Dealing with complexity in type 2 diabetes

Abstract

The management of people with type 2 diabetes (or type 2 diabetes mellitus) can be complex and sits largely within the portfolio of primary care. Unfortunately, despite an ever-increasing therapeutic armoury, many people with type 2 diabetes fail to achieve optimal control of their blood glucose and other metabolic indices, putting them at higher risk of diabetes-related complications. The situation has sadly changed little over recent years. People with type 2 diabetes often have other long-term health concerns that need to be recognised and addressed alongside more traditional parameters such as blood glucose and blood pressure. In this article, we will consider the recognition and management of two of the more common conditions that co-exist in people with type 2 diabetes: Diabetes distress and renal disease. Although there is undoubtedly some overlap with type 1 diabetes, the discussion in this article solely relates to the management of type 2 diabetes.

The GP curriculum and diabetes and multi-morbidity

Clinical module 3.17: Care of people with metabolic problems states that:

GPs should understand the role of good diabetes management in prevention and/or postponement of associated morbidity and mortality

Be aware that non-concordance is common for chronic metabolic conditions, e.g. diabetes, and respect the patient’s autonomy when negotiating management

Recognise the risk of co-morbid mental health problems in people with metabolic problems such as diabetes and obesity, and the effect of these on morbidity and mortality

Recognise that patients with diabetes mellitus often have multiple co-morbidities such as neuropathy, nephropathy and cardiovascular disease, and consequently polypharmacy is common

Understand and implement the key national guidelines that influence healthcare provision for cardiovascular problems associated with metabolic problems such as diabetes, e.g. National Institute for Health and Care Excellence guidelines

Recognise the psychosocial impact of diabetes mellitus and other long-term metabolic problems, e.g. the risk of depression

Diabetes distress

Diabetes distress can be thought of as the burden of living with a demanding long-term condition such as type 2 diabetes (Polonsky et al., 1995). The concept has gained increasing recognition over recent years. Healthcare professionals will have regularly encountered such patients, but may not have appreciated that the nomenclature and definition exist. Diabetes distress is estimated to affect around 36% of people with type 2 diabetes. It has been found to be at the root of most peoples’ coping struggles with self-care of diabetes, after controlling for clinical depression, and is resolvable within the diabetes clinic setting (Sturt, McCarthy, et al., 2015). It has the following three main components.

Despair

Despair refers to the sense of inevitability that someone may feel when faced with type 2 diabetes, for example, the inevitability of developing diabetes-related complications. Faced with despair, one should provide hope to people. Look at the following statement and ask yourself what is wrong with it:

‘Diabetes is the leading cause of blindness, amputation and kidney failure in the Western World’.

This statement is false. The statement below is true:

‘Poorly controlled diabetes is the leading cause of blindness, amputation and kidney failure in the Western World’.

Offering hope to people, that with good control of their diabetes there is no reason why they cannot lead a long and healthy life, helps to combat despair. There is good evidence for this as shown by the Zodiac-10 study (Lutgers et al., 2009).

Discouragement

Discouragement reflects the sense of failure someone may feel. Persistently raised blood glucose profiles when self-monitoring can be a cause of discouragement. People often need tangible evidence that what they are doing is making a difference to their health.

Perspective is needed. Clinicians need to recognise that perfect control of clinical indices is not achieved by the majority of people with diabetes. This is demonstrated in many data sets and epidemiological studies. You only need to look as far as your own disease registers to see that most people do not achieve an ideal target for blood pressure, lipid and glycaemic control. The average National Institute for Health and Care Excellence (NICE) three-treatment target composite (haemoglobin A1c (HbA1c) less than or equal to 58 mmol/mol, blood pressure less than or equal to 140/80 mmHg, cholesterol less than 5 mmol/L) currently stands at around 40% nationally, and this has changed very little over recent years (National Diabetes Audit, 2017). This means that the overwhelming majority of people with diabetes are not achieving nationally determined targets for optimal diabetes care.

