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July 2007: Achieving glucose control in diabetes

Symposium: Endocrinology

Symposium: Endocrinology

Hyperglycaemia is the defining characteristic of all the diabetes syndromes and carries the same risks for microvascular and macrovascular complications irrespective of its cause.

Minimising hyperglycaemic exposure reduces the risk of complications and is a key goal of diabetes management. But the natural histories of the two common diabetes syndromes, type 2 diabetes (more than 90% of diabetes cases) and type 1 (up to 10% of diabetes cases) are distinct and the approach to glucose control is radically different.

Why is it important to distinguish between different types of diabetes?

It is important to make a correct classification, as there are very important implications for patients. For example, patients with type 1 diabetes may die if not treated promptly with insulin, whereas patients with type 2 diabetes may gain weight and compound their metabolic syndrome if treated too early with insulin. However, it should be remembered that occasionally the distinction at first presentation is not entirely straightforward.

It is also important not to forget patients with rarer forms of diabetes. These include:

• Diabetes secondary to pancreatitis. This form is insulin dependent, often very unstable and occurs with associated exocrine pancreatic deficiency

• Maturity onset diabetes in the young (MODY). This has genetic implications, and is often treated with uniquely effective, type-specific treatments.

What is the difference in natural history between type 1 and type 2 diabetes?

Patients with type 1 diabetes usually present abruptly, with severe hyperglycaemia, when most of their pancreatic beta cells have been destroyed by immunological attack. Although this immunological attrition may have progressed over several years, hyperglycaemia does not occur until a few weeks or even days before diabetes becomes clinically apparent.

By contrast, in type 2 diabetes insulin resistance may have been present for many years, often decades, before the onset of hyperglycaemia, which occurs only when the beta cells begin to fail. Thus there may be a prolonged phase of moderate pre-diagnosis hyperglycaemia as this insidious process unfolds. Beta cell failure can be slowed down but not stopped, hence the need for treatment increases as time goes by.

How are the comorbidities different?

Apart from hyperglycaemia, the range of cardiovascular risk factors in type 1 diabetes is similar to that in the general population.

However, in type 2 diabetes the vast majority of patients have multiple coexisting cardiovascular risks, such as central obesity, hypertension and dyslipidaemia. These are standard components of the ‘metabolic syndrome' that provoked their beta cell failure in the first place.

How do the glucose control treatments differ?

Patients with type 1 diabetes have very few beta cells from the onset of their condition. Apart from a short and variable ‘honeymoon' phase, patients with type 1 diabetes are dependent on insulin replacement for survival.

In patients with type 2 diabetes, the clinical presentation is most often at a stage when there is still substantial beta cell function. This can be nurtured by:

• Reducing insulin resistance

• Other methods of reducing insulin requirements

• Enhancing insulin action

• Encouraging insulin production.

It is only at the very late stages of beta cell failure that insulin replacement becomes necessary.

When insulin becomes the only treatment option in a patient with type 2 diabetes, there is nevertheless still some residual insulin secretion. Good glucose control can therefore be obtained, at least initially, by using a long-acting insulin that supplements basal insulin secretion, provided that it is combined with oral agents that counteract insulin resistance, such as metformin or a thiazolidinedione (glitazone).

How do the complications of treatment differ?

In type 1 diabetes insulin omission may rapidly lead to life-threatening ketoacidosis. Insulin treatment is accompanied by a high risk of hypoglycaemia, particularly in patients who have had type 1 diabetes for more than five to ten years.1

Treatment omission in type 2 diabetes, even in patients who require insulin, is unlikely to lead to acute metabolic deterioration unless there is intercurrent major illness. At all stages of treatment, hypoglycaemia is either not a risk (in patients treated with lifestyle management, metformin or thiazolidinediones) or much less common than in type 1 diabetes (in patients treated with sulphonylureas, gliptins, GLP-1 agonists or insulin).

Some young women skip insulin doses so they can lose weight. If this is part of a formal eating disorder the risks of early severe complications are very high.

Outside a formal eating disorder the risks are those that attach to the relevant level of hyperglycaemia. If people with type 1 diabetes use basal bolus insulin regimens with insulin analogues or continuous subcutaneous insulin infusion (CSII) and carbohydrate counting there need be no conflict between optimisation of glucose control and weight management.

What are the benefits of good glucose control?

There is now abundant evidence, from the UKPDS study,2 that good glucose control in both type 1 and type 2 diabetes reaps huge long-term health benefits by reducing microvascular and macrovascular complications.

The long-term follow-up of the DCCT study of type 1 diabetes drew almost identical conclusions on the relationship between levels of glucose control and complication risk.3,4 These conclusions have been embedded in the NICE guidance.5

There is no doubt that achieving glucose control targets is immensely worthwhile. The personal costs of complications are high (for example disability and death), and the cost of diabetes represents at least 8% of the NHS budget, and 80% of that is spent on treating complications.6

Has the QOF produced improvements in blood glucose control?

Around 58.8% of patients not excluded from the QOF had a HbA1c <7.5% in the first year. This rose to 61.8% of patients in the second year. However, the HbA1c outcome target was among the highest exception rates for the QOF, at 12.03% (range 0% to 80%).

In contrast, 70.3% of patients in year one and 74.9% in year two achieved a blood pressure <145/85mmHg, and 71.8% and 79% of patients achieved a total cholesterol of <5mmol/l in year one and two respectively.7

Glucose control is improving, but it is clearly proving more difficult to achieve the QOF glucose control target than the blood pressure and lipid targets. See table 1,attached, for the relevant QOF2 targets.

