Uncovering unexpected effects of popular GLP-1 diabetes drugs

Uncovering unexpected effects of popular GLP-1 diabetes drugs

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

Study:Comparative results of GLP-1 RA and semaglutide prescription in individuals with type 2 diabetes. Photo credit: Millaf/Shutterstock.com

*Important Notice: MedrxivPublish preliminary scientific reports that are not peer-reviewed and therefore not considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

In a recently uploaded to the pre-posted on theMedrxiv ServerPresentResearchers used a large, real-world, registry-based dataset to evaluate the clinical outcomes of pharmacological anti-type 2 diabetes (T2D) interventions.

background

T2D is a chronic disease characterized by the body's compromised ability to process glucose, thereby increasing blood sugar levels. It is an alarmingly common condition estimated to affect 462 million individuals (~6.3% of humans), with the International Diabetes Foundation (IDF) predicting this number to reach nearly two to 853 million by 2050.

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

GLP -1 receptor agonists (GLP -1 RAS) have become excellent in the treatment of T2D and obesity due to their robust glycemic control and weight utilization. Since their introduction in 2005 (exenatide), GLP-1-Ras dipeptidyl peptidase 4 inhibitors (DPP4I) and sodium glucose cotransporter 2 inhibitors (SGLT2I) have joined 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 approval by the US Food and Drug Administration (FDA) in 2021, its use has become increasingly common in the US and other global regions. Unfortunately, the real effects of semaglutide and other GLP-1 RAs remain, particularly on holistic health outcomes.

About the study

The present study addresses this knowledge gap by utilizing the US Research Program (AOU), a large US cohort of nearly 20,000 adults, and comparing prescribed GLP-1 RAs (including semaglutide) with peers using SGLT2I or DPP4I therapies.

This cohort included a diverse population, with particular attention given to historically underrepresented biomedical research groups. The aim was to illustrate downstream clinical events across the entire phenomenon (kidneys, heart, mood and beyond). This could provide clinicians and health authorities with the information to personalize future second-line T2D treatment.

AOU data included electronic health records (EHRs) of 18,746 T2D patients (57% women) who initiated GLP-1 RA, SGLT2I, or DPP4I therapies on or after January 2018.

Although semaglutide was a GLP-1 RA, it was analyzed as a separate subcohort considering its increasing global popularity. EHR data were used for phenomenon-wide association studies (adherence-sensitive) and intention-to-treat analyses.

The study will use follow-up data (mean = 13.3 years) with time-to-event statistical models to track new diagnoses across the phenomenon, thereby identifying any health or mood events associated with each drug class studied. All models were adjusted for demographics such as gender, age, ethnicity, and medical (baseline comorbidities, medication history) factors.

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

Study results

The present study simulated the real-world efficacy and safety of eight GLP-1 RAS (n = 8,798 participants), eight SGLT2Is (n = 5,111), and seven DPP4Is (n = 4,337).

Participants who consumed GLP-1-Ras showed a significantly lower incidence of genitourinus conditions (e.g., urinary tract infections, bladder disease) and dental complications (e.g., dental caries, gum disease) than their SGLT2I or DPP4I-using counterparts.

There were no statistically significant differences in overall cardiovascular disease outcomes. However, semaglutide demonstrated a protective effect for specific outcomes such as cardiac rhythmias compared to SGLT2Is.

In contrast, SGLT2I and DPP4I users had a lower risk of dysthymic disorder (a form of persistent depression that is different from major depressive disorder) and had higher vitamin D levels than GLP-1 RA users.

Semaglutide demonstrated significant cardiovascular and renal-associated benefits over other GLP-1-Ras. Notably, cardiac rhythm, hyperglycemia, and CKD events were significantly lower in semaglutide users, indicating differential benefits for semaglutide in this large, real-world cohort.

Conclusions

The present preprint demonstrates the holistic phenom-wide impact of 23 anti-T2D pharmacological interventions, thereby informing personalized curation of evidence.

The study results suggest that GLP-1-Ras, particularly semaglutide, are among the most effective T2D interventions to date. Time-to-event results showed only modest delays, typically less than a month in users metabolic and renal in three years of follow-up.

This preprint suggests that while semaglutide offers significant benefits, clinicians should also monitor for potential mood-related side effects and nutritional deficiencies, such as:

Importantly, this study used real-world observational data, and although extensive measures were taken to adjust for confounding factors, these results represent associations rather than causation.

The results apply to adults with T2D and cannot be generalized to individuals who use these medications solely for weight loss. Additional research, including randomized trials and studies in non-diabetic populations, is needed to further clarify the benefits and risks of GLP-1-Ras and semaglutide.

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*Important Notice: MedrxivPublish preliminary scientific reports that are not peer-reviewed and therefore not considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

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