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For millions of adults struggling with excess weight, the last few years have brought dramatic change. Once relegated to the realm of diets and “eat less, move more,” weight management is increasingly supported by powerful medications that influence appetite, hunger signals, and body weight at deep physiological levels. These therapies aren’t “magic bullets” — they work best alongside lifestyle changes — but they are some of the most effective tools medicine has ever offered for losing and maintaining weight.

A recent report published in JAMA reviewed new data on three promising weight-loss medications that are moving toward approval or expanding use in the United States. This trend reflects a broader shift in how clinicians and patients think about obesity: not as a failure of willpower, but as a chronic disease that changes biology and is influenced by insulin, hormones, and metabolism.

In this article, we’ll break down what these medications are, how they work, and what it means for people living with unique metabolic challenges — especially those with hypothyroidism or women in perimenopause and menopause. You’ll come away with clear information you can use in discussions with your healthcare provider and in planning your own approach to weight management.

Traditionally, effective options for significant weight loss were limited: intensive lifestyle changes, rarely used medications with modest results, or bariatric surgery, which is highly effective but not accessible or desirable for everyone. Recent scientific advances have changed that landscape.

Modern medications, often referred to as anti-obesity medications (AOMs), target specific hormones involved in appetite, feelings of fullness, blood sugar regulation, and metabolism. Many of them are based on molecules originally developed for diabetes medications because the pathways that regulate blood sugar often overlap with those that influence weight.

The JAMA report highlights new therapies poised to expand treatment options:

• Orforglipron – this is a once-daily pill that regulates appetite in a way similar to GLP-1 receptor agonist drugs but works through a slightly different mechanism. In clinical trials, people taking orforglipron lost significantly more weight than those taking a placebo.
• High-dose semaglutide – this is a stronger version of one of the most widely used medications for weight management (commercially known as Wegovy). Higher doses – in both pill and injectable forms –  have shown even greater average weight loss in clinical trials.
• Combination therapy (cagrilintide + semaglutide) – this injectable combines two hormones that influence appetite and fullness, producing more weight loss than either drug alone in head-to-head studies.

Across multiple trials, these medications consistently led to clinically meaningful weight loss — generally defined as a sustained drop of 10% or more from initial body weight — when paired with lifestyle changes such as improved nutrition and increased physical activity.

Orforglipron is an oral, once‑daily GLP‑1 receptor agonist drug being developed by Eli Lilly for obesity, weight maintenance, and type 2 diabetes. 

As of early 2026, it is still considered investigational and does not yet have an approved brand name. Orforglipron is being evaluated in the phase 3 ATTAIN and ACHIEVE programs. Regulatory filings for obesity are generally expected once the phase 3 program is completed, but no firm approval date has been announced. 

Efficacy data 

• In a phase 3 trial in adults with overweight or obesity and type 2 diabetes, orforglipron produced statistically superior reductions in body weight versus placebo, with clinically meaningful weight loss alongside improved glycemic control. 
• Earlier phase data showed dose‑dependent weight loss; for example, one analysis reported greater weight reduction at higher doses (up to mid‑single‑digit percentage loss vs placebo over trial durations typical for diabetes studies), alongside improvements in fasting glucose and lipids. 

Weight‑maintenance role 

• In the phase 3 ATTAIN‑MAINTAIN trial, adults who had completed 72 weeks of Wegovy (semaglutide 2.4 mg) or Zepbound (tirzepatide) in SURMOUNT‑5 and then switched to orforglipron maintained their prior weight loss over 52 weeks significantly better than those who switched to placebo. 
• Participants switching from Wegovy to orforglipron had an average weight change of about 0.9 kg at 52 weeks versus substantially greater regain with placebo; those switching from Zepbound to orforglipron had an average change of about 5.0 kg, again clearly better than placebo. 

Safety/tolerability

Gastrointestinal side effects such as nausea, vomiting, and diarrhea are similar in nature to injectable GLP‑1s. 

Oral semaglutide 25 mg is a once‑daily investigational high‑dose tablet formulation for adults with overweight/obesity, designed to approximate the weight‑loss efficacy of injectable Wegovy. 

Novo Nordisk markets oral semaglutide at doses of 7 to 14 mg under the brand name Rybelsus for diabetes. The 25 mg dose for obesity remains investigational; no brand name or label for obesity is yet approved as of early 2026. 

