Elderly patients with Type 2 diabetes who find it hard to control their blood sugar with tablets are especially likely to benefit from a new once-daily oral drug in development, say diabetes researchers. Galvus (vildagliptin) is one of the first drugs in a new class that controls diabetes by boosting hormones called incretins which help regulate blood sugar.
Studies with Galvus, presented at the recent annual meeting of the European Association for the Study of Diabetes in Copenhagen, show it is not only largely free of side effects itself but, remarkably, it has also been shown to attenuate the notorious side effects of other antidiabetic medicines that make treatment difficult for older people. Studies also indicate that the drug works particularly well in people over age 65. Novartis, the company which pioneered the new incretin-based approach and which is developing Galvus, describes it as ' one of the major breakthroughs in diabetes research of the last 10 years.'
Incretin hormones, called GLP-1 and GIP, are naturally occurring substances produced in the intestines in response to food intake. They play an important role in regulating blood sugar by stimulating both the alpha and beta islet cells of the pancreas. Alpha cells secrete glucagon which mobilises glucose when blood sugar is low. Beta cells produce insulin which reduces high blood sugar taking it out of the circulation and into the liver, muscles and other tissues to be stored or used as energy. The incretin response is much less effective in people with diabetes and their pancreatic islet cells function progressively less well. The glucagon-insulin balance gets out of kilter, and over time many beta cells die.
However, the incretin response can be boosted by drugs such as Galvus, which inhibit DPP-4, an enzyme that breaks down incretin hormones before they have time to work effectively. There are hopes, based on animal studies, that DPP-4 inhibitors will keep beta cells alive as well as preserving their function and possibly even generate more of them.
Results in elderly diabetics "impressive"
Researchers presenting data at the Copenhagen meeting said of study results for Galvus, that those for patients 65 and older were among the most impressive. Elderly diabetes sufferers receiving Galvus as part of a treatment that also included another drug (pioglitazone) were able on average to reach a glycated haemoglobin (HbA1c) level of 6.2%, surpassing the recommended target of 6.5%. Two thirds of patients achieved HbA1c targets.
HbA1c - a measure of how well diabetes has been controlled over the previous few months - is regarded as healthy if it is below 6.5% but many diabetes patients, especially those with long-standing disease, struggle with levels of 11% or higher, either because treatments are not working well or because patients discontinue them. Galvus in combination with pioglitazone has been able to reduce the highest HbA1c levels by 2.8% - a highly impressive result.
"Older people often have trouble using the drugs currently available because they are more likely to experience intolerable side effects," explained Dr Martin Fitchet, Global Medical Director for Galvus from Novartis Pharma AG. In some cases, existing oral medicines are contra-indicated for older people with diabetes who frequently suffer from numerous other medical conditions for which they take other medicines, he added.
The most widely used oral anti-diabetic drug, metformin, is associated with a high number of unpleasant gastro-intestinal (GI) effects such as nausea or diarrhoea that elderly people find particularly troublesome, he noted.
Oral drugs in the sulphonylurea class and injected insulin can cause hypoglycaemic attacks, which are of especial concern in the care of older people. Use of these agents also leads to weight-gain.
Thiazolidinediones (TZDs), another class of oral drug, also known as glitazones, can cause weight-gain, too. In addition TZDs carry a risk of fluid retention and heart failure so are unsuitable for people with cardiovascular disease.
"We were pleased to see in the studies of Galvus that when it was added to other types of treatment, the side effects of those drugs were reduced," said Dr Fitchet. "When added to metformin we saw a significantly reduced incidence of GI side effects and a further reduction in HbA1c of 1.3% among older patients. A smaller reduction of 0.9% was observed among under 65s.
One study published during the meeting showed when Galvus was added to insulin therapy in people with poor diabetes control, patients, especially the over 65s, experienced fewer hypoglycaemic episodes than when they received insulin with placebo. A third of patients were over 65 and saw a highly significant improvement in HbA1c when Galvus was added to their insulin. The 33 patients on the two drugs experienced 113 mild hypoglycaemic events and no severe ones; the 45 patients receiving insulin and placebo experienced 185 mild hypos and 6 severe ones.
"Galvus is easy to use," commented Dr Fitchet. "It is taken once a day and the dose doesn't have to be reduced for patients with other medical problems or impaired kidney function. It doesn't interact with other medicines commonly used by people with diabetes and it doesn't put on weight or lead to hypos."
When used in conjunction with TZDs (rosiglitazone and pioglitazone), patients' weight was unchanged and the incidence of oedema was lower. " In one study presented at the Copenhagen meeting, Galvus was compared to the TZD drug rosiglitazone (Avandia) and shown be just as effective in reducing HbA1c in people with Type 2 diabetes. However rosiglitazone increased weight compared to patients taking Galvus by almost 3 kg.
A dream of preventing diabetes
Rosiglitazone was studied in a further trial, DREAM, and shown to reduce the incidence of Type 2 diabetes, in people at risk of developing it, by over 60 per cent. Patients gained weight however and a small number developed heart failure. This type of study has yet to be performed with Galvus but is likely to be carried out in the future. Novartis is announcing the design of further trials in a research programme "GLORIOUS" later this year.
Professor Jens Holst, the University of Copenhagen-based Medical Physiologist who discovered the importance of DPP-4 inhibition, believes DDP-4 inhibitors are likely to prevent diabetes by preserving functioning beta cells. If that hunch is correct - and it will take a study of several years to prove - he thinks DPP inhibitors would be an ideal safe and easy treatment that could be prescribed life-long. "DPP-4 inhibitors are proving to work well on their own, as well as in combination with other drugs and as add-on therapy. But I believe the really ideal role for them will be in the very early stages of disease or 'pre-diabetes'," he remarked. "They cause no side effects and so people should be able to take them as long as they need to without worrying."
Two UK diabetologists attending EASD, Professor Anthony Barnett of Birmingham University and Dr Andrew Krentz of Southampton University commented that, for them and probably most others, the emerging performance of drugs working via incretin hormones was the highlight of the conference. Dr Krentz remarked: "DPP-4 inhibitors are an undoubtedly exciting development. That they can be taken orally and once-daily will be welcomed by patients and their weight-neutrality is a huge bonus." He continued: "Doctors wrestle with the problem of getting patients to take medicines like sulphonylureas, TZDs and insulin, that promote weight gain. They are unwelcome to patients universally and cause all sorts of problems with compliance." DPP-4 inhibitors work physiologically at the times they are needed - mealtimes - then switch off, so the fear of hypoglycaemia can be allayed, he added. "The possibility they might rejuvenate islet cells and reduce cell death is tantalising".
Galvus is not yet available for prescription by medical practitioners. It has been submitted by manufacturer Novartis Pharma AG to regulatory authorities in Europe and the US and is currently awaiting marketing approval. Several other pharmaceutical companies are also developing DPP-4 inhibitors. Diabetologists in Copenhagen said they hoped to be prescribing the first ones in 2007.
Written by: Olwen Glynn Owen
olwenmacline.co.uk
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