on the diagnosis of diabetes (standard American Diabetes Association/World Health Organization criteria) and the recommendations underpinning the successful Scottish eye and foot screening programmes were also by and large retained.
There are two new major recommendations in the areas of assessment and screening:5
- Regular assessment of psychosocial problems in children and adults with type 1 diabetes is reiterated, including screening for anxiety, depression, and eating disorders (Grade B)
- People with no diabetic retinopathy can be screened every 2 years (Grade B) under the Scottish Diabetic Retinopathy Screening Programme (all other patients with diabetes should be screened annually). The evidence review indicated that this would safely permit better targeting of individuals at higher risk.
Management of type 1 diabetes
The SIGN 116 revision of the SIGN 55 chapter on Children and young people with diabetes is entitled Management of type 1 diabetes. The aim of optimising glycaemia towards a normal level is maintained, while a major change is the explicit recommendation of continuous subcutaneous insulin infusion (CSII or ‘pump’) therapy for individuals who are unable to achieve therapeutic targets (Grade A) or who are experiencing recurrent severe hypoglycaemia (Grade B).5
The original SIGN 55 guideline had no dedicated section on glucose-lowering agents in the management of type 2 diabetes:1 it was implicitly assumed that the benefits of the available glucose-lowering agents (metformin, sulphonylureas, and insulin) would be proportional to their effects on glycated haemoglobin (HbA1c) levels. The only entirely new chapter in SIGN 116 is therefore on this topic.
Targets for glycaemic control
There was a wealth of relevant new evidence available to help determine whether the original SIGN 55 HbA1c target of ‘around 7.0%’ should be revised (e.g. ACCORD,6 ADVANCE,7 VADT8 trials) against a background of NICE having set a target of ?6.5%.3,4 The final SIGN recommendation was an HbA1c target of 7.0%, with a lower target of 6.5% for patients with more recent-onset diabetes (in whom this can more easily be achieved) (Grade A).5 As in the NICE guideline,3,4 there is an emphasis on tailoring HbA1c targets to the individual, as agreed between them and their physician.
One difference from the advice recommended by NICE is that in the SIGN guideline, the target is not relaxed from 6.5% to 7.5% once dual therapy is prescribed.4,5
Management of glycaemic control
For non-pharmacological management of blood glucose, SIGN 116 recommends that people with diabetes should be offered lifestyle interventions based on a valid theoretical framework (Grade A). Patients should also have access to structured education programmes based on adult learning theories (Grade A). Psychological interventions to improve glycaemic control should be offered to patients (Grade A). Weight management programmes should be offered (Grade A) if needed.5
An algorithm (see Figure 1), which aims to be simpler than the one in NICE CG87, is provided to guide pharmacological management of glycaemic control.5 It is acknowledged explicitly as being based on both clinical evidence and the clinical experience of the GDG.
First-line drug therapy
The advent of several new oral glucose-lowering agents after publication of SIGN 55 in 2001 has not altered the original recommendation of using metformin as first-line choice for drug therapy in patients who are overweight (Grade A).5 This position was strengthened by post-randomisation long-term cardiovascular endpoint data from the UK Prospective Diabetes Study.9 Sulphonylureas are recommended as first-line therapy for patients who are not overweight, or for whom metformin is unsuitable (Grade A).5
Second-line drug therapy
The algorithm positions sulphonylureas as the usual second ‘add-in’ agent with metformin,5 although this is not supported by any direct evidence. Unlike metformin, sulphonylureas do not appear to improve cardiovascular outcomes, but neither do they cause some of the adverse effects that are associated with thiazolidinediones (TZDs) (e.g. fluid retention, fractures) and they also have a longer safety track record than dipeptidyl peptidase-4 (DPP-4) inhibitors.
