As the 2013 European Society of Cardiology Congress approaches (ESC 2013 opens on Saturday August 31), it is worth noting that among the most keenly discussed and debated findings will be the results of cardiovascular outcomes trials (CVOTs) for two antidiabetic agents; data for these CVOTs will be reported at Hot-line Session 3 on the morning of Monday, September 2. Such trials are becoming an increasingly important factor in the drug approval process owing to the strong link between type 2 diabetes and CV disease. The results from CVOTs for various antidiabetic drug classes, including glucagon-like peptide-1 analogues and sodium-glucose cotransporter-2 inhibitors, are expected by 2019.

The two trials presented at ESC 2013 assessed the long-term CV risks and benefits of dipeptidyl peptidase-4 (DPP-IV) inhibitors, or ?gliptins?, and are the first to be reported for antidiabetics since CVOTs became de rigueur for regulatory authorities assessing antidiabetic agents. Although the negative top line results from the CVOT (the SAVOR-TIMI 53 trial) for AstraZeneca and Bristol-Myers Squibb's Onglyza (saxagliptin) were announced in June this year, the scientific community will be keen to see where and how the primary outcome was missed. There will also be great interest in whether Takeda Pharmaceuticals? Nesina (alogliptin) will demonstrate any compromise in safety in its CVOT (the EXAMINE trial).

Saxagliptin CV efficacy data not to be SAVORed

In the 4-year Phase IV SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) clinical trial, saxagliptin was evaluated when added to the usual care of patients with diabetes who were at high risk of CV events. The composite endpoint included cardiovascular death, non-fatal myocardial infarction and non-fatal ischemic stroke. Although the trial met the primary safety objective of non-inferiority, it did not achieve the primary efficacy objective of superiority to placebo. Experts in the field will be curious to see just how close saxagliptin came to demonstrating a benefit, and to see how this data may show the way forward for future therapies.

Alogliptin EXAMINEd for CV safety: a sweet success?

Although the SAVOR-TIMI 53 results may have left physicians and patients, and AstraZeneca and Bristol-Myers Squibb, disappointed, the Phase III placebo-controlled EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) trial could at least provide further reassurance that the drug class is safe. Over almost 5 years, participants were evaluated for major adverse cardiac events, including cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. The lack of an unexpected safety signal will add to the evidence supporting the use of the DPP-IV inhibitors, and alogliptin in particular.

For the new and emerging diabetes therapies, demonstrating efficacy for CV outcomes would be a powerful tool for gaining market share. However, demonstrating long-term CV safety will have its own important ramifications. A positive CVOT safety trial could still differentiate drugs within an increasingly crowded space, where physicians have many, many pharmacotherapeutic options from which to choose. With more than 20 new agents in Phase III or preregistration, positive long-term safety data could certainly sweeten the position of an agent in the market, although less than positive results could leave a sour taste in the mouth for all concerned.

Tim Blackstock, M.B. Ch.B., is a business insights analyst in the Cardiovascular, Metabolic, and Renal Disorders team at Decision Resources.

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