If someone brings in their blood glucose readings showing high values most of the time, two different responses from the healthcare professional can influence that person’s distress. The first response could be: ‘It’s great that you brought this with you today, let’s have a look at it together’. This response is more likely to encourage engagement from the individual. The second response may be: ‘Oh dear, what have you been doing? All these numbers look high’. This is more likely to result in further feelings of discouragement and reaffirm a sense of failure. It is less likely they will bring in blood glucose readings again.

Overwhelmed

The perception that diabetes management is all-consuming and takes up an inordinate amount of both physical and mental strength on a daily basis can result in people feeling overwhelmed. We should try to promote reasonable self-care expectations. The principle of discovery learning is a powerful tool. This involves showing people that their own actions are making a difference (Saab et al., 2005). Encourage simple ‘experiments’ such as measuring pulse rate or blood glucose before and after different types of exercise or household chores; so that benefits can be appreciated, rather than conveying abstract concepts and often quoted mantras such as ‘lose weight and do more exercise’. Encourage effective self-care with care plans that focus on specific and achievable goals.

There are several clinically applicable and validated scales used to measure diabetes distress. The Diabetes Distress Scale (DDS2) is a useful and short tool which makes it ideal for general practice (Fisher et al., 2008). It is the average of two questions, each scored from 1 (not a problem) to 6 (a very serious problem) and based on the features already discussed:

Feeling overwhelmed by the demands of living with diabetes

Feeling that I am often failing with my diabetes routine

The score correlates well with HbA1c such that the higher the average score, the worse the glycaemic control. This is based on cross-sectional studies (Fisher et al., 2010). A cut-off score of greater than or equal to three defines significant distress interfering with self-management, and therefore, impacting on glycaemic control (Fisher et al., 2012).

One approach to the management of diabetes distress is to recognise that people are seldom unmotivated to live a long and healthy life. Trying to ‘fix’ the problem of distress, especially in a limited consultation time might not work. One way of starting to tackle it is to ask, acknowledge and normalise people’s feelings as shown in Box 1.

Box 1.

Three-question approach to diabetes distress.

Ask

‘What’s the one thing about diabetes that really gets to you or drives you crazy?’

Acknowledge

‘Given the nature of type 2 diabetes and what we know about it, feeling that way is perfectly reasonable’

Normalise

‘Many people feel the same way as you. It’s a really common problem’

Case study 1 can be used to demonstrate some of these concepts. Using the conversation constructs from Box 1, think of how best to ask, acknowledge and normalise emotions and any current apathy towards diabetes.

Case study 1.

Patient CM is a 54-year-old male. He has not been seen at the surgery for 18 months. His medication review shows that he has not collected any medication for the last 9 months, including his insulin, oral hypoglycaemic medications, antihypertensives and lipid-lowering medications. His current HbA1c is 86 mmol/mol (10.1%). He feels despondent and at a low ebb. He says he is tired of taking six different medications every day, amounting to 12 tablets per day in addition to once daily basal insulin. He therefore decided to stop everything. He recognises that medications are required to manage type 2 diabetes and that there are significant dietary changes he could make.

He currently exhibits feelings of being overwhelmed and despair. The following suggestions could be used to help tackle his diabetes distress:

What is the most important thing for him right now?

It may be that he is keen to reduce his medications. Can any of his medications be rationalised? If he is willing to only take a handful of medications, what should be restarted as a priority?

He sees little benefit in taking 12 tablets plus insulin every day

Can the impact of medication be demonstrated in a tangible way using the principles of discovery learning? Levels of total cholesterol are often a useful gauge to statin usage and show marked variability depending on adherence. Cholesterol levels can also show the benefits of consistent use of medication. Similarly, regular use of insulin should show improvement in blood glucose values and these could be measured for feedback. There may also be improvement in associated features such as thirst with regular medication use thus reinforcing the benefits of medication.

It is all getting too much for him

Acknowledging the fact that taking 12 tablets a day, which equates to 4380 tablets per year, is a lot may be all that he wants to hear. This medication burden is not uncommon in type 2 diabetes. Does he understand the rationale for each medication?

Structured education has been shown to be an effective tool to reduce diabetes distress (Sturt, Dennick, et al., 2015). The appropriate use of available psychological services is also an important part of management. Clinical depression can be a significant contributor to distress in up to a third of people with high diabetes distress and so effective multi-morbidity pathways for psychological assessment and support are necessary.

