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Diabetes: growing treatment options

Diabetes is a growing problem that is expected to present one of the 21st century's biggest medical challenges. The rapidly increasing prevalence of the disease is significant cause for concern.

Type I diabetes can only be treated with insulin and insulin analogues. Lifestyle modifications and exercise are the best treatments for Type II diabetes, however these are difficult to implement in practice. Various groups of drugs with different modes of action are available for the treatment of Type II diabetes. Metformin is usually the first-line treatment for all Type II patients. A combination of other classes such as the sulphonylureas may then be added to the treatment regimen to provide stricter glycaemic control.

Controversy surrounding Avandia and the TZDs

The thiazolidinediones (TZDs), also called the glitazones, have been available for several years. GlaxoSmithKline’s rosiglitazone (Avandia) and Takeda’s pioglitazone (Actos) have been used widely, particularly in the USA where their combined market share in terms of sales at the end of 2006 was 80% of the total oral antidiabetic market. Troglitazone was the first drug in this class to be launched, but was withdrawn from all major markets in 2000 owing to its association with liver side-effects. The newer glitazones are not associated with such adverse effects, however, careful monitoring of liver function is still required.

The TZD class has, however, recently come under scrutiny. These products are reportedly associated with significant side-effects, including fluid retention, increased risk of heart failure and bone fractures, and more recently Avandia has also been linked to an increased risk of osteoporosis.

In May 2007, results from a meta-analysis were published in the New England Journal of Medicine suggesting that Avandia increases the risk of a heart attack by 43% and the risk of cardiovascular death by 64%, compared with placebo or other treatment regimens. The study was limited by the lack of access to the original source data, which would have allowed further analysis to be conducted.

This has sparked a controversy with regard to the use of Avandia. Regulatory agencies around the world have since been reviewing the risk:benefit profile of the class as a whole, particularly focusing on Avandia, but studies have provided conflicting data. Many industry experts and physicians believe Avandia should be removed from the market; others believe that there is not yet sufficient data to warrant such a conclusion.

The FDA and the EMEA have completed their review of Avandia. At the FDA advisory meeting in July 2007, it was concluded that the use of Avandia was associated with a greater risk of myocardial infarction. The committee voted to recommend a ‘black box’ warning be applied to the labelling about the potential risk of heart attacks, and suggested extensive educational efforts be instituted immediately. They did not recommend removing the product from the market.

In November 2007, the boxed warning on the US label for Avandia was updated to add the FDA’s conclusion that, while an FDA meta-analysis of short-term studies – mostly against placebo – showed an association between Avandia and an increase in myocardial ischaemic events, that risk was not confirmed or excluded in three long-term clinical trials comparing Avandia against both placebo and other oral antidiabetics. The box will state that the available data on the risk of myocardial ischaemia are inconclusive. GSK has agreed to work with the FDA to plan and carry out a clinical trial to further investigate the cardiovascular effects of Avandia.

In Europe, the EMEA concluded that the benefits of Avandia and Actos outweigh the risks for their approved indications. The agency also requested that the labelling for Avandia should be updated to include a warning of cardiovascular side effects.

Sales of Avandia have seen a dramatic decline since the original meta-analysis was published, falling by 38% to £225 million for the third quarter of 2007, compared with 3Q06. As well as several other factors, this downturn in sales of Avandia was the catalyst for the company’s announcement of a major restructuring plan to generate savings of £700 million by 2010.

Since the cardiovascular risk of Avandia was originally highlighted, physicians have been prescribing alternative treatments. Despite the initial concerns regarding a potential class effect Actos has benefited from the situation. Trials have suggested that Actos is not associated with the same cardiovascular risks as Avandia. In the USA Actos’ market share, in terms of sales, increased by 7% from May to August 2007. Growth, however, was much slower in Europe, with an average increase of 0.6% for the top five country markets.

Newer pharmacological approaches

New therapies could benefit from the Avandia controversy. Two new classes of antidiabetic agents based on the incretin hormone glucagon-like peptide 1 (GLP-1) are novel treatment options for Type II diabetes that act through a variety of complementary mechanisms.

