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The place of new treatments in diabetes management

Sara Da Costa
MBA BSc(Hons) DipN(Lond) FETC RGN
Nurse Consultant, Diabetes
Worthing and Southlands Hospitals NHS Trust
Visiting Fellow
University of Brighton

The focus of diabetes management has shifted from glucose control alone, and there has been an explosion in new products aimed at improving patient outcomes and reducing cardiovascular risk. Sara Da Costa explains how these new treatments fit with existing therapies

The latest type 2 diabetes clinical guideline from the National Institute for Health and Clinical Excellence (NICE) has reviewed a broad range of oral and injectable treatments and recommended order of usage of these products.1 We know that compliance and concordance with treatments diminishes as the tablet burden increases; yet, consideration of daily slower-release or combination treatments is not usually discussed.

This article will describe the impact of polypharmacy, with key points to consider when prescribing or recommending treatment changes. Strategies to increase compliance will be discussed, in addition to the need to incorporate current research evidence, which recommends we consider not only glycaemia, but also reduction in cardiovascular risk when choosing from the many products available. Data from our primary care clinic audits will be included as they revealed compliance problems and prompted our specialist nursing team to change the way in which we assessed our patients' medication taking
and timing.
NICE guidelines
The NICE recommendations for the management of type 2 diabetes were published in May 2008, but did not include all current treatments; those omitted will be included in the full updated guideline due for publication in February 2009.1
The guidelines recommend metformin, followed by sulphonylurea when HbA1c control is >6.5%. However, as some of our patients are obese, we are reluctant to add sulphonylurea as it is likely to increase their weight and cardiovascular risk further. There is also a concern that sulphonylurea will increase the risk of hypoglycaemia, particularly in older people who live alone. For these reasons, many clinicians have chosen to add glitazone instead.

Following the latest American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) guidelines, rosiglitazone is not recommended in type 2 diabetes, because there are concerns that it increases cardiovascular risk.2 This is particularly worrying given that most of our type 2 patients have cardiovascular disease; hence, this contraindication has also been highlighted by the European Medicines Agency (EMEA). However, pioglitazone, unlike rosiglitazone, has evidence to demonstrate reduction in cardiovascular risk,3 and this is noted in the full updated guideline.4 It can also improve HbA1c and glycaemia, and does not cause hypoglycaemia. Glitazone should not be used in patients with heart failure, as it encourages fluid retention.

Exenatide is an injectable, twice-daily product, which suppresses glucagon secretion, slows gastric emptying, reduces weight and can be used in patients who are obese (body mass index (BMI) >35). It can be used with either metformin or sulphonylurea. Other options include the DPP4 inhibitors (eg, sitagliptin). These work by increasing glucose-mediated insulin secretion and suppressing glucagon secretion.

Case study
Mr X, a 52-year-old taxi driver, was diagnosed six years ago with type 2 diabetes, and on dietary and exercise advice was commenced on metformin, titrating up to 1 g twice a day. Like so many of our patients, he is overweight, with a BMI of 39. His HbA1c improved after dietary changes and treatment, but it is still 9%.

He has erratic mealtimes due to shift work, and considering his obesity, we avoided a sulphonylurea, and introduced pioglitazone, 15 mg daily, titrating doses up to 45 mg daily. He did not have heart failure (no swollen ankles or shortness of breath), and his liver function tests remain satisfactory. After 10 months, his HbA1c has reduced to 7.4% and his BMI is now 37, helped by some exercise and a new partner who has taken over the cooking!

With our patients' agreement, we aim in our nurse clinics to make immediate changes and plan further actions in three or six months. This strategy recognises that diabetes is a progressive disease, requiring more treatment or increased dosing to improve patient outcomes and reduce risk of complications.

In the treatment of Mr X, the next step could be insulin if his HbA1c deteriorates, except that he would lose his licence and a job he enjoys. An alternative could be exenatide. Although it is an injectable product, it does not cause the same employment restrictions as insulin, except when hypoglycaemia occurs due to use with a sulphonylurea (we would not consider using this as he is still overweight).

If he worked in an office, we may still have suggested exenatide, but if his weight did not reduce and his glycaemia did not improve, then we may have needed to replace this with insulin. In our experience, exenatide seems to work best if it is used early, and not as a last chance before insulin.

However, the range of insulin and insulin pens should enable him to use a regimen that matched his erratic lifestyle, and with specialist or practice nurse support, to be confidently self-injecting and adjusting insulin dosages.

Weight gain is often a problem when transferring to insulin, so to minimise this, we review diet and activity, and emphasise that weight will increase if lifestyles do not change, and try to help our patients find ways to manage diet or exercise. If they can use pioglitazone, we either leave them on it when they transfer to insulin, or reintroduce it, as it is the only glitazone with a licence for use with insulin. As an insulin sensitiser, less insulin is needed to achieve the same effect, which not only makes it a smaller and more comfortable injection, but also reduces weight gain (insulin is an anabolic hormone, hence the weight gain if calories exceed activity).

