What's New in The Management of Diabetes

1. GP Dilemmas over Hypertension Targets for Diabetes Patients

The British Hypertension Society's updated guideline for the management of patients with hypertension pays specific attention to diabetes in a number of regards. Patients with diabetes with BP>140mmHg systolic or 90mmHg diastolic should be offered treatment with a target BP of 130/80 or less. The guidance encourages the use of multiple blood pressure lowering therapy according to the AB/CD rule with a compelling indication to use angiotensin converting enzyme (ACE) inhibitors in type 1 diabetes with nephropathy and angiotensin II blockers in type 2 diabetes with nephropathy.

There is also the recommendation that type 2 diabetes patients should all receive 'secondary' or coronary equivalent cardiovascular prevention with low-dose aspirin, unless contraindicated, and statin therapy for ages up to at least 80 years and for initial total cholesterol of 3.5 mmol/I or more. The dilemma for clinicians is that these targets are lower than those in both the previous NICE guidance for type 2 diabetes and in the Quality and Outcomes Framework.

2. 'Designer' Insulins

Over recent years there has been a rapid expansion in genetically engineered insulin analogues, the so-called 'designer' insulins. Rapid-acting analogues such as insulin aspart (NovoRapid) and insulin lispro (Humalog), attempt to mimic the meal-related insulin profile of normal physiology and are now widely used as the bolus (with meals) component of basal-bolus therapy. Yet the advantages of treatment with rapid-acting insulin analogues can only be fully realised when replacement of basal (or background) insulin is also optimised and to this end, long-acting analogues are now being developed.

The first of these to be introduced into clinical practice, insulin glargine (Lantus), has a superior mean pharmacokinetic profile to conventional intermediate-acting human insulin and many studies have confirmed advantages in terms of reduced rates of hypoglycaemia, and improved glycaemic control along with the advantage of once daily administration. Insulin detemir (Levemir) is the second long-acting basal insulin analogue to be available in the UK and uses and alternative approach to prolong insulin action. Detemir is characterised by the removal of thereonine at position B30 and the acylation of a 14-carbon myristoyl fatty acid to lysine at position B29.

The acylation of detemir enables albumin binding, which contributes to a protracted action. A multinational study found that insulin detemir achieved similar improvement in HbA10 levels, provided significantly lower day-to-day variability in fasting blood glucose levels with lower risk of night-time hypoglycaemia and reduced weight gain compared with conventional intermediate-acting human insulin.

This study, along with 14 other research papers examining the role of insulin detemir in the treatment of diabetes, was presented at the recent meeting of the American Diabetes Association (ADA). Weight loss or weight neutrality appear to be a consistent feature of many of the studies, but this observation is so far unexplained. Head-to-head studies with insulin glargine are continuing and the results are awaited with interest. Insulin detemir (Levemir) was approved for marketing in the EU in June last year and has been launched in the UK. It is available as a cartridge (Penfill) for the Novopen III or as a pre-filled pen (Flexpen).

3. Self-management and Education for Patients

The National Service Framework and GMS contract have placed diabetes firmly on the healthcare agenda and have also highlighted the importance of emphasising and facilitating patient self-management. However, the NICE review of patient education models for diabetes was unable to make specific recommendations because of lack of evidence from good randomised controlled trials. DESMOND (Diabetes Education Self Management Ongoing and Newly Diagnosed) attempts to fill this gap. The model is person-centred with a philosophy based on seeing individuals as experts in their own condition. This in turn informs the training of educators delivering the programme.

The newly diagnosed programme includes six hours of contact time delivered by two trained DESMOND educators as one or two sessions, with a group of 8-10 patients who are within six weeks of diagnosis. The programme is supported by a structured curriculum, excellent patient materials, props, food models and a goal-setting tool for patients. The programme has been piloted in 15 PCTs across England with some 30 courses and more than 200 patients having gone through it. The RCT is now up and running and will involve more than 1,000 patients, making it one of the largest RCTs of an educational intervention.

4. NICE Type 1 Guidelines

The key message from the NICE guidelines on type 1 diabetes in adults published last year was patient-centred care, with the patient's views integrated into their management plan. This should include education, nutritional advice, therapeutics, identification and management of complications, foot care and psychological care. In terms of glycaemic control, a target HbA1c (6.5 per cent in those at increased risk) should be the aim, taking into account avoidance of hypoglycaemia. Screening for complications should be on an annual basis from diagnosis (after the age of 12) and in children and young people, coeliac disease and thyroid disease should also be screened for at diagnosis.

