There’s been no shortage of buzz about the GLP-1 family of drugs, but that was amplified in many ways this week. In conjunction with this edition of Ground Truths there’s a podcast with Daniel Drucker, the physician-scientist credited as one of the co-discovers of glucagon-like peptide (GLP-1) nearly 3 decades ago.(Sorry that you’re getting 2 emails from me today!) He helps explain some of the new findings that I’ll be going through here. Before getting into those, a notable award recognition related to GLP-1 drug expansion from diabetes to obesity. The American Association for the Advancement in Science (AAAS) gives out an annual breakthrough award. Last year it was for MedicGLP standout contributions for NASA’s James Webb Space telescope. This year it went to 2 scientists-Lotte Bjerre Knudsen and Richard DiMarchi-the individuals who pushed to get these drugs to treat obesity. While the 3 researchers -Daniel Drucker, Joel Haebner and Jens Juul Holst -who discovered GLP-1 have been widely and appropriately recognized for this groundbreaking work, it was developed exclusively for the treatment of diabetes.

That remained the case for nearly two decades. The interesting back story to this award was to find out who were the scientists that recognized and pushed for its potential use for obesity. I participated on the selection committee with John Bush, Katherine Saunders, and Holden Thorp. It wasn’t easy, and it required a lot of translation of things written in Danish and connecting with many key players in the field. Ultimately, Bjerre Knudsen of Novo Nordisk and Richard DiMarchi of Indiana Unviersity were verified as the individuals who shaped this critical expansion. As summarized in the award announcement, "Bjerre Knudsen and DiMarchi overcame significant obstacles in bringing these drugs to patients seeking to lose weight. Bjerre Knudsen, for example, figured out how to make the peptide underlying this drug class - an otherwise ephemeral substance - last long enough in the body to be a medication. Despite critics who doubted obesity was a disease at all, they relentlessly pursued this use case, well beyond being the first 2 to patent it.

Were it not for their efforts we might not have this unprecedented treatment for obesity, which has now unlocked many other potential clinical applications. That’s what we’ll get into now. It’s important to first point out that there are no disease-modifying interventions for Parkinson’s disease. All current treatments are for symptoms but nothing has yet been validated to stop or slow progression of the disease. In the New England Journal of Medicine a double-blind randomized trial of 156 participants with early Parkinson’s disease were assigned to lixisenatide or placebo. This is not the first randomized trial reporting benefit of GLP-1 drugs for Parkinson’s. In 2013, a single-blind trial of 45 patients with exenatide showed significant statistical benefit but the motor score difference was 2.7 points. In 2017, a small single-center randomized trial of 62 participants, but with longer follow-up, found benefit with exenatide given once weekly (see graph below). Of note, both trials had a washout period after the drug treatment ended and the benefit for motor symptoms persisted.

3-point benefit may accrue further over time: "The importance of this finding is not the magnitude of the change but what it portends… There are 2 other important considerations. Lixisenatide and exenatide are much weaker GLP-1 drugs compared with semaglutide, tirzepatide and several others that are in clinical trials as shown below for weight management capsules weight loss. The extent of weight loss likely also reflects the potency of anti-inflammatory effect, and biomarkers indicative of reduced inflammation have been shown to precede wight loss in multiple trials of this drug class. Also, we know that these drugs do not cross the blood brain barrier. As Daniel Drucker explained in the companion podcast, that isn’t necessary to achieve the GLP-1 mediated suppression of inflammation in the brain. There’s the gut-brain axis and enteric nervous system to relay signals, talk to the brain. As Drucker pointed out to me: " We know that GLP-1 is not getting directly to those neurons, but it's activating pathways that turn on those neurons.

So the new study provides some optimism for Parkinson’s disease. The GLP-1 drug mediated suppression of brain inflammation may turn out to be yet another key use case. More than half of patients with heart failure have preserved pump function, as quantified by election fraction. Their heart failure symptoms and physical limitations are due to impaired filling and relaxation of the left ventricle. At the American College of Cardiology meetings today, with simultaneous publication in NEJM, was a new randomized trial of semaglutide in 616 participants with heart failure with preserved ejection fraction, obesity and Type 2 diabetes. This new trial built on a previous one published in NEJM last fall (I previously reviewed here) for the same indication, but the only difference was the inclusion of people with diabetes. As you can see from the side-by-side Figure below, the new trial (at left) replicates the previous one for symptomatic benefit and reduced physical limitations (Y-axis, corresponding to the Kansas City score) with the primary endpoint findings remarkably similar.