This case study demonstrates the breadth of products, and the rationale for the order of prescribing, but local policies may well restrict the range available. It is not always easy in general practice to gain wide experience in using all these products, so I would suggest liaising with your local specialist nursing team for advice and support. In all of our 32 practices, we provide collaborative diabetes clinics (diabetes specialist nurse and practice nurse) and find these enable such updating and upskilling. They also happen on a regular basis, which is essential to improve patient safety and outcomes, and reduce clinical risk.

Compliance with medicines
These multiple therapies are a challenge for us as nurses, but they pose a greater challenge for our patients in terms of compliance. We must remember that our patients are not only taking the range of treatments discussed here, but they may also be taking antihypertensive agents and statins, and medication for other comorbidities such as steroids and diuretics. The latter drugs can cause glucose control to deteriorate, and require adjustments or additions to current treatments. Diabetes is a progressive disease, and HbA1c will continue to rise over time,5 which by itself will increase the tablet burden.

Complicated treatment regimens and perceived lack of the importance of regular tablet taking have been blamed for noncompliance. As nurses, we cannot assume that everything prescribed is taken, and it is important to find out the facts from
our patients.

Patient audit
We audited compliance in one of our collaborative diabetes clinics, and found that, on average, 50% of tablets were not taken regularly, and 15% were not taken at the right time. Commonly, if tablets were prescribed twice a day, they would be taken with breakfast, and the second dose would be taken with the patient's statins before bed.

Problems caused by sulphonylurea or metformin when taken without food include nocturnal hypoglycaemias and gastric irritation and this can cause patients to stop taking these tablets regularly, as well as hospital admissions for hypoglycaemias, and endoscopies for gastric symptoms. These side-effects caused by inappropriate timing can also lead to some patients stopping their medication completely.

Using treatments that reduce the risk of hypoglycaemias is important for patient safety, particularly when nursing older people, whose ability to experience early signs of hypoglycaemias can be reduced. It is also important for the working population, as hypoglycaemias can affect employment, as can insulin use (HGV and PSV drivers cannot continue if using insulin treatment). It is important to remember, as for most of our patients, that hypoglycaemias are their worst fear, and confidence is quickly lost in a treatment that causes them.

Using these data, we changed our nursing assessments so that we now ask all our patients, whether in hospital or in our practice clinics, if they take all their tablets every day, and when they are taken. This enables us to understand our patients' beliefs, and work out individual solutions, which may mean changing dosing, timing or product.

Ensuring successful compliance
Given all these facts, it is worth considering ways of making compliance easier. Scaring patients with the threat of complications can be counterproductive. Instead, if we explain our concerns for their health and add a good plan of action, compliance can improve. If a major problem for the patient is remembering to take all their tablets at different times of day, it can help to use a daily, slow-release product. There are several available, such as gliclazide MR and metformin SR, which can also reduce the risk of hypoglycaemia and gastric symptoms, respectively.

Reducing the number of tablets with combination treatments can help the pill burden and thereby increase compliance. Pioglitazone and metformin are combined as Competact, which is taken twice-daily. This combination reduces the risk of hypoglycaemia compared to sulphonylurea, and the need to blood glucose monitor, which reduces costs. Research suggests that both products provide cardiovascular benefit, which is highly advantageous to this patient group.5 Avandamet contains both rosiglitazone and metformin and is not recommended for the reasons previously discussed.
Interestingly, neither combination nor modified/slow-release products were mentioned in the NICE recommendations, although NICE has recommended further research into how concordance rates vary according to the complexity of the regimen.3 Sometimes, it is something as simple as reducing the number of pills that can motivate our patients to improve their control, so we should not overlook this in our prescribing, as small successes often lead to ongoing success.

The NICE guidelines and forthcoming updated guideline have demonstrated the breadth of our treatments, and also suggested an order of use. The case study has explored this in the real world, and demonstrated that patients' needs must also be considered, not just the formulary.

Diabetes care is more than just glycaemic control, and as nurses we need to consider our patients' wishes and the number of treatments we suggest they take, as well as implementing evidence-based prescribing. We also need to recognise that our patients may have a very different view of the importance of taking the medication, and be prepared to discuss this honestly with them. If we try to frighten our patients, we are unlikely to help them, whereas giving information with a plan they can agree to may be much more helpful.

Simple strategies, such as reducing pill burden, can increase motivation and compliance, so consideration of the benefits of modified-release or combination tablets has been highlighted. Given the increasing complexity and choice of treatments, collaboration with your specialist team, in particular your diabetes specialist nurses, could increase both your confidence and competence, and support you in improving your patient outcomes.

1. National Collaborating Centre for Chronic Conditions/National Institute for Health and Clinical Excellence (NICE). Type 2 diabetes: the management of type 2 diabetes (update). London: NICE; 2008.
2. Rosiglitazone no longer recommended. Lancet 2008;372:1520.
3. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007;298:1180–8.
4. Savage MW. Newer agents for blood glucose control in type 2 diabetes: the NICE draft proposals. Practical Diabetes international 2008;25(9):353.
5. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999;281:2005–12.