Welcome to The Wellness Ledger
A weekly- health led newsletter grounded in evidence based medicine along with prospective randomized controlled trials by medical specialists. Our goal is to help you make sense of complex scientific information and turn it into clear, evidenced based practices you can use to make better decisions about your health and wellness.
The Obesity Pandemic
Obesity is no longer a niche health concern. According to the World Health Organization, more than 1 billion people globally are living with obesity (defined as a BMI greater than 30), making it one of the most pressing health challenges today.
It is not simply a matter of weight or appearance. Obesity is a chronic condition derived from a multitude of factors, both linked to metabolic dysfunction, insulin resistance, and long-term health risks.
In this issue, we focus on two emerging treatments, tirzepatide and retatrutide, and examine how they are reshaping the way obesity is understood and managed through targeted physiological pathways.
So, What Does the Evidence Based Research Say?
RETATRUTIDE
What is it?
Retatrutide is a novel triple receptor agonist that targets glucagon-like peptide-1 (GLP), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. It is a GLP -1 agonist that has been producing groundbreaking results in the treatment of obesity and Type 2 diabetes. As of early 2026, Retatrutide is not yet FDA-approved. It is still in Phase 3 clinical trials under Eli Lilly's TRIUMPH program. Phase 2 results published in the New England Journal of Medicine showed up to 24% average body weight loss at 48 weeks, and the latest Phase 3 data pushed that to 28.7%, the highest ever recorded in an obesity trial. If trials stay on track, FDA approval is expected sometime in 2027, but late is also possible.
How it works (simplified)
To understand how retatrutide works, we need to understand its effect on GLP-1, GIP and glucagon receptors:
1.GLP-1: It is a hormone released after meals that is released after meals and helps as follows:
Promotes insulin (blood sugar/glucose-lowering hormone) release. This keeps your blood sugar stable after meals, reducing energy crashes and cravings
Decreases glucagon (blood sugar/glucose-increasing hormone) secretion.
Reduces food intake
Delays gastric emptying by about 36 minutes, causing you to feel full early and prevents over eating. Check here.
2.GIP receptors: It is a protein released after meals that works synergistically/together with GLP-1 by increasing insulin release and reducing gastric emptying.
But unlike GLP-1, GIP increases glucagon release, thereby raising blood sugar levels, helping in hyperglycemic states (low blood sugar).
Retatrutide also acts as an agonist of this protein, amplifying weight loss and improving insulin sensitivity.
3.Glucagon: Glucagon is a hormone released in low-blood-sugar states and increases blood glucose levels.
It also increases energy expenditure by burning more calories.
Helps with fatty acid oxidation by breaking down the body's stored fat for fuel rather than using readily available glucose in the blood.
The reason retatrutide has better weight-loss results is its unique ability to target glucagon receptors. This triple-receptor approach is what sets retatrutide apart from other weight-loss drugs. Most weight-loss drugs target one receptor, and the best ones available today target two. Each additional receptor means your body gets a stronger, more coordinated signal to burn fat, control blood sugar, and reduce appetite. Hitting all three is like pressing all the right buttons at once, which is why early trial data shows significantly greater weight loss than anything currently on the market.
Key Idea: The combination affects both how much you eat and how much you burn. |
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What does the clinical data show?
Let's review a few trials (Triple–Hormone-Receptor Agonist Retatrutide for Obesity and Efficacy and Safety of Retatrutide) that were conducted to evaluate the efficacy and safety of Retatrutide, yielding the following findings:
People who received retatrutide experienced significant weight loss over 24-48 weeks compared to those who received placebo (inactive drug).
The degree of weight loss is directly dependent on the drug dose, meaning higher doses cause greater weight loss.
The participants selected for this trial had different baseline characteristics, yet the drug still worked effectively for them.
Commonly experienced side effects were nausea, vomiting and stomach discomfort. These are similar to other hormonal weight loss drugs and sometimes even reported with placebo.
Does the clinical data show any data preserving muscle with this drug ?
This trial established that retatrutide is more effective than other drugs on the market because it acts on three receptors at once rather than just one or two, suggesting that targeting multiple receptors could be a promising approach for treating obesity in the future. For patients, this means the drug isn't just suppressing appetite through one pathway, it is simultaneously improving how your body processes sugar, stores fat, and regulates energy.
TIRZEPATIDE (MOUNJARO/ZEPBOUND)
Now, what is this another drug in the same realm?
Tirzepatide is an FDA approved drug for the treatment of Type-2 diabetes. It is also used to treat obesity as it helps in weight loss. It is a synthetic polypeptide that acts as a dual agonist targeting the GLP-1 and GIP receptors. Targeting both receptors together produces a stronger combined effect on appetite and blood sugar than either one alone, which is why it outperforms older single-receptor drugs.
How it works (simplified)
Let's understand the dual action of tirzepatide in aiding weight loss:
GLP-1 agonistic action: helps improve insulin sensitivity and decrease appetite.
