Impact of cardiovascular events on diabetes treatment pipeline

Diabetes mellitus has reached global epidemic proportions with approximately 346 million patients worldwide living with this burgeoning metabolic disorder and approximately 90 per cent of these having type 2 diabetes mellitus (T2DM). T2DM represents one of the leading disease areas for development of novel pharmacological therapies, with over 400 agents or programmes in active development.

Despite this, there is still no cure for diabetes and development efforts by pharmaceutical companies have been subjected to greater regulatory scrutiny after rosiglitazone (Avandia, GlaxoSmithKline) was withdrawn from EU markets in 2010 following reports of an increased frequency of heart attacks (myocardial infarction [MI]) following treatment with rosiglitazone.

Cardiovascular (CV) disease is the most important cause of mortality and morbidity among patients with T2DM. The US Food and Drug Administration (FDA) issued an industry guidance document in 2008, which stated that studies of new drugs in development would have to demonstrate that they did not increase the risk of CV events and drugs already on the market would need to carry stronger safety warnings, ultimately resulting in fewer safe options for clinicians to prescribe.

While T2DM has a complex pathophysiology, it is primarily characterised by insulin resistance that can result in abnormally high blood glucose levels (hyperglycaemia). Over time, hyperglycaemia can lead to increased deposits of fatty materials on the inner walls of blood vessels and increase the chance of atherosclerosis and development of heart disease and stroke, which are leading CV causes of death in diabetic patients in developed countries.

Risk factors
Diabetes itself is a risk factor for heart disease and stroke. The chance of developing such CV diseases in diabetic patients can be further increased if they have other risk factors, such as a family history of coronary heart disease (CHD), obesity, high levels of LDL cholesterol, high blood pressure and smoking. In patients with T2DM, elevated serum triglyceride levels and low HDL cholesterol are characteristic abnormalities, often referred to as dyslipidaemia, and are important in the aetiology of the accelerated vascular disease in these patients.

Tighter regulations
In December 2008, the FDA issued an industry guidance document stating that before a new T2DM therapy is approved by the agency, companies must be able to demonstrate in the phase II and III trials that the therapy will not result in an unacceptable increase in CV risk that is over and above any pre-existing risk. These trials should also include patients at higher risk of CV events, such as those with relatively advanced disease, those who are elderly and those with some degree of renal impairment.

Dapagliflozin (BMS 512148, Bristol-Myers Squibb [BMS]) is just one potential T2DM therapy to have faced regulatory issues in the US. Approval applications were filed in the US and EU in December 2010 and the drug is still awaiting approval for use as an adjunct to diet and exercise in adult patients with T2DM. In July 2011, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee recommended nine to six against approval of dapagliflozin. inThought analysts have indicated this was primarily due to increased rates of breast and bladder cancers seen in dapagliflozin recipients (up to a five-fold increase). The FDA has requested additional data from BMS and its co-development partner AstraZeneca (AZ), and consequently delayed completion of its review until later in 2012.

In terms of CV risk, a prespecified meta-analysis of data from 14 phase IIb/III trials has shown that dapagliflozin was not associated with an increased CV risk, but rather tended to decrease the CV risk in adult patients with T2DM. This meta-analysis involved 6,228 patients who were treated with dapagliflozin (4,287 patients), or control treatment (placebo or active comparator; 1,941 patients).

If approved, BMS and AZ plan to conduct a large, randomised, postmarketing CV outcomes study in patients with T2DM in an effort to obtain long-term safety data of dapagliflozin and to examine whether the drug may provide a cardioprotective effect. However, it is possible that the potential risk of cancer associated with dapagliflozin could overshadow any positive cardioprotective effects demonstrated in future studies.

Alogliptin (Takeda Pharmaceuticals) is another compound to face delays in regulatory review in the US. The original New Drug Application (NDA) was submitted in December 2007. However, the FDA informed the company in June 2009 that it did not believe the amount of existing alogliptin clinical data was sufficient to meet certain statistical requirements outlined in its 2008 industry guidance.

The FDA requested that Takeda conduct an additional CV safety trial that satisfied its guidance. In response, the company initiated a multinational CV outcomes trial (EXAMINE) in September 2009 in approximately 5,400 patients with T2DM and acute coronary syndrome. The trial is due for completion in December 2014. Takeda refiled its NDA in July 2011 and a FDA decision is not expected until April 2012.

A pivotal phase III trial (ELIXA) is also underway in several markets to assess CV outcomes in approximately 6,000 patients

Concerns regarding CV adverse events associated with a widely used antidiabetic agent, rosiglitazone (Avandia, GlaxoSmithKline), were brought to the attention of the European Medicines Agency (EMA) by the FDA in early 2010. The FDA stated that there was strong evidence to suggest that Avandia conferred an increased rate of MI and heart failure, compared with pioglitazone (Actos, Takeda).

