While the political battle over diabetes care rages on, our patients continue to need sensible care in tune with their own personal needs. New drugs are on the horizon, and the range of treatment options now equals the range of phenotype, age and other characteristics among people with type 2 diabetes. Can we match our treatment to the individual and can we persuade the person with diabetes to meet us half-way in the battle against this progressive disease? Sure we can! This article is a personal protocol for doing just that.

The mists of time

Briefly, we have to go back to the origins of type 2 diabetes. We know that a number of factors combine to cause diabetes, including family history and a sedentary lifestyle with overweight. However, only half of type 2 diabetes is related to overweight; and we all have patients who are very overweight, yet their glucose levels remain normal. Type 2 diabetes only starts when a person has insulin resistance and a significant decline in insulin-producing beta cells. It is estimated that up to 50% of beta cells may be lost by the time of diagnosis. 

Type 2 diabetes is progressive, with different people moving along at different rates. This progression is caused almost entirely by the continuing loss of beta cells. Why does this matter? Because tailoring someone’s treatment requires us to make some assumptions about the relative contribution of insulin resistance and beta cell loss to their raised glucose levels. This then leads us to considering the most appropriate lifestyle, dietary and medication options. 

Diabetes as a process

At its simplest, soon after diagnosis, most of a person’s difficulties can be attributed to insulin resistance. After 20 years, most of their problems will be due to beta cell decline. Insulin resistance tends to be stable throughout, unless, through lifestyle or other measures, it declines as a factor. The rate of progress in terms of beta cell loss might be measured, for example by regularly assessing serum insulin or C-peptide levels, but this is not necessary and is not done in clinical practice. A much simpler way is to monitor the pace of progress through treatments.

While some guidelines now recommend metformin treatment from diagnosis, I personally do not follow this line provided fasting glucose is below around 13mmol/l and there is no ketonuria. Besides the benefit of giving someone a chance to delay glucose tablets by making changes in lifestyle, the time from diagnosis to needing metformin can give an early indication of the pace of beta cell loss, and can be short (ie. just a few months) or very long (perhaps two years). The same observations will be seen when adding second and further medications. 

So what can we do to manage these contributing factors to the person’s diabetes? Some management options are: 

How important is insulin resistance really?

Like insulin levels, insulin resistance can be measured, although this is difficult and possible only in a controlled laboratory environment. It is clear that despite the rising importance of beta cell loss as a factor as diabetes continues over many years, insulin resistance remains a significant factor and hence, managing it remains a useful weapon at all stages of type 2 diabetes. This came home to me recently when a thin gentleman with type 2 for around 10 years, who had been through a number of treatments and was about to embark on insulin treatment, developed myeloma. During his subsequent successful treatment his glucose levels fell as his weight declined through the normal range, such that at one point he no longer needed any glucose-lowering treatment. This was despite his never having been overweight in the first place.

Another older patient with type 2 diabetes for over 20 years, who had been overweight, lost most of this weight once she started dialysis for diabetes-related renal disease. Again, her glucose-lowering treatment became unnecessary during this time. My conclusion from this is that even late in the disease when insulin production has fallen significantly, there is still value in efforts to continue fighting insulin resistance, and clear merit in trying not to make it worse.

Diet and lifestyle

Prescribing is a very powerful medical tool, especially in modern diabetes. It is not, however, a short cut to avoiding the critical step of leading our patients towards a healthy lifestyle. Lifestyle change in diabetes is really important: it’s enduring, it’s empowering and it can seem impossible. But not completely, and the most critical message in this article is that facilitating this change is worth pursuing with a lot of enthusiasm, right from diagnosis (if not before) and throughout the person’s life with diabetes. 

It is fair to say that most of us are not very knowledgeable about the details of the diet for people with diabetes. Thankfully, the information is all contained in an excellent booklet, Healthy eating for people with type 2 diabetes, prepared by the Diabetes Interest Group of the Irish Nutrition and Dietetics of Ireland (INDI), which is available free from Diabetes Ireland (1850 909 909) and can be downloaded from www.diabetes.ie/downloads/booklets/

As has been stated many times, the surprise is that the ideal diet does not say much about sugar; rather the focus is on a healthy diet which is low in fat, high in fibre and with moderate amounts of complex carbohydrate. Discussion about alcohol, sugary foods, calcium and omega-3 fish oils is relevant, but not the most important issue. Can people with type 2 diabetes eat the occasional treat? Do you?

Research certainly supports the notion that nurses are better than doctors at education, and I use that word in a wholesome sense that goes far beyond the transfer of information into motivation, self-efficacy and actual long-term behaviour change. Recent evidence has moved much further and it is now recommended that education is delivered by professionals with training in motivational skills, and that it should follow a structured process with a defined curriculum, clear goals, and regular audit and review. 