Renal disease

Around 30–40% of people with diabetes develop nephropathy. This is more common in those of South Asian and African or Caribbean background. The rate of progression is also faster in these groups of patients (Dreyer et al., 2009). This progression varies between 2 and 3% per annum, and is affected by factors such as the degree of baseline albuminuria, glycaemic control, blood pressure, smoking and dyslipidaemia (Karalliedde and Thomas, 2015). The presence of retinopathy is often taken as a prerequisite for making a diagnosis of diabetic nephropathy, but nephropathy can occur even in the absence of retinopathy. Data from the United Kingdom Prospective Diabetes Study (UKPDS) showed that at diagnosis (baseline) 12.8% of people with type 2 diabetes had microalbuminuria and 2.1% had evidence of proteinuria. After 15 years of follow-up, these figures had increased to 39% and 12.6% for microalbuminuria and proteinuria, respectively in the control group (UKPDS Group, 1998). Hence, the duration of diabetes, as well as poor glycaemic and blood pressure control are important predictors of disease progression.

Proteinuria from non-diabetic renal disease can occur in up to 30% of people with diabetes. Important other causes to exclude are urinary tract infections, exercise and acute illness. The diagnosis of microalbuminuria and proteinuria requires a urine sample which is one of the least performed and recorded checks as part of the routine care process measures (National Diabetes Audit, 2017). This has coincided with its removal from the general practice Quality and Outcomes Framework. The level of renal dysfunction is usually graded using a scale and nomenclature to indicate stage of chronic kidney disease (CKD) and degree of albuminuria (KDIGO Work Group, 2013). This is shown in Fig. 1.
Figure 1.
Classification of CKD.

Some anti-diabetic drugs are metabolised and primarily excreted by the kidney, therefore doses often need to be reduced and adjusted depending on the degree of renal impairment. This is particularly true for elderly patients where the risk of hypoglycaemia can be high in cases of CKD, especially when sulphonylureas and insulin are being prescribed. This is shown in more detail in Table 1.
Table 1.
Common blood glucose therapies and renal implications of prescribing.

Metformin Sulphonylureas and prandial glucose regulators Thiazolidinediones Dipeptidyl peptidase-4 inhibitors Sodium glucose transporter 2 inhibitors Glucagon-like peptide-1 receptor agonists

Caution and dose adjustment may be required if eGFR less than 45 mL/min e.g. 50% maximal dose (500 mg twice daily). Avoid if eGFR less than 30 mL/min and/or creatinine more than 150 mL/min Varying hepatic metabolism. Use with caution and dose adjustment if eGFR less than 50 mL/min. Avoid if eGFR more than 30 mL/min Avoid if eGFR less than 15 mL/min, otherwise no dose adjustment required Linagliptin safe to use in end stage renal disease and preferred if eGFR less than 30 mL/min. For others, dose reduction (half maximum dose) is required if eGFR less than 50 mL/min Avoid initiation if eGFR less than 60 mL/min. Canagliflozin and Empagliflozin can continue to be used if the eGFR falls to 45 mL/min. Avoid if eGFR less than 45 mL/min Dulaglutide and Liraglutide safe to use up to eGFR of 30. Others require caution if eGFR less than 50 mL/min (exenatide QW not recommended). Avoid if eGFR less than 30 mL/min

SUs: Sulphonylureas (e.g. gliclazide, glipizide, glibenclamide, glimepiride)

TZDs: Thiazolidinediones (e.g. pioglitazone)

DPP-4i: Dipeptidyl peptidase-4 inhibitors (e.g. sitagliptin, linagliptin, saxagliptin, vildagliptin, alogliptin)

SGLT2i: Sodium glucose transporter 2 inhibitors (e.g. dapagliflozin, empagliflozin, canagliflozin)

GLP-1a: Glucagon-like peptide-1 receptor agonists (e.g. liraglutide, exenatide, lixisenatide, dulaglutide, albiglutide)

When dealing with renal disease, it is common to look at renal function as a snapshot value. The trend of renal decline can sometimes be obvious and dramatic, but will not be noted if looking at numbers in isolation. This is highlighted in Case study 2, which shows renal function decline that may be encountered in people with type 2 diabetes and conceptualised in Fig. 2.
Figure 2.
Patient JK: A story of renal decline.

