On June 4, 2021, the FDA approved a new weight loss drug called Wegovy (Semaglutide).
That said, technically the drug is not new – it was initially approved in 2017 under the brand name Ozempic as an adjunct treatment for type 2 diabetes.
Wegovy (Semaglutide) is administered by injection (2.4 mg) once per week for weight management in: (1) adults with obesity; OR (2) overweight adults with at least one weight-related comorbitity (e.g. high blood pressure; type 2 diabetes; high cholesterol; high triglycerides).
Since its approval, an onslaught of “front page” news articles have been published to hype this drug up.
This is a result of numerous motivations (not limited to):
- Strategic marketing: A calculated marketing campaign by Novo Nordisk (multinational pharma company).
- Clicks, views, & ad revenue ($): The realization that obese people want a new quick fix (and thus will click on headlines related to this drug)… advertising revenue is generally high for weight loss ads (so the publishers benefit significantly)
- “Spreading the word”: Some have published articles about Wegovy (semaglutide) simply to get the information out to overweight/obese individuals that there’s a novel/new weight management option that might improve health and decrease disease risk.
A safe and effective treatment for obesity/being overweight is much-needed in many first-world countries where the biggest problem has become overeating – as opposed to (formerly) a lack of food.
If you’re interested in Wegovy (Semaglutide), it may be useful to read more and understand its mechanism of action (i.e. how it works); side effects; long-term effects; and more.
Semaglutide (Brief History)
- Synthesized in 2012 by a team of researchers at Novo Nordisk.
- Intended to be a longer-acting alternative to the drug Liraglutide (i.e. Victoza) as an anti-diabetic medication for T2DM; obesity; weight management.
- Clinical trials of Semaglutide were initiated in 2015 and Phase III completed in 2016.
- In 2017, the University of Leeds & Novo Nordisk reported that Semaglutide appears efficacious in the treatment of obesity.
- Phase 3 RCT reported -14.9% body weight reduction after 68 weeks of once-weekly administration relative to -2.4% with placebo.
- United States FDA received a New Drug Application (NDA) December 2016 and October 2017 – and the FDA Advisory Committee voted unanimously (16-0) in favor of the drug’s approval.
- It was officially approved by the U.S. FDA in 2017 – then by the European Union, Japanese Ministry of Health, and Health Canada – in 2018.
- Semaglutide was also approved for medical use in Australia for the treatment of adults with “insufficiently controlled type 2 diabetes.”
Semaglutide Brand Names; Formats; Dosages
- Ozempic (injectable) (2017): 0.25 mg & 0.5 mg
- Rybelsus (oral) (2019): 3 mg; 7 mg; 14 mg
- Wegovy (injectable) (2021): 0.25mg/0.5mL; 0.5 mg/0.5mL; 1mg/0.5mL; 1.7mg/0.75mL; 2.4mg/0.75mL
Semaglutide: Official uses (Indications)
- Glycemic control (Type 2 diabetes): Semaglutide was first approved (2017) as an injectable adjunct intervention to improve glycemic control in adults with type 2 diabetes. (For this it was sold under the brand name Ozempic). An oral version of Semaglutide was later approved in 2019 under the brand name Rybelsus).
- Weight management: Semaglutide was later approved (2021) as an injectable intervention for weight management in adults who are either: (1) obese or (2) overweight with a weight-related medical condition (e.g. hypertension; dyslipidemia; type 2 diabetes).
Semaglutide Mechanism of Action (How It Works)
Glucagon-like peptide-1 (GLP) receptor agonist
- Semaglutide is ~94% chemically similar to human glucagon-like peptide-1.
- Semaglutide binds to GLP-1 receptors (receptors located on Beta cells of the pancreas & within the brain) and activates them.
- GLP-1 receptor activation stimulates the adenylyl cyclase pathway which causes the body to synthesize and release insulin (a hormone that lowers blood sugar).
- Semaglutide has also been observed to promote growth of Beta cells in the pancreas (which are sites of insulin production).
- As a result of the increased insulin synthesis and release, Semaglutide is beneficial for glycemic regulation in type 2 diabetes.
