The number of patients with diabetes mellitus continues to escalate dramatically. Rates of diabetes are increasing across the world. In 2007 it was estimated that 2.45 million people in the UK population had diabetes (Yorkshire & Humber Public Health Observatory, 2007). In 2012 this has risen to 2.9 million people, and it is predicted that by 2025 there will be 5 million people in the UK with diabetes (Diabetes UK, 2012). Worldwide there were thought to be 366 million people with diabetes in 2011 – 90% of patients with diabetes have type 2 diabetes (Whiting et al, 2011). The commonest cause of death in diabetes remains cardiovascular disease, and it accounts for 44% of all deaths in people with type 1 diabetes and 52% of deaths in people with type 2 diabetes (Morrish et al, 2001). Life expectancy is shortened considerably by both types of diabetes – more than 20 years for type 1 diabetes and up to 10 years for type 2 (Department of Health [DH], 2001).
Allied to this increase in prevalence of type 2 diabetes is the growing number of people with intermediate or borderline hyperglycaemia (often known as pre-diabetes). This condition carries a raised cardiovascular risk (Tabák et al, 2012) and the challenge to primary care still remains that of early diagnosis, effective intervention and, if possible, prevention of both of these disorders.
Recent changes in diagnosis will soon have a major impact on primary care, but the major issues remain: how can we define diabetes and pre-diabetes and how can we prevent people developing these potentially life-threatening conditions and their complications?
What is diabetes?
It is recognised that chronically raised blood glucose (hyperglycaemia) has numerous implications for the health of the individual. Diabetes mellitus is “a group of metabolic diseases characterised by hyperglycaemia resulting from defects in insulin secretion, action or both”. This definition by the American Diabetes Association (ADA; 2009) illustrates the fact that diabetes is a syndrome with multiple causes. The vast majority of people with diabetes fall into two main groups, i.e. type 1 and type 2 (ADA, 2009).
Type 1 diabetes is caused by an absolute deficiency of insulin, thought to be due to auto-immune destruction of pancreatic islet cells. Type 1 diabetes accounts for between 5 and 10% of all cases, and is often seen in younger people. Type 2 diabetes, however, is far more common (90% of all cases) and is usually diagnosed in people over 45 years of age who are often obese or physically inactive. It is rapidly increasing in prevalence and is the driver for the current diabetes epidemic. It is strongly dependent on ethnicity and is more common in South Asian or Afro-Caribbean populations. In these populations in the UK, people may develop type 2 diabetes at an earlier age and at a lower BMI. Unlike type 1 diabetes, type 2 diabetes is characterised by a relative insulin deficiency and is often associated with insulin resistance and features of the so-called metabolic syndrome (an increase in waist circumference and raised blood pressure, low high-density lipoprotein cholesterol, raised plasma triglycerides or a raised blood glucose; Alberti et al, 2005).
Type 2 diabetes usually develops after a long prodromal period of several years of gradually increasing glucose levels (Harris et al, 1992) and most people pass through a period of pre-diabetes before their hyperglycaemia reaches the diabetes threshold. Research published from the Whitehall II prospective study shows that people diagnosed with type 2 diabetes had a slow increase in their blood glucose levels over the 13 years of the study but then their blood glucose levels rose rapidly in the 2 or 3 years preceding the diagnosis (Tabák et al, 2009). A recent study by the Cambridge team, following up their Ely study, suggested that this lead time for diagnosing diabetes has shortened from the 9–12 years suggested in the original US study in 1992 (Harris et al, 1992) to 3.3 years in 2012 (Rahman et al, 2012). This may of course be due to greater screening and awareness of diabetes on the part of primary care teams.