The algorithm favours TZDs and DPP-4 inhibitors as second-line options where sulphonlyureas are not tolerated or where there are specific reasons to be concerned about hypoglycaemia as an adverse effect of sulphonylureas.5 A DPP-4 inhibitor will be chosen where there is congestive heart failure or may be chosen where there are concerns about TZD-induced weight gain. In these difficult decisions, the evidence base is clearly insufficiently robust to derive formal evidence-based guidance: healthcare professionals should be in a position to discuss the advantages and disadvantages of the available therapeutic choices with their patients. The short safety track record and as yet uncertain cardiovascular effects of DPP-4 inhibitors should be borne in mind, as well as data suggesting potential reductions in cardiovascular disease event rates with one of the TZDs (pioglitazone).5
Third-line drug therapy
The algorithm allows a number of options for third-line treatment, which can either be added in as ‘triple therapy’ or substituted for therapy seen as ineffective at the second-line stage.5 As there are few ‘head-to-head’ clinical trials to inform these decisions, the development of the algorithm was also based on the clinical experience of the GDG.
A major factor at this stage is the readiness of the individual to consider using an injectable agent. In some cases, a third oral agent will be added in as a ‘stopgap’ with the expectation that it may at least control symptoms during a period of adjustment to the prospect of injections.
For patients with a BMI >30 kg/m2 who are willing to use injectable therapy, either a glucagon-like peptide-1 (GLP 1) agonist (exenatide or liraglutide) or a basal insulin are available options. Many patients and healthcare professionals perceive GLP-1 agonists as a more acceptable initial injectable therapy in view of their ability to control or reduce weight, and a lower probability of hypoglycaemia. However, these agents are associated in some individuals with nausea and even vomiting,5 particularly where calorie excess is maintained. Metformin and sulphonylurea therapy will usually be continued during treatment with GLP-1 agonists with the dose of sulphonylurea reduced at least in the first instance.5
Insulin, with associated self monitoring of blood glucose and the risks of weight gain and hypoglycaemia, is often considered a more intensive treatment option than GLP-1 agonist therapy. It requires additional patient education and expertise on the part of healthcare professionals.
Although there is no clear evidence to indicate the optimum stage at which to start insulin, the SIGN guideline contains several recommendations to guide the process once the decision is taken.5 These recommendations are informed by the 3-year results of the ‘4-T’ study published in October 2009.10
Thus, insulin should be initiated as a bedtime basal injection (Grade A) of intermediate acting (isophane) insulin, or a long-acting insulin analogue where nocturnal hypogylcaemia is a concern (Grade A). The dose should be titrated against the morning fasting blood glucose, with oral metformin and sulphonylurea therapies continued (Grade A). If blood glucose cannot be maintained during the daytime on this regimen, additional doses of prandial short-acting insulin (either soluble human insulin or rapid-acting analogue insulin) can be added (Grade A) as necessary to ‘intensify’ treatment; at this stage, sulphonylureas are usually discontinued.5
|Figure 1: Pharmacological management of glycaemic control5|
HbA1c=glycated haemoglobin; DPP-4=dipeptidyl peptidase-4; NPH=neutral protamine hagedorn; GLP-1=glucagon-like peptide-1; BMI=body mass index
Preventable risk factors
As in SIGN 55,1 and in contrast to many other guidelines, the SIGN 116 recommendations on blood pressure, cholesterol, and smoking management in diabetes are presented conveniently in the same document as those for glycaemia.5 Many of the recommendations are unchanged from SIGN 55.
