GLP-1 Drugs in Diabetes Don’t Raise Suicidality Risk, New Data Confirm

For patients with diabetes, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) don’t appear to increase suicidality over what’s seen with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT2) inhibitors, according to a large cohort study from the United Kingdom.

The new findings, which follow investigations by both the European Medicines Agency and the US Food and Drug Administration exploring earlier worries and concerning case reports, are the latest to reassure that the drugs aren’t likely to increase suicidal ideation, self-harm, and suicide. The data have been vexingly mixed: some studies have even suggested GLP-1s are protective against suicidal thoughts and actions.

“All of these studies had their own strengths, but also their own shortcomings,” said Samantha B. Shapiro, MS (Jewish General Hospital and McGill University, Montreal, Canada), lead investigator of the new paper, which was published Wednesday in the BMJ. To dig further, she told TCTMD, they wanted to apply a more rigorous design that took steps to avoid various biases.

The conflicting results of prior reports may stem from confounding and immortal time bias (wherein a study design results in chunks of time being misclassified or missed entirely) and key differences among the populations studied, she said.

In terms of baseline characteristics that might impact suicidality, there are a lot of overlapping factors at play, too. “What we found really interesting in our data was when we conducted our crude analysis, . . . we saw about twofold increases in the risk of suicidality in those taking the GLP-1s compared to those taking other antidiabetic medications,” said Shapiro. “But when we actually accounted for all these different confounding factors—things like [body mass index], socioeconomic status, history of mental health, age, other comorbidities, etc—that’s when we saw the relationship go to no association. We went from a doubling of risk to no effect on the risk, so we can see that there’s definitely a lot of confounding at play here.”

While doctors should continue to monitor the mental and emotional well-being of their patients, as they would normally, “at least in the populations who’s using GLP-1 RAs for diabetes, I think clinicians can be relatively assured that these drugs are psychiatrically safe,” Shapiro confirmed, adding that the medications have numerous “beneficial effects in terms of diabetes control, cardiovascular effects, and renal effects, so we definitely don’t want to just throw these out the window.”

We went from a doubling of risk to no effect on the risk. Samantha B. Shapiro

For their study, Shapiro and colleagues obtained data from primary care practices participating in the UK Clinical Practice Research Datalink as well as from the Hospital Episodes Statistics Admitted Patient Care and Office for National Statistics Death Registration databases. They compared two cohorts of patients with diabetes.

The first group, spanning January 2007 and December 2020, included approximately 36,000 GLP-1 RA users (median follow-up 1.3 years) and 234,000 DPP-4 inhibitor users (median follow-up 1.7 years). In crude analyses, use of GLP-1 drugs was linked to twice the risk of suicidality compared with use of DPP-4 drugs (3.9 vs 1.8 cases per 1,000 person-years; HR 2.08; 95% CI 1.83-2.36). But with adjustment for confounders, there was no longer a significant association between GLP-1 use and suicidality (HR 1.02; 95% CI 0.85-1.23).

The second group included around 32,000 people taking GLP-1 RAs and 96,000 people on SGLT2 inhibitors taking their medications between January 2013 and December 2020 (median follow-up for both 1.2 years). Again, crude analyses found greater risk of suicidality with GLP-1s than with the comparator drug (4.3 vs 2.7 cases per 1,000 person-years; HR 1.60; 95% CI 1.37-1.87), but adjustment for confounders eliminated that association (HR 0.91; 95% CI 0.73-1.12).

Patterns were similar for the endpoints of suicidal ideation, self-harm, and suicide. Additionally, Shapiro et al found no signals of harm when analyzing the data by “individual drug, age, sex, body mass index, history of suicidal ideation, history of depression, or socioeconomic status.”

The investigators note that, from a biological standpoint, there are several avenues through which GLP-1 RAs could lead to suicidality. Possible mechanisms include “hyperactivity of the hypothalamic-pituitary-adrenal axis, sudden weight loss leading to elevated suicide risk, and underexpression of brain derived neurotrophic factor linking low body weight and increased anxiety,” they suggest.

Strengths and Weaknesses

“At this point in time, data from clinical trials and observational studies in broad populations do not indicate that GLP-1 receptor agonists increase the risk of suicidality,” write Peter Ueda, MD, PhD (Karolinska Institutet and Academic Specialist Centre, Stockholm, Sweden), and Björn Pasternak, MD, PhD (Karolinska Institutet, Stockholm, Sweden, and Statens Serum Institut, Copenhagen, Denmark), in an accompanying editorial.

Ueda and Pasternak point out the study’s strengths. Among them are that the researchers used comparator drugs that were appropriate and had an active comparator new user design, which helps rule out time-related biases. “In this broad study population, event rates were low and the analyses ruled out moderate magnitudes of increases in risk on both the relative and the absolute scale,” they write.

However, the editorialists also highlight some limitations. Suicidal ideation, which is often inconsistently defined by databases, accounted for two-thirds of events; most of the remaining third were instances of self-harm. Just 11 deaths from suicide were captured among patients taking GLP-1s, “yielding imprecise and inclusive estimates,” they say, adding that approximately 23-40% of the GLP-1 patients in the study’s two cohorts were on drug types (exenatide and lixisenatide) not commonly used in today’s practice. Just 10% of patients on a GLP-1 drug took semaglutide and none were on tirzepatide, which in addition to being a GLP-1 RA also blocks glucose-dependent insulinotropic polypeptide.

“Future studies may specifically assess the safety of semaglutide and tirzepatide, which have surpassed other GLP-1 receptor agonists in popularity owing to their larger effects on weight reduction and glucose control,” Ueda and Pasternak conclude.

Moving forward, a similar study among patients taking GLP-1 RAs for obesity also is warranted, said Shapiro. “ It’s a different subset of people.”