Diabetes is often asymptomatic until glucose levels rise. Whatever the cause of the hyperglycaemia, however, the symptoms of diabetes include polyuria, urinary frequency and polydipsia (often waking up needing a drink in the middle of the night), all caused by an osmotic diuresis due to glycosuria. Other symptoms are weight loss (sometimes dramatic), tiredness, blurred vision and susceptibility to infections such as vaginal or penile candidiasis. Long-term complications can be disabling, even fatal, and include neuropathy, retinopathy, cardiovascular disease, sexual dysfunction and a significant impact on the individual’s quality of life and social functioning. However, even at diagnosis, around 25% of people may already have complications (UK Prospective Diabetes Study [UKPDS] Group, 1998). It has also been noted at diagnosis that by that stage nearly half of the patients’ insulin secretion had been lost (UKPDS Group, 1995), indicating that the progressive loss of insulin secretory reserve underpins the progression of diabetes with time, and, hence, the onset of symptoms.
Rarer causes of diabetes
Type 2 diabetes is generally considered to be a polygenic disorder. Monogenic, as opposed to polygenic, causes of diabetes are seen less frequently (1–2% of all cases) but nevertheless can present to GPs. For example, it is thought that each GP practice has at least one patient whose diabetes is due to maturity-onset diabetes of the young (MODY), although this is unlikely to have been recognised as such. MODY is a monogenic autosomal dominant condition often causing hyperglycaemia in people before their 20s and hence is likely to be diagnosed as either type 1 or early type 2. The chromosomal defects and functional deficiencies have now been determined. The commonest form involves a mutation in one of the liver transcription factors known as hepatocyte nuclear factor (HNF)-1 alpha. Treatment options in these people are often dependent on the patient’s genetic sub-type (e.g. the use of low-dose sulphonylureas in people with HNF-1 alpha; Murphy et al, 2008). A very practical and educational website is www.diabetesgenes.org run by Professor Hattersley’s team in Exeter.
Latent autoimmune diabetes of adulthood (LADA) is a variant of diabetes that, like MODY, is receiving more attention of late. It is relatively common and has been estimated to constitute up to 12% of people initially diagnosed with type 2 (Naik et al, 2009). It is frequently misdiagnosed but should be considered in people who do not fit the typical picture of type 2 diabetes (Appel et al, 2009). LADA is an autoimmune disorder that often presents with chronic hyperglycaemia and rarely diabetic ketoacidosis. People may be only marginally overweight and lack the other classical features of insulin resistance. Other autoimmune conditions such as thyrotoxicosis or coeliac disease are often seen in the same patient. However these people have progressive hyperglycaemia not responding to treatment and hence people with LADA will frequently need insulin treatment within several years of diagnosis as the remaining beta cells fail. In LADA, anti-pancreatic antibodies including anti-glutamic acid decarboxylase (GAD) are often positive. LADA, rather confusingly, is also known as type 1.5 diabetes as it has some characteristics of both types of diabetes! If you need advice on this type of patient your local diabetologist would be happy to help.
Coding of diabetes
With the changes in the Quality and Outcomes Framework (QOF) in 2006 there has been a steady demand for effective and accurate coding of type 1 and type 2 diabetes in general practices. In the light of the diagnostic issues described above, GPs need to be clear what type of diabetes the patient has, in order to optimise treatment and prevent complications. For example MODY can often be diagnosed as type 1 diabetes (yet insulin is often not needed); type 1 diabetes can occur in older people as highlighted in the BMJ recently (Lasserson et al, 2012), and type 2 diabetes is now seen in younger people.
A recent Working Group commission by NHS Diabetes and the Royal College of General Practitioners (RCGP) produced an excellent report in 2011 (NHS Diabetes and RCGP, 2011). This followed on from a systematic review which investigated incorrect coding and classification of diabetes (Stone et al, 2010). The Working Group identified three common failings: Misdiagnosis (the patient doesn’t actually have diabetes); Misclassification (the patient is coded as having the wrong type of diabetes); and Miscoding (when the wrong computer code is used). The Group agreed that accurate coding was a complex and exacting task but offered a simple algorithm to support classification: www.diabetes.nhs.uk/information_and_data/classification_of_diabetes_/.