- Semaglutide has also been observed to decrease appetite and slow down digestion – both of which can lead to reduced calorie intake and inevitable weight loss – making the drug useful for weight management.
Friedrichsen et al. (2021) report (R):
“The body weight‐lowering effects of once‐weekly s.c. semaglutide 2.4 mg are likely to be related to reduced energy intake in response to effects on hedonic and homeostatic control of eating, manifesting as decreased appetite, increased satiety, reduced hunger, better control of eating and reduced food cravings.”
Semaglutide Duration of Effect & Half-Life (R)
Duration of action: ~1 week. Evidence suggests that injected Semaglutide remains biologically active for approximately one week – hence the need for once-weekly dosing.
Half-life: ~7 days (165-184 hours)
- As was mentioned, Semaglutide exhibits ~94% chemical similarity to human glucagon-like peptide-1.
- The only key differences are 2 amino acid substitutions at positions 8 and 34 (alanine and lysine, respectively, are replaced by 2-aminoisobutyric acid and arginine).
- Amino acid substitution at position 8 prevents chemical breakdown by an enzyme dipeptidyl peptidase-4 and lysine at position 26
- Acylation with a spacer and C-18 fatty acid diacid chain increases the drug binding to blood protein (albumin) which enables longer presence in blood circulation.
How long does Semaglutide stay in your system?
Semaglutide stays in your system approximately 38.5 days after injection.
Why? The half-life is approximately 1 week – multiply by 5.5 (# of half-lives it takes for a drug to be removed from the body) and you’ve got 38.5 days.
If we use the hour range (165-184 hours) referenced above, complete elimination could range from ~37.81 days to ~42.17 days.
Keep in mind that elimination may vary slightly among users based on individual variables (blood chemistry, genetics, organ function, co-administered substances, etc.).
In other words, you should expect Semaglutide to remain circulating throughout your body for over a month after discontinuation.
Semaglutide Side Effects (Common Reactions) (R1, R2)
The top side effects of Semaglutide seem to be (listed in order of prevalence): nausea; diarrhea; vomiting; constipation; and abdominal pain.
Most common (10+% of users)
- Nausea: Nausea is the most common side effect associated with Semaglutide – occurring in ~44% of Wegovy recipients (relative to 16% of placebo recipients).
- Diarrhea: Diarrhea is the second-most common side effect associated with Semaglutide – occurring in ~30% of Wegovy recipients (relative to 16% of placebo recipients).
- Vomiting: Vomiting is another common side effect of Semaglutide – occurring in ~24% of Wegovy recipients (relative to 6% of placebo recipients).
- Constipation: Semaglutide causes constipation in a significant percentage of users (~24% of Wegovy trial recipients vs. 11% of placebo recipients).
- Stomach pain: Abdominal pain or upset stomach was documented in ~20% of Wegovy trial recipients compared to just 10% of placebo recipients.
- Headache: Semaglutide is known to cause headaches in some individuals. Trial data revealed headaches in ~14% of Wegovy recipients versus 10% of placebo recipients.
- Tiredness: ~11% of Wegovy trial recipients experienced tiredness, fatigue, or lethargy – which was more than the 5% reported in placebo recipients.
Somewhat common (5-10% of users)
- Indigestion: Based on Wegovy trial data, it seems as though Semaglutide causes indigestion (i.e. dyspepsia) in around ~9% of users (relative to 3% of placebo users).
- Dizziness: Trial data revealed that dizziness occurred in ~8% of Wegovy users relative to 4% of placebo users.
- Bloating: Bloating is caused by the accumulation of gas or fluid in the abdomen – causing stomach expansion (i.e. abdominal distention). Abdominal distention was reported in ~7% of Wegovy recipients (versus 5% of placebo recipients).
- Belching: Medically termed “eructation,” belching (or burping) can be caused by Semaglutide – and is estimated to occur in around ~7% of Wegovy users.
- Low blood sugar (T2DM): Hypoglycemia or low blood sugar occurred in ~6% of Wegovy users with type 2 diabetes (T2DM) during clinical trials (relative to 2% of placebo users). If you have type 2 diabetes, be cognizant of this potential reaction. (Signs: dizziness; lightheadedness; sweating; shakes; blurred vision; confusion; jitteriness; weakness; headache; slurred speech; hunger; irritability; rapid heartbeat; anxiety).