Case study 2.

Patient JK is a 63-year old patient of Caribbean origin with type 2 diabetes. She has end stage renal failure and is on dialysis. She was diagnosed with type 2 diabetes in 1990, when she had no complications and her estimated glomerular filtration rate (eGFR) was more than 90 mL/min. Subsequently, she developed microalbuminuria and her albumin-creatinine ratio (ACR) was raised in the range of 5–20 mg/mmol for many years with concomitant sub-optimal blood pressure control (mean systolic blood pressures between 150 and 165 mmHg).

She moved to London in 2009 and when she was first seen by her new GP, her eGFR was 86 mL/min corrected for ethnicity (note eGFR needs to be multiplied by 1.21 for persons of African or Caribbean origin). Her blood pressure (152/72) and HbA1c (75 mmol/mol) were both elevated and she had a raised ACR of 36 mg/mol indicating albuminuria.

She had two reviews per year for her diabetes with the diabetes nurse at her practice. Over the following few years her eGFR dropped from 81 mL/min to 71 mL/min. This was noted but no action was taken as the eGFR was still considered to be acceptable. Her blood pressure and glycaemic control remained sub-optimal. The following year at a routine review, her eGFR again dropped further to 57 mL/min. She continued to be seen for routine reviews. Between these periods, her HbA1c fluctuated between 65 and 79 mmol/mol and her blood pressure averaged 156/93 mmHg.

Later in 2011, her eGFR dropped further to a level indicating chronic kidney disease (CKD3). At this point, she was referred to a diabetes renal clinic for a review to exclude non- diabetic causes for her rapid progression due to the rapid fall in eGFR and increasing proteinuria (urine showing +4 protein, ACR more than 200 mg/mmol). She also had bilateral background retinopathy at the time. Her eGFR briefly stabilised with better blood pressure control, but this was not sustained and her eGFR soon began to decline further and in 2013 she needed dialysis. Her number of attendances to both primary and secondary care increased dramatically, particularly when her eGFR had fallen by more than 50% from baseline.

Case study 2 highlights the need to look at not just the ‘raw’ numbers but also the trend of renal decline and the importance of early multifactorial interventions to optimise blood pressure and glucose, and reduce ACR to either prevent or significantly delay the progression of nephropathy. In parallel, as such patients are at high cardiovascular disease (CVD) risk, other CVD risk factors should also be optimised.

As this case illustrates, once eGFR has fallen significantly, it can be difficult to prevent progression to end stage renal disease. Early identification of risk factors and intervention is needed to prevent or significantly delay progression of renal disease in diabetes. Metrics such as HbA1c, blood pressure and eGFR often show variability and the patterns behind the numbers are just as important as the numbers themselves.

In cases where further follow-up is required, obtain a minimum of three GFR estimations over a period of not less than 90 days and in people with a new finding of reduced eGFR, repeat the eGFR within 2 weeks to exclude causes of acute deterioration of eGFR, for example, acute kidney injury (NICE, 2015). Some cases in which specialist opinion should be considered are listed in Box 2.
Box 2.
Cases of renal disease for which a specialist opinion should be considered.

• eGFR is less than 30

• There is rapid progression of kidney disease as defined by NICE renal guidelines (NICE, 2015):

A sustained decrease in GFR of 25% or more and a change in GFR category within 12 months or

A sustained decrease in GFR of 15 mL/min per year

• Hypertension remains poorly controlled despite the use of at least four antihypertensive drugs at therapeutic doses

• Atypical features exist, such as, the presence of haematuria or heavy proteinuria

Complexity and guidelines

Various international, national and local guidelines exist for the management of type 2 diabetes. Guidelines also cannot answer every conceivable scenario that may be encountered in clinical practice, and so, a certain level of independent thinking is also required. This is particularly true when dealing with complexity.

