Semaglutide and Metformin
Weight loss shots.
The hype around the newest FDA-approved weight loss injections is well-founded. At first, I was very skeptical, and about a year ago, I wrote a blog about the drug semaglutide (branded as Wegovy® for weight loss in the US) and it's massive cost.
A brief review of the semaglutide and weight loss studies will be followed by an overview of what we have done with our staff who want to lose weight and now offer to our patients. The idea to change the process was based on the drug's very high cost, the unique nature of the immediate effect of starting and discontinuing the medication, and combining semaglutide with another safe, well known, and inexpensive drug to help keep the weight off.
Key points for this article:
- Semaglutide works very fast to help lose weight starting at 1/10th the dose that is needed to keep the weight off for maintenance.
- The maintenance dosage of commercial semaglutide is about $1,600 a month.
- Individuals in the FDA clinical study gained weight back quickly after stopping semaglutide.
- There is another drug that costs less than $10 a month that appears to maintain weight loss after discontinuing semaglutide.
- Individuals in our clinic have lost 15-35 lbs. in a few months for less than $1,000.
Sold under the name Wegovy®, semaglutide is FDA approved for weight loss. The drug was initially developed for the treatment of type 2 diabetes.
During clinical trials, it was noted that individuals with diabetes taking semaglutide had the benefit of significant weight loss and other health benefits, such as reduced markers of cardiovascular disease.
A 68 week study compared the weekly use of semaglutide injections at a higher dose than that of diabetic indications on weight loss. Each group was instructed to do 150 minutes of exercise weekly, such as walking, as well as reducing calorie intake by about 25%.
At the end of the study, participants taking the active drug, semaglutide, participants lost an average of 17% of body weight, while those on a placebo lost 2%.
At the end of the 68 week study, they asked a group of participants to discontinue the drug and the lifestyle interventions (such as diet and exercise) and followed them for another year.
A year after discontinuing the drug (or placebo), weight gain was recorded. Those on placebo gained 2% of weight back when they stopped light exercise and increased their daily calorie intake. The people on semaglutide gained weight, and most of the weight gain occurred immediately after discontinuation of the drug and lifestyle interventions.
The weight gain was rapid when the individuals who were taking semaglutide discontinued the drug. In 3 months, they gained 6% of their body weight back, and then weight gain slowed. At the end of one year after cessation of semaglutide, they gained about 11% of their body weight back but were still 6% lighter than 2 years earlier when they started the drug.
There is a timing aspect to these studies that we can consider. When the individuals were put on semaglutide (or placebo) for 68 weeks, the most significant weight loss occurred very rapidly in the first three months.
When the individuals who were selected to discontinue the intervention for a year (semaglutide or placebo plus lifestyle changes) made the change, the most rapid weight gain occurred early, within three months.
The mechanism of action of semaglutide is complex and not fully understood. Still, the principal effect is on glucagon-like peptide 1 (GLP-1) receptors that positively impact blood sugar levels, sensation of fullness, and insulin secretion.
Another, more common type 2 diabetes drug, metformin, also acts on the GLP-1 pathway by increasing GLP-1 secretion, resulting in a favorable blood sugar level, and favors weight loss in non diabetic individuals.
Going back to the semaglutide weight loss trials, we see that the weight loss was rapid in the first three months, slowing down between 3-12 months, and then a little additional weight loss in the next four months while on the medication. A tolerance occurs and further weight loss isn't seen, but weight loss is maintained.
Additionally, the most rapid weight loss occurred at a much lower drug dosage than what was needed to maintain weight loss. Semaglutide is prescribed as a weekly shot, and in the first three months, the dosage is minimal. In fact, the first four weeks dosage is 1/10th of the dosage that is used at one year to maintain the weight loss.
To test semaglutide for shorter periods (to reduce the cost of the very expensive drug), we have prescribed it at the starting small dose, escalating the dosage every four weeks, and never getting to the much higher (and difficult to tolerate) weight maintenance dosage.
At the end of 3 months (when the most rapid weight loss occurs), the semaglutide is stopped, and the medication is switched to metformin.
Metformin can be safely used in non diabetics, has been shown to lower weight, and is currently being tested as an anti-aging or longevity, drug intervention.
Our patients are instructed to follow a Mediterranean diet consisting of nonprocessed foods, fruits, and vegetables, nuts, legumes, poultry, and fish. Consumption of extra virgin olive oil (independently shown to reduce body fat), moderate alcohol consumption, and avoidance of red meat is also recommended.
We purchase meals for our staff during working hours from local businesses to help with a healthy lifestyle and pay for our staff's initial three months of semaglutide injections.
Our employees who opted for the program have seen an average of 25 lbs of weight loss in the first three months of semaglutide. After that they discontinue the semaglutide and are put on metformin. Unlike the clinical studies to promote life long use of semaglutide (which costs about $1600 a month for the Wegovy® version), we do not see weight gain after cessation of semaglutide as was noted in the original clinical trials.
But two things differ from what our staff (and patients) are doing vs the clinical trials. First, we do not recommend that they stop the exercise or resume old, unhealthy eating habits.
The second is the use of metformin (oral pill daily), that is safe and synergistic with semaglutide. Semaglutide works by agonizing (optimizing or turning on) the GLP-1 pathway, and metformin up regulates GLP-1.
Those who want to lose more weight after 2-3 months of metformin, they can resume a three month pulse of semaglutide, starting again at the lower, more tolerable, and more effective weight loss dosage.
At the time of this publication, the Wegovy® brand of semaglutide is having supply chain issues and not readily available. This has led to lack of FDA protection, and it is being produced as a generic compounded version at a fraction of the cost. The FDA allows for pharmacists to use generic sources when a commercial product isn’t available for consumers. The compound pharmacists can also add in other ingredients such as vitamin B12 that may make the medication more effective or more tolerable.
Semaglutide is injected into your skin weekly. The main side effects are gastrointestinal, and this is generally tolerated by starting at a very low dose and increasing the dosage over time. Only a licensed healthcare provider can prescribe semaglutide after a medical evaluation.
Individuals with type 2 diabetes generally qualify for a different form of semaglutide and have a much better chance of getting it covered by their health insurance. For individuals who want to use semaglutide, health insurance may, in some cases, cover it, but would have to wait for the manufacturer to be able to make it. The generic version of semaglutide would not be covered.
Both semaglutide and metformin are very safe drugs, but not without risks, so they will remain prescription only and are not available over the counter. Both semaglutide and metformin are being evaluated for extending life expectancy or adding disease free years of life to individuals on these mediations.
Dr. Charles Mok
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Once-Weekly Semaglutide in Adults with Overweight or Obesity. n engl j med 384;11 March 18, 2021
Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022;24:1553–1564.
Estimated Life-Years Gained Free of New or Recurrent Major Cardiovascular Events With the Addition of Semaglutide to Standard of Care in People With Type 2 Diabetes and High Cardiovascular Risk. CARDIOVASCULAR AND METABOLIC RISK| MARCH 09 2022 Volume 45, Issue 5 May 2022