Mazdutide

The molecule. Mazdutide (IBI362, LY3305677) is based on oxyntomodulin, a naturally occurring product of the proglucagon gene that activates both the GLP-1 and glucagon receptors. It was discovered at Eli Lilly and licensed to Innovent Biologics for development in China [4][5].

The trials, all in China. The phase 1b studies established dose ranges in Chinese adults with type 2 diabetes [4] and with overweight or obesity, the latter reaching 6.4% weight loss over 12 weeks at up to 6 mg [5]. Phase 2 in 248 participants gave -6.7%, -10.4% and -11.3% at 3, 4.5 and 6 mg over 24 weeks, against +1.0% on placebo [6].

GLORY-1, the phase 3 trial, randomised 610 Chinese adults with obesity or overweight plus a weight-related condition. At 32 weeks, weight change was -10.09% at 4 mg and -12.55% at 6 mg against +0.45% on placebo; at 48 weeks, -11.00% and -14.01% against +0.30%, with 35.7% and 49.5% losing at least 15% against 2.0% on placebo [1]. GLORY-2 took the dose to 9 mg in 461 participants over 60 weeks and reported -16.65% against -1.50% [2]. A further phase 2 examined 9 mg specifically in people with BMI of 30 or above [7].

Why the population matters. Mean baseline weight in GLORY-1 was 87.2 kg; in STEP 1 it was about 105 kg [1][8]. Chinese obesity cohorts differ from Western ones in baseline weight, body composition and the distribution of metabolic disease. Percentage weight loss in one does not automatically predict the other, in either direction. Until a trial runs elsewhere - and the DREAMS-3 head-to-head against semaglutide is designed to help with this [3] - the honest reading is that these are excellent results in the population studied.

Tolerability. This is where mazdutide looks unusually good. In GLORY-1, discontinuation for adverse events was 1.5% at 4 mg, 0.5% at 6 mg and 1.0% on placebo [1]. In GLORY-2 at the higher 9 mg dose it was 2.9% against 0% on placebo - despite vomiting in 53.1% and nausea in 46.9% [2]. High symptom rates, very few people stopping.

Oxyntomodulin is the natural template: a proglucagon-derived peptide that activates the GLP-1 receptor and the glucagon receptor, and which reduces food intake and raises energy expenditure in humans. Mazdutide is an engineered analogue of it, acylated for weekly dosing [4].

The two arms divide the labour. GLP-1 reduces intake and holds glycaemia; glucagon raises resting energy expenditure and acts on hepatic lipid handling. The theoretical hazard of glucagon agonism - raised blood glucose - is offset by the incretin arm and by weight loss itself, which is why HbA1c falls in these trials rather than rising [4].

Mazdutide and Survodutide are the same idea executed by different companies, and their weight results are broadly comparable once the population difference is taken into account.

A once-weekly subcutaneous injection. The peptide is acylated to a fatty diacid for albumin binding, the standard approach to a week-long half-life [5].

The gastrointestinal profile is typical of the class and dose-dependent: in GLORY-2 at 9 mg, vomiting affected 53.1% against 1.3% on placebo, nausea 46.9% against 3.2% [2].

What is striking is how few people stopped. Discontinuation for adverse events was 1.5% and 0.5% at 4 and 6 mg in GLORY-1 against 1.0% on placebo [1], and 2.9% at 9 mg in GLORY-2 against 0% [2]. Those are low numbers for a dual agonist at these doses. Whether that reflects the escalation schedule, the population, or trial conduct is not something the abstracts can settle.

What is not known. No cardiovascular outcome trial has reported. No data exist outside Chinese populations. Long-term exposure beyond 60 weeks has not been published. As with survodutide, glucagon receptor agonism is a mechanism that warrants long-term cardiovascular follow-up.

Class precautions - perioperative gastric emptying, hypoglycaemia with insulin or sulfonylureas - should be assumed [9][10].

No dedicated interaction studies have been published. Dulaglutide and semaglutide have appeared as comparators rather than combination partners [3][4].

Class considerations apply: slowed gastric emptying affects oral drug absorption, and combination with insulin or a sulfonylurea raises hypoglycaemia risk.