Figure 3 shows five key questions that would be reasonable to ask when managing people with type 2 diabetes, and excerpts from current NICE guidance that can be used to help answer them (NICE, 2017). Using this guidance, it can be readily seen that there are key messages to consider as shown in Box 3.
Figure 3.
Using NICE guidance to help with type 2 diabetes management: Key questions to consider.

Box 3.
Key messages from NICE guidance for management of type 2 diabetes.

• Adopt an individualised approach to each person

• Aim for a target HbA1c of 48 mmol/mol (6.5%) initially if metformin is being used as a first line treatment

• Aim for a target HbA1c of 53 mmol/mol (7.0%) if a medication associated with hypoglycaemia (e.g. sulphonylurea class) is being used first line

• Aim for a target HbA1c of 53 mmol/mol (7.0%) if combinations of medications are being used with a tolerance up to 58 mmol/mol (7.5%) at which point, intensification should occur

• Reviews should be scheduled every 3 or 6 months depending on whether therapy changes are being actively made

Adapted from NICE (2015).

When treating blood glucose, it is useful to bear in mind the purpose of treatment and intended benefits, as these will influence both the choice of treatment and the targets being set for that person. Broadly, the benefits can be thought of as being either short term, medium term or long term as shown in Box 4.
Box 4.
Benefits of glycaemic control in adults with type 2 diabetes.

Short term

These might be immediate benefits from osmotic symptoms such as thirst and polyuria. They could also be benefits in cognition for someone with dementia and raised glycaemic levels

Medium term

These tend to be microvascular benefits such as the prevention or slowing of retinopathy and nephropathy

Long term

CVD and other macrovascular complications often develop over a long time

These concepts lend themselves to the notion of individualised care for people with diabetes (Inzucchi et al., 2012). The premise here is that everybody should have an individualised target for their HbA1c. There are many determinants to this based on factors including multi-morbidity and disease duration. The intended benefits of treatment need to be set against these constructs. For example, trying to aggressively treat an elderly person with other co-morbidities in order to prevent a long-term complication such as a stroke may not be in their best interests. However, if the same person had dementia and the intention of treatment was to improve cognition, then an improvement in HbA1c might be beneficial. Sometimes we need to treat to safety, not treat to target.

Unfortunately, this approach to the management of type 2 diabetes means that it is difficult to be prescriptive in terms of answering the question: ‘What medication should I give this patient’, as many things need to be considered in each case. Using the concept of individualised care and some of the discussion points in this article, think about how you might handle Case study 3.

Case study 3.

Patient LS was referred to a specialist diabetes clinic by her GP. She is a 51-year-old female of Caribbean ethnicity who works as a cleaner. She was diagnosed in 2013 and has a BMI of 32 kg/m² with central obesity. Her renal function is satisfactory and stable (eGFR 82 mL/min corrected for ethnicity). She is currently using maximum doses of metformin, gliclazide and sitagliptin as part of triple therapy for her glycaemic control. She consistently takes her medications and has a low diabetes distress score. There are no diabetes-related complications. She does not currently monitor her blood glucose and has only ever used oral medications. She is keen to avoid injectables including insulin. On referral 2 months ago, her HbA1c was 87 mmol/mol and her current level is recorded as 76 mmol/mol.

If you were seeing this lady in clinic, what would you do next? Here are some options:
Three-month follow-up, no changes made

Add in an SGLT-2 inhibitor, e.g. dapagliflozin?

Add in a GLP-1 analogue, e.g. liraglutide?

Start insulin

Perhaps the most interesting thing about cases such as this one is that all the management options above are invariably given a positive response. This succinctly highlights the difficulty of management in type 2 diabetes. Any of these options could be selected and justified to some degree. What is most important is to think about the justification and rationale for each option. Let us demonstrate this point.

Three-month follow-up, no changes made

As per NICE guidance (NICE, 2017), her HbA1c has improved with no medication changes made. There may be issues related to medication use here. The current trend is that there has been a significant improvement in her HbA1c without the need for an additional medication, and probably more than any single medication could have achieved apart from insulin. It would be reasonable to see if and how this improvement continues and perhaps where the nadir is reached.