It also has made available six MIQUEST queries that practices can download and use to look for evidence of misdiagnosis or misclassification in their patients. These are well worth doing as an audit in your practice and sharing with your staff or putting in your revalidation portfolio. The associated British Medical Journal editorial (Farmer and Fox, 2011) is also helpful.
Diagnosing diabetes
Diabetes can and should be diagnosed in primary care without specialist referral unless the patient’s condition is potentially life-threatening, such as diabetic ketoacidosis (DKA), or his or her hyperglycaemia is severe and needs immediate insulin treatment.
Until recently, the diagnosis of diabetes or pre-diabetes was based upon blood glucose estimations. The World Health Organization (WHO) and International Diabetes Federation (IDF; 2006) and the ADA (2009) recommended that the diagnosis of diabetes (and pre-diabetes states) was based on a blood glucose measurement that was random, fasting or after a glucose load (oral glucose tolerance test [OGTT]). Traditionally the OGTT was promoted as the gold standard for the diagnosis of diabetes and has been used extensively in epidemiological studies. However, the recommended use of repeated fasting plasma glucose estimations, which were cheap and more convenient for both doctor and patient, meant that GPs in the UK moved away from the OGTT.
However, in 2011 the WHO recommended the use of HbA1c as a diagnostic test for diabetes (WHO, 2011). It recommended that a level of ≥48 mmol/mol (6.5%) was the cut-off for diagnosing diabetes and this guidance was reiterated in UK-wide guidance via a recent consensus statement (John et al, 2012). HbA1c is known to reflect elevated levels of blood sugar (hyperglycaemia) over the preceding 2–3 months and an analysis of a venous blood sample in an accredited laboratory using quality assurance tests was recommended.
Point-of-care HbA1c tests are not recommended for diagnosis unless their performance can match that of other laboratory methods. However HbA1c, which does not need a fasting test, is far more practical than either fasting glucose tests or an OGTT and may well promote more widespread screening for diabetes. It is generally accepted that HbA1c testing identifies fewer people with diabetes than glucose tests (fasting glucose or OGTT; Inzucchi, 2012), although many people consider an OGTT to be not feasible in a primary care setting due to the need for fasting, waiting and double appointments.
John et al (2012) recommended that an HbA1c level of ≥48 mmol/mol (6.5%) should be used to diagnose diabetes in most situations but in people without diabetes symptoms, a repeat HbA1c in the same laboratory within 2 weeks was recommended. In people symptomatic of hyperglycaemia with relatively slow onset of symptoms, a single result would suffice. However, there are some clinical situations when HbA1c should not be used for diagnosis (Table 1). Perhaps the most important situation is not to use HbA1c when considering a diagnosis of type 1 diabetes. There are also difficulties in using HbA1c in people with haemoglobinopathies, anaemia or disorders causing an altered red cell lifespan.
The report also concludes that a value less than 48 mmol/mol (6.5%) does not exclude diabetes diagnosed on glucose tests. The expert group also recommended that those people with an HbA1c of 42–47 mmol/mol (6.0–6.4%) should be considered to be at high risk and the equivalent of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT; i.e. pre-diabetes). A value under 42 mmol/mol (6.0%) was considered to be “normal”. However, unlike in the UK, the ADA suggested that pre-diabetes should include people with an HbA1c of 37–47 mmol/mol (5.7–6.4%). This group they have termed increased glycated haemoglobin (IGH).
The NHS Health Check programme in the UK advocates the same use of HbA1c with a cut-off of ≥48 mmol/mol (6.5%) as diagnostic of diabetes (NHS Health Check Programme, 2009) as does the recently published NICE guidance (NICE, 2012).
It should be noted that any of these glucose or HbA1c cut-offs for the development of diabetes are in effect arbitrary thresholds along the continuum of hyperglycaemia as they are considered to be the level above which diabetic retinopathy (a specific diabetes-related microvascular complication) is more prevalent.