GIP agonistic action: works together with GLP-1 to further amplify weight loss and insulin sensitivity.
Key Idea: This dual action makes tirzepatide effective for obesity treatment by improving insulin sensitivity and reducing appetite. Ultimately, this means patients lose significantly more weight with fewer blood sugar spikes compared to older GLP-1 drugs making it one of the most effective obesity treatments currently available. |
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What does the clinical data show?
Evaluating the findings of a few clinical trials gives us further insight into the efficiency of tirzepatide:
A.SURMOUNT-1, NEJM trial (Tirzepatide Once Weekly for the Treatment of Obesity):
Participants experienced weight loss of 15% (5 mg dose), 19.5% (10 mg dose), 20.1% (15 mg dose) with tirzepatide, which is significantly higher that 3.1% with placebo by 72 weeks.
Side effects such as nausea, vomiting and stomach discomfort were observed.
This means that tirzepatide supports significant weight loss with minimal side effects.
B.SURMOUNT-4, JAMA trial (Continued Treatment With Tirzepatide for Maintenance of Weight Reduction):
In this trial, all participants received tirzepatide for the first 36 weeks and lose 21% of their body weight. After this, they are divided into two groups for a year:
Group 1: continues tirzepatide and loses an additional 5.5% weight.
Group 2: switches to placebo and regains 14% of the lost weight.
The clinical insight from this trial is that obesity also acts like a chronic condition (for example, high blood pressure) and needs long-term treatment. After stopping tirzepatide, you may regain the weight you lost.
Interpretation: Weight loss is significant, but maintaining it often requires continued treatment. This suggests obesity behaves more like a long-term condition than a short-term problem. |
Side Effects
1. RETATRUTIDE
Possible side effects for retatrutide include nausea, vomiting, diarrhoea, constipation and stomach discomfort.
Though retatrutide is extremely efficient for weight loss, competitive market pricing makes it a barrier for many people who could benefit from this medication.
Since Phase-3 trials are pending, we have yet to evaluate the long-term efficacy and safety of retatrutide. As of early 2026, Phase 3 trials are still ongoing under Eli Lilly's TRIUMPH program, with results expected through the course of this year. Full safety and efficacy data will only be available once these trials conclude and the FDA completes its review.
2. TIRZEPATIDE
Possibly experienced side effects include nausea, vomiting, diarrhoea, constipation, stomach discomfort and reduced appetite.
Potential redness, swelling or itching at the injection site.
Less commonly documented potential side effects include hypoglycemia, gallstones and pancreatitis.
EDITOR’S NOTE
“Retatrutide Should be used in patients refractory to weight loss on tirzepatide. Tirzepatide has been shown to have a greater reduction in HgA1c in Type 2 DM vs Semaglutide”
- Frederick Sabido MD, FACS
READER’S PULSE
Do you see these treatments as a long-term solution or a short-term aid?
What this changes?
These therapies represent a shift in how obesity is understood and treated. This moves obesity care from a purely behavioural model toward a more physiologically supported approach.
Peptide-based therapies, such as tirzepatide and retatrutide, are emerging as revolutionary drugs in the treatment of obesity. Clinical trials highlight their significance not only in achieving substantial weight loss but also in improving the biological drivers of obesity.
What does this look like in practice?
For Healthcare Professionals:
These drugs aren't a cheat code to losing weight. They are used to aid weight loss in individuals who are unable to achieve desired results with lifestyle changes. They are in no form a substitute for a poor lifestyle.
HCPs should always encourage patients to adopt lifestyle habits such as regular exercise, healthy dietary intake, avoiding smoking and alcohol, and improving sleep. This, combined with medication, helps maintain long-term weight loss.
For Researchers:
The emergence of multi-receptor agonists has opened up new avenues of research in the management of obesity. In the near future, the focus should be on evaluating the long-term safety and efficacy, and on identifying potential benefits, in treating other metabolic conditions as well.
In a nutshell
Obesity is increasingly being treated as a physiological condition, not just one driven by external causes.
New therapies like tirzepatide and retatrutide work by targeting specific hormones that regulate appetite, metabolism, and energy use.
Clinical trials show 15-21% weight loss, with newer drugs potentially going even further by increasing energy expenditure.
These treatments improve outcomes, but long-term weight management still requires sustained lifestyle changes.
Current evidence suggests obesity behaves like a chronic condition, meaning stopping treatment may lead to weight regain.
Multi-receptor therapies represent a new direction in metabolic research, with potential applications beyond weight loss.
We’d love to hear from you.
Reply to this email and tell us what health topic you’d like us to break down in a future issue. Whether it’s a treatment, trend, supplement, symptom, or study you keep hearing about, send it our way. Your questions will help shape what we cover next.
References:
The Big Takeaway
These drugs do more than reduce hunger. They target the biological systems involved in appetite, metabolism, and energy use, which is why they may represent a major shift in how obesity is treated.