OASIS 4 phase 3 results

• In OASIS 4 trials, 25 mg oral semaglutide plus lifestyle change produced significantly greater mean weight loss at 64 weeks compared to placebo in adults with overweight or obesity. 
• More participants achieved at least 15% body‑weight loss compared with placebo. 
• Other analyses showed greater improvements in hemoglobin A1c (HbA1c), fasting glucose, fasting insulin, C‑reactive protein, and triglycerides compared with placebo, indicating cardiometabolic benefit alongside weight loss. 

Regulatory outlook

Novo Nordisk has framed oral 25 mg as a potential obesity therapy, calling it “Wegovy in a pill.” Phase 3 results support regulatory submissions, but the specific approval timeline remains to be finalized. 

STEP UP is a phase 3b trial testing a higher‑than‑approved injectable Wegovy dose (investigational 7.2 mg weekly) vs the standard 2.4 mg in adults with obesity. 

Efficacy

• Over 72 weeks, individuals receiving semaglutide (investigational 7.2 mg) achieved an average body-weight reduction of about 21%, with about one‑third losing more than 25% of their baseline weight. 
• A higher proportion of those on the investigational 7.2 mg dose reached a body mass index (BMI) <27 and a waist‑to‑height ratio <0.53, and many who hit both targets also normalized at least two cardiovascular disease and metabolic risk factors (e.g., blood pressure, cholesterol, glucose). 

Status 

The 2.4 mg weekly dose is already marketed as Wegovy; the 7.2 mg dose remains investigational, and regulatory submissions will depend on full STEP UP program results and safety assessments. 

CagriSema is the development name for a once‑weekly fixed‑dose combination of cagrilintide (an amylin analogue) and semaglutide (a GLP‑1 receptor agonist), designed to help increase a feeling of fullness, manage gastric emptying, and control appetite pathways. 

As of early 2026, CagriSema is still investigational and under phase 3 evaluation in the REDEFINE program. 

Phase 3 REDEFINE‑1 obesity trial 

REDEFINE‑1 is a 68‑week, double‑blind phase 3a trial that randomized 3,417 adults with obesity to once‑weekly CagriSema, cagrilintide alone, semaglutide alone, or placebo, all with standardized lifestyle interventions. 

Efficacy

• CagriSema produced weight reductions “in the highest range of existing weight‑loss interventions,” exceeding the effects of each individual component and placebo. 
• More than one in five participants (over 20%) achieved body-weight loss of more than 30% with CagriSema, a level of weight loss typically associated with bariatric surgery. 
• Large proportions of participants achieved weight loss of more than 5% to more than 25% of body weight compared with placebo, with substantial improvements in waist circumference, BMI, and cardiometabolic risk markers. 

Phase 2 background

Earlier trials of cagrilintide and semaglutide in overweight/obesity showed significant, clinically relevant weight reductions vs placebo, with high proportions achieving 20–30% weight loss. 

Status 

Novo Nordisk has indicated strong confidence in CagriSema and is advancing multiple REDEFINE trials to support global submissions. Specific regulatory filing dates and launch timing have not yet been made public. 

To understand how these new medications – as well as the currently available GLP-1 and GIP/GLP-1 drugs -- help with weight loss, it helps to think of appetite as a conversation between your gut, brain, and hormones.

When you eat, your gut releases signaling molecules that send messages to your brain about fullness and hunger. Some of these are glucagon-like peptide-1 (GLP-1) and amylin, which tell your brain “I’m satisfied” or “I’ve had enough.” Many of the newest medications mimic these signals, enhancing the body’s natural feedback loops that reduce appetite and increase feelings of fullness.

Instead of working like typical diet pills that simply suppress appetite through stimulant effects, these therapies tap into physiological pathways — the same ones your body already uses to regulate energy balance. That’s why they can produce more significant and sustained weight loss than older medications, especially when used alongside behavioral support and healthy lifestyle changes.

People taking GLP-1-based medications like semaglutide or combination therapies in clinical trials often lost a double-digit percentage of their body weight compared with placebo groups — far more than most older medications. This level of weight loss is not only visible on the scale but also meaningful for health outcomes, including improvements in blood pressure, glucose regulation, and risk factors associated with heart disease and diabetes.