The introduction of diagnosis based on HbA1c now means that diabetes can be diagnosed in four ways (see Table 2). There has been considerable discussion in the international diabetes community about this change (Bonora and Tuomilehto, 2011). The situation remains rather complex and potentially confusing to those of us working in primary care. How these changes will impact on primary care and the prevalence of diabetes in the UK is not known at this time and will need to be watched carefully.
Defining pre-diabetes
Another area which is still much debated is the diagnosis of the intermediate hyperglycaemic states collectively known as pre-diabetes. All these conditions have in common the fact that blood glucose levels or HbA1c are raised, yet are not above the threshold that is diagnostic of type 2 diabetes. The two most important features of pre-diabetes in primary care are the increased risk of cardiovascular disease (CVD), which is two to three times that of normoglycaemic individuals (Coutinho et al, 1999), and the increased risk of progression to type 2 diabetes. Hence the potential for prevention of both diabetes and CVD in this high-risk group.
The term pre-diabetes has been considered by some as being potentially misleading, as a large proportion of people with pre-diabetes do not progress to diabetes. Other terms such as non-diabetic hyperglycaemia (NDH), intermediate hyperglycaemia (IH) and impaired glucose regulation (IGR) are therefore gaining in popularity. The RCGP guidelines recently suggested the term “Non-Diabetic Hyperglycaemia” as its preferred term and included IGT, IFG and gestational diabetes in this group (NHS Diabetes and RCGP, 2011).
Both IFG and IGT, for example, are increasingly prevalent. It is estimated that 5.1% of the UK population aged 20–79 may have IGT (IDF, 2003). Pre-diabetes carries an increased risk of progression to type 2 diabetes although this can vary dependent on ethnicity and other factors (Unwin et al, 2002). It is widely accepted that people with these conditions are at greater risk of both type 2 diabetes and cardiovascular disease (Coutinho et al, 1999) and interventions designed to prevent diabetes have in the main been targeted at this group. The ADA recently concluded that at least 70% of people with pre-diabetes will eventually progress to frank diabetes and it is estimated that by the year 2030, 470 million people globally will have pre-diabetes (Tabák et al, 2012).
Education of people with pre-diabetes
Our previous work in developing a pragmatic screening programme using the GP database identified a large proportion of people with pre-diabetes (Greaves et al, 2004). Studies had previously shown that people and health professionals alike were confused about the implications of the diagnosis (Wylie et al, 2002; Whitford et al, 2003; Williams et al, 2004). We therefore developed an educational package for people with pre-diabetes and their healthcare professionals. This package, known as WAKEUP (Ways of Addressing Knowledge Education and Understanding in Pre-diabetes), was found to be acceptable to both patients and healthcare professionals (Evans et al, 2007). Even in 2012, this is still one of the few resources available to give to people with pre-diabetes.
Primary prevention of diabetes
As the transition from normoglycaemia through impaired glucose regulation to type 2 diabetes takes several years it is logical to try to intervene and aim to prevent or delay the onset of diabetes before its onset. This can be at a population level or at the level of the individual patient. The best evidence exists in high-risk people with IGT or IFG.
There is now substantial evidence from large-scale randomised trials in various populations across the world that progression to diabetes can be prevented or delayed in high-risk groups both by behavioural (Tuomilehto et al, 2001; Knowler et al, 2002; Ramachandran et al, 2006) and by pharmacological interventions (Chiasson et al, 2002; Knowler et al, 2002; Torgerson et al, 2004; Gerstein et al, 2006). Box 1 gives a case study highlighting some common problems encountered in primary care.
Lifestyle
A meta-analysis has shown that lifestyle interventions can produce a 50% relative risk reduction in the incidence of type 2 diabetes at 1 year (Yamaoka and Tango, 2005). Typically these interventions are in high-risk individuals, such as those with pre-diabetes (usually IGT), and interventions are targeted at halting or slowing beta-cell dysfunction and hence incident type 2 diabetes. The majority of behavioural interventions are intensive and designed to increase an individual’s physical activity levels and encourage weight loss and dietary change. Relatively modest changes in lifestyle such as a 5% reduction in weight or an increase in moderate physical activity to 4 hours a week can have important benefits in reducing the risk of diabetes.