Add in an SGLT-2 inhibitor, e.g. dapagliflozin?

We know that she is keen to avoid insulin. She has no contraindications to the use of an SGLT-2 inhibitor. It may have some beneficial effect on her weight. Would it get her to an individualised HbA1c target?

Add in a GLP-1 analogue, e.g. liraglutide?

She is keen to avoid insulin, but that does not mean she would turn down other injectables. Although her body mass index (BMI) is below 35 kg/m², a GLP-1 analogue could be justified on the basis of her ethnicity. She has central obesity and so would benefit from weight loss that she may get with this class of medication.

Start insulin

Considering her current young age and the fact that she was diagnosed at around the age of 46 years, she is at high risk of long-term macrovascular complications.

Let us take this same case and make a few changes involving multi-morbidity. Imagine that you are seeing the same lady, but that she is now 10 years older and has had type 2 diabetes for 10 years longer. She has diabetes distress and her renal function has deteriorated. The same case with the changes is highlighted in Case study 4.

Case study 4.

Patient LS was referred to a specialist diabetes clinic by her GP. She is a 61-year-old female of Caribbean ethnicity who works as a cleaner. She was diagnosed in 2003 and has a BMI of 32 kg/m²with central obesity. Her renal function shows stable CKD3 and microalbuminuria (eGFR 54 mL/min corrected for ethnicity). She is currently using maximum doses of metformin, gliclazide and sitagliptin as part of triple therapy for her glycaemic control. Her medication use is variable and impacted by her work and has a high diabetes distress score. There are no diabetes-related complications. She does not currently monitor her blood glucose and has only ever used oral medications. She is keen to avoid injectables including insulin. On referral 2 months ago, her HbA1c was 87 mmol/mol and her current level is recorded as 76 mmol/mol.

How would this now influence your choice(s) for management? What would her individualised HbA1c be now? Given the new co-morbidities, increased age, longer disease duration and reduced life expectancy, her HbA1c target should perhaps be less stringent than it was previously. Both diabetes distress and renal disease influence the medication choices available to her and the flow of the consultation. The HbA1c target should be both personalised and pragmatic. Further information about the pragmatic management of type 2 diabetes in adults can be found through the Health Innovation Network (see resources).

KEY POINTS

People with type 2 diabetes often have other long-term health concerns that need to be recognised and addressed

Both renal disease and diabetes distress add an additional complexity to the consultation and disease management

Diabetes distress is common and encompasses feelings of despair, discouragement and being overwhelmed

Trying to ‘fix’ the problem of distress, especially in a limited consultation time, does not work; ask about, acknowledge and normalise people’s feelings instead

Metrics such as HbA1c and eGFR often show variability and the patterns behind the numbers are just as important as the numbers themselves

People with type 2 diabetes and multi-morbidity require an individualised and pragmatic approach to medical management

Metformin	Sulphonylureas and prandial glucose regulators	Thiazolidinediones	Dipeptidyl peptidase-4 inhibitors	Sodium glucose transporter 2 inhibitors	Glucagon-like peptide-1 receptor agonists
Caution and dose adjustment may be required if eGFR less than 45 mL/min e.g. 50% maximal dose (500 mg twice daily). Avoid if eGFR less than 30 mL/min and/or creatinine more than 150 mL/min	Varying hepatic metabolism. Use with caution and dose adjustment if eGFR less than 50 mL/min. Avoid if eGFR more than 30 mL/min	Avoid if eGFR less than 15 mL/min, otherwise no dose adjustment required	Linagliptin safe to use in end stage renal disease and preferred if eGFR less than 30 mL/min. For others, dose reduction (half maximum dose) is required if eGFR less than 50 mL/min	Avoid initiation if eGFR less than 60 mL/min. Canagliflozin and Empagliflozin can continue to be used if the eGFR falls to 45 mL/min. Avoid if eGFR less than 45 mL/min	Dulaglutide and Liraglutide safe to use up to eGFR of 30. Others require caution if eGFR less than 50 mL/min (exenatide QW not recommended). Avoid if eGFR less than 30 mL/min

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