It’s worth noting that while these drugs can have side effects — most commonly nausea, diarrhea, or constipation — these tend to diminish over time as the body adjusts. The key is close communication with your clinician about dosing and expectations.

In real-world settings, many people using these medications have also reported changes in food preferences — tending to choose lower-calorie, less processed options — which suggests that these drugs may influence appetite and reward pathways in the brain.

Before diving into special populations, it’s important to recognize that obesity is not simply a matter of willpower. A complex interplay of genetics, metabolism, gut hormones, lifestyle, stress, sleep, and other health conditions influences body weight. This is why two people eating the same diet and exercising similarly can have very different results on the scale.

Medications help shift the biology that often resists weight loss. But biology doesn’t act in isolation — it interacts with other hormone systems, especially in people with thyroid disorders or those experiencing hormonal changes in midlife.

If your thyroid gland doesn’t produce enough thyroid hormone — a condition called hypothyroidism — your body’s metabolism slows down. Thyroid hormones are central players in regulating energy use and calorie burning. When they are deficient, the body becomes more efficient at conserving energy, making it easier to gain weight and harder to lose it.

Common symptoms of hypothyroidism include:

• Persistent fatigue
• Weight gain or resistance to weight loss
• Cold intolerance
• Dry skin
• Constipation
• Depression and low mood
• Brain fog

Even when treated with thyroid hormone replacement, when you’re hypothyroid, you may find your metabolism remains somewhat slower than average, especially if your thyroid levels are not fully optimized or if you have other hormonal influences at play, such as perimenopause or menopause.

This metabolic reality matters in weight loss because a slower metabolism burns fewer calories at rest — and that means the calorie deficit required to lose weight must be larger than for someone with normal thyroid function. In practical terms, fitness and diet plans that work for others might produce smaller results for someone with hypothyroidism unless hormone balance is addressed.

Importantly, when thyroid hormone levels are optimized with appropriate medical therapy, many people find that weight loss becomes more achievable — not magically easier, but more proportionate to their efforts.

Perimenopause — the transition years leading up to menopause — and menopause itself are times of dramatic hormonal change for many people. Estrogen levels fluctuate and decline, progesterone levels fall, and the balance of sex hormones shifts, affecting metabolism, fat distribution, and hunger signals.

Midlife weight changes result from several factors:

• Loss of estrogen is associated with increased abdominal fat and changes in how the body stores energy.
• Muscle mass declines naturally with age, reducing resting metabolic rate.
• Sleep disturbances, stress, and changes in insulin sensitivity can make appetite harder to control.

It’s not uncommon for people in perimenopause or menopause to find that the same diet and exercise routine that used to work — even years earlier — no longer produces the same results. Hormonal changes alter not only weight but also how the body responds to food and exercise.

This doesn’t mean weight loss is impossible. Rather, it means that strategies need to be adapted to the hormonal context. Medications that enhance satiety and decrease appetite may level the playing field somewhat, especially when used in tandem with targeted nutrition and strength training to offset muscle loss.For people with hypothyroidism or those in perimenopause or menopause, approaching weight loss is not a one-size-fits-all endeavor. Here’s a practical framework:

‍1. Get a thorough hormone assessment

Before starting any weight loss plan, it’s important to evaluate your thyroid function with a complete thyroid panel (TSH, Free T3, Free T4, and thyroid antibodies) and discuss life stage changes like perimenopause or menopause with your clinician. Optimizing your thyroid hormone levels with thyroid hormone replacement medication can remove a major metabolic barrier.

            

            

              

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2. Balance nutrition with hormone health

Protein intake supports muscle maintenance; fiber and healthy fats slow digestion and stabilize blood sugar. Combining appetite-suppressant medications with a nutrient-dense diet often leads to better long-term success.

3. Prioritize strength training

Muscle tissue burns more energy than fat even at rest. Strength training combats age-related muscle loss and enhances your metabolic rate, which is crucial when hormones shift.

4. Expect medications to be long-term tools, not quick fixes

Evidence suggests that stopping weight-loss medications often leads to weight regain unless lifestyle changes are deeply rooted. These drugs may be best understood as long-term management tools for a chronic condition, much like antihypertensives for blood pressure or statins for cholesterol.

5. Monitor and adjust

Everyone responds differently. Dosage adjustments, medication switching, or pairing with other lifestyle strategies may be needed over time.

