Tirzepatide Real-World Safety Profile “Reassuring,” So Far

MADRID — Real-world data on tirzepatide (Eli Lilly and Company) from a large population database suggest a safety profile of the drug consistent with that in clinical trials and similar to that of anti-obesity glucagon-like peptide 1 (GLP-1) receptor agonists, with the key caveat of a relatively short reporting period, a new study showed.

“Overall, our data perpetuate the safety concerns surrounding the incretin-based therapies, but maybe the most interesting finding is that, reassuringly, while tirzepatide displays an unprecedented glucose- and weight-lowering efficacy, it comes with a similar or even improved safety profile vs GLP-1 receptor agonists,” said first author Irene Caruso, MD, PhD, of the Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy, while presenting the research at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

The study was also published in the Journal of Endocrinological Investigation.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, has been shown to be among the most efficacious drugs in glucose lowering and weight loss compared with other GLP-1 receptor agonists such as semaglutide.

Despite those stronger effects with tirzepatide, randomized trials generally suggest similar rates of the most common adverse events — gastrointestinal adverse events, as reported with GLP-1 medications, and reports of less common adverse events, including diabetic retinopathy, pancreato-biliary disorders, and medullary thyroid cancer risks.

In the SURPASS clinical trial program, tirzepatide showed limited pancreato-biliary adverse events, with very few cases of diabetic retinopathy and no cases of medullary thyroid cancer.

To investigate the rates of those events in real-world practice outside of clinical trials, Caruso and her colleagues evaluated data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) post-marketing surveillance database.

For the analysis, adverse events reported with tirzepatide use between 2004 and 2023 were compared with those reported with insulin, SGLT-2 inhibitors, metformin, and GLP-1 receptor agonists, individually and as a class.

Of a total of 20,409 reports involving tirzepatide related to 1432 adverse events, the researchers analyzed 7460 reports referring to 286 selected adverse events, including gastrointestinal (GI) adverse events, pancreato-biliary disorders, eye-related disorders, and thyroid cancer. Of them, 22 showed a signal of being disproportionately reported.

The results showed that compared with all other drugs used as a reference, tirzepatide was associated with higher rates of gastrointestinal adverse events, including eructation (reporting odds ratio [ROR], 30.25), nausea (ROR, 4.01), dyspepsia (ROR, 4.02), constipation (ROR, 4.12), pancreatitis (ROR, 3.63), diabetic retinopathy (ROR, 4.14), and medullary thyroid cancer (ROR, 13.67).

However, compared with GLP-1 receptor agonists, tirzepatide was associated with generally similar rates of gastrointestinal adverse events, with notable increased risks in constipation (ROR, 1.39) and eructation (ROR, 1.51). The risks were also reduced with tirzepatide vs GLP-1s in measures of diarrhea (ROR, 0.91), nausea (ROR, 0.83), and vomiting (ROR, 0.69).

Tirzepatide was also associated with a decreased risk for pancreatitis (ROR, 0.28), diabetic retinopathy (ROR, 0.38), and thyroid mass (ROR, 0.41) compared with GLP-1 receptor agonists, with similar risks for biliary colic and medullary thyroid cancer between the two.

In other comparisons, tirzepatide showed an expected increase compared with sodium-glucose cotransporter-2 inhibitors in the risk for GI adverse events, with the remaining adverse events showing a similar risk.

The safety profile of tirzepatide in comparison with insulin was generally similar, with the main difference being a reduced risk for diabetic retinopathy with tirzepatide (ROR, 0.14), which is consistent with randomized trials comparing GLP-1 drugs with insulin, and a higher risk for medullary thyroid cancer (ROR, 2.88).

Of note, the database used in the study did not include full information regarding whether patients were being treated with tirzepatide for type 2 diabetes or obesity.

Nevertheless, “it was indeed reassuring to confirm that the unprecedented weight- and glucose-lowering efficacy of tirzepatide did not come with meaningful downsides in terms of tolerability,” senior author Francesco Giorgino, MD, PhD, told Medscape Medical News.

“Preclinical studies have highlighted that GIP receptor agonism might activate GABAergic neurons in the brainstem, which in turn hinder GLP-1 RA–induced malaise and emesis, and this could explain why tirzepatide is more efficacious with similar tolerability,” added Giorgino, who is a professor of endocrinology and director of the Department of Precision and Regenerative Medicine and Ionian Area Head, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.

Caveats of the study include that the FAERS database is based on the spontaneous reporting of adverse events, meaning that “underreporting of some adverse events, especially those occurring several years following drug initiation (ie, thyroid cancer) could occur, [and] public awareness of the association between a drug and a given adverse event might affect reporting frequency,” Giorgino noted.

Furthermore, some numbers of adverse events were very low, such as only three cases of thyroid cancer and 10 cases of diabetic retinopathy, with a relatively short exposure time to tirzepatide, Caruso reported. She added that the data did not include information on whether patients were being treated for type 2 diabetes or obesity.

“Overall, our results should be considered as thought-provoking and suggest the need of carefully designed observational studies for confirmation,” Giorgino said.

Commenting on the study, Jason Halford, PhD, head of the School of Psychology, at the University of Leeds, Leeds, England, underscored the need for longer-term data when it comes to fully understanding potential safety issues.

“From a general perspective it is very important, beyond clinical trials, to follow populations using these drugs,” he told Medscape Medical News.

“In the past, sides effects of previous anti-obesity drugs such as d-fenfluramine, sibutramine, and rimonabant have only come to light years after the launch,” he noted.

Specifically, d-fenfluramine was withdrawn due to heart valve damage, sibutramine was withdrawn due to cardiovascular events, and rimonabant was linked to GI and serious neuropsychiatric adverse events.

“Importantly, those were not GLP-1–based pharmacotherapies,” Halford noted. “The new generation of GLP-1 and GLP-1 GIP combinations do have some distinct and well-known side effects, particularly at the start of treatment.”

“However, it is good to have this real-world data to confirm what we have seen in trials,” he said.

Caruso reported relationships with Eli Lilly and Company, Novo Nordisk, and Abbott. Halford had no disclosures to report.