This is reinforced by the data from the National Diabetes Audit, which includes all patients with diabetes (there are no exceptions) and showed that only 58.4% of patients had HbA1c <7.5% in 2004-5.8

How effective is structured education?

There is no doubt that systematic education to a defined curriculum improves diabetes self-management, which is the key to success at all stages of treatment.

Structured education programmes, such as X-PERT and DESMOND, are now being widely implemented under the auspices of the NSF for Diabetes and NICE guidance. These programmes have the potential to enable many more patients to achieve glucose control targets by improving their understanding of their condition, providing lifestyle advice, and motivating them to adhere more regularly to medication regimens.

What is the role of weight loss management?

Weight loss management is beginning to deliver real benefits in some patients.9

A body weight loss of around 5–10% has a significant metabolic benefit. Evidence is emerging that long-term weight loss can be facilitated by the use of orlistat, combined with intensive dietetic support (necessary to mitigate the predictable gastrointestinal side-effects) or rimonabant (although there are concerns about its depressant effect on mood in some patients).10

Rimonabant is an endocannabinoid receptor agonist, targeted at specific receptors involved in the complex and still emerging endocrinology of weight regulation.

What is the role of new treatments?

Glucagon-like peptide 1 (GLP-1) is a gut hormone, released postprandially, that stimulates insulin gene expression, insulin secretion and pancreatic beta cell growth. Together with glucose-dependent insulinotropic polypeptide it is responsible for the incretin effect, the augmentation of insulin secretion following oral administration of glucose (in contrast to intravenous administration).

In addition to stimulating insulin secretion and increasing beta cell mass, GLP-1 also suppresses glucagon secretion, delays gastric emptying and inhibits food intake. These properties are all potentially beneficial for the management of type 2 diabetes.

Therefore, in people with type 2 diabetes who still have an appreciable number of functioning beta cells, increasing the action of GLP-1 would seem to have pharmacological potential. This is now beginning to be realised.

In normal physiology GLP-1 is metabolised extremely rapidly by the enzyme dipeptidyl peptidase 4 (DPP-4). Therefore GLP-1 itself cannot be used therapeutically because it would need to be infused continuously. However, a DPP-4 resistant analogue, exenatide, is now available for injection, and others, such as liraglutide, are in development.

In addition, inhibitors of the DPP-4 enzyme (gliptins, for example sitagliptin) are also being considered for approval.

One of the major benefits of these agents is that, unlike sulphonylureas, thiazolidinediones and insulin, their use is not associated with weight gain. Indeed, with the GLP-1 agonists most patients seem to lose weight. Weight management is a challenging aspect of type 2 diabetes care, and weight gain frequently confounds other attempts to improve glucose control. Therefore the emergence of pharmacological agents that offer the prospect of both improving glucose control and facilitating weight loss is potentially very welcome.

However, insulin will always be necessary for the treatment of patients with type 2 diabetes who have progressed to the point where they have negligible residual beta cell function. Incretin-related agents such as GLP-1, like sulphonylureas, are not going to benefit patients without beta cells.

How should you decide on a treatment strategy?

The treatment choices in type 2 diabetes are becoming more varied. They offer both patients and healthcare professionals a range of options that should reap significant long-term health benefits by enabling more patients to achieve and maintain target glucose control.

At any given time, 40% of patients with type 2 diabetes will be at the earliest stage, requiring lifestyle management with or without metformin. Provided that there is access to a structured education programme, patients with early stage disease will be reasonably straightforward to manage.

Slow-release metformin is worth trying in those intolerant of conventional metformin. However, metformin tolerance can be maximised if it is introduced gradually over a few weeks.

Beyond this stage, when target glucose control is not being achieved with these basic interventions, a greater range of options need to be considered. GPs should consider the next level of treatment if the patient fails to achieve their glucose control target for more than six months, despite maximisation of lifestyle management and adherence to current medication.

I would advocate using sulphonylureas only in the minority of patients who are near normal weight. For the majority of patients, who are overweight, intensifying weight management should be considered, possibly with pharmacological supplementation or referral of morbidly obese patients (BMI >40) for discussion about bariatric surgery.

After this the introduction of gliptins or thiazolidinediones should be considered. Notwithstanding the concerns recently raised about the adverse cardiovascular and osteoporotic effects of some drugs in the class, thiazolidinediones have undoubtedly been a very effective addition to the range of glucose control strategies in type 2 diabetes. Despite their contraindication in cardiac failure and promotion of weight gain, it is likely that they will still have a place in the management of patients with type 2 diabetes.

The DPP-4 inhibitors, the gliptins, will find a position at this stage of treatment, once their side-effect profiles and potential mitigation of weight gain have been clarified.

At the final stage of type 2 diabetes, those who still have some beta cell function are now likely to be considered for GLP-1 agonists, such as exenatide.

Finally, there will always be a need for some patients to move on to insulin therapy. In my opinion this, as with all the more complex interventions, should be introduced in the context of a structured and properly supported implementation programme, usually delivered by specialist nurses and dietitians.

table 1: QOF2 diabetes Table 1: QOF2 targets for glucose, blood pressure and cholesterol control Dr Bob Young Author

Dr Bob Young
consultant physician and diabetologist, Hope Hospital, Salford

Achieving glucose control in diabetes

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