Raising the Bar: What will new weight loss medications bring to the table?

I was recently asked to give lectures on emerging obesity medications at a symposium at the European Congress of Obesity, as well as a keynote presentation at the Canadian Obesity Summit. I am sharing highlights from these exciting discussions with you today!

KEY POINT #1: We are now getting well into double-digit weight loss efficacy, with some emerging medications demonstrating an average of over 20% weight loss, and some predicted to show 25% or more in longer term studies (currently underway).

KEY POINT #2: In studying weight loss medications, we are focusing more on the benefit of weight loss medication to improve health issues associated with elevated weight, rather than focusing on weight effect alone. For example, in people with osteoarthritis and obesity, does weight loss medication X improve knee pain (in addition to weight loss)? In people with sleep apnea and obesity, does weight loss medication Y improve sleep apnea? In people with cardiovascular disease and obesity, does medication Z reduce the risk of heart attacks and strokes?

There are many medications that are in early phases of development for weight management. Most of them are hormonally-based treatment strategies, using higher doses of existing medications, or more commonly combining more than one hormone into one medication. The medications in the most advanced phases of study include GLP1 receptor agonism. GLP1 receptor agonists (GLP1RAs) have been in use for close to 20 years to treat type 2 diabetes, and nearly a decade as an obesity treatment. GLP1 is a hormone our intestines make, that helps to control blood sugar when blood sugars are elevated (by increasing insulin and suppressing glucagon), reduces appetite in the hunger/fullness center of our brain, and can reduce cravings.

Here are the most advanced contenders in emerging strategies:

GIP/GLP1 dual agonism: GIP is also involved in blood sugar control, and reduces appetite. There are a number of GIP/GLP1’s currently in development for type 2 diabetes, obesity, and/or fatty liver disease (NASH). Tirzepatide (Mounjaro) is the only one that is currently in use, approved for type 2 diabetes. Tirzepatide is currently under study as a treatment of obesity, NASH, heart failure with preserved ejection fraction (HFpEF), and has cardiovascular outcome trials underway in people with type 2 diabetes and in people with obesity.

Oral GLP1RA (pill form) has been avaiable for several years for the treatment of type 2 diabetes, as semaglutide (Rybelsus) up to 14mg daily. It has now been studied at higher doses of 25mg and 50mg for type 2 diabetes, and at 50mg daily as an obesity treatment. Several non-peptide GLP1RAs are also under development, with the thinking that they may be better absorbed and perhaps (??) could then be produced and made available at lower cost to patients.

(on the note of higher-dose existing GLP1RAs, injectable semaglutide (known as Wegovy for weight management up to 2.4mg, and Ozempic for type 2 diabetes up to 2mg weekly) is also being studied up to 7.2mg weekly)

Amylin analog+GLP1RA: Amylin is a hormone secreted by our pancreas when we eat. It works to regulate postmeal glucagon, and slows stomach emptying. Amylin reduces appetite in our brain, both by stimulating the satiety center (homeostatic effect), and may also be involved in areas involved in the wanting/liking/cravings for food (hedonic effect). Cagrilintide is an amylin analog that is being combined with semaglutide 2.4mg (Wegovy) as a once weekly injection, currently called CagriSema. It is currently under study both as a treatment for obesity, planning for further study in type 2 diabetes, as well as a cardiovascular outcome trial.

GLP1/glucagon dual agonists: Glucagon works to reduce appetite, increases energy burn (energy expenditure), releases sugar from the liver, and stimulates hepatic lipid (liver fat) metabolism. Releasing sugar from the liver is not desirable in a weight loss medication as this could cause blood sugars to become elevated; however, GLP1 reduces sugars, so if the right balance of GLP1 and glucagon agonism can be struck, we might expect to see weight loss, benefit to fatty liver, and potentially a benefit to blood sugars overall. There are several GLP1/glucagon dual agonists in development, with heterogenous effects. Some look quite impressive for weight loss, some not so much; some improve blood sugars whereas others do not; and some look very impressive for fatty liver disease. Thus, some are being pursued as obesity treatment, some for type 2 diabetes, and/or some for fatty liver disease.

GLP1/GIP/glucagon triple agonists: Now that we’ve discussed some aspects of how each of these hormones work, we can see the potential benefits of using all three together: blood sugar control with GLP1 and GIP, reduction in appetite afforded by all three hormones, beneficial effects of glucagon on energy burn and fat metabolism in the liver, as well as potential benefits of GIP in fat tissue. Again here, I think it’s going to be about getting the right balance and potency of these three hormones.

It was hoped that by using combination hormone strategies, we might see a lower gastrointestinal side effect profile than the current GLP1 treatments. So far, this has not panned out, as these emerging groups all have GI side effects as the most common concern. Slower dosage escalation and/or various doses are being looked at in trials of many of these candidate medications, to see if this may reduce GI side effects.

KEY POINT #3: We need to embrace the new concept (both clinically and in research studies) that obesity medications should be titrated to desired effect. As older generations of weight management medications didn’t result in as much weight loss, we were prescribing maximum dose in most cases (if tolerated). With new and emerging highly effective medications, some people may experience excessive weight loss on the highest dose, and may only need a lower than maximum dose to achieve treatment targets of weight management and improvement in weight-related health issues.

Stay tuned: a whole new wave of new data will be released on these emerging medications (disclosure: some of which I am presenting and/or coauthoring) at the American Diabetes Association meeting next week!

Further disclosures: I am an investigator in clinical trials for each of these groups of medications. I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide (Novo Nordisk) and tirzepatide (Eli Lilly).

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