Introduction
Struggling with obesity is frustrating. Losing weight through eating less and exercising more takes lots of effort. And most people end up regaining the pounds later on. So it feels like you can’t win.
That’s why the only option that seems to work long-term is surgery – like gastric bypass or gastric sleeve procedures. But who wants their stomach stapled or guts re-routed if there was an alternative? To make matters worse, people gain weight after surgery.
Well, new medications that target appetite signals in the brain could finally offer that alternative. And we’re not talking about taking a pill to lose 5 pounds. We’re talking about pounds melting off to the tune of over 20% of your body weight or more!
How is that possible without surgery? Well, obesity doesn’t happen because of a lack of willpower. It’s a disease influenced by issues in appetite regulation. See, your gut sends signals to your brain affecting how hungry you feel and how many calories you burn.
The Appetite Control System
For example, hormone signals like GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) make you feel fuller. Others like glucagon rev up your metabolism. New breakthrough drugs called “combination therapies” bind to multiple appetite targets at once. Almost like a key fitting in different locks.
The most exciting ones? Tirzepatide, targeting GLP-1 and GIP, leads to 22% weight loss. And Retatrutide, tripling down on GLP-1, GIP, and glucagon for nearly 25% loss. These results are without surgery. Beyond the weight loss, they lower risks for heart disease and diabetes.
Of course, new treatments have some challenges. Like making sure they stay safe for long-term use. And managing costs for all the people who need them. But for the first time, we can visualize a future free from the countless physical, emotional, and social burdens caused by obesity. Keep hope alive. A new day is dawning in sustainable medical weight loss care!
Appetite Regulation Pathways
Obesity treatments that help people lose lots of weight and keep it off target signals to the brain that control hunger and fullness. See, your stomach and gut have cells in them that release different hormones. These “chemical messengers” all serve various functions. They either:
Make your brain feel hungry (increase appetite)
Make your brain feel full (decrease appetite)
Speed up how many calories your body uses (increase energy spending)
Some of the major "appetite actors" are:
GLP-1 - Helps you feel fuller
GIP - Also reduces appetite
Glucagon - Energy booster that may curb hunger too
Amylin - Blunts appetite and slows digestion
PYY - Released to signal you’re full during and after meals
GDF-15 Receptor - Growth/differentiation factor 15 (GDF-15) is a stress hormone that seems to play a role in appetite regulation.
The hottest new substances for weight loss either turn up the dial on fullness hormones. Or they crank up energy-burning signals. It’s like hacking your body’s appetite remote control!
Ozempic, Wegovy, And The Other First Wave of GLP-1 Weight Loss Medications
First Generation Medications
The first anti-obesity medications to harness appetite hormones paved the way. Specifically, semaglutide under the brand names Ozempic and Wegovy. This injectable drug activates GLP-1 receptor targets. Those signals tell your brain you’re full and can stop eating.
In 2021, Wegovy made headlines for helping people lose around 17% of their weight. Far better than anything previously available without surgery!
A few other “first-gen” meds include:
Liraglutide (Victoza) - Also a GLP-1 agonist injection causing 12% weight loss
Danuglipron – Despite high dropout rates, trials saw over 11% reduction
Pramlintide (SymlinPen) - An amylin receptor shot leading to around 8% loss
Oral semaglutide (Rybelsus) – Ozempic’s cousin in pill form
These single hormone meds blazed the trail. But pumping one brake pedal (GLP-1) instead of two or three has its limits. New-era “combination drugs” go further...
Combination Therapies - This Is The Future
Like assembly lines building cars faster, combination drugs target multiple appetite pathways at once. The more brakes you hit, the more weight comes screeching off!
The leader of the pack so far is tirzepatide. This one-two punch activates receptors for both GLP-1 and GIP. Those fullness boosters working together pulled off 16-22% weight loss in studies. Without the risks of surgery. In 2023, it became the first combo med officially approved for obesity with the brand name Zepbound.