It was also noted that the beneficial effects observed in the Finnish Diabetes Prevention Study persisted when the people were followed up a median of 3 years after the intervention had finished (Lindström et al, 2006) and up to 10 years in the case of the Diabetes Prevention Program (DPP) in the US (DPP Research Group, 2009). Also, lifestyle change has other general benefits for the patient. Hence lifestyle interventions are the cornerstone of the treatment of pre-diabetes (Tabák et al, 2012).
Drugs
As well as lifestyle interventions, drugs have also been shown to reduce progression to type 2 diabetes. These include metformin (Knowler et al, 2002; Ramachandran et al, 2006), acarbose (Chiasson et al, 2002), orlistat (Torgerson et al, 2004) as well as troglitazone (Azen et al, 1998) and rosiglitazone (Gerstein et al, 2006) – the latter two of which have now both been withdrawn. A meta-analysis (Gillies et al, 2008) showed that drug interventions were both less effective and less cost-effective than lifestyle. There is also much debate about whether these drugs simply mask progression to diabetes by lowering blood glucose, which then rises in the subsequent wash-out period once treatment has finished. On balance, however, it is generally recognised that diabetes prevention through lifestyle or drugs is cost-effective and should be actively promoted in clinical practice (Gillies et al, 2008). However, it was only in 2012 that NICE offered formal guidance on preventing type 2 diabetes (NICE, 2012).
NICE: Preventing type 2 diabetes
Although population screening for diabetes is not thought to be appropriate (Wareham and Griffin, 2001), targeted or selective screening for both diabetes and pre-diabetes is now considered to be both effective and cost-effective (Waugh et al, 2007). NICE guidance (NICE, 2012) does not recommend a national screening programme for diabetes; instead it recommends a two-stage process of risk identification and screening. It was designed to run alongside the NHS Health Check programme (NHS Health Check Programme, 2009) and complements its previous advice on population interventions to prevent diabetes (NICE, 2011).
Initially people at high risk of diabetes will be identified using a stepped approach conducted in surgeries, pharmacies or other primary care venues. Firstly a validated risk assessment score is recommended and, secondly, a blood test (glucose or HbA1c) is taken. Those at high risk are then provided with a quality-assured, evidence-based, intensive lifestyle-change programme as outlined above.
Other screening methods such as opportunistic screening by GPs and their teams as described in our practice (Evans et al, 2008) could provide a complementary screening system but have tended to be overlooked in the recent guidance, despite the cost of a new diagnosis being £377 (Pereira Gray et al, 2012).
Validated risk assessment tools suggested include the FINDRISC and Leicester questionnaires (Lindström and Tuomilehto, 2003; Gray et al, 2010), which are both patient-completed tools and can be done online. GPs can also identify high-risk people from their practice computers using the QDScore (Hippisley Cox et al, 2009) or the Cambridge score (Griffin et al, 2000). Interestingly NICE recommends the use of metformin in treating pre-diabetes, although it is not licensed for this indication.
In the NHS Health Checks programme, (NHS Health Check Programme, 2009), which is now up and running, all people aged 40–74 who are not on a vascular disease or diabetes register will be called in for a face-to-face check and assessment of their broader vascular risk. Those who are overweight or obese or have a raised blood pressure will also be screened for diabetes along the lines that NICE recommends.
The initial pilot for the NHS Health Check programme was promising in many respects (Goyder et al, 2008). However, it has been acknowledged that uptake amongst primary care trusts in England has been variable. NICE has also suggested that other community settings such as optometrists, pharmacists and dental surgeries would be appropriate places for diabetes screening within their recommendations, although initiatives involving non-general-practice screening are in the majority at a pilot stage.
Despite all these initiatives, the challenge still remains for primary care to prevent both type 2 diabetes and its complications.
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