Novo Nordisk Q2'26: ZEUS failure overshadows obesity pipeline advances

Novo Nordisk A/S (NOVO) held its Q2 2026 earnings call on August 5, 2026, during which the Phase III failure of ziltivekimab in cardiovascular outcomes dominated the R&D discussion, , while management defended CagriSema's competitive positioning versus tirzepatide and the outlined the next wave of obesity assets led by zenagamtide.

The call also suggested Novo is entering a transition period. While CagriSema remains an important near-term asset, management increasingly framed zenagamtide and its broader amylin-based pipeline as the next wave of obesity innovation, while continuing to defend investment in higher-risk cardiovascular inflammation programs despite the ZEUS setback.

Adjusted sales grew 7% at constant exchange rates to DKK 78.5 billion (USD 12.1 billion) in Q2; full-year adjusted sales growth guidance was revised to 0% to minus 6% at constant exchange rates, an improvement from prior guidance driven by GLP-1 volume growth.

ZEUS Failure Leaves Cardiovascular IL-6 Hypothesis Unresolved

The single most consequential pipeline disclosure was the ZEUS trial failure. EVP of R&D and Chief Scientific Officer Martin Lange confirmed that once-monthly ziltivekimab 15 mg, an anti-interleukin-6 (IL-6) monoclonal antibody, did not reduce major adverse cardiovascular events (MACE) versus placebo in more than 6,300 patients with established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and elevated high-sensitivity C-reactive protein (hsCRP), with a hazard ratio of 0.99. Ziltivekimab did produce expected reductions in free IL-6 and hsCRP, confirming target engagement, but this did not translate into clinical benefit. Serious infection rates were higher with ziltivekimab, consistent with IL-6 pathway inhibition.

Lange said the result does not establish that inflammation is irrelevant to cardiovascular outcomes. He noted that the CANTOS trial demonstrated benefit with anti-IL-1 beta inhibition, and suggested IL-6 may be too far downstream in the inflammatory cascade in this specific population, or that the trial enrolled a heterogeneous disease population. Two further ziltivekimab cardiovascular outcomes trials — ARTEMIS in acute myocardial infarction and HERMES in heart failure with preserved ejection fraction (HFpEF) — will continue, with readouts expected in H1 2027.

TD Cowen's Michael Nedelcovych pressed Lange on whether the ZEUS result, given the reduction in inflammatory biomarkers without MACE benefit, implies that hsCRP and IL-6 are correlates rather than causal drivers of cardiovascular risk. Lange declined to draw that conclusion, citing the upstream NLRP3 inflammasome pathway as a mechanistic rationale for continuing cardiovascular inflammation research. Novo said it has NLRP3 assets in both clinical and preclinical development and intends to advance them.

CagriSema: Non-Inferior on Weight, Inferior on Glycemic Control

The REIMAGINE 4 open-label head-to-head trial comparing CagriSema 2.4 mg (cagrilintide 2.4 mg/semaglutide 2.4 mg) versus tirzepatide 15 mg reported 68-week results. Lange said patients on CagriSema achieved 15.2% weight loss and a 1.9 percentage point reduction in HbA1c. CagriSema demonstrated non-inferiority to tirzepatide on weight reduction but failed to demonstrate non-inferiority on HbA1c reduction, the dual primary endpoint.

JPMorgan's Richard Vosser challenged management on the diabetes positioning given that HbA1c reduction is central to prescribing decisions in type 2 diabetes. Rather than focusing solely on glycemic efficacy, management increasingly positioned CagriSema as a differentiated amylin-based therapy, highlighting potential benefits in blood pressure, lipid metabolism and bone preservation alongside weight loss.

Novo confirmed the US regulatory decision for CagriSema in obesity remains on track for end-2026, with a potential launch in 2027. A new Phase IIIb trial has been initiated testing a higher fixed-dose combination of CagriSema comprising cagrilintide 2.4 mg and semaglutide 7.2 mg, with two substudies: one in obesity without diabetes and one in obesity with type 2 diabetes. The trial evaluates this higher dose against CagriSema 2.4 mg of each component and semaglutide 7.2 mg alone.

Separately, REDEFINE 9, a 68-week efficacy and safety trial testing lower CagriSema maintenance doses of 1.0 mg and 1.7 mg of each component in people with overweight or obesity, was completed. Lange said both lower doses achieved superior weight loss versus placebo with a safety and tolerability profile consistent with prior CagriSema trials. Detailed data are expected later in 2026.

Zenagamtide and the Triple Agonist Signal Novo's Next-Generation Obesity Bet

Lange confirmed Novo plans to initiate AMBITION, the Phase III development program for zenagamtide, a GLP-1/GIP/amylin unimolecular agonist, before year-end. In response to a question from UBS's Matthew Weston about titration risk — given CagriSema's dosing challenges — Lange said Novo has incorporated learnings from CagriSema into the zenagamtide program, including an additional titration step, and said Phase II data showed 24% weight loss over approximately six months. He added that zenagamtide will be developed in both subcutaneous and oral formulations. Phase II results are expected in H2 2027.

Jefferies' Michael Leuchten asked whether the REIMAGINE 4 result — suggesting that combining a GLP-1 with amylin does not achieve additive glycemic control — undermines the zenagamtide rationale as a unimolecular GLP-1/amylin combination. Lange said he could not speculate definitively but indicated the Phase II data suggest zenagamtide will be a "substantial addition" in both obesity and diabetes, and that the individualized dosing approach being tested in REDEFINE 11 may yet demonstrate further benefit with CagriSema itself.

Novo also initiated a Phase II trial for its GLP-1/GIP/amylin receptor triple agonist, evaluating different dose escalation regimens for up to 39 weeks, with a readout expected in H2 2027. A Phase II trial for UBT251, a once-weekly agent in type 2 diabetes, was also initiated, with results expected by end-2027.

Oral Wegovy emerges as Novo's next commercial growth driver

While much of the R&D discussion centered on pipeline setbacks and next-generation obesity assets, management repeatedly highlighted the strong early performance of oral Wegovy as a key commercial growth engine. Novo said the product has now surpassed 5 million prescriptions in the US, captured around 90% of the oral obesity market, and continues to expand the treated population, with approximately 80% of patients being GLP-1 treatment naïve. The company also pointed to a rapid international rollout, citing strong uptake following launches in the UK and UAE, with Germany scheduled to follow in September. Management argued the once-daily oral formulation is expanding the obesity market rather than simply cannibalizing injectable Wegovy, while also providing an important competitive response as additional oral GLP-1 therapies approach the market.

In sum, the call highlighted a company in transition. While the failure of ZEUS removed one of Novo's most ambitious cardiovascular programs and CagriSema continues to face competitive questions against tirzepatide, management increasingly framed zenagamtide and its broader amylin-based pipeline as the next generation of obesity innovation. At the same time, the commercial success of oral Wegovy provides Novo with an additional growth engine as it seeks to defend its leadership in an increasingly competitive GLP-1 market.

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