FDA approves Novo Nordisk’s Victoza (liraglutide) for reduced risk of major CV events – August 25, 2017

A highly-anticipated and exciting news release came through from Novo Nordisk this morning, announcing that the FDA has approved a new CV indication for GLP-1 agonist Victoza (liraglutide). This indication for reduced risk of major adverse CV events will be added to the Victoza product label, and will apply to all type 2 diabetes patients with established CV disease. Victoza is the first diabetes drug with an indication to prevent heart attack, stroke, and CV death in patients with established CV disease. We’ve been eagerly awaiting this FDA decision since an Advisory Committee panel voted 17-2 in favor of the label change this past June. Given that a major theme of the Advisory Committee’s discussion was liraglutide’s different CV effects in higher-risk vs. lower-risk participants in the LEADER trial, we’ve also been curious to see which patient population would be implicated for CV risk reduction in the updated label. Overall, LEADER reported a 13% risk reduction for the primary outcome of three-point MACE (non-fatal MI, non-fatal stroke, and CV death) with liraglutide vs. placebo (p=0.01 for superiority), but a subgroup analysis found that the hazard ratio point estimate was 0.83 in favor of liraglutide for a higher-risk subset of patients (95% CI: 0.74-0.93) vs. 1.2 in favor of placebo for a lower-risk subset (95% CI: 0.66-1.67, which crosses the line of unity, meaning this finding is not statistically significant). Based on this breakdown of the data, a majority of voting members at the FDA Ad Comm suggested that liraglutide only showed compelling evidence for cardioprotection among patients facing very high CV risk. Indeed, FDA seems to have opted for more stringent language in the new CV indication, noting a benefit specifically for people with type 2 diabetes and established CV disease. The EMA approved a similar indication for Victoza’s EU label last month (following a CHMP endorsement in June), with CV risk reduction extending to type 2 diabetes patients facing high CV risk. That said, if full LEADER data is included as part of the US product label (as it is in Europe), providers will still be able to see liraglutide’s significant cardioprotective benefit across the broader patient population enrolled in the study. We certainly hope that the revised label encourages greater real-world uptake of Victoza alongside better reimbursement prospects, so that as many diabetes patients as possible gain access to this glucose-lowering, weight loss-promoting, cardioprotective therapy.

• Victoza is now the first GLP-1 agonist and second of all diabetes drugs (after Lilly/BI’s SGLT-2 inhibitor empagliflozin, branded Jardiance) with a CV indication on its product label. Note that the Jardiance label was updated to reflect risk reduction specifically for CV death, while the Victoza label will reflect risk reduction for all major CV events as encompassed by the three-point MACE outcome (MI, stroke, and CV death).
• This is a massive win for patients, and for the diabetes field. With positive CVOT results come updated product labels – and with that, patients/HCPs who until now have settled for treating a biomarker (A1c/blood glucose) can start to treat toward improving concrete health outcomes. Indeed, disease modification is the “gold ring” and now the field has it in two classes. CV disease remains the leading cause of death for people with diabetes (accounting for 31% of all diabetes-related deaths in the US in 2015, per CDC estimates), and so agents that protect against CV complications will go a long way in lowering the population-wide burden of diabetes (not to mention the incredible, life-extending impact these therapies can have for individuals). We cannot remember such a success for people with type 2 diabetes since the results of UKPDS.

Close Concerns Questions

Q: How will Novo Nordisk roll out the new CV indication for Victoza (and how quickly)? What will patient-facing and provider-facing education efforts look like?

Q: How will this label change affect Victoza volume and sales going forward? Novo Nordisk’s GLP-1 agonist continued to lead the class with 56% market share by value in 2Q17 (46% market share by volume in the US). That said, we’ve learned from the Jardiance story that even after a resoundingly positive CVOT and a label update, it can take time for these tailwinds to appreciably boost product and whole class sales – indeed, in our view, this has barely begun! The REWIND trial for Lilly’s Trulicity (dulaglutide) – an increasingly tough competitor for Victoza, capturing 30% of pooled sales and 34% of US GLP-1 prescriptions in 2Q17 – is expected to complete in July 2018.

Q: How will Novo Nordisk leverage this CV indication in payer negotiations henceforth? We’re reminded of the perfect quote from Dr. John Buse at Keystone 2017: “It is immoral that as a society we mandate a certain set of trials be done from a regulatory perspective, and then not require that insurance companies cover these drugs if they’re shown to reduce mortality. We’re not talking about reducing toenail fungus. We’re talking about reducing mortality.”

Q: Are plans for a semaglutide post-market CVOT still in the works? This once-weekly GLP-1 candidate from Novo Nordisk showed significant 26% risk reduction for three-point MACE in the SUSTAIN 6 trial (p=0.02 for superiority vs. placebo), but this was a smaller study than is typical for CVOTs, and management has previously stated intentions to launch a larger trial if/when the drug is approved. An FDA decision on semaglutide is expected in 4Q17. We imagine the once-weekly product could greatly grow Novo Nordisk’s GLP-1 agonist business, and that it could spur further class growth as well.

Q: What opportunities may there be for Novo Nordisk and Lilly/BI to collaborate in generating more awareness of the diabetes/CV disease overlap? This education will be vital – 75% of Americans and 66% of Americans with type 2 diabetes are unaware that chronic hyperglycemia increases risk for CV events and death. We’d love to see concerted and collaborative initiatives to address this public health obstacle, and who better to lead the way than manufacturers of diabetes therapy with now-proven CV efficacy? The impact on this news for PCPs and cardiologists, in particular, will be vital.

-- by Payal Marathe and Kelly Close