Semaglutide (CSPC Zhongqi)

Medtronic Chief Scientific, Medical and Regulatory Officer Dr. Laura Mauri drills into GLP-1 drug trial results to estimate their impact across the portfolio. The impact of glucagon-like peptide-1 (GLP-1) drugs like Ozempic and Wegovy on medtech manufacturing is one of the biggest uncertainties heading into 2024. Industry leaders like Medtronic, Stryker and Intuitive have faced questions from investors about whether these weight loss drugs will reduce demand for certain medical devices and procedures. Despite a portfolio spanning some of the fields that would seem likely to be affected — such as cardiovascular, diabetes, surgical and neurovascular — Medtronic Chair and CEO Geoff Martha recently said the drugs won’t impact his company’s growth in the medium or long term, aside from a temporary, modest impact to baratric procedures. That assertion is based on “extensive, science-based work,” Martha said on the company’s second-quarter earnings call. “The areas that we get questions on — type 2 intensive, hypertension, AFib, obesity — besides the fact these are just woefully underpenetrated from a medtech perspective, we’ve done all the analysis,” he said. To offer more detail, Martha asked Medtronic SVP and Chief Scientific, Medical and Regulatory Officer Dr. Laura Mauri to explain how the world’s largest device manufacturer estimated its exposure to GLP-1 drugs — a process that other device developers could apply to their own portfolios. How Medtronic updated its cardiovascular models to account for GLP-1 drugs Mauri and her team used data from the SELECT trial for Novo Nordisk’s semaglutide GLP-1 drug in obese patients with a history of cardiovascular disease. (SELECT is a forced acronym for “Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity.”) Novo Nordisk released headline results from that trial in August 2023, showing a reduction in major adverse cardiovascular events. In November, the drugmaker offered more detailed data at the American Heart Association (AHA) Scientific Sessions 2023 and published them in the New England Journal of Medicine. “The SELECT trial results that were presented at AHA gave us a lot more detail beyond the top line that we heard about back in August, to really look at the endpoints, look at the drug adherence and understand the details of the trial results,” Mauri said. Those more detailed results supported Medtronic’s hypothesis that the drugs will have a negligible effect on cardiovascular procedure volumes, she said. “First, the number needed to treat was much higher. And that means it’s setting a higher bar for treatment compared with other things that are used in guidelines,” Mauri said. “And then we saw that there was a lack of effect on cardiovascular death, and that’s something that if it had been present would have spurred more adoption. And the lack of that is important, because it will not spur the wide adoption and coverage that we might have been looking at if that had been positive.” The only effect on the composite endpoint was non-fatal myocardial infarction, not stroke or cardiovascular death, she said. And nearly a third of patients stopped using the drugs due to nausea and gastrointestinal side effects. “Clearly we know from practice that rates of adherence are even lower, and that results in lower treatment effects,” Mauri said. She also called out a couple of interesting findings from the trial: “The higher BMI population didn’t seem to have as much benefit, and there was no significant treatment effect in the North American subgroup, which is certainly something that we’ll want to understand better going forward.” Medtronic already models cardiovascular procedure volumes across the U.S., so Mauri’s team used the prevalence of obesity for each of those procedure populations. They then applied “a range of penetration and adherence assumptions [for GLP-1 drugs] all the way up to including what we’ve seen over time with statins, which are really well tolerated and freely available and part of guidelines for the past 30 years.” “And then we also input, obviously, the risk reductions seen in each of the endpoints from the SELECT trial or literature based on weight loss to look at treatment effects,” Mauri continued. “And the bottom line is that the reduction to [total addressable market] growth over the next 10 to 30 years is really negligible on the cardiovascular procedure outlook.” GLP-1 drugs and Medtronic’s diabetes business Medtronic EVP and Diabetes Operating Unit President Que Dallara offered some details on how her business has studied the potential impact of GLP-1 drugs on products like the MiniMed 780G automated insulin delivery (AID) system. “There’s some evidence from SELECT that would say there may be a slowdown in the pre-diabetic population towards insulin dependency, and maybe some in type 2 come off insulin, but we believe this number to be very small and more than offset by the fact that there is low penetration of type 2 using AID,” Dallara said. “When you look at the funnel of 3 to 4 million who require basal insulin, 25 million noninsulin type 2s, as well as the over 100 million prediabetic population, it doesn’t change our point of view on the long-term size of the market as well as the growth rates,” she continued. What Medtronic’s analysis doesn’t include Mauri said the company’s projections don’t include potential offsets of rapid growth in underpenetrated markets or new markets such as renal denervation or pulsed-field ablation. The analysis also doesn’t include the potential benefits of GLP-1 drugs for medical device developers. Stryker officials, for example, have said the drugs may allow obese patients to lose weight ahead of joint replacement surgeries that they otherwise wouldn’t qualify for due to the potential for complications. From the perspective of Medtronic’s cardiovascular business, “there’s potential upside for patients and procedure growth because of the potentially longer survival or lower BMI that makes a greater funnel of patients eligible for cardiovascular procedures,” Mauri said.

The European Medicines Agency’s risk assessment committee on Friday said that it requires further information on the risk of suicidal thoughts and thoughts of self-harm potentially linked to GLP-1 receptor agonists. The review of the drugs began in July with an initial focus on Novo Nordisk’s medicines containing semaglutide or liraglutide, with it subsequently expanded to include all marketed GLP-1 receptor agonists.According to the EMA, its Pharmacovigilance Risk Assessment Committee (PRAC) has now assessed all available evidence from clinical trials, post-marketing surveillance and published literature on reported cases of suicidal thoughts and thoughts of self-harm related to GLP-1 receptor agonists. The agency noted that while “no conclusion can be drawn on a causal association,” there are several issues that require clarification from the manufacturers.Along with Novo Nordisk - which markets semaglutide as Ozempic, Rybelsus and Wegovy, and liraglutide as Saxenda, Victoza and Xultophy – the PRAC will send questions to AstraZeneca, Eli Lilly and Sanofi. The EMA said that it will discuss the review again at its next meeting in April.The probe was initiated following reports from the Icelandic Medicines Agency of two cases involving Saxenda, and one case involving Ozempic and Wegovy. The review was also based on at least 170 case reports found in the EudraVigilance system.Meanwhile, in the US, the FDA’s own adverse-event database has reportedly received 265 reports of suicidal thoughts or behaviour in patients taking GLP-1 receptor agonists since 2010. The agency is currently evaluating the reports – which include 36 deaths from suicide or suspected suicide – before deciding if any action is needed.