Obesity drugs seem to be everywhere these days. Just last week, Novo Nordisk announced that it was halting its study of semaglutide early for efficacy. The phase 3b FLOW trial explored the effects of once-weekly injectable semaglutide on kidney outcomes in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). Over the weekend, Lilly announced that its GLP-1 drug tirzepatide supported a 26.6% body weight reduction in the phase 3 SURMOUNT-3 study. Other companies including Pfizer have also thrown their hat into the GLP ring.

With so much focus on the drug class, and convincing efficacy results from a range of phase 2 and 3 studies, drug developers could shift their focus from mere weight loss to improving the quality of weight loss, as a briefing note from Truist explains. This goal could entail ensuring weight loss is durable, maintaining lean body mass, and curbing side effects. 

One potential wildcard is Lilly’s retatrutide, a triple hormone receptor agonist of GLP-1, GIP, and GCGR receptors, that set a record for weight loss earlier this year in a phase 2 study for speed of weight loss. In the phase 2 study (NCT04881760), participants had -8.7% with a 1 mg dose, -17.1% with a 4 mg dose, -22.8% with an 8 mg dose, and -24.2% with a 12 mg dose after 48 weeks. While Lilly’s tirzepatide supported more total weight loss in the phase 3 SURMOUNT-3 trial, the time for participants to reach a total mean weight loss of 26.6% was 84 weeks after a 12-week intensive lifestyle intervention and subsequent tirzepatide treatment. 

Durability questions

Although GLP-1 drugs are effective at supporting weight loss, evidence from long-term follow-up studies for drugs such as semaglutide and tirzepatide suggests that a majority of subjects regain most of their lost weight within a year of discontinuing the medication. Data from the STEP1 semaglutide study and tirzepatide’s SURMOUNT-4 study indicate that many individuals who received the drugs regain 75% or more of their weight within a year. On the other hand, the potential need for chronic therapy could mirror treatments of other chronic conditions.

Maintaining lean body mass

One data point that can be easy to overlook when assessing impressive weight loss data from GLP-1 is the percentage of weight loss from fat versus muscle. Some data from semaglutide users indicate significant loss in lean muscle. A Japanese meta-analysis, for instance, found a significant decrease in fat-free mass (FFM) associated with the use of semaglutide compared to placebo, in patients with type 2 diabetes. Not all studies, however, have reached that conclusion.

In any event, companies such as Versanis and 35Pharma are aiming to develop therapies such as bimagrumab and HS235, respectively, that preserve lean body mass during weight loss.

Bimagrumab is an activin receptor type 2B antagonist — a novel obesity therapy — that has entered phase IIb studies. In a phase 2 study, the drug candidate facilitated fat loss while promoting a lean mass gain of 4.5%. Versanis has tested the drug in 21 clinical trials with more than 1,000 patients to date. In a study presented at ObesityWeek 2022, the drug also supported fat mass loss while offsetting the lean mass loss induced by incretins like semaglutide and tirzepatide​.

On the other hand, 35Pharma’s HS235 is an activin receptor ectodomain-based Fc-fusion protein intended to inhibit ligands controlling body composition in obesity​. HS235 addresses both vascular remodeling and Metabolic Syndrome (MetS) in pulmonary hypertension. In vivo testing of HS135, a related molecule, yielded promising effects on body composition and efficacy in pulmonary arterial hypertension, hinting at the potential benefits these therapies for maintaining weight loss​​.

Addressing side effects 

While GLP-1 drugs are generally well-tolerated, gastrointestinal adverse events have been problematic for some patients taking the drugs. For Wegovy, the most common adverse reactions associated with discontinuation of the drug were nausea, vomiting, and diarrhea when compared to a placebo​. The side effect profile for tirzepatide are similar, with the most common adverse events also gastrointestinal in nature. 

Truist noted in their briefing note that gradual titration can mitigate such GLP-1 side effects like nausea and vomiting, an ongoing quest remains to limit them in next-gen approaches. Combining GLP-1 drugs with peptides such as amylin or glucagon is one approach. Truist also points to the use of shrews as a novel preclinical model, which have a human-like gag reflex and vomiting tendencies. Truist also noted that while bimagrumab appeared to have an advantage in terms of muscle preservation, it also had gastrointestinal side effects and muscle spasms for some clinical trial participants. 

While GLP-1 drugs such as semaglutide and tirzepatide could mark a shift in the battle against obesity, the next frontier of drug development of obesity drugs could yield a more holistic and sustainable approach to obesity management. While the playing field is now limited, patients in the future could have a variety of novel treatment options to explore.