2: Recent advances in therapy of diabetes

Intensive therapy is more demanding for patients and their families, and adherence is obviously critical to its success. Patient views are therefore central to management decisions. For example, an adolescent who struggles to comply with two injections a day is unlikely to manage four injections (see case report, Box 1). However, for most patients, the demands of achieving good control are less than the consequences of poor control.5 In adolescents, good control improves quality of life and reduces the burden perceived by their parents.5

The limiting factor preventing ideal glycaemic control remains hypoglycaemia. Glucagon secretion is blunted early in the course of type 1 diabetes, increasing the patient’s vulnerability to hypoglycaemia. Furthermore, the blood glucose threshold for release of catecholamines, which both stimulate glucose production and produce warning symptoms such as sweating and trembling in response to hypoglycaemia, is lowered in patients with better glycaemic control, even more so during sleep.6 Continuous glucose monitoring devices reveal the frequency of nocturnal hypoglycaemia and the limitations of conventional blood glucose monitoring. Both the new insulin analogues and continuous subcutaneous insulin therapy hold promise of improving control without the attendant risk of hypoglycaemia.

In the past, the pharmacokinetic characteristics of insulin preparations have been modified by mixing with substances that delay absorption (eg, protamine and zinc) and by varying crystal size. Recombinant DNA technology has now made possible the creation of analogues of human insulin with altered pharmacokinetic characteristics (Box 2).

Rapid-acting analogues: These are also known as rapid-onset and ultra-short-acting insulins and include insulin aspart and insulin lispro. They were created by modifying the amino acid sequence of the insulin B chain (substituting aspartic acid for proline at position 28 [aspart] and reversing proline and lysine at positions 28 and 29 [lispro]).

These analogues have the advantages that:

• they follow better the rise in blood glucose level after eating than conventional short-acting insulins, thereby reducing postprandial hyperglycaemia and between-meals hypoglycaemia;

• their very rapid onset of action allows them to be injected immediately before meals or even after eating, which is especially useful in young children with erratic eating patterns.

Their disadvantages are:

• shorter duration of action than traditional short-acting human insulins, which could cause preprandial hyperglycaemia.

The short-acting analogues are available on the Pharmaceutical Benefits Scheme.

Long-acting analogues: These were created by substituting and adding amino acids to the insulin molecule (glargine) and by adding a fatty acid chain, which enhances binding to albumin (detemir).

The long-acting analogues have the advantages of:

• more reproducible absorption than conventional long-acting insulins;

• a flat dose profile with a low peak of action, which provides more predictable background control than the intermediate-acting insulins, without the unwanted peaks of action around lunchtime and during the night.

Initial studies indicate that the long-acting analogues reduce the risk of nocturnal hypoglycaemia and produce a modest reduction in fasting blood glucose levels compared with intermediate-acting preparations.7 Neither is as yet available on the Pharmaceutical Benefits Scheme (PBS). There are few data on the relative benefits of administration by pump versus multiple daily injections for glargine or detemir as the basal insulin, but better night-time blood glucose control with pump therapy has recently been described.8

Pump therapy: The effectiveness of continuous subcutaneous insulin infusion (pump therapy) has been rediscovered (Box 3). First used in the 1970s and 1980s, pump therapy has been reintroduced with improved technology. Small amounts of a rapid-acting insulin analogue are infused, usually into the abdomen or buttocks, at a basal rate, which can be varied, with extra boluses calculated for each meal and snack. The major advantages are less variable absorption and improved insulin pharmacokinetics. Varying the basal rate can help regulate overnight blood glucose levels. Pump therapy is suitable for motivated patients, particularly those with frequent hypoglycaemic episodes or hypoglycaemic unawareness, as most studies show reduced hypoglycaemia.9,10 Because the infused insulin is rapid-acting, mechanical interruption of the pump can rapidly lead to ketosis, which is of particular concern in pregnancy. Pump therapy must therefore be accompanied by frequent blood glucose monitoring. Private health insurance companies now subsidise the cost of the pump and some consumables, but there is no government funding. As for all therapies, it is essential that the patient is central to the choice of pump therapy. This is also important when the patient is a child or adolescent, whose views may differ from those of their parents.