One significant change is the reversal of the SIGN 55 recommendation to prescribe aspirin 75 mg daily to all people with type 2 diabetes with a 10-year coronary heart disease risk of >20% (Grade B).1 SIGN 116 recommends that aspirin is not recommended for primary prevention of vascular disease in diabetes (Grade A) on the basis of evidence from the POPADAD study and subsequent meta-analyses.5,11
The systolic blood pressure target in SIGN 116 has been reduced from 140 mmHg in SIGN 55 to 130 mmHg in line with other guidelines including those published by the Joint British Societies (JBS 2).13 It should be noted that the evidence review upon which this was based predated the results of the ACCORD blood pressure lowering study, which did not show any benefit in reducing blood pressure below 140 mmHg in patients with type 2 diabetes mellitus.13 The SIGN guideline endorses the British Hypertension Society ‘A/CD algorithm’ in recommending combination therapy as required with agents that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers), calcium channel blockers, and thiazide diuretics.14
Rather than recommending any statin for primary prevention in those with a total cholesterol >5.0 mmol/l as in SIGN 55, SIGN 116 recommends simvastatin 40 mg or atorvastatin 10 mg for all patients with type 2 diabetes who are aged >40 years (Grade A), with intensification to atorvastatin 80 mg for those in a secondary prevention category (Grade A). In type 1 diabetes, simvastatin 40 mg is recommended for all patients who are >40 years of age (Grade B).
The GDG found no evidence that counselling strategies or pharmacological interventions aimed at smoking cessation should differ from those used in individuals who are non-diabetic. The guideline recommends intensive management plus pharmacological therapies for all those patients wishing to stop smoking (Grade B).5
Diabetes in pregnancy
The recommendations on managing women with diabetes who are pregnant have been extensively revised and extended from SIGN 55. Much of this section is beyond the remit of primary care. In particular, the guideline endorses the use in Scotland of new criteria for diagnosis of diabetes in pregnancy.15 Of note it provides safety reassurance for women treated in early pregnancy with metformin (Grade B) and for the first time recommends metformin as an initial treatment for gestational diabetes (Grade B).5
Diabetic kidney disease
SIGN 116 recommends the use of albumin:creatinine ratio (ACR) (at least two of three first pass morning specimens positive) rather than just urinary albumin concentration in screening for microalbuminuria/diabetic kidney disease (Grade B). Once proteinuria is confirmed, it should be reduced to the lowest possible level regardless of the baseline urinary protein excretion (Grade A).5
Diabetic foot disease
The SIGN 116 section on managing diabetic foot disease maintains the SIGN 55 ‘traffic-light’ grading system of individuals at low, moderate, or high risk of foot ulceration at annual screening, although it has been redrawn in a more attractive format. The guideline now explicitly states that patients with active foot disease should be referred to a multidisciplinary diabetic foot care service (Grade C).5
Promoting best practice in primary care and improving patient care
In many parts of Scotland, diabetes care is increasingly led from primary care, particularly between diagnosis and initiation of injectable therapy. Although the setting for injectable therapy initiation is not specified by SIGN, the guideline is seen as advocating increased use of injectable (GLP-1) therapy, and many GPs have drawn the conclusion that they will have to do this in primary care (this was evident in the workshops held at guideline launch). This is likely to involve a need for continuing medical education for healthcare professionals, which will be organised by the SIGN implementation groups, most likely with assistance from the Association of the British Pharmaceutical Industry Scottish Diabetes Industry Group.
General practitioners were involved in the GDGs for both SIGN 55 and SIGN 116. This reflects the close collaboration between primary and secondary care in the management of diabetes in Scotland via managed clinical networks (MCNs) and is in itself a powerful tool towards implementation. SIGN is now engaging with the MCNs in an implementation phase following a successful launch conference in March 2010, which was well attended by healthcare professionals from all disciplines from across Scotland.
Many of the SIGN guideline recommendations have been adopted at a political level by the Scottish Government’s ‘Diabetes action plan’, which will be launched in May 2010.16 This will reinforce and help resource the SIGN 116 recommendations on access to structured education, and make provision for the training of healthcare professional teams (e.g. in psychological support skills). Diabetes UK (Scotland) was represented on the overall guideline Steering Group, and is playing an active role in publicising the guideline among patients with diabetes in Scotland.