Both rosiglitazone and pioglitazone belong to a class of anti-diabetic drugs called thiazolidinediones. FDA reviewers concluded that the risks of Avandia were serious and exceeded those associated with use of Actos. In September 2010, the EMA recommended the licence for Avandia be suspended and the drug was subsequently withdrawn from EU markets. Although the FDA conducted a parallel investigation based on the same data as was given to the EMA, the FDA recommended that the drug stay on the market in the US on a restricted basis and with greater safety warnings of its potential increase in CV events. 

Earlier in 2011, a study was published in the British Medical Journal that seemed to justify the EMA's decision to suspend Avandia in the EU. The study was a systematic review and meta-analysis of 16 observational studies involving a total of 810,000 patients with T2DM treated with either rosiglitazone (429,000 patients) or pioglitazone (381,000 patients). Overall, the risk of MI (primary endpoint) was significantly higher with rosiglitazone versus that with pioglitazone. Both agents were associated with similar increased risks of heart failure and overall mortality (secondary endpoints).

Mixed results
Over the past few years, there have been several trials that have aimed to determine if various antidiabetic medicines do, in fact, increase the risk of CV outcomes in patients with T2DM. However, results from such trials have not always been conclusive in their findings.

The RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) trial showed that in patients with inadequately controlled T2DM, the overall risk of CV hospitalisation or CV death (primary endpoint) did not appear to be greater following treatment with Avandia plus metformin or sulphonylureas, compared with metformin plus sulphonylureas alone. However, results from an earlier interim analysis were deemed inconclusive when, after more than 3.5 years, the incidence of hospitalisation or death due to CV causes was similar in the two treatment groups, but Avandia was associated with a significantly greater risk of congestive heart failure.

Pioglitazone (Eli Lilly, Takeda) is widely available for treatment of T2DM. The phase III PROactive (PROspective PioglitAzone Clinical Trial In macroVascular Events) trial was conducted specifically to assess CV implications following treatment with oral pioglitazone given in addition to other antihyperglycaemic agents.

A ten per cent reduction in the primary composite endpoint (fatal and nonfatal MI, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries and amputation above the ankle) was seen in pioglitazone recipients. This result was not significantly different from that seen with placebo. However, a 16 per cent reduction in all-cause death, nonfatal MI or stroke (secondary composite endpoint) significantly favoured treatment with pioglitazone. More recently, there have been growing concerns about the increased risk of bladder cancer with pioglitazone and the drug has been withdrawn from France and Germany, with other markets considering similar actions.

A number of T2DM therapies in the pipeline are undergoing a large trial specifically to assess CV outcomes. One such therapy is lixisenatide (Sanofi), for which a regulatory application was recently filed in the EU seeking approval of an immediate-release formulation as monotherapy in patients with T2DM.

A pivotal phase III trial (ELIXA) is also underway in several major markets to assess CV outcomes in approximately 6,000 patients with T2DM who have also experienced a spontaneous, biomarker-positive acute coronary syndrome event. The primary endpoints will assess the time to the first occurrence of CV death, non-fatal MI, non-fatal stroke and hospitalisation for unstable angina.

Aleglitazar (Roche) and dulaglutide (Eli Lilly) are two specific compounds that are currently in phase III development for the treatment of T2DM and reduction in the risk of CV disorders in this population. The AleCARDIO trial is a long-term multinational pivotal trial that will assess the ability of aleglitazar to prevent CV disorders in approximately 7,000 patients with T2DM. The primary endpoint will measure the major adverse CV event rate at 4.5 years (composite of CV mortality, non-fatal MI and stroke). The REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial will assess similar CV outcomes when dulaglutide is added to patients' anti-hyperglycaemic regimen. The primary endpoint is the first occurrence of CV death, non-fatal MI or non-fatal stroke.

According to the World Health Organisation (WHO), diabetes is predicted to become the seventh leading cause of death worldwide by the year 2030, and diabetes-related deaths are projected to rise by more than 50 per cent in the next ten years. These figures are not ones that world authorities can ignore and there is a long way to go until this epidemic will be effectively managed. Drug development for T2DM will become more challenging, as companies are obliged to show that the potential candidate molecules do not increase the risk of CV events and other serious adverse effects, such as increased risk of cancer.

The Author
R&D Pipeline was written by Asha Vaidya of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For further information on Adis services, contact Kuljeet Sohanpal on +44 (0)207 981 0714 or email Kuljeet.Sohanpal@wolterskluwer.com