- Flatulence: Flatulence (passing gas, farting) may become more frequent while taking on Semaglutide. It is estimated that increased flatulence occurs in ~6% of users (relative to 4% of placebo users).
- GERD: Gastroesophageal reflux disease (GERD) occurred in ~5% of Semaglutide users during a clinical trial – relative to 3% of placebo users. (Signs: Burning pain in chest after eating, worsens when lying down).
Less common (less than 5% of users)
- Gastritis: ~4% of people report gastritis (inflammation of the stomach lining) while taking Semaglutide. (Signs: Upper belly pain, nausea, vomiting).
- Flu-like symptoms: It was reported that ~4% of Semaglutide recipients developed viral gastroenteritis during clinical trials (relative to 3% of placebo recipients). Although Semaglutide doesn’t cause viral infections, it may cause flu-like symptoms.
- Hair loss: It seems unlikely that hair loss would be caused by Semaglutide – but it was documented in ~3% of users (relative to 1% of placebo users).
Note: Davies et al. (2021) reports that gastrointestinal disorders are the most common adverse events of Semaglutide – and these events are typically transient and of mild-to-moderate severity. (R)
Serious adverse effects
Semaglutide can cause serious adverse events/reactions in a subset of users.
If you’re considering Semaglutide OR are currently taking Semaglutide for a medical condition – it’s important to review these potential adverse reactions (so that you’re aware).
(This should be obvious – but: seek emergency medical attention if you’re experiencing any adverse reaction from Semaglutide).
Thyroid tumors & cancer: Semaglutide comes with a “black box warning” making it clear that it may increase risk of developing thyroid C-cell tumors (e.g. medullary thyroid carcinoma).
- Why? In rodents, Semaglutide causes C-cell tumors at clinically relevant exposures.
- Whether the same types of tumors will develop in humans who take Semaglutide remains unclear.
- (If this drug does cause tumors in humans, its production will be discontinued in the future – and lawyers will be ready to pounce on some juicy lawsuits).
Pancreatitis: Inflammation of the pancreas can occur – it was documented as having occurred in Semaglutide clinical trials. (Signs: upper abdominal pain, nausea, vomiting).
Gallbladder problems: Acute gallbladder disease (e.g. gallstones & inflammation) was documented as having occurred in Semaglutide clinical trials. (Signs: pain in upper stomach/abdomen; jaundice (yellow skin/eyes); clay-colored stools; fever).
Kidney problems: Acute kidney injury may be caused by Semaglutide – particularly in persons with preexisting kidney dysfunction. Why? Diarrhea, nausea, vomiting (common side effects) can lead to dehydration – which could exacerbate preexisting kidney impairment and cause further damage. (Monitoring kidney function is recommended in at-risk patients).
Allergic reaction: Some people are “hypersensitive” to Semaglutide which can result in allergic reactions. Though rare, signs of allergic reactions include: swelling of face, lips, tongue; rash/itching; difficulty breathing/swallowing; fainting or extreme dizziness.
Blurred vision & retinopathy (T2DM): Blurred vision can be caused by low blood sugar – but also by retinopathy (an adverse reaction reported in Semaglutide trials). (Signs of retinopathy: floaters; blurriness; dark areas of vision; difficulty perceiving colors).
Depression & suicidal thoughts: Oddly enough, a side effect listed from Semaglutide is depression with possible suicidal thoughts. If you become depressed or suicidal from Semaglutide, report this reaction to your doctor immediately. (Psychiatric intervention may be necessary until the medication is out of your system).
Note: Side effects & adverse reactions are subject to significant interindividual variability based on things like: dosage, genetics, current health/habits, organ function, co-administered substances, biochemistry, and more.
How much weight will you lose with Semaglutide?
It depends. Most studies report average weight reductions of 9-15% as a result of long-term, once-weekly Semaglutide (2.4 mg) administration.
The effects seem to be dose-dependent (highest dose of 2.4 mg has stronger effect than lower doses of 1.0 mg and 0.5 mg) AND time-dependent (68 weeks of administration yielded greater weight loss than 20 weeks of administration).