This approach has been widely adopted in the UK and elsewhere in Europe, and is now gaining ground here. Structured education programmes such as the X-PERT and DESMOND programmes are available from many community dietitians nationally, and the free CODE-2 programme is offered by Diabetes Ireland in all parts of the country on request. Simply phone them to arrange a course in your own practice. All are run in groups over several weeks, with peer support an added benefit of the training. All are structured programmes, delivered by professionals with training in adult learning skills. Diabetes Ireland also offers training in these skills to practice nurses free of charge so that they can deliver CODE and similar programmes locally. Considering that the future of general practice involves a lot of chronic illness care besides diabetes, this training is exceptionally useful.

The aim of lifestyle change is to achieve or maintain a healthy weight with a BMI < 25. This is a challenge for many people, so to start with seeking weight loss of 0.5kg weekly towards an initial target of 5% weight loss, then another 5%. While commercial services concentrate on large amounts of weight loss over a short period (with meals replaced by expensive food supplements), this is not recommended by diabetes professionals. Personally, I feel that most people can sustain smaller dietary changes in the longer term, which will achieve a better long-term outcome. Exercise levels can be increased to at least one hour of vigorous exercise five times a week. Many people are reluctant to change what they eat, and hope to lose weight through exercise alone. This is not realistic and around 70% of their intended weight loss will be achieved by dietary change. 

Most people who are very overweight will admit that they use eating as a way to relax. We need to be understanding about the complex drivers of excessive eating and to be more sensitive to possible underlying psychological problems, anxiety and depression, all of which are very common in diabetes and must be addressed before we can achieve any of our targets in managing the diabetes.

If someone loses some weight and exercises more, their glucose and HbA1c may fall into the normal range. Does this mean they don’t have diabetes anymore? I prefer to see them as diet-controlled, and continue to review them regularly, continue to manage cardiovascular risks aggressively and keep up the emphasis on maintaining a healthy lifestyle as time goes on. Eventually, beta cell loss may well catch up with them again and, even if it doesn’t, the protection from heart disease is second to none.

Medication

For most people with diabetes, glucose levels rise either at the start or after a year or so, to the point where medication is needed. We are now faced with a huge array of glucose-lowering treatments, each with their own advantages and adverse effects. None is perfect; equally, none is useless, and at this point it would be hard to suggest we couldn’t find a combination to suit most people with diabetes.

There are no longer any rules relating to medication choice. Guidelines have come full circle, to an acceptance that no two people with diabetes are the same. There is, however, one outstanding option – use metformin first. 

What’s so great about metformin? Well, firstly it deals with the underlying issue for most people early on, in that it helps with glucose dispersal into muscle, hence undermining insulin resistance. So it is likely to work for most people and so it does. Additionally, early use of metformin has been shown to offer a significant long-term reduction in cardiovascular risk in a UKPDS follow-up study, as well as immediate reduction in diabetes complications. Add to this the fact that metformin does not cause weight gain or hypoglycaemia and is cheap, and it is a compelling first choice.

Metformin does cause some stomach upset, but I find this can be minimised by warning the person in advance, reassuring them that this will settle with time and starting with a small dose such as 500mg once a day. The dose can be gradually increased and I tend to move up to a maximum of 850mg three times a day with meals. 

Next steps

It is possible to tailor the next choice of medication to the individual’s circumstances. In general terms, certain characteristics will suggest that insulin resistance remains the main problem and should be the focus of our attention. These include recent diagnosis (less than seven years), overweight and obesity, sedentary lifestyle and slow progress in terms of rising glucose levels. On the other hand, a thin person whose glucose is rising rapidly may in fact be losing beta cells at a significant rate and become insulin naive sooner. In reality this situation is not very common.

For me, the second choice medication becomes a choice between pioglitazone, an incretin drug (DPP4 inhibitor or incretin analogue) or a sulphonylurea such as gliclazide.

Pioglitazone is related to rosiglitazone, which is no longer available. However, pioglitazone is quite different. It acts at the level of insulin resistance and is quite effective. It is associated with improvements in lipids and a reduction in cardiovascular risk (where rosiglitazone had the opposite effect on lipids and CVD risk), and it does not cause significant hypoglycaemia. One problem is weight gain of up to 4kg however, so users need a focus on weight control and the prescriber needs an eye on their glucose target to use only as much as you need. Since pioglitazone has been linked with bone problems and a slight increase in bladder cancer risk, it is not suitable for older people. 

