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Managing type 2 diabetes: an overview

Adam Robinson
Consultant Physician in Diabetes
Bolton Primary Care Trust

Type 2 diabetes is a progressive disorder and this is clearly reflected in the classification system for diabetes, devised and published by the World Health Organization (WHO) in 1999 and widely used by diabetes healthcare workers in the UK.1

Indeed, diabetes is no longer a disease entity in its own right, but rather a clinical "stage" in an underlying disorder of glycaemia. The earlier stages are defined as "impaired glucose regulation" and, before that, normal glucose tolerance.

One may ask if this is of any importance – most of our patients present in the diabetic stage of the disorder and there is good evidence that rigorous management of cardiovascular risk factors, combined with appropriate screening for complications, improves their long-term outlook. The Quality and Outcomes Framework that drives so much of our work in primary care encourages the identification of diabetic stage patients and the explicit targeting of cholesterol, blood pressure and hyperglycaemia along with entry into retinal and foot screening programmes.2

However, the "staging" system emphasises one very important point: patients can move up the stages – obvious and perhaps usual – but they can also move back down. This is worth exploring further.

Nearly all of us are born with normal glucose tolerance. As we age, we become slightly more resistant to insulin and a significant number of people will develop impaired glucose regulation and then diabetic stage disease. We are all familiar with the drivers of this progress and they include ethnicity, birth weight, ageing, obesity and a sedentary lifestyle. The first three are fixed and we cannot change them (not yet anyway!); but obesity and sedentary lifestyles can be addressed and doing so can move people back down the stages and in others halt or delay progress to a higher stage.

Diabetes and obesity
The Nurses' Health Study clearly demonstrated the increased risk of developing diabetes with obesity; but that in itself does not prove that weight loss reverses the diabetic stage.3 Evidence for this has been most clearly demonstrated in laparoscopic gastric banding studies. One recent study of banding in type 2 diabetes showed the rate of remission for diabetes was 73% at 2 years. However, the control group in this study achieved a 13% remission from diabetes with lifestyle modification programmes individually structured to reduce energy intake, to reduce intake of fat (

Motivating and empowering patients to successfully self-manage their condition is vital to good outcomes and, in this context, understanding that diabetes is a stage in a glycaemic disorder that can be reversed is vital. Clearly, not all our patients will achieve normoglycaemia or even impaired glucose regulation stages, but some will and many others will slow the progression to insulin requirement. Understanding that obesity is the principal modifiable driver is also key to success.

Treatment options
Within this context, there has been a therapeutic paradox facing diabetes carers for decades and it is this: the majority of the treatments we offer to patients in the diabetic stage of their disorder are associated with weight gain. Indeed, it is far from clear that the benefit for patients derived from improving their hyperglycaemia outweighs the negative effects of the weight gain so often associated with it. This is not just in terms of the complications of diabetes but also the general mental and physical wellbeing of people who are constantly harangued about their excessive weight and given treatments likely to increase it.

Until recently, metformin has stood alone as being the therapeutic option in our armoury associated at least with weight neutrality if not slight weight loss.5,6 This is one reason that it is the firstline treatment in nearly all diabetic stage patients and this is reflected in the latest National Institute for Health and Clinical Excellence (NICE) guideline.7

Disadvantages include the well-known gastrointestinal side-effects, which can be largely overcome by gradual titration from a single 500 mg tablet taken with the main meal. In those who cannot tolerate base metformin, a trial of the slow release preparation is worthwhile. This has recently become available in 1,000 mg strength tablets enabling a reduction in these patients all too frequently high tablet burden. Metformin is also the therapy with the best evidence base for reducing the long-term complications of diabetes. It is contraindicated in patients with significant renal dysfunction and is generally not used in patients with an estimated glomerular filtration rate (EGFR) below 30. In a small number of patients in whom a quick therapeutic response is required because of symptomatic hyperglycaemia, a sulphonylurea may be appropriate firstline with a view to substituting with metformin in due course. How long metformin will control glycaemia is very individual, but, typically, a secondline agent will need to be introduced within a year or two.

At this point, NICE suggests adding a sulphonylurea to metformin therapy and it is here that the contradiction of treating a weight-driven condition with a weight-increasing therapy first occurs. Typically, sulphonylureas are associated with 3–4 kg weight gain within the first year, although it tends to level off thereafter. This is significant and often demoralising for the patient. The mechanism of action, boosting pancreatic insulin secretion for the prevailing glucose level, also predisposes those taking them to hypoglycaemia.

It is, however, only where hypoglycaemia is a significant risk, or its consequences are, that NICE suggests an alternative secondline agent might be appropriate. The deleterious nature of weight gain is not considered sufficient reason to use an alternative. In terms of preventing long-term complications of diabetes, the evidence base for sulphonylureas is somewhat contradictory, although a recent study using glicalazide MR showed evidence of a significant reduction in microvascluar events but not macrovascular events.

Two other classes of antihyperglycaemic have also been available for more than a decade. Acarbose, an alphaglucosidase inhibitor, reduces HbA1c by up to 1% by slowing the breakdown of carbohydrate by enzymes in the bowel. As a consequence, carbohydrated tends to ferment and the gas produced gives the side-effect that has so limited its acceptability as a treatment for diabetes. Acceptable perhaps for an outdoor occupation but not a taxi driver or foundary worker!

Glitazones have been available in the UK for a decade and were badged as the first treatment that targeted insulin resistance. A tendency to cause fluid retention and a consistent association with increased bone fractures has reduced confidence in their use as has contradictory evidence of their long-term effects on cardiovascular disease. Furthermore, these are another class of drug associated with weight gain, in the ADOPT study being 7 kg more than the metformin group at 5 years.

Two relatively new treatments for diabetes are now available: the DPP4 inhibitors and the incretin mimetics. The former are oral therapies, sitagliptin and vildagliptin, that improve HbA1c by up to 1% and are weight neutral. Incretin mimetics are injectable therapies taken once or twice daily, exenatide and liraglutide, and are the first therapies for diabetes that both lower glucose levels and at the same time lead to significant weight loss. Although often associated with nausea, which usually settles, and having the disadvantage of having to be injected, they have been readily taken up by the diabetes community because they are the first treatment that drives weight down and experience to date has been very encouraging.

Conclusion
To summarise, the main driver of type 2 hyperglycaemic disorders is obesity and it is vital that this is addressed adequately in all patients, especially those who reach the diabetic stage of their disorder. Apart from metformin, treatments have often improved glucose levels at the expense of weight gain. Recently new treatments have become available that, for the first time, combine improvements in hyperglycaemia with weight loss and they are welcome additions to are therapeutic armoury.

References
1. World Health Organization (WHO). Definition, diagnosis and classification of diabetes mellitus and its complications. Geneva: WHO; 1999.
2. NHS Employers, General Practitioners Committee. QOF Changes and New Indicators for 2009/10. London: NHS Employers; 2009.
3. Rana JS, Li TY, Manson JE, Hu FB. Adiposity compared with physical inactivity and risk of type 2 diabetes in women. Diabetes Care 2007;30(1):53–8.
4. Dixon JB, O'Brien PE, Playfair J et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA 2008;299(3):316-23.
5. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317(7160):703–13.
6. Kahn SE, Haffner SM, Heise MA et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355(23):2427–43.
7. National Institute for Health and Clinical Excellence (NICE). Type 2 diabetes: The management of type 2 diabetes. London: NICE; 2009. Available from: http://guidance.nice.org.uk/CG66/Guidance/pdf/English