A double-blind trial by Wilding et al. (2021) that included a combination of 1961 obese (BMI > 30) and overweight participants with preexisting condition (BMI >27 + one weight-related comorbidity) reported mean change in body weight of -14.9% after 68 weeks of 2.4 mg Semaglutide administration. (This compared to body weight change of -2.4% in the placebo group). (R)
Davies et al. (2021) analyzed results of a randomized, placebo-controlled, double-blind, double-dummy trial that included 1210 overweight adults (BMI > 27) with weight-related conditions – and found that 2.4 mg Semaglutide administered once weekly for 68 weeks induced a mean weight loss of -9.6% from baseline (relative to -3.4% with placebo). (R)
A double-blind, parallel group study involving 72 obese adults by Friedrichsen et al. (2021) reported that once-weekly Semaglutide (2.4 mg) reduced body weight by 9.9% (10.4 kg) in adults with obesity relative to almost zero change (0.4% reduction) in the placebo group. (R)
A double-blind RCT by Rubino et al. (2021) with 741 overweight/obese adults documented the effect Semaglutide (2.4 mg/week) administered over a 68-week term. Weight loss among Semaglutide recipients was -7.9% (relative to placebo +6.9%). (R)
O’Neil et al. (2018) documented mean weight losses in Semaglutide users [over a 52-week span] of: -6% (0.05 mg); -8.6% (0.1 mg); -11.6% (0.2 mg); -11.2% (0.3 mg); and -13.8% (0.4 mg) – relative to -2.3% for placebo users. (This was a double-blind RCT with 238 obese adults). (R)
Analysis: Ahren et al. (2018) documented weight loss ranging from 2.3 kg to 6.3 kg (5.07 lbs. to 13.89 lbs.) across 5 trials involving once-weekly Semaglutide at 0.5 and 1 mg. (R)
In sum, the amount of weight you’ll lose with Semaglutide likely depends upon:
- Dosage: Higher dosage (2.4 mg) tends to yield greater weight loss than lower dosages. (Particularly, the higher the dosage relative to one’s body weight – the more substantial the effect is likely to be).
- Duration of administration (i.e. how long you’ve been taking it): Longer-term use tends to yield more weight loss than shorter-term use.
- Co-administered substances: Certain meds/supplements might enhance its weight loss effect – whereas others might negate it.
- Health conditions: Certain conditions may cause weight gain and limit the amount of weight loss potential.
- Additional weight-management efforts: Such as calorie reduction, healthy food choices, exercise regimens, etc.
Assuming you aren’t using any drugs that might offset the weight loss effect of Semaglutide (e.g. antidepressants; corticosteroids; antipsychotics) and don’t have any health conditions that cause weight gain (e.g. hypothyroidism) – you should lose weight as suggested by Semaglutide trials.
Weight loss may be most noticeable in persons who combine Semaglutide with negative energy balance (i.e. energy expenditure exceeds energy intake) such as from implementing dietary changes and/or exercising regularly.
Should you use Semaglutide for weight loss?
Cost-benefit analysis. Do a cost-benefit analysis with a medical doctor and make your own decision.
Nobody can tell you whether this is an ideal drug for your particular circumstances other than a medical doctor.
Keep in mind that there are other weight loss strategies (e.g. surgeries; non-invasive fat freezing; diet/exercise; etc.) that might prove more useful than Semaglutide.
Also know that there are other weight loss medications – some of which may be easier for you to tolerate and/or have a safer long-term effect profile.
Can you use Semaglutide while pregnant?
According to packaging information, Semaglutide may cause fetal harm and should NOT be taken during pregnancy.
It is also noted that Semaglutide should be stopped at least 2 months before a planned pregnancy as a result of its long half-life (~1 week) and elimination time (over a month).
Does Semaglutide cause withdrawal symptoms?
Unknown at this time. There are zero available data to substantiate the idea of withdrawal symptoms resulting from Semaglutide discontinuation.
However, lack of data does NOT automatically mean that withdrawal symptoms do not exist. It is certainly plausible that withdrawal symptoms might occur in a subset of people following Semaglutide cessation.