Incretin drugs are very popular now, with good justification. The incretin hormone GLP-1 is naturally released from the small intestine in response to a meal. It then has a number of effects including triggering insulin release and reducing liver glucagon output, controlling appetite and increasing feelings of fullness. A key point is that the insulin release is glucose-dependent, in other words it only happens if glucose levels are rising, by contrast with sulphonylureas, which trigger insulin release regardless. The difference is important in keeping the extra insulin to an efficient minimum, to minimise weight gain and avoid hypoglycaemia. Incretin effects are replicated either by injecting incretin analogues such as exenatide or liraglutide, or by inhibiting the DPP4 enzyme which breaks down GLP-1. DPP4 inhibitors or gliptins are oral medicines such as vildagliptin or saxagliptin. 

While sulphonylureas are associated with weight gain and a small but important risk of hypoglycaemia, incretin drugs have a very low risk of hypoglycaemia; gliptins are weight-neutral, while GLP-1 analogues are associated with significant and sustained weight loss in most patients. From personal experience, there is no doubt that these powerful agents have a positive impact on diabetes well beyond their important glucose lowering effect – I have often found myself able to reduce other glucose-lowering treatments following the weight loss associated with these agents. Side effects such as nausea are an issue, while rumoured concerns about pancreatitis seem to be unfounded. For selected patients, these medicines are extremely useful and we should be prepared to use them.

There is no doubt that DPP4 inhibitors or gliptins are, like sulphonylureas, relatively easy to prescribe and use. As a result they are most people’s second line choice. They are available in once or twice daily doses, and increasingly in combination with metformin, which reduces the tablet-taking burden. Sulphonylureas, usually gliclazide, are still widely used as second line but, aside from a cost advantage, they offer no special advantages over DPP4 inhibitors.

In practice, I would consider pioglitazone for a younger person under 60 with significant insulin resistance along with adherence to a healthy diet, otherwise DPP4 for most. I would offer GLP-1 analogue injection as a second line agent to someone whose weight is a significant factor in their diabetes, that is BMI >35 and limited impact of dietary measures so far. I do not find most patients fear injection when this is introduced as an effective treatment option, most are enthusiastic and readily learn the self-injection technique when trained by a confident prescriber. 

What about third line?

At this point the need to analyse which point the patient has reached along the track from insulin resistance to insulin deficiency becomes more difficult, but it is more important than ever if we want our treatment to be efficient and effective. Typically, patients in this situation have had diabetes for 10-15 years, are in their mid-60s or early 70s, and have made slow, inexorable progress through their treatments to date. Should we add a third oral agent or move on to insulin? Do we need to keep chasing targets with the same vigour or can we let go a little? Should we continue to be concerned about microvascular complications at this stage, or should we focus our attention more on cardiovascular risk? Are issues such as declining renal function, reduced mobility, failing sight or cognitive decline an issue?

Clearly, associated health problems are an issue and make it necessary to simplify the treatment regime and minimise the risk of accidental hypoglycaemia. If my mantra that ‘life begins at 70’ rings true for you, then we do continue to need reasonably tight targets for blood glucose as well as for CVD risks. We should anticipate some decline in renal function in this age group, only half of which will be diabetes related. Rather than seeing this as a reason to back off on treatment, however, it should prompt an increased effort at tight BP control and consideration of further tightening up on glucose targets as well.

Regarding choice of agents, I am back where I started. We do not have any easy measure of insulin resistance, but rather than going on BMI alone, I would urge an assumption that insulin resistance remains a factor which can be reversed even at this stage. That means that a re-emphasis on education around diet and exercise is as appropriate now as at diagnosis. Diabetes is a marathon, not a sprint, and people need egging on at every mile marker and certainly every time we consider revising medication upwards. Hopefully, access to dietitians or nurse educators allows for this re-emphasis on lifestyle education, and the threat of injections can be an effective motivator to make another effort at weight control. Of course this is needed even if the patient is starting another medication.

If a patient is on metformin and a DPP4 inhibitor and needs further medication to control glucose levels, really the choice is between adding a sulphonylurea or insulin, or switching the DPP4 to an incretin injection. This latter option is reasonable if obesity remains a factor, although next year the first SGLT2 inhibitors will offer another glucose-lowering option with weight loss as a positive side-effect. Neither sulphonylurea nor insulin offers any cardiovascular advantages, so a trial of sulphonylurea is essentially a test of remaining insulin capacity: If it doesn’t work, the person has little residual insulin production and now needs insulin. 

Summary

There is really only one take home message in this article. Glucose, weight and medication are an interacting triad and changing each will have knock-on consequences on the others. View excess weight as an avoidable risk for worsening diabetes control, and plan and monitor medication changes carefully to reach goals without exceeding them. Finally, never give up trying to improve lifestyle, and use modern educational approaches and your secret weapon in behaviour change, your practice nurse, to achieve this.