In a recent study published in Clinical medicineA bunch of researchers assessed 12-month neurological and psychiatric outcomes of semaglutide use in patients with type 2 diabetes (T2DM) (chronic high blood sugar brought on by insulin resistance or deficiency) using a propensity-matched cohort.

Background

Semaglutide, a glucagon-like peptide 1 receptor agonist (GLP1-RA) approved for the treatment of type 2 diabetes and obesity, is a scientific breakthrough in 2023. Healthcare spending on GLP1-RA is predicted to extend with recent applications and formulations. Randomized controlled trials (RCTs) reveal semaglutide’s efficacy on metabolic and cardiovascular outcomes. Studies indicate potential neurobiological advantages for neurological, psychiatric, and substance use disorders.

Nonetheless, safety reviews by the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA) within the UK, prompted by reports of mood changes, have raised concerns. Further research is required to make clear the neuropsychiatric safety and overall impact of semaglutide and GLP1-RAs on brain health in patients with type 2 diabetes.

In regards to the study

This study follows the Reporting of Studies Conducted using Observational Routinely-collected Health Data (RECORD) guidelines. Using the TriNetX United States (US) Collaborative Network, a big federated database, this study analyzed de-identified electronic health records (EHRs) of greater than 100 million patients in 62 U.S. healthcare organizations. This platform includes patient demographics, diagnoses, medications, and procedures.

Researchers identified people aged 18 years and older with a diagnosis of type 2 diabetes and a primary prescription for semaglutide between December 1, 2017, and May 31, 2021. Comparator cohorts were created for sitagliptin, empagliflozin, and glipizide. The study matched the cohorts based on 179 covariates, including demographics, socioeconomic aspects, lifestyle, health care use, comorbidities, and treatment history.

The study assessed the danger of twenty-two neurologic and psychiatric outcomes inside 1 12 months of the index event using International Classification of Diseases, tenth Revision, Clinical Modification (ICD-10-CM) codes. The danger of 15 negative follow-up outcomes was also estimated to handle unmeasured confounders. Propensity rating matching and subsequent analyses were performed using R and the TriNetX interface, with statistical significance set at a p value of lower than 0.05 and adjustment for multiple testing.

4 secondary analyses were performed: a subgroup evaluation by age, stratification by 12 months of index prescription, a competing risks evaluation with death as a component, and an exploration of outcomes at 2 years of follow-up. The funding sources of the study had no influence on the design, data collection, evaluation, interpretation, or writing of the manuscript.

Findings

After applying the inclusion/exclusion criteria, a complete of 23,386 patients were included in each cohort for the semaglutide vs. sitagliptin comparison (48.6% women, mean ± SD age 56.6 ± 12.8 years), 22,584 patients in each cohort for the semaglutide vs. empagliflozin comparison (48.9% women, mean ± SD age 57.6 ± 12.4 years), and 19,206 patients in each cohort for the semaglutide vs. glipizide comparison (49.3% women, mean ± SD age 56.3 ± 13.0 years). Propensity rating matching was achieved for every comparison and covariance, providing standardized mean differences (SMDs) of lower than 0.1.

Hazard ratios (HRs) below 1 indicate a lower risk with semaglutide compared with other drugs, whereas HRs above 1 indicate the next risk. Semaglutide was not related to an increased risk of any neurological or psychiatric conditions; it was related to a lower risk of cognitive deficits compared with sitagliptin (HR 0.72) and glipizide (HR 0.72), but similarly to empagliflozin (HR 0.96).

The danger of dementia (a decline in cognitive function affecting memory and pondering) was also lower with semaglutide compared with sitagliptin (HR 0.52) and glipizide (HR 0.63). As well as, semaglutide showed a significantly lower risk of nicotine dependence compared with glipizide (HR 0.72) and empagliflozin (HR 0.77).

Other notable results include a lower risk of depression and ischemic stroke (stroke as a consequence of blocked blood flow to the brain) compared with sitagliptin. The negative control (NCO) results consistently showed no difference in any comparison (HR for combined NCO between 0.97 and 1.03, all p values ​​>0.4). The danger of all-cause mortality was lower with semaglutide compared with sitagliptin (95% CI 0.50–0.66, p < 0.0001, HR 0.58), empagliflozin (p 0.035, HR 0.86, 95% CI 0.75–0.99), and glipizide (p < 0.0001, HR 0.55, 95% CI 0.47–0.64).

Secondary analyses confirmed these findings. Age subgroup analyses showed stronger associations in older patients with cognitive deficit and dementia and in younger patients with less substance use disorder. The association of semaglutide with lower risk of death and other outcomes remained significant. Stratification by time of prescription, including periods before and after coronavirus disease 2019 (COVID-19), showed consistent results. Similar patterns were observed at 2 years of follow-up, with a further potential association with a lower risk of psychosis compared with sitagliptin and glipizide.

No significant violation of the proportional hazards assumption was observed, aside from a couple of comparisons, resembling cognitive deficit between semaglutide and sitagliptin, where the HR decreased over time but remained below 1.

Conclusions

In conclusion, this huge study of semaglutide, a GLP1-RA approved for the treatment of type 2 diabetes and obesity, didn’t reveal an increased risk of twenty-two neurological and psychiatric outcomes over 12 months compared with other antidiabetic agents, excluding the next risk of migraine with glipizide. Semaglutide was related to possible advantages on cognitive outcomes and nicotine abuse, consistent with meta-analyses suggesting advantages of GLP1-RAs on cognitive outcomes. The robustness of the study is as a consequence of extensive propensity rating matching and a big sample size. These results support the potential of semaglutide to stop cognitive deficits and substance abuse, informing regulatory and public health reviews.