Note: Combination drugs are not approved by the U.S. government. US Food and Drug Administration (FDA) They may also carry greater risks than FDA-approved treatments.
The findings come from preprint research funded by Lilly and have not yet been peer-reviewed. That is, the results have not been independently evaluated by outside researchers for publication in medical journals.
“We have notified the U.S. Food and Drug Administration (FDA) of these findings and recommended that anyone using these untested products contact their physician to discuss advice and alternative treatments,” Lilly said in a statement.
This study identified a chemical reaction between tirzeptide and vitamin B12
Lilly’s clinical testing found that the interaction between tirzepatide and vitamin B12 produces a larger molecule than tirzepatide alone. This change could theoretically affect how the drug is absorbed, distributed, metabolized, and excreted in the body, the study authors wrote.
The findings are concerning because nothing is known about the short- or long-term effects of this molecule in humans, or whether there are any potential effects on the drug’s efficacy, toxicity or immune response, according to Lilly’s statement.
Lilly said the combination of tirzepatide and B12 has never been studied before, and the formulators who make these combinations are not required to monitor or report negative patient reactions, known as “adverse events.”
The study also reported that the efficacy of formulated tirzepatide samples was inconsistent, with some samples containing only 43 percent of the amount of drug listed on the label.
Although it is unclear whether this finding poses any real risk to patients, the study authors concluded that “the identification of widespread impurities further heightens existing quality concerns posed by formulated tirzepatide.”
Formulated GLP-1 is not FDA approved
Jorge Moreno, M.D., assistant professor of obesity medicine at Yale School of Medicine in New Haven, Connecticut, said the study’s findings highlight widespread concerns among obesity specialists about combinations of GLP-1 drugs.
Drugs approved by the FDA, such as Zepbound and Mounjaro, go through a lengthy process to ensure safety and effectiveness. Combination drugs that are not FDA-approved do not undergo the same rigorous review.
In the case of counterfeit drugs, “If the recipe doesn’t follow the same methods as the FDA-approved drug, we don’t know if it’s safe or effective because the recipe has been changed,” says Dr. Moreno.
The formulators haven’t shared any data about this new molecule, which is produced from the interaction of tirzepatide and vitamin B12, “so we don’t know what its safety profile is or whether it might affect the effectiveness of the drug,” Moreno said.
Additionally, although extremely rare, taking too much vitamin B12 can cause toxicity, says Yuval Pinto, M.D., an obesity and family medicine physician at Johns Hopkins School of Medicine in Baltimore. “We have seen such cases in our clinic. Large doses of vitamin B12 can cause headaches, nausea, diarrhea, vomiting and facial flushing,” he says.
Why add B12 to composite GLP-1?
Combined versions of GLP-1 drugs have become widely available after the FDA cleared them for manufacture at a time when brand-name drugs were in short supply. But now that drug supplies are no longer in short supply, compounders can no longer legally make counterfeit products, and the FDA is cracking down on counterfeits.
Some formulators have devised workarounds to continue offering lower-cost versions of GLP-1 by adding vitamins and other ingredients and selling the mixture as individualized formulations. This is a legal loophole.
Vitamin B12, also called cobalamin, is a nutrient involved in red blood cell formation and energy metabolism. Some formulators claim that adding B12 to GLP-1 may help combat fatigue, especially in people with vitamin deficiencies. In theory, correcting low B12 levels could improve your energy and help you maintain lifestyle changes that support weight loss.
However, there is no evidence that adding B12 directly to tirzepatide injections is safe or improves weight loss results.
Other additives identified in the formulated GLP-1 samples included glycine, niacinamide, pyridoxine, and carnitine, but these combinations also had not been vetted for safety or efficacy.
Formulation group says Lilly’s announcement “raises more questions than answers”
Compounding pharmacy industry leaders say Lilly’s announcement lacks key details needed to evaluate the claims.
Scott Brunner, CEO of the Alliance for Pharmacy Compounding (APC), said in a statement that the report was concerning but incomplete. APC is a nonprofit trade association representing compounding pharmacies nationwide.
“In the nearly four years since we began using prescriber-approved combinations of Zepbound and B12, we have not seen any alarming trends in patient adverse events associated with this combination,” said Bruner.
Brunner also questioned where Lilly obtained the samples used in the tests, noting that drugs sold on unlicensed websites and medical spas may not meet the same standards as drugs prepared at state-licensed pharmacies. “Medical spas are not pharmacies,” he said.
If Lilly identified a real problem with tirzepatide and vitamin B12 prepared by a legitimate, state-licensed compounding pharmacy, the APC would take it very seriously, Brunner said, but more information would need to be shared for scientists outside Lilly to evaluate the claims.
What should I do if I am taking Zepbound with vitamin B12?
For people currently using compounded GLP-1 drugs, experts recommend talking to your health care provider about alternative medications.
If affordability or insurance coverage for weight loss is an issue, you may be able to qualify for GLP-1 even if you have another medical condition, such as obstructive sleep apnea or type 2 diabetes, Moreno says.
In some cases, the price gap between compound and brand-name drugs has also narrowed, Moreno said.
“Copay options for branded drugs are coming down in cost and can sometimes be less expensive than combination drug options,” he says.
