The Pitfalls of Mounjaro: Metabolic Risks Often Overlooked by the Japanese by 3AI

Mounjaro (tirzepatide) is a hot topic.

"Just inject it and lose weight," "Appetite disappears"—social media is overflowing with such claims. In fact, the effects are real. However, there is a pitfall for Japanese people that is rarely discussed.

First, the facts

Mounjaro/Zepbound (generic name: tirzepatide) is a hot topic.

"Just inject it and lose weight," "Appetite disappears"—social media is overflowing with such claims. In fact, the effects are real.

Tirzepatide is a GIP/GLP-1 dual agonist. It suppresses appetite, slows gastric emptying, and promotes insulin secretion in a glucose-dependent manner. As a result, it becomes easier to reduce intake.

Looking at the numbers for its effectiveness, it is certainly powerful.

In the SURMOUNT-J (a Phase 3 study targeting Japanese adults with obesity without diabetes), the body weight of the 15mg administration group decreased by an average of -22.7% at 72 weeks. The placebo group was -1.7%. The difference is significant.

The problem is "what is being lost"

This is the entrance to the pitfall.

In the DXA substudy of SURMOUNT-1, body weight decreased by an average of -21.3% at 72 weeks.

Let's look at the breakdown.

Fat mass: -33.9%
Lean mass: -10.9%

Approximately 25% of the lost body weight was lean mass.

The lean mass referred to here is not just skeletal muscle itself. It also includes water, organs, connective tissue, etc. Therefore, one cannot say that "25% of muscle was lost."

However, it is a fact that the functional parts of the body, including muscle, are decreasing.

"Fat is mainly lost" is correct.

At the same time, it is not the case that "only fat conveniently falls off."

If you only chase the weight number without protein intake, resistance training, or checking body composition, the number will go down. The content will become weaker.

It is possible that you have not lost weight, but rather have been whittled down.

Risks unique to the Japanese

This is where the real issue begins.

The ERA JUMP study compares Japanese men aged 40-49 with white American men without diabetes.

In this data, the HOMA-β% of Japanese men was approximately 66% that of white American men.

Compared to white Westerners, the Japanese appear to lean toward 'low resistance, low secretion' rather than 'high secretion, high resistance.' In other words, they are closer to a body that functions on low secretion rather than one that processes energy by producing large amounts of insulin.

From here on, these are not directly proven conclusions, but structural hypotheses that should be treated with caution.

Tirzepatide reduces intake. Body weight drops. Fat also decreases. At the same time, lean mass also decreases.

At this point, 'what, in what order, and how much' is lost in the Japanese population deserves more scrutiny.

SURMOUNT-J showed significant weight loss in the Japanese. However, the issue raised in this article is not 'whether weight drops.'

It is about how much of the body's functional components remain after the weight has dropped.

Furthermore, there is an evolutionary medicine hypothesis called the 'thrifty gene hypothesis.' This is the idea that metabolism adapted to cycles of famine and abundance acts as a risk factor for obesity and diabetes in the modern environment of overeating, lack of exercise, and high-energy diets.

This is not a matter to be decided by a crude dichotomy of agricultural versus hunter-gatherer societies.

The problem is how dietary patterns, physical activity levels, Westernization, insulin secretion capacity, and changes in body composition overlap.

Structural issues

Major clinical trials (such as SURMOUNT-1) have Westerners as their primary cohort.

While SURMOUNT-J has been conducted for the Japanese, its primary focus is on 'whether weight decreases.' Detailed comparisons of body composition—specifically 'in which ethnic group, what is lost, and in what order'—have not yet been sufficiently explored.

Are both those prescribing and those receiving the injections looking only at the result of 'losing weight'?

Conclusion

Mounjaro is certainly effective. However, it is not a "fat-burning drug," but rather a "drug that creates a calorie-deficient state."

What happens during a calorie deficit depends on the user's metabolic profile.

If Japanese people are going to use this, there are minimum requirements they must follow.

- Consciously increase protein intake
- Combine with resistance training
- Evaluate based on "how body composition has changed" rather than "weight loss"

Losing weight and becoming healthy are two different things.

Reference Links

SURMOUNT-1 DXA / Body Composition

SURMOUNT-J / Japanese Obese Adults

ERA JUMP study / HOMA comparison between Japanese men and US white men

Kodama et al. / Ethnic differences, insulin sensitivity, and secretory response

East Asian β-cell function meta-analysis

Neel / Thrifty genotype hypothesis

O’Dea / Overview of the thrifty genotype hypothesis

Hunter-gatherers as models in public health

Paleolithic / hunter-gatherer type diet and insulin sensitivity

Protein intake and glucagon secretion

SURPASS J-mono / Japanese Type 2 Diabetes

SURPASS J-combo / Japanese Type 2 Diabetes, add-on to oral medication

PMDA / Tirzepatide Obesity Review Report

https://www.pmda.go.jp/drugs/2024/P20241223001/530471000_30600AMX00288_A100_1.pdf

1️⃣ Compression/Writing: Claude
2️⃣ Medicine/Evidence: ChatGPT
3️⃣ Claims/Observations: Gemini
✅️ Dedicated to the Temple: gemgpt