The paper describes a data-driven approach to studying possible beneficial and adverse effects of GLP-1 agonists like semaglutide (Ozempic), which are widely used to treat diabetes and obesity. The sophisticated statistical data techniques employed by the researchers are like those used to study effects of human genetic variations. In genomic analysis the data come from genome sequencing, but here they come from routine diagnostic, treatment and administrative records of millions of patients.

The researchers compare event rates in users of GLP-1 agonists with those observed in patients selected for other diabetes treatments. Rather than testing prior hypotheses about benefits and harms of these new medicines the analysts look for patterns in the data that might signal previously unsuspected effects. Some of the beneficial effects seen in their data, particularly in neuropsychiatric and substance abuse disorders, are supported by other studies. Some may be related to improvements in control of weight and metabolism, well known effects of the drugs. Others may be due to the play of chance or bias, because of differences between patient groups who are chosen to start different diabetes medications.

This is an observational study, not a randomised trial, and the authors caution against basing treatment recommendations on these data, without further confirmation. Such reticence is justified. Flawed observational studies of another diabetes drug, metformin, concluded erroneously that the drug prevented cancer. Analysis of data from randomised trials disproved that theory. This type of ‘big data’ research will generate lots of statistical associations, some of which will be spurious. It is not yet clear whether these data driven methods for exploring beneficial and harmful drug effects are a genuine advance over traditional inferential approaches.

Studies such as these have to be interpreted very cautiously as the people studied have not been randomly allocated to GLP1 receptor agonist treatment, so any difference between those taking and not taking the class of drug could potentially be attributable to factors other than the drug. As the data comes from the UK Veterans Administration it is heavily skewed to older white males.

That said , the study provides useful reassurance about the safety of this class of drugs. The expected benefits on heart disease, stroke and other cardiovascular and most kidney diseases are clearly seen. There is also a reassuring reduction in the incidence of several cancers, including pancreatic. Importantly, as there has been discussion in the media about possible adverse effects of the drugs on mental health, the group taking the drug had a lower incidence of schizophrenia, alcohol and drug use disorders, and less suicidal ideation. In terms of other disorders affecting the brain there was a small but statistically significant reduced risk of seizures and of dementia in those taking GLP1RAs.

In terms of the list of conditions and/ or symptoms that are reported to be increased by GLP1 receptor agonists, as expected gastrointestinal upset of various kinds is most common adverse effect. The small but significant increase in people with low blood pressure and with kidney stones are likely attributable to the fact that a combination of diarrhoea and reduced oral intake can lead some people to become somewhat  fluid-depleted. The most surprising finding is an increase in a range of symptoms relating to joint pain. It is possible that the increased physical activity that is made possible when people lose substantial amounts of weight could result in the appearance of joint  symptoms that were previously masked by inactivity. On the other hand,  the fact that receptors for GLP1 are present on subsets of immune cells means that until we have deeper knowledge, the effects of these drugs on inflammatory responses are somewhat unpredictable. While some inflammatory disorders may be assisted by these drugs others might conceivably be exacerbated. Further research is needed.

Overall the results of this study,  which followed over 200,000 people with diabetes who were treated with GLP1RAs and compared them to over 1.5 million people on other forms of diabetes treatment,  is reassuring regarding the risk/benefit ratio for the long term use of GLP1RAs in people with diabetes. Future studies of people treated with these drugs for obesity, without accompanying diabetes, are awaited with interest.