Uncovering unexpected impacts of popular GLP-1 diabetes drugs

By Hugo Francisco de SouzaReviewed by Lauren HardakerJun 17 2025

Real-world data analysis reveals GLP-1 drugs can protect kidneys and hearts in diabetic patients but also introduce surprising new health risks.

Study: Real-world comparative outcomes of GLP-1 RA and semaglutide prescription among individuals with type 2 diabetes. Image credit: MillaF/Shutterstock.com

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

In a recent preprint uploaded to the medRxiv server, researchers used an extensive real-world, registry-based dataset to assess the clinical outcomes of pharmacological anti-type 2 diabetes (T2D) interventions.

Background

T2D is a chronic condition characterized by the body’s compromised ability to process glucose, thereby elevating blood sugar levels. It is an alarmingly common condition, estimated to impact 462 million individuals (~6.3% of humans), with the International Diabetes Foundation (IDF) predicting this number to almost double to 853 million by 2050.

When poorly managed, T2D can have devastating medical and economic outcomes, including cardiovascular diseases (CVDs), hypertension, and chronic kidney disease (CKD). Thankfully, recent advances in pharmacology have helped manage T2D by facilitating improved glycemic control.

GLP‑1 receptor agonists (GLP‑1 RAs) have become prominent in managing T2D and obesity due to their robust glycemic control and weight‑loss benefits. Since their introduction in 2005 (exenatide), GLP-1 RAs have joined dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) at the forefront of second-line anti-T2D interventions.

Semaglutide, a novel GLP-1 RA, has demonstrated unprecedented efficacy in T2D management and weight loss. Since its US Food and Drug Administration (FDA) approval in 2021, its use has been increasingly common across the US and other global regions. Unfortunately, the real-world impacts of semaglutide and other GLP-1 RAs remain understudied, especially on holistic health outcomes.

About the study

The present study addresses this knowledge gap by leveraging the All of Us Research Program (AOU), a large US cohort of almost 20,000 adults, comparing those prescribed GLP‑1 RAs (including semaglutide) against peers using SGLT2i or DPP4i therapies.

This cohort included a diverse population, with special attention to historically underrepresented biomedical research groups. It aimed to illustrate downstream clinical events across the phenome (kidneys, heart, mood, and beyond). This could give clinicians and public health agencies the information to personalize future second-line T2D treatment.

AOU data comprised electronic health records (EHRs) of 18,746 adult T2D patients (57% female) who initiated GLP‑1 RA, SGLT2i, or DPP4i therapies on or after January 2018.

Despite being a GLP-1 RA, semaglutide was analyzed as a separate subcohort, considering its increasing global popularity. EHR data were used for per-protocol (adherence-sensitive) phenome-wide association studies (PheWAS) and intention-to-treat analyses.

The study further utilizes follow-up data (mean = 13.3 years) with time-to-event statistical models to track new diagnoses across the phenome, thereby identifying any health or mood events linked to each drug class under investigation. All models were adjusted for demographics like sex, age, ethnicity, and medical (baseline comorbidities, medication history) confounders.

Outcomes of interest included any CVDs, CKDs, infections, bone or dental conditions, and neuropsychiatric disorders. Semaglutide-specific analyses compared the drug to other GLP-1 RAs to supplement the lack of real-world anti-T2D and weight loss efficacy and safety data.

Study findings

The present study simulated the real-world effectiveness and safety of eight GLP-1 RAs (n = 8,798 participants), eight SGLT2is (n = 5,111), and seven DPP4is (n = 4,337).

Participants consuming GLP-1 RAs demonstrated a significantly lower incidence of genitourinary conditions (e.g., urinary tract infections, bladder disorders) and dental complications (e.g., dental caries, gum disease) than their SGLT2i or DPP4i-using counterparts.

There were no statistically significant differences in general cardiovascular disease outcomes. However, semaglutide showed a protective effect for specific outcomes such as cardiac arrhythmias compared to SGLT2is.

In contrast, SGLT2i and DPP4i users were at lower risk of dysthymic disorder (a form of persistent depression distinct from major depressive disorder) and demonstrated higher vitamin D levels than GLP-1 RA users.

Semaglutide demonstrated significant cardiovascular and kidney-associated benefits over other GLP-1 RAs. Notably, cardiac arrhythmia, hyperglycemia, and CKD events were substantially lower in semaglutide users, suggesting distinct advantages for semaglutide in this large, real-world cohort.

Conclusions

The present preprint demonstrates the holistic phenome-wide impacts of 23 anti-T2D pharmacological interventions, thereby informing evidence-backed personalized care.

Study findings suggest that GLP-1 RAs, particularly semaglutide, are among the most effective second-line T2D interventions studied to date. The time-to-event results showed only modest delays, typically less than one month over three years of follow-up, in metabolic and renal outcomes among users.

This preprint suggests that while semaglutide carries significant benefits, clinicians should also monitor for potential mood-related side effects and nutritional deficiencies, such as increased risks of dysthymic disorder and vitamin D deficiency, as these associations require further investigation and do not prove the drugs caused these outcomes.

Importantly, this study used real-world observational data, and while extensive measures were taken to adjust for confounders, these findings represent associations rather than causation.

The results apply to adults with T2D and may not generalize to people using these medications solely for weight loss. Additional research, including randomized trials and studies on non-diabetic populations, is needed to further clarify the benefits and risks of GLP-1 RAs and semaglutide.

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*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.