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Dr Stephen Nicholls Discusses the Systemic Effects of Incretin-Based Therapies


With a broad research focus on heart disease risk reduction through the development of novel treatment strategies, Stephen Nicholls, MBBS, PhD, Monash University and Victorian Heart Hospital, Melbourne, Australia. discusses contributions in the space from therapies with systemwide effects.

With a broad research focus on heart disease risk reduction through the development of novel treatment strategies, Stephen Nicholls, MBBS, PhD, professor of cardiology, Monash University, and director, Victorian Heart Hospital, Melbourne, Australia, discusses contributions in the space from incretin-based therapies glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and tirzepatide, a dual GIP/GLP-1 receptor agonist. The therapies have several systemic effects, including reducing gastric emptying and hemoglobin A1c (HbA1c) and increasing insulin production and release.


Can you describe the mechanism of the GIP hormone in promoting weight loss for patients who have tried other treatments and strategies but without success?

I think there's a range of incretin-based therapies, which are being developed for the management of type 2 diabetes, but also for weight loss. Traditionally, these therapies have targeted a factor called GLP-1 receptor, and a number of agents are already in the clinic that target GLP-1. GIP is another incretin-based therapy; it does a number of the same things that GLP does, but it has some complementary functions.

We expect these therapies will reduce food intake, will have some central nervous system effects, which will lead to weight loss. But in addition, you'll see a reduction in gastric emptying; you'll see complimentary effects on the pancreas, including increasing insulin production and release. You also see direct effects on the adipose tissue. And so while some of the effects are the same, there's other effects, which kind of are complementary, and that's why we are seeing, in these early trials, greater weight loss with a dual incretin therapy and better metabolic risk factor control.

Can you discuss the “additive effect” of GIP and GLP-1 that appears to make tirzepatide “greater than the sum of its parts” in helping patients control their A1c and lose weight?

Because we see a little bit more weight loss with tirzepatide compared to your standard GLP-1 receptor agonists, such as dilaglutide and semaglutide, you're going to see a greater improvement in metabolic risk factors. We know that there's a greater reduction in HbA1c. We see a greater proportion of patients with type 2 diabetes having reductions in HbA1c greater than 2%, we're seeing a reduction in C-reactive protein, we're seeing improvement in blood pressure and lipid parameters.

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