Others coming down the pipeline take the combo concept even further:
Retatrutide: With receptors for GLP-1, GIP, and glucagon all firing at once, phase 3 data shows obese patients losing a jaw-dropping 24% in one year besting even gastric bypass results.
Cagrisema: This match made in heaven links GLP-1 and amylin, another hormone lowering food intake and calorie absorption. Early phase 1b data shows the combination resulting in up to 17.1% weight loss. Ongoing phase 3 trials will see if this dynamic duo can maintain results comparable to the best combination therapies.
Survodutide: GLP-1 plus glucagon from the tag team sparking trials showing 18% bodyweight reduction. How? Glucagon turns up your energy burner in addition to some appetite effects.
Mazdutide: Almost an offshoot of survodutide, this GLP-1/glucagon mixture also torched up to 18% of patients’ pounds in international testing.
Pemvidutide: Here GLP-1 joins forces with glucagon as well targeting improved metabolic markers in addition to 15.6% weight loss.
Orforglipron: - A yet-to-be-approved daily oral tablet stimulating GLP-1 receptors that's testing up to 14.7% reduction
The list keeps marching on with many others recruiting multiple appetitive allies for shielding against weight regain. It’s like hiring more security guards to protect your health!
Beyond Gut Hormones
Hacking hunger signals and digestion speed are fat-burning gold. But they’re not the only paths to substantial, maintainable weight loss.
Other emerging medication classes take different angles attacking obesity’s barriers:
Bimagrumab: Instead of suppressing appetite, this IV medication stimulates muscle growth. It blocks activin receptors making the body more efficiently use calories to build lean mass. One trial saw obese diabetics’ fat mass plummet over 20% in just 48 weeks! More muscle means more metabolism boost too.
GDF15 Agonists: Want to use obesity's weapons against itself? GDF15 is a hormone produced by fat cells tied to less hunger and food intake. Early evidence shows artificially turning up GDF15 activity with drugs like LY3463251 makes weight slide off. Though larger studies are still needed.
Y2 Receptor Agonists: Peptide YY and its effects through Y2 pathways are better researched for cutting appetite. But more testing is underway to develop safe, effective meds targeting these “fullness receptors” in the brain.
GPR40 Agonists: Even insulin and blood sugar pathways in the pancreas and gut might have untapped weight loss potential via G protein receptors.
Cagrilintide: Rather than a gut hormone, this medication activates amylin receptors involved in appetite signaling. Though not as strong as some multi-agonists, one study still showed almost 10% weight loss at 6 months.
Other Compounds That Are In Testing
AZD6234
ZP8396
HM15136
NNC0165-1562
Y-14
VK2735
SCO-094
CT-388
Amycretin
Dacra QW II
NNC0165-1562 and Semaglutide
HM15211
NNC0247-0829
JNJ-9090/CIN-109
SCO-267
ZP6590
Conclusion
Promise and Challenges Ahead
New-era weight loss medications let us envision a future free of obesity’s burdens. But work remains to make the most of their potential. Researchers still need to confirm long-term safety and determine who responds best to which treatments.
Other hurdles include:
Access & Cost - With loads of combo drugs coming, approval and insurance coverage lags. Out-of-reach costs could stop many from getting life-changing prescriptions.
Maintenance - More studies on preventing regain after med-assisted weight loss are important. Can lower doses work? What about periodic re-treatment?
Lifestyle Fit - Diet, activity, and behavior changes are still obesity foundations. Where do intensive programs fit alongside meds for ideal results?
Safety - These are new drugs and we really don’t know the long-term safety of all of these drugs. So far, they appear to be safe and actually improve health.
While questions persist, the progress is still worth celebrating. The obesity struggle is real. But for the first time, sustainable medical weight loss looks achievable for the masses!
Melson, E., Ashraf, U., Papamargaritis, D., & Davies, M. J. (2024). What is the pipeline for future medications for obesity? International Journal of Obesity. https://doi.org/10.1038/s41366-024-01473-y
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