Peptide weight loss in the Wegovy® shortage era.
Semaglutide (Wegovy®) is FDA approved for weight loss. It has been so popular due to the drug's effectiveness that the company that makes it cannot keep up. This demand has led to prolonged shortages of a medicine that costs about $20,000 a year.
We undertook a pilot trial using a generic (compounded) version of semaglutide for 12 weeks and then switched to metformin. The purpose was to determine if there is an alternate way to dose weight loss medications in the face of a national, prolonged shortage.
Individuals employed with a medical practice who were overweight or obese and wanted to lose weight were recruited. Lunchtime meals were supplied four days a week based on a Mediterranean diet. Study medication (semaglutide) was given weekly at a dose that mimics the commercial drug that was not available at the time of the study.After three months of weekly semaglutide injections, subjects were switched to metformin and continued the free lunches. Body weight was measured, and BMI was calculated.
After four months, three months on semaglutide, and one month on metformin, weight loss was seen in 100% of participants. The average weight loss was 23.4 lbs., with a range of 21-28 lbs. lost. Body weight reduction was 10-14% at four months, or almost double the weight loss expected with semaglutide alone. No weight gain was noted during the transition into metformin maintenance.
An employer-sponsored group undertaking (the subjects all worked together and had meals together) of weight loss can be very effective. Weight loss combining two drugs with better lunchtime meals lacks the distress of typical weight loss strategies.
Semaglutide (Branded Wegovy®) is a peptide that is FDA approved for weight loss in overweight and obese individuals. In 2021, the FDA made semaglutide the first weight loss drug since 2014. Another form of semaglutide had been FDA approved for the treatment of type 2 diabetes.
In clinical trials, semaglutide use for 68 weeks led to a 14.9% weight loss compared to a 2.4% weight loss in people taking the placebo. Both groups were instructed to perform moderate activity for 150 minutes a week (such as walking) and reduce their caloric intake modestly.
Some prescribers have been prescribing another form of semaglutide, Ozempic®, which is not FDA-approved for weight loss (it is approved for type 2 diabetes) and is still very expensive. The drug was introduced at approximately $1,600 monthly (as a weekly self-administered shot), and due to unexpected massive success, the company quickly ran out of supplies. People seeking semaglutide for weight loss were told to use something else or wait for the manufacturer to catch up, which could take a year or so.
Most people do not have insurance coverage for weight loss drugs. Using your insurance to pay for diabetic medication when you do not have diabetes (in this case, to lose weight) is risky for you and your prescriber.
When a drug is not commercially available, it can be compounded. This has led compounding pharmacies to legally make semaglutide for individuals through a 503(a) FDA process. Wegovy® is not fully commercially available.
In the clinical trial for weight loss with semaglutide, they followed people for 68 weeks on the active drug or placebo.A group of participants were asked to discontinue the study medication, stop the exercise (150 minutes a week), and go back to their old diet habits.
The people who were on the placebo quickly gained the weight back. Those on semaglutide who had the most weight loss had about ½ of the weight gain in the next year, mainly in the first three months after stopping the intervention. Those on semaglutide who had the most minor weight loss over the first year gained almost all of it back in the next year.
Why did the “Biggest Losers” have the most sustained weight loss? The study was not powered to detect that feature. It was powered to justify taking their $ 1,600-a-month drug for the rest of their life.
In the statistics, we can see another pattern emerges. The data suggests this peptide can be used intermittently and along with lifestyle interventions lose weight faster and keep it off longer.
Another diabetes drug, metformin, works in a remarkably similar fashion to semaglutide. They both act on the same metabolic pathway to reduce hunger, process sugar better and reduce weight. Metformin is often prescribed for weight loss. It has been shown to work, but not at the magnitude of semaglutide.
Another aspect of semaglutide is drug tolerance. The starting dose (where weight loss occurs the fastest) is much smaller than the maintenance dose (10 times higher than the initial dose). As the dosage of semaglutide gradually increases, it does not work better for weight loss. The most significant loss of body weight occurs in the first 3 months of use. Each month the dose of semaglutide is increased, with the final dosing having ten times more semaglutide (in milligrams) than the first 4 weeks.
Our bodies have a metabolic pathway called GLP-1 or glucagon like peptide one that is the target of semaglutide. GLP-1 activity is found throughout our bodies and turning this pathway on leads to favorable effects. The drug turns the switch on, which lowers blood sugar, decreases hunger, and leads to weight loss.
Metformin also acts on GLP-1, but not by turning the switch on, but by making more of it available. This also regulates blood sugar, reduces appetite and is helpful for weight loss.