Aerosols: Aerosolised insulins for delivery by inhalation are under active investigation, with Phase III studies completed. These insulins provide effective cover for meals in combination with once-daily, long-acting, subcutaneous insulin. However, aerosol delivery requires six times as much insulin for the same effective dose as subcutaneous injection, which may create a cost barrier to widespread use. Also, the long-term safety of delivering large amounts of insulin to the alveolae is not known.

At present, all systems deliver insulin to the systemic circulation rather than the enteroportal circulation. Systemic delivery contributes to the insulin resistance associated with obesity and adolescence and is a major barrier to physiological insulin replacement. However, a method of accessing the enteroportal circulation is not currently in sight.

Continuous blood glucose monitoring: Intermittent measurements of capillary blood glucose give a limited glimpse of blood glucose levels, which may fluctuate widely over 24 hours. The recent introduction of systems for continuous blood glucose monitoring is an exciting advance11,12 (Box 4). Continuous monitoring reveals postprandial fluctuations in glucose level and asymptomatic nocturnal hypoglycaemia, and is likely to be especially useful in programming overnight basal insulin rates for pump therapy. Continuous monitoring systems available in Australia measure interstitial blood glucose via an indwelling cannula in the abdomen or buttocks. However, they are expensive ($5000 or more) and, at present, are most applicable for use by diabetes centres which lend devices to patients for restabilisation. Devices under investigation have alarms to alert patients to glucose levels outside a target range and provide immediate read-outs.

Non-invasive blood glucose monitoring: Frequent automatic glucose readings can be obtained non-invasively through the process of reverse iontophoresis, in which a low electric current pulls glucose molecules through the skin for collection in a gel disc. A device that is worn like a wristwatch is approved for patients aged over 7 years in the United States, but its cost (about US$1000 for the device and more than US$100 per disposable 12-hour sensor) limits more widespread use. It is not yet available in routine practice in Australia.

HbA1c measurement: Measurement of glycosylated haemoglobin (HbA1c) remains the criterion standard to judge the outcome of diabetes management. Rapid measurement with a desktop device expedites assessment and education. Results of longitudinal studies now allow accurate prediction of the risk of vascular complications for a given HbA1c level3,4 (Box 5). This can be very useful when counselling patients. For example, a teenager can be advised that large trials show that reducing the HbA1c level from 9% to 8% and maintaining the reduction during adolescence reduces the risk of proliferative and severe non-proliferative retino-pathy in young adulthood by 70%–80%.3

Education and psychological support: With the advent of intensive therapy and its greater demands on patients and their families, counselling and education are becoming even more important in achieving compliance, particularly in adolescents. However, as long-term risk of vascular complications can be predicted more accurately from HbA1c level, it is easier for doctors to counsel and encourage intensive management.1-4 Furthermore, as doctors have become more certain about the need for intensive management, it is our impression that patients and their families have accepted and coped better with it. Indeed, mean HbA1c levels in Australian children have improved from 10% in the 1980s to around 8% in 2003.14

Coping-skills training has been shown to improve metabolic control and quality of life in adolescents.15 This intervention, like all successful interventions in type 1 diabetes, needs to be intensive, and support must be sustained.

The indispensable role of the diabetes educator and dietitian in the multidisciplinary team has long been recognised. Dietary management and education is now more comprehensive and includes the concept of the glycaemic indices of food.16 Educators’ roles are becoming more specialised, both for different age groups and, as technology progresses, for different monitoring and delivery systems.

New use of old drugs: Adding metformin to the treatment regimen for type 1 diabetes can improve metabolic control by reducing insulin resistance, a problem in both obese patients and adolescents with diabetes, in whom the physiological insulin resistance of puberty is exaggerated, necessitating high insulin doses.17 However, metformin is suitable only for patients with low alcohol intake and normal renal and hepatic function who remain compliant with insulin therapy.