While trials often focus on short-term weight loss, they don’t always capture long-term quality of life, financial cost, or how hormonal conditions interact with outcomes. Questions people commonly ask include:

• Will I keep the weight off if I stop the medication? Research suggests that many people regain weight after discontinuing the drug, underscoring the importance of ongoing lifestyle changes.
• How do these drugs affect mood and energy? Some studies show potential improvement in emotional well-being without increased psychiatric risk, though individual experiences vary.
• Will weight loss cause muscle loss? Intentional weight loss typically reduces both fat and a small amount of muscle, but the proportion favors fat loss when paired with resistance exercise.

What’s clear from the JAMA report and broader research is that weight loss science is rapidly evolving. For people who have struggled for years — trying diets, feeling discouraged, or seeing minimal results despite effort — these medications represent hope that biology can be harnessed in service of health goals.

But context matters. Hormonal conditions like hypothyroidism and life stages like perimenopause and menopause add complexity to metabolism and weight. The most successful approaches integrate medical support, hormone balance, tailored nutrition, strength training, psychological well-being, and patience.

Weight loss isn’t just about shedding pounds — it’s about improving your metabolic health, reducing your risk of chronic diseases, and feeling stronger and more confident in your body. With new tools on the horizon and smarter strategies grounded in science, more people are finally gaining meaningful traction.

If you’re considering weight-loss medications, the best first step is to have a conversation with your healthcare provider about your overall health picture, including thyroid status, hormone levels, lifestyle factors, and personal goals. Together, you can decide whether these new options fit your journey — and how to use them in a way that supports long-term success.

Semaglutide and tirzepatide are currently among the most effective medications available for weight loss, helping many people achieve meaningful, sustained reductions in body weight by targeting the hormonal signals that regulate hunger, fullness, and metabolism. Clinical trials and real-world use have shown double-digit percentage weight loss for many patients, along with improvements in blood sugar control and cardiometabolic health. At the same time, a new generation of weight-loss drugs now in development—including oral formulations, higher-dose options, and combination therapies—offers the potential for even greater and more durable results, with added convenience and the possibility of fewer or better-tolerated side effects. These advances signal a rapidly evolving future in which weight-loss treatment becomes more personalized, effective, and sustainable in the long term.

At Paloma, we’re closely tracking the fast-moving science behind weight loss medications—from semaglutide and tirzepatide to emerging oral and combination therapies. Our clinical team actively works with patients using these medications, particularly those of you with hypothyroidism or in perimenopause or menopause, when weight loss can be uniquely challenging.

We believe your successful weight management starts with understanding hormones. That means optimizing your thyroid levels, accounting for life-stage changes, and integrating medication with personalized nutrition, strength-focused movement, and long-term metabolic support. As new drugs come to market and guidelines evolve, Paloma remains committed to evidence-based care that helps you lose weight safely, sustainably, and in a way that supports your whole-body health.

THYROID GUIDE

GLP-1 Medications & Hypothyroidism

Struggling with weight loss and hypothyroidism? GLP-1 medications may help. This guide explains how they work, why they’re helpful for thyroid patients, and how to use them safely.

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How are these new weight loss drugs different from older diet pills?

They target natural gut and brain hormones involved in hunger and fullness, rather than relying solely on stimulants or appetite suppressants.

Are these medications meant to replace diet and exercise?

No—studies show they work best when combined with lifestyle changes like nutritious eating, physical activity, and strength training.

Can people with hypothyroidism safely use GLP-1 or dual-hormone weight loss drugs?

In most cases, they can. Thyroid levels should be well-managed and treatment closely monitored by a knowledgeable clinician.

Why is weight loss harder during perimenopause and menopause?

Hormonal changes, muscle loss, sleep disruption, and insulin resistance all affect metabolism and fat storage during midlife.

How much weight do people typically lose on these medications?

Clinical trials often show average weight loss of 10–20%, with some newer therapies producing even greater results.

Are oral weight loss drugs really as effective as injections?

Early data suggest high-dose oral formulations may approach injectable results, though approvals are still pending.

What happens if someone stops taking a weight loss medication?

Many people regain weight if the medication is stopped without sustained lifestyle and metabolic support.

Are these drugs intended for long-term use?

Increasingly, yes—experts view obesity as a chronic condition that may require ongoing treatment, similar to high blood pressure or diabetes.