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New drug therapies

Recent years have seen a raft of new therapeutic modalities for type 2 diabetes. Professor Anthony Barnett outlines the role of the latest drug therapies

Although metformin is likely to remain a first-line therapy because of its cardioprotective properties, there is a great deal of interest in new agents that more directly target the underlying pathophysiology of type 2 diabetes, which includes a combination of insulin resistance and pancreatic islet dysfunction.

Drugs targeting insulin resistance


These act on an intranuclear hormone receptor (PPARgamma) and directly target insulin resistance. They have similar efficacy in blood glucose lowering to metformin and sulphonylureas, and also improve blood pressure, lipid profile and inflammatory markers. More recently, trials have suggested reduction in cardiovascular endpoints in high-risk individuals and progression from glucose intolerance to type 2 diabetes. The downside is weight gain and sometimes peripheral oedema.

Several companies are studying glitazones or glitazone-like agents which might have an even more profound effect on insulin resistance and a better side-effect profile.

Dual agonists (glitazars)

These agents act on PPARgamma receptors and are therefore predicted to show the benefits of glitazones plus the added benefit of even more marked improvement in the lipid profile through PPAR effects. But there have been many problems and development of these drugs has been discontinued.

Endocannabinoid-1 receptor antagonists

(EC-1 blockers)

The first of this new class of agents, rimonabant, has recently been given a European licence as a weight management agent in people with BMI >30kg/m2 or >27kg/m2 if there is an associated co-morbidity such as type 2 diabetes or dyslipidaemia. It is not licensed for use as an antidiabetic agent but could be particularly useful in some patients.

The endocannabinoid system is

important in the control of appetite and food intake, and EC-1 receptors are present not just in the brain but in other

tissues, including fat cells. These agents, therefore, have the potential not to only

affect appetite control but also visceral fat.

Large-scale phase 3 clinical trials suggested some improvement in glucose tolerance, and in a diabetes trial there was a significant drop in HbA1c of about 0.7 per cent when used in combination with either metformin or a sulphonylurea. All trials show significant weight loss, reduction in waist circumference and increase in HDL and reduction in triglycerides. The main side-effects are gastrointestinal, particularly nausea, in around 12 per cent of patients and also a small increase in reports of anxiety and depression. They should not be used in people with a significant psychiatric history or who are on antidepressants.

Drugs that act on the

pancreatic islets

Glucagon-like peptide 1 (GLP-1) is an incretin hormone secreted from the GI tract during food intake which has been implicated in the pathogenesis of type 2 diabetes.

There are two current approaches to enhancing endogenous GLP-1 action in vivo:

• Incretin mimetic agents – exenatide

This agent was approved in the US last year and will soon be available in Europe. It exhibits activity similar to the naturally occurring hormone GLP-1, improving glycaemic control through:

– glucose-dependent stimulation of insulin secretion from the pancreatic ß cells

– suppression of glucagon secretion from the pancreatic a-cells

– slowing of gastric emptying (reducing post-meal hyperglycaemia)

– reducing appetite

– enhancing ß-cell function (based only on animal data so far).

Stimulation of insulin secretion only

occurs in the presence of elevated blood

glucose so the risk of hypoglycaemia should be low.

Clinical trials demonstrated significant improvements in HbA1c in combination with sulphonylurea or metformin or with both agents. Importantly, use of exenatide is associated with significant weight loss and extremely low risk of hypoglycaemia in combination with metformin (but not sulphonylureas). On the downside, exenatide has to be injected twice daily and there is a significant incidence of nausea. There is now also a long-acting form in development.

• DPP-4 inhibitors

DPP-4 breaks down endogenous GLP-1, and DPP-4 inhibitors are predicted to improve glycaemic control by preventing the rapid degradation of incretin hormones. This would enhance ß-cell insulin secretion and also reduce glucose production from the liver by inhibition of glucagon from the a-cells. Three DPP-4 inhibitors are in development. They show promising evidence for preservation of pancreatic ß cell function and improvements in glycaemic control.

Where are we now ?

Meformin is likely to remain first-line oral therapy for the foreseeable future since it is cheap, well tried and has evidence for

cardioprotective properties and reduction in microvascular risk. Beyond this, there will be a whole range of agents for second- or third-line therapy. Sulphonylureas are likely to remain widely used but the increasing

evidence base for glitazones may also

encourage more use at an earlier stage.

Anthony Barnett is professor of medicine

at the University of Birmingham and consultant physician at the Heart of England NHS Foundation Trust

Competing interests Professor Barnett has received honoraria for lecturing and advisory work from Sanofi-Aventis, MSD, Novartis, Eli Lilly, GSK and Takeda

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