Why? Semaglutide has a pronounced biological effect. Any drug taken long-term to modulate various receptors in one’s body could have “rebound effects” and/or withdrawal syndromes associated with discontinuation.
Keep in mind that things like regaining weight and poorer glycemic control might be more related to reversion back to pre-Semaglutide homeostasis rather than indicative of actual “withdrawal.”
A true withdrawal would likely be evidenced by symptoms that: (1) were NOT present prior to Semaglutide usage; and/or (2) symptoms that emerged after Semaglutide was fully eliminated (~1 month after cessation).
Unexpected “rebound effects” such as gaining weight more rapidly than ever before or experiencing worse glycemic control than prior to taking Semaglutide may be evidence of a “withdrawal” wherein the body needs to recalibrate to functioning without the drug after being under its influence for an extended duration.
What are the long-term effects of Semaglutide?
Nobody really knows. If you consider 68 weeks (over a year) to be “long-term” then we know Semaglutide causes normal mild-to-moderate side effects – but nothing serious in most people.
Had it caused “serious” side effects in a significant number of users, the U.S. FDA (along with foreign regulators in Europe, Japan, and Canada) would NOT have unanimously approved the medication for diabetes, obesity, weight-related conditions.
There is some concern that Semaglutide might increase one’s risk of developing C-cell thyroid tumors/cancer. (This is probably the most serious potential long-term effect, but hasn’t been documented in humans).
Should cancer rates dramatically increase among long-term Semaglutide users – it’s likely that the drug will be permanently shelved (withdrawn from markets) while lawyers rake in big profits from class-action lawsuits against the manufacturers.
How does Semaglutide compare to other FDA-approved weight loss drugs?
The major advantage of Semaglutide relative to other weight loss medications is that it can be injected once-weekly. Most other weight loss drugs require daily administration which is inconvenient and could result in lower rates of compliance.
Other FDA-approved weight loss drugs:
- Bupropion-naltrexone (Contrave)
- Liraglutide (Saxenda)
- Orlistat (Xenical)
- Phentermine-topiramate (Qsymia)
It also seems to be more effective than other weight loss drugs.
A statement issued by obesity researcher Rachel Batterham (University College London) (R):
“No other drug has come close to producing this level of weight loss – this really is a game changer.”
That said, there haven’t been large-scale studies directly comparing weight loss agents (e.g. Semaglutide vs. others) – so it’s difficult to know how Semaglutide compares in: (A) tolerability and (B) magnitude of effect (i.e. amount of weight loss relative to time taken).
Furthermore, I’m of the mindset that older drugs are usually smarter to try before newer drugs due to: (1) more long-term safety data; (2) lower cost (usually generic); (3) overhyping of new drugs (often making them seem better than they are).
Talk to your doctor if you want a more thorough breakdown of these medications and need help deciding which one is ideal for your current situation (i.e. health status).
Does Semaglutide cause weight loss by inducing nausea or vomiting?
Obviously if a drug causes frequent nausea and/or vomiting – weight loss will probably occur. Why? Most people don’t particularly enjoy eating when they’re nauseous and/or vomiting all the time.
In any regard, according to Ahren et al. (2018), only a small amount of weight loss (0.07 kg to 0.5 kg) is attributable to nausea or vomiting – among Semaglutide users. (R)
Can you build up tolerance to Semaglutide?
Unknown. It’s unclear as to whether long-term Semaglutide users build-up tolerance to the drug such that, after a certain duration of usage, weight regain occurs.
Weight regain after long-term Semaglutide usage would likely be a sign of tolerance due to the fact that one’s physiology likely adapted to the drug and recalibrated itself in response to chronic dosing.
Weight maintenance isn’t necessarily a sign of tolerance, but there’s likely diminishing returns over time. For example, if you lose 15% of your bodyweight after 1.5 years of Semaglutide – it’s possible that you’ll experience zero additional loss with continued usage.
You may simply need to continue taking Semaglutide indefinitely (i.e. for life) in order to maintain the lower weight that it helped you achieve.
Can Semaglutide improve other aspects of health?