Of particular practical help is the advice regarding arterial risk assessment in type 1 patients. The guidelines suggest we abandon use of risk factor tables that are often not relevant to our type 1 patients and grossly underestimate their risk. The criteria suggested for classification of `high' risk are microalbuminuria or features of the metabolic syndrome. Metabolic syndrome is classified as two of:

triglyceride >1.8 mmol/I

BP>135/80 waist circumference>100cm for men (>90cm if South Asian) or waist circumference >90 cm for women (>80 cm for women if South Asian) an HDL cholesterol

5. Increasing Numbers of People with Diabetes

A fascinating study from the WHO was published in Diabetes Care last autumn. This looked at estimating diabetes in the year 2000 and projecting numbers for the year 2030. In 1998 similar work was done and it was estimated that by the year 2000 there would be 154 million cases of diabetes worldwide. Estimates from this work showed that in 2000 there were actually 171 million cases, this figure being 11 per cent higher than the previous estimate.

The current figures were based on previous work and include epidemiological data that has become available, particularly in areas such as Africa, the Middle East and India. The study estimates the worldwide prevalence of 2.8 per cent in 2000 will increase to 4.4 per cent in 2030. Therefore, the projected number of people with diabetes will rise from 171 million in 2000 to 366 million in 2030. This data offers an updated quantification of the growing public health problem of diabetes across the world. The human and economic costs of this epidemic are enormous. Mortality from communicable disease and infant and maternal mortality in developing countries are declining. In association with increasing diabetes prevalence, this will inevitably result in increasing proportions of deaths from cardiovascular disease in these countries, as well as increased prevalence and associated consequences of other complications of diabetes. Diabetes UK published its own report last year which said the current figure of 1.8 million people with diabetes in the UK will rise to 3 million by 2010.

And on its way ........... five treatments we will hear more about over the next five years.

1. Endocannabinoid Receptor Blockers

The endocannabinoid system is thought to be overactive in obesity and in smokers and may play a key role in increasing appetite and motivating people to continue to eat and smoke. Endogenous cannabinoids have been identified and in the 1990s receptors and then specific blockers were identified. The first endocannabinoid receptor blocker, rimonabant, is in phase 3 trials, with early results showing weight loss of 9kg, reduction in waist circumference of 9cm, reduction in insulin resistance and triglyceride levels and increase in HDL cholesterol levels (23 per cent) after a year's therapy. These results along with 36 per cent reporting smoking cessation make it an exciting prospect for obese patients with diabetes.

2. Agents Targeting Insulin Resistance

PPARy agonists, the glitazones, are now established as oral agents for use in patients with type 2 diabetes. The field continues to expand with at least two PPARy in phase 2 studies. There is also the development of dual alpha and gamma agonists. As alpha agonists essentially have a fibrate effect, the option of combining a glucose-lowering and lipid-lowering action in one therapeutic agent is attractive. At least two such agents (Muraglitazar and Tesaglitazar) are in development, and animal studies have shown promising effects. However, the reports of bladder tumours in animal studies with some of the earlier agents will require longer pre-clinical studies and may delay ` these agents becoming available for clinical use.

3. Glucagon-like Peptide (GLP-1)

Glucagon-like peptide (GLP-1) is a potent incretin hormone produced in the L cells of the distal ileum and colon. GLP-1 has the ability to augment insulin release in a glucose-dependent manner as well as increasing insulin biosynthesis, inhibiting glucagon secretion, delaying gastric emptying and hence inhibiting food intake, thus making it an ideal candidate to treat type 2 diabetes. Lizard venom (from the gila monster) contains exendin 4 which is more potent than native GLP-1: Exenatide, the first of these agents to be used in phase 2 studies, has been shown to reduce HbA1c by around 1 per cent along with weight reductions of around 2-3kg when used in combination with metformin, a sulphonyl-urea or both. Exenatide is formulated as a sterile product. The US Food and Drug Administration is expected to make a decision on Exenatide as a proposed treatment for type 2 diabetes later this month.

4. Agents Which Complement GLP-1

Dipetidyl peptidase IV (DPP-IV) is the enzyme responsible for degrading GLP-1 and so a DPP-IV inhibitor could be used to delay breakdown of GLP-1 and prolong its action. One agent, LAF 237, an oral agent with longer duration of action requires once-daily dosing. Phase 3 studies have shown effective glucose lowering without an increase in insulin levels. This is an attractive alternative to GLP-1 agonists which require injection, as it is orally administered, although it could be used in combination with GLP-1 agonists.

5. Inhaled Insulin

Subcutaneous administration of insulin by injection is the only currently available option. However, insulin can be given by inhalation, as first demonstrated in 1971. But it has only been since 2000 that the modern era of inhaled insulin has begun. A Cochrane review of randomised controlled trials comparing inhaled with conventional injected soluble insulin concluded that inhaled insulin provided equivalent control to injected regimes.

The bioavailability is 10-15 per cent and the dose about three times that of injected insulin: A number of companies are pursuing this option, including Exubera, a dry powder inhaler. The insulin powder is packaged into a single dose blister containing 1 mg or 3mg, the 1 mg blister equating to approximately 3 units of insulin. Exubera was submitted to the European Medicines Evaluation Agency in Feb 2004 for approval in Europe and is still awaiting a decision.

Dr Qazi Zaman and Dr Melanie Davies outline five big developments in their field

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