In a recent video, Dr. Mike ranked the five most powerful fat loss drugs ever made, from weakest to strongest.
His warning: the strongest one may also be the most expensive subscription you will ever sign.
Why? Because stop paying, and the weight comes back.
One patient, 61-year-old Dr. Gregory, was on Wegovy and scared to quit.
By drug number four, you will see exactly why.
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One Dial, Five Different Hands
I want you to think of hunger like a volume dial, an appetite dial.
After meals, your gut releases GLP-1, a hormone that turns appetite down and slows stomach emptying, so meals keep you full longer.
Natural GLP-1 gets chewed up by enzymes within minutes. Every drug below keeps a hand on that dial far longer.
Drug 1: Liraglutide (Saxenda)
Approved for weight loss in 2014, this lab-made GLP-1 lasts about a day, hence the daily injection.
In the SCALE trial, published in the New England Journal of Medicine, 3,700 adults were followed for 56 weeks.
- Liraglutide group: about 8% lost, roughly 16 pounds for a 200-pound person
- Placebo group: 2.6%, about 5 pounds
Side effects included nausea, diarrhea and constipation, mostly in the first weeks. Dr. Mike says some of his clients even reported hemorrhoids.
His mistake to avoid: writing off the whole category after one modest result. The next four are the same hand, just on longer.
Drug 2: Orforglipron, the Pill
Stomach acid destroys most hormone-style drugs, so this once-daily tablet is a small molecule built to be swallowed. Wegovy also has a daily pill, but this one was designed for it from the start.
The ATTAIN-1 trial, published in the New England Journal of Medicine in September 2025, followed 3,127 adults for 72 weeks.
- Top dose: 12.4% lost, about 25 pounds on a 200-pound frame
- Placebo: 2%, about 4 pounds
- Dropouts from side effects: 5 to 10%, versus 3% on placebo
No needle and no fridge means it may reach far more people. The catch, per Dr. Mike: people treat a tablet like a vitamin.
It is the same hand on the same dial, and it drips all the way back up when you stop taking the tablet.
Drug 3: Semaglutide (Wegovy)
This is Dr. Gregory’s drug. Semaglutide lasts about a week, so one weekly shot keeps the hand on the dial around the clock.
In the STEP 1 trial, also in the New England Journal of Medicine, about 2,000 adults were tracked for 68 weeks. Average loss hit 14.9%, roughly 30 pounds on a 200-pound person, against 2.4% on placebo.
About a third of participants lost 20% or more, numbers Dr. Mike compares to bariatric surgery.
The Part Many Videos Skip
A subgroup of roughly 140 people had DEXA body scans. In that group, about 40% of lost weight was lean mass, mostly muscle.
The sample is small, but Dr. Mike calls it the best data available. Lose 50 pounds and do nothing else, and about 20 of them could be muscle.
After the trial extension, participants who stopped regained about two-thirds of the weight within a year.
People like to celebrate the weight scale and they glorify it.
Drug 4: Tirzepatide (Zepbound, Mounjaro)
Two hands now. Tirzepatide activates GLP-1 plus a second hormone receptor, GIP, which appears to help the body handle fat and blood sugar.
SURMOUNT-1, published in the New England Journal of Medicine, found 20.9% average loss at the top dose: about 42 pounds for a 200-pound person. That is roughly 12 pounds beyond semaglutide’s result.
In a DEXA subgroup of about 160 people, roughly a quarter of lost weight was lean mass. Looks better than semaglutide’s 40%, yet the groups were small, came from different trials, and were never compared head-to-head.
Dr. Mike’s takeaway: both drugs take muscle along unless you act.
What Happens When You Stop
Here is the clearest stopping data. In SURMOUNT-4, people who had lost about 21% were switched to placebo for a year, and a JAMA follow-up analysis found that 82.5% regained at least a quarter of what they lost.
Blood pressure, cholesterol and fasting insulin drifted back toward baseline as weight returned.
A crutch will only hold you up as long as you lean on it.
His warning: people hit goal weight, quit cold turkey, and have no plan for the next 12 months.
Drug 5: Retatrutide, Three Hands
Not approved yet and without a brand name, retatrutide is a triple agonist. It adds a glucagon receptor to GLP-1 and GIP, which appears to push the body toward burning more fat for fuel.
Results come from Lilly’s phase three TRIUMPH-1 study, reported by the manufacturer rather than independently. Full paper pending, so bias is possible.
- 80 weeks, top dose: 28.3% lost, about 70 pounds from a 248-pound average start
- Two-year extension: 30.3% in the heaviest group, averaging 268 pounds, roughly 85 pounds
- Counting everyone who started: about 25%, still a record
Percentages are the honest figure. A 200-pound person losing 30% sheds about 60 pounds.
The Price in Side Effects
- Nausea: 42%
- Diarrhea: 32%
- Vomiting: one in four
- Dysesthesia (tingling or odd skin sensations): 12.5%, versus under 1% on placebo
- Stopped because of side effects: about 11%
Lilly says most dysesthesia cases were mild and resolved during treatment.
Approval filing is not expected until 2027, so pharmacy shelves may be 2028 territory. Dr. Mike cautions against pausing training and protein while waiting, because two years of lost muscle never comes back as a refund.
The Real Bill: Money
By Dr. Mike’s figures, Wegovy costs $349 monthly through the manufacturer’s cash program and $1,349 at list price.
Take STEP 1 results: 30 pounds over roughly 16 months costs about $5,584, or $186 per pound lost. If two-thirds returns, only 10 pounds stay, pushing the cost to about $558 per pound kept.
Are you the customer or are you the subscription?
He is no drug opponent. He expects these medications to keep improving and save many lives; his objection is to how they are used today.
The Bigger Bill: Muscle
Picture muscle as your car’s engine and fat as cargo in the trunk. Dr. Mike estimates a pound of muscle burns about six calories daily at rest, versus roughly two for fat.
By his math, losing 15 pounds of muscle trims about 90 calories per day. That adds up to roughly 33,000 calories yearly, or about 9 pounds of fat your body once burned for free.
Trials did not scan people on the way back up. Still, Dr. Mike says his clients’ DEXA scans, plus decades of weight-cycling research, show regained weight returns as fat.
The same number on the scale and a worse body that you began with.
How to Use These Drugs Smarter
For Dr. Gregory, the medication proved that a leaner version of himself existed. Dr. Mike’s view is that the drug is a band-aid unless the underlying cause is fixed.
His example: poor sleep worsens insulin sensitivity, so more carbohydrates get stored as fat.
- Track body composition, not just the scale, ideally with a DEXA scan
- Train and eat protein from day one, not after the goal weight arrives
- Plan the exit before the first injection, especially the 12 months after stopping
- Investigate root causes such as sleep, hormones and blood biomarkers
That is the philosophy behind his coaching program, Sculpt by Science, which pairs 100-plus blood biomarkers with psychology and habit work. His goal: results that last because clients learn to turn the dial themselves.
Are you on one of these drugs, or have you come off? Dr. Mike wants to hear what happened in the 12 months after.