Glucagon in small frequent doses (< 0.15 mg up to 6-hourly) can prevent hypoglycaemia (and resulting hospital admissions) in patients with reduced oral intake, including children with viral gut infections.18

Therapy for type 2 diabetes should be tailored to the pathological process that is most prominent at different stages of the disease (see case report, Box 6).

Increase insulin sensitivity: Early in the disease process, the aim should be to target insulin resistance with diet and exercise plus metformin therapy. A weight loss of 5 kg leads to a 25%–50% reduction in insulin resistance (J Prins, unpublished data). Metformin is tolerated by most patients if started at a low dose (eg, 250–500 mg/day), which is slowly increased depending on blood sugar response and tolerance.

The thiazolidinediones (rosiglitazone and pioglitazone) are newer insulin-sensitising agents which are effective, but have the disadvantage of causing some weight gain and fluid retention. However, unlike metformin, they are safe in patients with renal impairment. They are widely used overseas but are not currently available on the PBS.20

Increase circulating insulin: If strategies to increase insulin sensitivity are ineffective, the next step is to increase circulating insulin level. Oral agents currently available in Australia for this purpose are the sulfonylureas and the newer glitinides. Metformin should be continued if the patient is obese.

As sulfonylureas are potent and long-acting, hypoglycaemia is a significant clinical problem, but can be avoided with careful dose titration. Sulfonylureas cause weight gain of a few kilograms in most patients and lose efficacy with time, either because of increasing insulin resistance (usually due to the weight gain) or “secondary” pancreatic β-cell failure. Other than half-life differences, there is little to distinguish later-generation sulfonylureas.

Glitinides (eg, repaglinide) are short-acting drugs that increase insulin secretion. They are well tolerated but less potent in clinical practice than the sulfonylureas. Their advantage lies in their short half-life, making hypoglycaemia less common, but pre-meal dosing is a disadvantage for many patients. Glitinides are not currently available on the PBS.

Exogenous insulin: If diabetic control remains, or becomes, suboptimal when taking oral combination therapy with metformin and a sulfonylurea, then insulin is indicated.21,22 As evidence supporting the benefits of good diabetic control is now overwhelming,13 any delay in introducing insulin in these patients is now considered unacceptable. It is important to educate patients that insulin is usually necessary because of natural progression of the disease and not necessarily because of any “failure” on their part. It is therefore advisable to introduce the concept well before necessary. A good “selling point” is that insulin often substantially improves how patients feel.

With currently available insulin preparations and administration devices, it is straightforward to develop an acceptable “physiological” insulin-replacement regimen for almost all patients.21,22 Newer analogue insulins (including mixtures) have a definite place in the management of type 2 diabetes and contribute to the excellent choices available.

There is little point in continuing sulfonylurea or glitinide therapy after introducing insulin. Advantages of ceasing oral agents are simplification of therapy, less chance of drug interaction, reduced costs and improved compliance. However, metformin should be continued in obese patients, as it helps maintain weight and allows lower insulin doses to be used. Pioglitazone is the only insulin-sensitiser available for combination with insulin in Australia for patients with renal impairment.

Orlistat: This lipase inhibitor is currently indicated for use in obesity. Clinical trials have demonstrated its usefulness as an insulin-sensitising agent, with the added benefit of weight management.23 Overall efficacy appears similar to that of metformin or sulfonylurea.

Insulin secretagogues: These include the gut-derived hormones (incretins), such as glucagon-like peptide-1 (GLP1) and gastric inhibitory peptide. GLP-1 analogues and receptor agonists are currently under clinical trial and show definite promise for patients with type 2 diabetes. Administration is parenteral, but initial trial results demonstrate efficacy in blood sugar control, minimal risk of hypoglycaemia, and the associated benefit of weight loss. A related approach is oral administration of dipeptidase IV inhibitors, which effectively increase GLP-1 levels.24