Metformin is one of the top three drugs prescribed in the world due to its high safety, tolerability, and beneficial effects on health. Metformin is currently being studied as an anti-aging drug.
Metformin and semaglutide can safely be taken together, and this is common and safe for the treatment of diabetes. There is no known risk of hypoglycemia (low blood sugar) with either of these drugs alone or in combination with each other.
The study aimed to determine if using the smaller ramp-up doses of semaglutide for 3 months (when the fastest weight loss occurs), and then switching over to metformin to reduce tolerance would be superior to semaglutide alone.
Measurement: A group of employees in the South Carolina region of a national medical practice were offered to enter a program for corporate sponsored weight loss. Of 10 employees, 5 participated. Reasons for not participating were pregnancy (1), breast feeding (1), and no desire or need to lose weight (3).
BMI is Body Mass Index. BMI is calculated by weight and height. While imperfect, BMI is useful for determining the likelihood of normal weight (BMI 18.5-<25), overweight (25.0-<30), or obese (30.0 or higher).
The FDA indication for semaglutide is a BMI over 30, or a BMI over 27, and one weight related ailment.This study was testing a compounded, or generic, version of semaglutide so we allowed 2 participants with a BMI <30 and did not have weight-related disease to participate.
Initial BMI calculated by height and weight were 26.4-41.4 in the five individuals. A standard scale was used for all participants, and height was self-reported.
Meals: Meals were purchased through Healthletics Meal Prep (Greenville, SC) by the employer. The meals offered were designed for various needs, so the specifications were based on a traditional Mediterranean diet base. This included vegetables, fruits, tubers, legumes, and chicken. We did not offer fish as none of the participants were fans, and we supplied extra virgin olive oil and condiments. No processed foods or red meat was included, and cheese was kept at a minimum.
Medications: Each individual was prescribed a 2 ml vial of semaglutide, 5mg/ml (10 mg total dose). This was supplied from a single compound pharmacy and paid for by the study.The dosage was 0.05ml weekly for weeks 1-4.In Weeks 5-8, the dose increased to 0.1ml.Weeks 9-12 were dosed at 0.2 ml. After week 12, the dosage went up to 0.35 ml weekly until the study drug ran out, typically at 13 weeks, or three months.
After the semaglutide was completed, the individuals were placed on metformin 850 mg. The metformin was started at once daily and increased to twice daily as tolerated. Metformin occasionally causes mild gastrointestinal side effects, but typically is managed by slow dose escalation.
Other interventions: There were discussions and education on the American diet and assurance that eating like an American will increase your likelihood of looking like an American (that is the majority of us are overweight). We also replaced the waiting room snacks with less processed and healthier alternatives. The group was encouraged to engage in healthy behavior, but no exercise recommendations were actively involved.
At approximately 4 months subjects were re-measured using the prior methods. No surveys of lifestyle were undertaken.
There were 4 females and one male that participated. At 4 months, all participants lost weight. Meal adherence was observed by lack of meal waste (4 meals per employee were ordered weekly for a 4-day work week).
The subjects' start weight ranged from 149 lbs. to 237 lbs. The final weights ranged from 128 lbs. to 209 lbs.
All subjects lost at least 10% of their body weight with a range of 10% to 14%. The range of weight loss was 21lbs. to 28 lbs. in the four months. All subjects reported steady continuous weight loss throughout the semaglutide period and weight maintenance or slight additional weight loss during the metformin period.
There was no correlation between starting weight (or BMI) and total weight loss. They were all in the range of 24 lbs +/- 4 lbs.
There was no drop out due to side effects or any reason. The food supplied was perceived as very tasty, and individuals reported changing their families’ eating habits, at least somewhat, to those of a healthy Mediterranean pattern.
With overweight and obesity being endemic in the USA and elsewhere, novel attempts must be made to reign in this disturbing trend. Semaglutide has taken Hollywood by storm and is the subject of a social media frenzy, but it is too expensive for the average person at $20,000 annually.
Using a mechanism of ramping up GLP-1 activity with semaglutide, then discontinuing the drug before tolerance occurs is phase one. Phase two is adding another GLP-1 stimulating mechanism, metformin, to keep the weight off and allow tolerance to decrease. Phase three will be adding semaglutide back in for another 3 months for those wanting to lose additional weight.
Further studies with a larger population group, randomly selected and placebo controlled would go much further to prove this pattern.This pilot study demonstrated that this is a viable alternative during a time when semaglutide for weight loss is not commercially readily available.
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