The annual Scottish Diabetes Survey,17 which requires health boards to provide detailed statistics on key quality indicators of diabetes management, plays a major role in improving the quality of diabetes care in Scotland. Year-on-year improvements have been documented in glycaemia, blood pressure, and lipid control at a population level, along with improved screening coverage for complications.17 This process is greatly facilitated by the national clinical information system, Scottish Care Information—Diabetes Collaboration (SCI-DC).18
It is gratifying that recent evidence from some areas of Scotland, particularly Tayside, indicates falling rates of microvascular complications, including eye disease (as measured by requirement for laser therapy),20 and foot disease (as measured by rates of amputations).20
The updated SIGN guideline and its associated Quick Reference Guide and Plain English booklet provide a comprehensive and accessible framework of clinical practice recommendations for GPs based on a high quality and up-to-date review of the clinical evidence.
- The SIGN guideline produced for Scotland differs in its recommendations compared with the NICE guidance for England and Wales
- Commissioners will need to be sensitive to these differences in designing and adapting local care pathways
- Commissioners should always ensure patients have access to structured educational programmes (e.g. DESMOND)—these can help save costs on pharmacological therapies, but are not universally available at present
- The advice on self monitoring of blood glucose (Grade B) is useful in limiting its routine use to patients taking insulin and sulphonylureas as this can add £92 a year to health costs
- The guideline supports a target HbA1c level of 7% or under in line with the DM 23 domain in the quality and outcomes framework, but differs from NICE guidance
- Aspirin is no longer recommended for primary cardiovascular disease prevention
- The Scottish Intercollegiate Guidelines Network. Management of diabetes. SIGN 55. Edinburgh: SIGN, 2001.
- 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. Available at: www.nice.org.uk/guidance/CG66
- Goenka N. GPs should familiarise themselves with newer agents for diabetes. Guidelines in Practice 2009; 12 (9): 13–21.
- National Institute for Health and Care Excellence. Type 2 diabetes: newer agents. Short clinical guideline 87. London: NICE, 2009. Available at: www.nice.org.uk/guidance/CG87
- The Scottish Intercollegiate Guidelines Network. Management of diabetes. SIGN 116. Edinburgh: SIGN, 2010. Available at: www.sign.ac.uk/guidelines/fulltext/116/index.html
- Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein H, Miller M, Byington et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358 (24): 2545–2559.
- ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358 (24): 2560–2572.
- Duckworth W, Abraira C, Moritz T et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Eng J Med 2008; 360 (2): 129–139.
- Holman R, Paul S, Bethel M et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359 (15): 1577–1589.
- Holman R, Farmer A, Davies M et al; 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med 2009; 361 (18): 1736–1747.
- Belch J, MacCuish A, Campbell I et al; The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. Br Med J 2008; 337: a1840.
- British Cardiac Society, British Hypertension Society, Diabetes UK et al. JBS 2: Joint British Societies guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 (Suppl 5): v1–52.
- The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; Mar 14 (Epub ahead of print).
- Williams B, Poulter N, Brown M et al. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004; BHS IV. J Hum Hypertens 2004; 18 (3): 139–185.
- International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010; 33 (3): 676–682.
- Diabetes UK Scotland. Diabetes action plan 2010–2013: a summary. Diabetes UK Scotland, 2010. Available at: http://www.diabetesinscotland.org.uk/Publications/Diabetes%20Action%20Plan%202010-2013%20Summary.pdf
- Scottish Public Health Observatory website. Diabetes: Scottish Diabetes Survey. www.scotpho.org.uk/home/Healthwell-beinganddisease/Diabetes/Data/diabetes_scottishsurvey.asp (accessed 7 May).
- Diabetes in Scotland website. Scottish Care Information—Diabetes Collaboration. www.diabetesinscotland.org.uk/Groups.aspx?catId=C6 (accessed 7 May).
- Vallance J, Wilson P, Leese G et al. Diabetic retinopathy: more patients, less laser: a longitudinal population-based study in Tayside, Scotland. Diabetes Care 2008; 31 (6): 1126–1131.
- Schofield C, Yu N, Jain A, Leese G. Decreasing amputation rates in patients with diabetes—a population-based study. Diabet Med 2009; 26 (8): 773–777.G