The Silent Admission: How the Next Generation of Weight-Loss Drugs Reveals What Pharma Won’t Say Aloud

When the first GLP-1 receptor agonists arrived—liraglutide, semaglutide, and their cousins, terzepatide—they were hailed as miracles of modern medicine. They lowered blood sugar, curbed appetite, and delivered impressive weight loss. For millions of people with diabetes or obesity, they offered hope that had long been missing.

But as real-world experience and clinical data accumulated, a quieter pattern began to emerge: muscle loss, fatigue, and metabolic slowdown. The very drugs that made our bodies lighter were also, in many cases, making them weaker.

The overlooked hormone behind the paradox

The common thread is glucagon—a hormone that works as insulin’s counterbalance.

Insulin stores energy; glucagon releases it. Together they form a natural rhythm between anabolism and catabolism, feeding and fasting, storage and renewal.

GLP-1 drugs, however, suppress glucagon almost completely.

That’s helpful for short-term blood-sugar control—but over time it flattens the body’s adaptive rhythm. When stress, fasting, or repair demands arise, the liver can no longer recycle amino acids efficiently.

Cortisol steps in to do the job, pulling those amino acids from muscle instead.The result: every stress response—mental, physical, or metabolic—costs a bit of lean mass.

This pattern, which I described in my commentary on glucagon suppression and stress adaptation, mirrors a broader concept I’ve called Exposure-Related Malnutrition (ERM)—a state of under-recovery driven by chronic energy and substrate misallocation.

Enter the dual agonists: a quiet course correction

Now, a new wave of drugs such as Mazdutide (IBI362) has arrived.

Developed by Innovent Biologics in partnership with Eli Lilly, Mazdutide activates both the GLP-1 receptor and the glucagon receptor.

At first glance, it seems counterintuitive: why turn on glucagon, the very hormone older drugs tried to silence?

Yet the results are striking. In a 2025 Diabetes, Obesity and Metabolism clinical trial, Mazdutide produced up to 15 percent body-weight reduction with healthy glucose levels intact.

And in a companion eBioMedicine mechanistic study, the same dual agonism preserved neuronal integrity, improved synaptic plasticity, and increased energy expenditure in diabetic mice—outperforming dulaglutide, a GLP-1-only drug.

The message between the lines is unmistakable:

Pharma has learned that prolonged glucagon suppression comes at a cost, and the fix is to bring glucagon back—carefully.

But you won’t see the press releases say that.

Instead, the language shifts toward “enhanced energy expenditure,” “optimized lipid metabolism,” and “improved substrate utilization.”Those phrases are simply polite ways of describing controlled glucagon reactivation.

Innovation without confession

In truth, dual agonists like Mazdutide represent both an advancement and an apology—a biochemical correction without a public admission. The industry has quietly redesigned its molecules to restore the very hormone it once muted, yet still frames the change as “next-generation innovation” rather than “restoration of physiologic balance.”

This is how science often moves forward: not by admitting error, but by designing around it.

Beyond weight loss: re-learning metabolic rhythm

Even with this improvement, the story isn’t finished.

Long-acting weekly injections still create a tonic hormonal signal, flattening the natural oscillation of fed and fasted states. They solve what to activate, but not when. True metabolic health depends not only on which pathways are switched on, but on their timing, rhythm, and recovery—the same principles that govern sleep, stress adaptation, and muscle regeneration.

That’s why the next frontier may not be another molecule, but a strategy that re-teaches the body to cycle energy rather than suppress it—through personalized nutrition, fasting windows, and movement that restore the natural conversation between insulin and glucagon.

A new understanding

The dual-agonist era marks a turning point. It confirms what many clinicians and researchers have sensed: Weight loss alone is not metabolic health. Suppressing glucagon for too long is like holding your breath while trying to run—it works for a moment, but not for the long journey.

Mazdutide shows that when we let the body’s signals speak in harmony again, metabolism becomes not just thinner—but smarter.

References

1. Dong W et al. Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: mechanistic insights from multi-omics analysis. eBioMedicine. 2025;117:105791.

2. Ji L et al. Mazdutide reduces body weight in adults with overweight or obesity: a randomized phase 2 trial. Diabetes Obesity Metabolism. 2025.

3. Tippairote, T., Hoonkaew, P., Suksawang, A., & Tippairote, P. (2025). Glucagon Suppression under GLP-1RA Therapy: Hidden Trade-Offs for Muscle and Resilience. Preprints. https://doi.org/10.20944/preprints202510.0716.v1

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