Yes. Weight loss in general tends to improve many aspects of health – it’s essentially a “force multiplier.” Conditions like type 2 diabetes, insulin resistance, dyslipidemia, hypertension, sleep apnea, et al. often improve with weight loss.
In some cases, even cognitive impairment, anxiety, and depression improve with weight loss (due to a combination of psychological and neurochemical/hormone changes).
Davies et al. reported that participants receiving the 2.4 mg Semaglutide were more likely to experience improvements in: waist circumference; BMI; systolic blood pressure; fasting plasma glucose; C-reactive protein; and lipids – relative to the placebo group. (R)
Drew’s final thoughts on Semaglutide (Wegovy)
- 70% of adults in the U.S. are either overweight or obese – this is insane… interventions to curb calorie intake and increase physical activity are desperately needed.
- Semaglutide seems to be safe and effective when taken for up to 68 weeks (1 year ~3.6 months). Longer-term research data are not available.
- If you are obese (BMI >30) and/or overweight (BMI >25) with weight-related health conditions (dyslipidemia; hypertension; type 2 diabetes; sleep apnea; etc.) – it’s reasonable to consider trying this medication (at least temporarily to improve your health).
- It is convenient that Semaglutide (Wegovy) can be injected once-weekly (making it relatively easy for patients who struggle with adherence to daily medication).
- Most people taking Semaglutide will have some side effects of mild-to-moderate intensities – particularly in the first month (although the body should eventually adjust such that side effects become less problematic).
- The cost of Semaglutide (Wegovy) is estimated to be around $1000 per month – which isn’t that bad of a deal if you have decent insurance and/or are plagued with morbid obesity.
- The risks associated with Semaglutide are certainly worth evaluating prior to treatment – particularly the development of C-cell thyroid cancer in animals (this is of major concern).
Would Drew take Wegovy (Semaglutide) if obese/overweight?
Depends on the magnitude of obesity/overweightedness.
If severely obese or morbidly obese – then yes I wouldn’t hesitate to take Wegovy (Semaglutide).
Why? Risk of dying soon is so significant that long-term effects are irrelevant.
However, if mildly obese or just overweight – I’d avoid it.
Why? My concerns are multi-fold:
- Longer-term data lacking: What happens if I take this drug for years? Maybe I’d be fine. Maybe I’d get cancer. Maybe I’d develop tolerance to the dosage. I’d prefer NOT to be a guinea pig here and take unnecessary risk. (Although cancer in animal trials can’t be extrapolated to humans – it’s still a concern, hence the “black box” warning).
- Alternative weight loss strategies exist: Weight loss is (1) part psychology/routine – and (2) part fat cell removal (many selectively ignore one of the two). A 2-pronged approach involving negative energy balance via habits (e.g. calorie tracking, exercise, thermogenesis) AND fat cell removal (e.g. non-invasive fat cell freezing/melting, liposuction, bariatric surgery, etc.) is probably smarter than taking a drug long-term.
- Alternative weight loss drugs exist: If I were attempting to lose weight – I’d first try most other FDA-approved weight loss drugs. Why? They’ve been around longer and thus have more long-term safety data. Even if they’re less efficacious, I’d feel safer taking them long-term (e.g. years). Additionally, most alternative drugs are likely cheaper than Semaglutide (as of 2021).
- Cost: For most, Semaglutide (Wegovy) won’t be very affordable. The cost is estimated to be around $1000 per month – or $12,000 per year. Though it may be well-worth taking if morbidly obese and/or struggling with weight-related health conditions – you’ll literally pay the price. (That said, you may pay considerably less if you have good insurance).
If I’d tried everything else (high protein/high fiber diet; calorie reduction; other weight loss drugs; weight loss surgeries; exercise regimens; etc.) and still got zero results – only then would I use Wegovy (Semaglutide).
If you’re not really concerned about the future and are more living for the moment (i.e. morbidly obese and need to lose weight now) – then Wegovy (Semaglutide) may be a good choice for you.
In any regard, I’m not a doctor and will NOT attempt to convince you what you should do with your life.
The above are only my opinions – nothing in this article is medical advice. Moreover, I may change my opinions over time with newer/updated information.