GLP-1 stimulates glucose-dependent insulin secretion from the pancreatic islets. But, it is broken down by the dipeptidyl peptidase-IV (DPP-IV) enzyme to inactive metabolites. Therefore, products that either mimic GLP-1 or inhibit DPP-IV are gaining interest in the market for treating diabetes.

Byetta (exenatide), a twice-daily injectable GLP-1 analogue developed by Amylin in collaboration with Lilly, was the first GLP-1 product to become available. It was launched in the US in 2005 for use as an adjunctive therapy to improve blood sugar control in patients with Type II diabetes who have not achieved adequate control on metformin and/or sulphonylureas. The agent has demonstrated sustained improvements in blood sugar control and body weight reductions in patients who previously did not receive adequate control with oral medication. In clinical trials this has led to a decrease in insulin doses required. The product has since been launched in several countries including the UK and Germany, although reimbursement issues have meant a slower uptake of the product.

Amylin and Lilly are also developing a long-acting version of exenatide (exenatide LAR), a once-weekly injectable formulation, which would provide a significant dosing advantage. Recent data suggests that the once-weekly version of Byetta has superior blood glucose control compared with the twice-daily version of the drug.

Byetta has not provided a side-effect free treatment option, however. The FDA has recently issued an alert to warn of the potential risk of acute pancreatitis, which could delay regulatory filings of exenatide LAR. The companies plan to seek US approval of exenatide LAR in the first half of 2009, later than originally expected.

Novo Nordisk is conducting Phase III trials of the second GLP-1 analogue liraglutide. Liraglutide is a naturally occurring peptide, which stimulates insulin release in response to increases in blood sugar levels. Liraglutide is much closer to human GLP-1, showing 91% homology, compared with approximately 53% homology for Byetta. The dosing, however, would not be as convenient as the long-acting version of Byetta, as liraglutide requires a once-daily injection, and this may be a significant battle in the development of the GLP-1 products.

Analysts have predicted that liraglutide will capture significant market share from long-acting insulin analogues such as sanofi-aventis' Lantus (insulin glargine) and the original twice-daily formulation of Byetta, particularly as liraglutide appears to have fewer side-effects than Byetta.

Working via an alternative pathway to affect GLP-1, Merck & Co launched its first-to-market DPP-IV inhibitor Januvia (sitagliptin) in the US and Mexico in the latter half of 2006, and in the UK and Germany in March and April 2007, respectively. Novartis’ Galvus (vildagliptin) is the second DPP-IV inhibitor to become available: it has been launched in Mexico and Brazil, with approval pending in the USA. This new class is expected to be commercially important because of the side-effect benefits over existing therapies, and will be covered separately in a future article.

Table 1: Advantages and disadvantages
of newer Type II diabetes therapies

 

GLP-1 agonists
and analogues

DPP-IV inhibitors
Advantages

Complementary effects with other antidiabetic agents including metformin, sulphonylureas and TZDs.
 

Once/twice-daily dosing

Once-daily dosing
 

Weight loss – through appetite suppression

High bioavailability
 

Slows gastric emptying allowing for better nutrient absorption and reduces food intake

Low potential of drug-drug interaction
 

Effectively decreases A1c levels through glucose-dependent insulin secretion

Oral formulation
 

Long acting exenatide is in development (once-weekly)

May have a role in delaying disease progression and help to restore beta-cell function
Disadvantages

Reimbursement issues – treatment is expensive
 

Side-effect concerns over acute pancreatitis

Side-effect concerns include hypersensitivity reactions
 

Injectable formulation

  

 

Finally, there are several other new classes in the pipeline, still in early-stage development, which could potentially have a significant role in the treatment of diabetes, if trial data confirms their safety and efficacy profiles. These include:

This article was written by Sangita Halai, Forecasting Specialist, IMS Therapy Forecaster. IMS Therapy Forecaster is a unique pharmaceutical forecasting system that utilises detailed quantitative and qualitative methodologies to project key issues affecting markets at a therapy level. IMS Therapy Forecaster provides 10-year sales and volume forecasts covering 45 ATCs across 10 countries. For further information, please contact Rupesh Chudasama, or call +44 203 075 5757.